Subtypes Of Neovascular Age-related Macular Degeneration Research Articles

Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes

Neovascular age-related macular degeneration (nAMD), along with its clinical subtype known as polypoidal choroidal vasculopathy (PCV), are among the leading causes of vision loss in elderly Asians. In a genome-wide association study (GWAS) comprising 3,128 nAMD (1,555 PCV and 1,573 typical nAMD), and 5,493 controls of East Asian ancestry, we identify twelve loci, of which four are novel (P , < , 1.19times {10}^{-8}). Substantial genetic sharing between PCV and typical nAMD is noted (rg = 0.666), whereas collagen extracellular matrix and fibrosis-related pathways are more pronounced for PCV. Whole-exome sequencing in 259 PCV patients revealed functional rare variants burden in collagen type I alpha 1 chain gene (COL1A1; P=1.05times {10}^{-6}) and potential enrichment of functional rare mutations at AMD-associated loci. At the GATA binding protein 5 (GATA5) locus, the most significant GWAS novel loci, the expressions of genes including laminin subunit alpha 5 (Lama5), mitochondrial ribosome associated GTPase 2 (Mtg2), and collagen type IX alpha 3 chain (Col9A3), are significantly induced during retinal angiogenesis and subretinal fibrosis in murine models. Furthermore, retinoic acid increased the expression of LAMA5 and MTG2 in vitro. Taken together, our data provide insights into the genetic basis of AMD pathogenesis in the Asian population.

Triglyceride-derived fatty acids reduce autophagy in a model of retinal angiomatous proliferation.

Dyslipidemia and autophagy have been implicated in the pathogenesis of blinding neovascular age-related macular degeneration (NV-AMD). VLDL receptor (VLDLR), expressed in photoreceptors with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acids. Since fatty acid uptake is reduced in Vldlr–/– tissues, more remain in circulation, and the retina is fuel deficient, driving the formation in mice of neovascular lesions reminiscent of retinal angiomatous proliferation (RAP), a subtype of NV-AMD. Nutrient scarcity and energy failure are classically mitigated by increasing autophagy. We found that excess circulating lipids restrained retinal autophagy, which contributed to pathological angiogenesis in the Vldlr–/– RAP model. Triglyceride-derived fatty acid sensed by free fatty acid receptor 1 (FFAR1) restricted autophagy and oxidative metabolism in photoreceptors. FFAR1 suppressed transcription factor EB (TFEB), a master regulator of autophagy and lipid metabolism. Reduced TFEB, in turn, decreased sirtuin-3 expression and mitochondrial respiration. Metabolomic signatures of mouse RAP-like retinas were consistent with a role in promoting angiogenesis. This signature was also found in human NV-AMD vitreous. Restoring photoreceptor autophagy in Vldlr–/– retinas, either pharmacologically or by deleting Ffar1, enhanced metabolic efficiency and suppressed pathological angiogenesis. Dysregulated autophagy by circulating lipids might therefore contribute to the energy failure of photoreceptors driving neovascular eye diseases, and FFAR1 may be a target for intervention.

Eyes that Do Not Meet the Eligibility Criteria of Clinical Trials on Age-Related Macular Degeneration: Proportion of the Real-World Patient Population and Reasons for Exclusion.

Background To evaluate the proportion of eyes that do not meet the eligibility criteria of clinical trials on neovascular age-related macular degeneration (AMD) and the reasons for exclusion. Methods This retrospective, observational study included 512 eyes of 463 patients diagnosed with treatment-naïve neovascular AMD. The proportion of eyes that did not meet the eligibility criteria of the Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies were evaluated. The two most common reasons for exclusion were also evaluated in each subtype of neovascular AMD (typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), and type 3 neovascularization). Results Among the 512 eyes, 229 (44.7%) did not meet the eligibility criteria. In all the included eyes, the most common reasons for exclusion were good or poor visual acuity (169 eyes, 33.0%), followed by the presence of subretinal hemorrhage (47 eyes, 9.5%). Moreover, good or poor visual acuity was the most common reason for exclusion in all three subtypes of neovascular AMD. The second most common reason was a fovea-involving scar or fibrosis in typical neovascular AMD, subretinal hemorrhage in PCV, and other vascular diseases affecting the retina in type 3 neovascularization. Conclusions Among the included cases, 44.7% did not meet the eligibility criteria for VIEW study, suggesting that the conclusion derived from clinical trials may not directly reflect the real-world outcomes. Additionally, the reasons for ineligibility differed among the different subtypes of neovascular AMD.

