Corrigendum to "Nutritional Risk Factors for Age-Related Macular Degeneration".

[This corrects the article DOI: 10.1155/2014/413150.].

Long-term alterations of systemic vascular endothelial growth factor levels in patients treated with ranibizumab for age-related macular degeneration.

PURPOSE: To analyze long-term changes of systemic vascular endothelial growth factor (VEGF) levels in patients treated with ranibizumab for neovascular age-related macular degeneration. METHODS: Sixty-one patients with neovascular age-related macular degeneration and 68 age-matched controls were included in the study. Patients were treated with ranibizumab on a pro re nata regimen. Plasma samples were collected before initiation of treatment and after 1 year (30 patients) or 2 years (31 patients) of treatment. Vascular endothelial growth factor was measured by Luminex microbead analysis. RESULTS: At baseline, patients with neovascular age-related macular degeneration and controls did not differ significantly in VEGF levels (P = 0.062). There was a significant decline in systemic VEGF levels of 39.5% after 1 year (34.2 ± 17.2 pg/mL to 20.7 ± 14.0 pg/mL; P = 7.50 × 10(-5)) and of 46.7% after 2 years (40.4 ± 24.1 pg/mL to 21.5 ± 23.3 pg/mL; P = 2.48 × 10(-4)) of treatment. Patients with persistent activity of choroidal neovascularization showed a significantly smaller decrease of plasma VEGF levels than patients with dry intervals despite the higher number of injections (P = 0.048). CONCLUSION: In addition to immediate effects limited to days if not hours, ranibizumab also leads to long-term alterations of systemic VEGF to subnormal levels. Patients with persistent choroidal neovascularization activity showed a less pronounced VEGF decrease. Therefore, VEGF levels might be a useful marker for treatment response.

Nutritional risk factors for age-related macular degeneration.

PURPOSE: To evaluate the role of nutritional factors, serum lipids, and lipoproteins in late age-related macular degeneration (late AMD). METHODS: Intake of red meat, fruit, fish, vegetables, and alcohol, smoking status, and body mass index (BMI) were ascertained questionnaire-based in 1147 late AMD cases and 1773 controls from the European Genetic Database. Serum levels of lipids and lipoproteins were determined. The relationship between nutritional factors and late AMD was assessed using logistic regression. Based on multivariate analysis, area-under-the-curve (AUC) was calculated by receiver-operating-characteristics (ROC). RESULTS: In a multivariate analysis, besides age and smoking, obesity (odds ratio (OR): 1.44, P = 0.014) and red meat intake (daily: OR: 2.34, P = 8.22 × 10(-6); 2-6x/week: OR: 1.67, P = 7.98 × 10(-5)) were identified as risk factors for developing late AMD. Fruit intake showed a protective effect (daily: OR: 0.52, P = 0.005; 2-6x/week: OR: 0.58, P = 0.035). Serum lipid and lipoprotein levels showed no significant association with late AMD. ROC for nutritional factors, smoking, age, and BMI revealed an AUC of 0.781. CONCLUSION: Red meat intake and obesity were independently associated with increased risk for late AMD, whereas fruit intake was protective. A better understanding of nutritional risk factors is necessary for the prevention of AMD.

Nongenetic risk factors for neovascular age-related macular degeneration.

PURPOSE: To create a risk model for neovascular age-related macular degeneration (nAMD) based on nongenetic factors. METHODS: In this case-control study, 1459 individuals were included, 445 patients showed nAMD and 1014 were healthy controls. Participants were randomly assigned into a training set (containing two-thirds of individuals) and a validation set. Stepwise logistic regression analysis was performed for 25 environmental risk factors in the training set. The risk model with the remaining factors was then validated in the validation set using receiver operating characteristics (ROC) curve and Hosmer-Lemeshow-Test. Additionally, a genetic risk model including variants in the complement factor H gene (CFH, rs1061170) and the age-related maculopathy susceptibility 2 gene (ARMS2, rs10490924) was generated. RESULTS: The environmental risk model with the factors age, alcohol use, allergy, education, sunlight exposure, fish consumption, and physical exercise showed an AUC of 0.80 (95% confidence interval [CI] 0.76-0.84) in the training set. Validation of the model showed adequate calibration (Hosmer-Lemeshow P = 0.81). The AUC for the genetic model was 0.77 (95% CI 0.730-0.808), for the combined environmental and genetic model 0.92 (95% CI 0.887-0.947). CONCLUSIONS: Seven nongenetic factors are able to provide equivalent discrimination between nAMD patients and controls to genetic risk models. Most of them are modifiable and give the opportunity for counseling patients.