Progression of macular atrophy in patients undergoing anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration.

To assess differences in the progression of macular atrophy (MA) between neovascular age-related macular degeneration (AMD) subtypes and to identify the risk factors associated with the foveal involvement among patients with MA undergoing long-term anti-vascular endothelial growth factor (VEGF) treatment. Eighty eyes of 80 patients with neovascular AMD who developed incident MA following anti-VEGF therapy were retrospectively included. Macular atrophy (MA) was quantified using autofluoresence (AF) images within 24months after the onset of MA, and the enlargement rate was compared between neovascular AMD subtypes. Regression models were constructed to explore relationships between foveal involvement in MA and baseline characteristics. The growth rate of MA was 0.18mm2 /year for type 1 neovascularization (NV), 0.24mm2 /year for type 2 NV, and 1.21mm2 /year for type 3 NV; differences between groups were significant (p=0.022). Multivariate logistic regression analysis revealed that thin subfoveal choroidal thickness (p=0.028), presence of subretinal drusenoid deposit (p=0.005), type 2 or 3 NV (p=0.023), and geographic atrophy in the fellow eye (p=0.035) were significant risk factors for MA with foveal involvement. The number of injections showed no significant association with the progression or the foveal involvement in MA. The progression of MA in patients with neovascular AMD undergoing anti-VEGF treatment differed significantly depending on the subtype of neovascularization. The risk of foveal involvement in MA was associated with the baseline factors or phenotype of neovascular AMD rather than with injection frequency of anti-VEGF.

NATURAL COURSE OF PATIENTS DISCONTINUING TREATMENT FOR AGE-RELATED MACULAR DEGENERATION AND FACTORS ASSOCIATED WITH VISUAL PROGNOSIS.

To evaluate the 24-month natural course of visual changes in patients discontinuing treatment despite persistent or recurrent fluid and factors predictive of visual prognosis. This retrospective, observational study included 35 patients (35 eyes) who initially received anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD), but discontinued treatment despite persistent or recurrent fluid. The best-corrected visual acuity (BCVA) at treatment discontinuation was determined and compared with the 24-month BCVA, which was then compared between polypoidal choroidal vasculopathy and other neovascular age-related macular degeneration subtypes. Baseline characteristics predictive of visual outcome and the degree of visual change were also analyzed. The mean number of anti-vascular endothelial growth factor injections before treatment discontinuation was 4.0 ± 1.6. The mean logarithm of minimal angle of resolution of BCVA at treatment discontinuation and that at 24 months were 1.02 ± 0.20 (Snellen equivalents = 20/209) and 1.60 ± 0.56 (20/796), respectively (P < 0.001). The 24-month BCVA was not different between polypoidal choroidal vasculopathy and other neovascular age-related macular degeneration subtypes (P = 0.803). The type of fluid (intraretinal fluid vs. no intraretinal fluid) was predictive of 24-month BCVA (P = 0.004) and the degree of changes in BCVA (P = 0.043). Marked deterioration in visual acuity was noted in patients discontinuing treatment, regardless of neovascular age-related macular degeneration subtypes. The presence of intraretinal fluid was associated with worse visual prognosis, suggesting that patients with intraretinal fluid should be strongly warned about their poor prognosis before they decide to discontinue treatment.

Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Retinal Angiomatous Proliferation: A Review of the Literature and Therapeutic Considerations

Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (AMD). In the past, this peculiar type of neovascularization was considered to be refractory to treatment, and the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in RAP was not thoroughly evaluated in the early clinical trials. However, more recent studies focusing on treatment outcomes in RAP have shown that visual acuity can be improved or at least maintained in the majority of eyes using anti-VEGF therapy. Favorable results were achieved regardless of the regimens used which included fixed-dosing, as-needed, and treat-and-extend regimens. Nowadays, anti-VEGF therapy is a widely used first-line therapy for RAP. RAP shows several characteristics that distinguish it from other subtypes of neovascular AMD. The choroid is usually very thin and the incidence of geographic atrophy or retinal pigment epithelial tear is relatively high in RAP compared to the other subtypes. It is helpful for clinicians to consider these characteristics, which may influence the treatment outcome. In this article, the results of previous studies on anti-VEGF therapy for RAP are reviewed and important therapeutic considerations are discussed.

DIAGNOSIS OF TYPE 3 NEOVASCULARIZATION BASED ON OPTICAL COHERENCE TOMOGRAPHY IMAGES.

To evaluate the concordance of an optical coherence tomography (OCT)-based diagnosis of Type 3 neovascularization and an indocyanine green angiography (ICGA)-based diagnosis in neovascular age-related macular degeneration (AMD). This observational case series includes 263 eyes from 263 patients who were diagnosed with treatment-naive neovascular AMD. Patients exhibiting at least three of the following OCT features were diagnosed with Type 3 neovascularization: subfoveal choroidal thickness <200 μm, presence of intraretinal fluid accumulation, absence of subretinal fluid, gently-sloping dome-shaped retinal pigment epithelial detachment or trapezoid-shaped retinal pigment epithelial detachment without an obvious peak, and intraretinal mass lesion. The incidence of cases exhibiting three or more OCT features was compared among different subtypes of neovascular AMD. Additionally, the concordance of OCT-based diagnosis and ICGA-based diagnosis was evaluated. Three or more OCT features were noted in 8 of 82 (9.8%) eyes with typical neovascular AMD, 4 of 147 (2.7%) eyes with polypoidal choroidal vasculopathy, and 30 of 34 (88.2%) eyes with Type 3 neovascularization, respectively. The incidence was significantly greater in Type 3 neovascularization than in the other subtypes of neovascular AMD (P < 0.001). Of patients diagnosed with Type 3 neovascularization using ICGA-based methods, 88.2% were also diagnosed with Type 3 neovascularization using OCT-based methods. Only 5.2% of patients diagnosed with other subtypes of neovascular AMD using ICGA-based methods were diagnosed with Type 3 neovascularization using OCT-based methods. Optical coherence tomography-based diagnosis of Type 3 neovascularization showed relatively high concordance compared with ICGA-based diagnosis. This method may be useful in clinical practice.

Short-term choroidal thickness changes in patients treated with either ranibizumab or aflibercept: a comparative study

PurposeTo compare, in neovascular age-related macular degeneration (AMD) patients, short-term choroidal thickness changes in eyes treated using ranibizumab with those in eyes treated using aflibercept.MethodsThis retrospective, observational study included 240...

Factors Associated with Recurrence of Age-Related Macular Degeneration after Anti-Vascular Endothelial Growth Factor Treatment: A Retrospective Cohort Study

To investigate the predictive factors associated with recurrence after anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). Retrospective cohort study. A total of 343 eyes of 326 patients with subfoveal neovascular AMD who were treated with an as-needed regimen after 3 monthly loading doses of intravitreal ranibizumab. Patients were followed up by an as-needed regimen for more than 1 year after the first injection. Baseline data and CFH I62V and ARMS2 A69S polymorphisms were analyzed for their association with recurrence after anti-VEGF treatment. Regression analysis was used to identify independent predictors of visual acuity (VA) prognosis. The primary end point was the presence or absence of recurrence. The secondary end point was VA improvement. In total, 236 eyes (68.8%) showed complete resolution of retinal exudative change after the 3 loading injections, and 81 eyes (34.3%) experienced no recurrence during the first year. Of the 236 eyes, 139 (58.9%) were followed for more than 2 years and 35 (25.2%) showed no recurrent retinal exudation during 24 months. Visual acuity improvement was significantly better in eyes without recurrence than in eyes with recurrence during the 2-year period. Baseline characteristics and genotypes had no influence on response to ranibizumab loading treatment. Stepwise analysis revealed that age (P<0.001), subtype of AMD (P=0.041), and VA at baseline (P<0.001) were associated with VA at 24 months. Older patients (P=0.006) and male patients (P=0.018) tended to require re-treatment for recurrence during the first year, yet the statistical significance disappeared when evaluated in 2 years. The subtypes of neovascular AMD were solely associated with the interval to the recurrence, which was shorter in eyes with polypoidal choroidal vasculopathy (PCV) than in eyes with typical AMD (P=0.015). Older age and male sex may predict recurrence after 3 monthly ranibizumab injections, and PCV may be associated with shorter interval to recurrence. Predicting the risk of recurrence would help us to choose the most appropriate follow-up treatment strategy for patients with AMD.

Secondary polypoidal choroidal vasculopathy (PCV)

AbstractPolypoidal choroidal vasculopathy (PCV) was first described as polypoidal, subretinal, vascular lesions associated with serous and hemorrhagic detachments of the retinal pigment epithelium (RPE) in a series of patients (10/11 were women) by Yannuzzi. PCV is most commonly diagnosed in patients between the ages of 50 and 65 years. Although more frequently being an primary disease associated to high blood pressure, it may also be secondary to others diseases such as AMD, Central Serous Chorioretinopathy (CSC), ocular radiotherapy, Pseudoxanthoma Elasticum not related to systemic hypertension. Secondary PCV was first reported to occur in AMD patients. Prevalence rates of 4%, 7.8%, 8.2%, and 9.8% have been reported in Caucasian patients with presumed age‐related macular degeneration (AMD). In Asian patients with diagnosed AMD the prevalence rates are even higher, between 23.9% and 54.7%. PCV was categorized as a subtype of neovascular AMD. Vascular proliferative changes associated with PCV in AMD form a network of vessels ending with saccular polypoidal lesions. ICG angiography can be used to distinguish it from classic or occult CNV as usually seen in AMD. PCV is demonstrated by ICG angiography as a prominent vascular network in the early stages of the study and an area of clearing or so called “washout” of the dye in the late stage. On OCT examination the polypoidal lesions are seen as more steep domelike elevations of the highly reflective RPE layers with underlying moderate reflectivity then seen in PEDs. The regions of the branching choroidal vascular networks are visualized as double reflective layers comprising nodular RPE and another highly reflective layer beneath the RPE. According to the EVERST and LAPTOP studies either Anti‐VEGF monotherapy alone or associated to Photodynamic therapy is the best therapeutic option actually available to treat PCV in AMD patients and should be considered as first line therapy in all secondary cases.

Review of Ranibizumab Trials for Neovascular Age-Related Macular Degeneration

Ranibizumab, a recombinant, humanized, monoclonal antibody antigen-binding fragment that neutralizes all VEGF-A isoforms, is the first US FDA-approved therapy for neovascular age-related macular degeneration (AMD) to result in improvement in visual acuity. The benefit of intravitreal ranibizumab applies to all angiographic subtypes of neovascular AMD and across all lesion sizes. The two original phase III studies (ANCHOR and MARINA) demonstrated sustained visual acuity (VA) gains over a two-year monthly dosing schedule. Following these trials, several studies looked at ways to decrease the treatment burden while maintaining similar visual gains. These trials included PIER, PrONTO, EXCITE, SUSTAIN, HORIZON, and CATT. Visual acuity data shows that monthly dosing of ranibizumab produces superior vision outcomes compared to a less-frequent, fixed-dosing schedule. Intravitreal ranibizumab is well tolerated and shown to have a very low rate of adverse ocular or systemic side-effects.

The Natural History and Prognosis of Neovascular Age-Related Macular Degeneration: A Systematic Review of the Literature and Meta-analysis

To describe the natural history and progression of visual loss in eyes with untreated neovascular age-related macular degeneration (AMD). Systematic review and meta-analysis. Four thousand three hundred sixty-two untreated neovascular AMD patients from published interventional studies. A systematic review of the literature from 1980 to August 2005 was performed. Studies reporting disease progression outcomes for untreated patients with neovascular AMD were included. Outcome measures were summarized using simple counts and means. Random effects meta-analyses were conducted and tests of heterogeneity were performed where appropriate. Changes in visual acuity (VA) loss, development of comorbidities, and fellow eye involvement. Fifty-three primary studies were included. Nearly half of the studies (28) were randomized clinical trials. The quality of the studies was high, with over 80% providing level I or II evidence. Mean baseline VA among study patients was 0.64 logarithm of the minimum angle of resolution (logMAR) (approximately 20/87 Snellen). The mean VA change in logMAR progressed from 0.1 (1 line lost) at 3 months to 0.3 (2.7 lines lost) after 12 months and 0.4 (4 lines lost) after 24 months. The proportion of patients who developed severe vision loss (>6 lines) from baseline increased from 21.3% at 6 months to 41.9% by 3 years. The proportion of patients with VA worse than logMAR 1.0 (20/200 Snellen) increased from 19.7% at baseline to 75.7% by 3 years. Neovascular AMD developed in the fellow eye in 12.2% of patients by 12 months and in 26.8% by 4 years. Meta-analyses of vision outcome by subtype of neovascular AMD were not possible. A doubling of the visual angle of presenting VA may be expected to occur in the year after initial presentation in eyes with untreated neovascular AMD. No conclusions can be drawn as to the differences in rates of disease progression by neovascular AMD subtype. The diversity of reporting formats, paucity of long-term natural history data, and heterogeneity among the reported clinical studies impose limits to the clear understanding of long-term prognosis for visual function in neovascular AMD.

Clinical Characteristics of Exudative Age-related Macular Degeneration in Japanese Patients

To clarify the clinical characteristics of exudative age-related macular degeneration (AMD) in Japanese patients. Retrospective, observational, consecutive case series. Two hundred and eighty-nine patients with neovascular AMD were examined. The authors classified the patients into three subtypes of neovascular AMD: polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. One hundred and fifty-eight patients (54.7%) were diagnosed with PCV and 102 patients (35.3%) with typical AMD. RAP was observed in 13 patients (4.5%). In 16 patients (5.5%), one eye had PCV and the other eye had typical AMD. Most patients with PCV and typical AMD had unilateral disease (81.6% and 94.1%, respectively) with a male preponderance (77.8% and 71.6%, respectively). Nine of 13 patients with RAP were female (69.2%). Patients with RAP were older (mean, 80.3 years for men and 75.3 years for women) than patients with other subtypes. Serous and hemorrhagic pigment epithelial detachment developed in 69 patients (43.7%) with PCV, 22 patients (21.6%) with typical AMD, and nine patients (69.2%) with RAP. In the patients with unilateral disease in each subtype, large drusen in the unaffected eye were seen in 24.0% with PCV, 30.2% with typical AMD, and 77.8% with RAP. Neovascular AMD in Japanese patients has different demographic features compared with that in White patients. In Japanese patients, there is a preponderance of PCV, male gender, unilaterality, and absence of drusen in the second eye, with the exception of RAP.

Safety and Efficacy of Intravitreal Bevacizumab Followed by Pegaptanib Maintenance as a Treatment Regimen for Age-Related Macular Degeneration

Vascular endothelial growth factor (VEGF)-A, both necessary and sufficient in promoting ocular neovascularization, is an attractive therapeutic target. Combining nonselective and selective VEGF blockade may provide clinical benefit with minimal risks in the treatment of neovascular age-related macular degeneration (AMD). Twenty patients with all subtypes of neovascular AMD and a broad range of baseline vision were treated with intravitreal bevacizumab followed by pegaptanib sodium for 54 weeks. Visual acuity measurements, biomicroscopy, funduscopy, fluorescein angiography, optical coherence tomography, and adverse event assessments were performed. Mean visual acuity improved from approximately 20/200 at baseline to 20/80. All patients experienced an improvement in retinal thickness, ranging from -47 to -297 microns. Adverse events were limited to transient irritation or redness. No significant elevation in intraocular pressure occurred following either bevacizumab or pegaptanib injections. Nonselective VEGF blockade with bevacizumab induction and selective VEGF165 blockade with pegaptanib as maintenance therapies may offer clinically meaningful outcomes with acceptable safety profiles in patients with AMD.

Konsenspapier der Retinologischen Gesellschaft, der Deutschen Ophthalmologischen Gesellschaft und des Berufsverbandes der Augenärzte - Stellungnahme zur aktuellen Therapie der neovaskulären AMD

Until recently, only two options were available for the treatment of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD): laser photocoagulation and photodynamic therapy (PDT) with verteporfin. However, potential new treatments for CNV are under development, and data from phase III clinical trials are now available. Referring to these data, expert guidance is required to supply ophthalmologists with expertise in the management of AMD to select and use the most appropriate therapies in the treatment of neovascular AMD. The therapeutic modalities discussed include thermal laser photocoagulation, PDT with verteporfin, triamcinolone acetonide and the possible combination with PDT, anecortave acetate, pegaptanib sodium and ranibizumab. After a short description of the treatment principles, a summary of the discussion of all relevant study results of the different treatment options with respect to the different subtypes of neovascular AMD is presented. These discussions resulted in an "up-to-date" recommendation of therapeutical strategies in neovascular AMD. For subfoveal lesions with predominantly classic CNV, or with occult with non-classic CNV and a lesion size < or = 4 macular photocoagulation study (MPS) disc areas (DA), PDT with verteporfin is recommended; for subfoveal lesions with minimally classic CNV, treatment with PDT or pegaptanib sodium is possible, even if there are some problems with the statistics in the studies with both treatment modalities. PDT with verteporfin should be considered for juxtafoveal lesions that are so close to the fovea that laser photocoagulation would almost certainly extend under the center of the foveal avascular zone, and for all other juxtafoveal lesions and for extrafoveal lesions laser photocoagulation is suggested. Therapy should be performed not later than one week after the initial fluorescein angiogram upon which the clinical decision for treatment is based. At each follow-up best-corrected visual acuity and a fundus examination should be performed as well as a fluorescein angiography every three months. These recommendations provide good clinical guidance for the choice and use of laser and pharmacotherapies for the management of CNV due to AMD. Revisions of the recommendations will be required as new data become available.