Environmental and genetic risk factors for retinal angiomatous proliferation.

PURPOSE: To identify genetic and environmental risk factors in patients with retinal angiomatous proliferation (RAP), a clinical subtype of age-related macular degeneration (AMD). METHODS: In this case-control study, 108 AMD cases with RAP, 258 AMD patients with choroidal neovascularization (CNV) without RAP and 443 healthy controls were evaluated. Single nucleotide polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and various environmental risk factors were analysed. Statistical analysis was performed by univariate and multivariate regression analysis. RESULTS: High age, female sex and genetic variants in CFH and ARMS2 were identified as risk factors for developing any CNV. In RAP patients, arterial hypertension was also identified as a risk factor (OR 2.39; p = 0.0005). Compared with the 'non-RAP' CNV group, the association with high age (OR 1.05; p = 0.008) and arterial hypertension (OR 1.82; p = 0.02) was significantly higher in RAP patients, while the association with CFH risk alleles (homozygous OR 0.40; p = 0.003) was significantly lower, which was confirmed in a multivariate analysis (OR 0.41; p = 0.03 for the heterozygous risk allele and OR 0.38; p = 0.03 for the homozygous risk allele). CONCLUSION: The association with the CFH Y402 risk allele was less pronounced in RAP patients than in 'non-RAP' CNV patients, while the association with high age and arterial hypertension appeared to be stronger. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes and their different risk factors and disease mechanisms.

Analysis of rare variants in the C3 gene in patients with age-related macular degeneration.

Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P=0.04), Arg735Trp (OR=17.4, 95% CI=2.2-136; P=0.0003), and Ser1619Arg (OR=5.2, 95% CI=1.0-25; P=0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.

Genetic and environmental risk factors for age-related macular degeneration in persons 90 years and older.

PURPOSE: We studied associations of genetic polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) in nonagenarians with age-related macular degeneration (AMD). METHODS: This case-control study comprised 2737 persons (1204 controls, 1433 AMD cases), including 166 nonagenarians (52 controls, 114 AMD cases). Single nucleotide polymorphisms (SNPs) in the genes ARMS2 and CFH were determined. Risk scores were computed by multiple logistic regression analysis, including genetic and environmental risk factors (smoking, hypertension, body mass index, diabetes) for different age groups (<70, 70-79, 80-89, ≥ 90 years [nonagenarians]). RESULTS: In nonagenarians, ARMS2 showed the weakest associations with AMD (odds ratio [OR] = 1.52, P = 0.127) compared to the other groups (OR, 70 years = 2.23, P = 1.03 × 10(-13); OR, 70-79 years = 2.70, P = 1.00 × 10(-13); OR, 80-89 years = 3.11, P = 6.56 × 10(-8)). For CFH, ORs for AMD increased with age (<70 years OR = 1.96, P = 1.80 × 10(-11); 70-79 years OR = 1.89, P = 4.48 × 10(-13); 80-89 years OR = 2.71, P = 1.28 × 10(-7)), but decreased again in the nonagenarians (OR = 2.21, P = 0.005). Compared to the group <70 years, reduced minor allele frequencies (MAFs) for AMD patients were observed in the nonagenarians (CFH 0.54 vs. 0.43, P = 0.009; ARMS2 0.44 vs. 0.29, P = 2.97 × 10(-5)), while the MAFs in controls were not significantly different. The genetic risk score revealed the lowest discriminative power in the nonagenarians with an area-under-curve (AUC) of 0.658 for receiver-operating characteristics (AUC 80-89 years = 0.768, 70-79 years = 0.704, <70 years = 0.682), while no significant difference was seen for the environmental risk score (AUC < 70 years = 0.579, 70-79 years = 0.567, 80-89 years = 0.600, >90 years = 0.608). CONCLUSIONS: Risk alleles in CFH and ARMS2 have a significantly smaller effect on AMD development in nonagenarians, while environmental factors retain a similar effect.

Impact of the common genetic associations of age-related macular degeneration upon systemic complement component C3d levels.

Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56 × 10(-7)), AMD phenotype (p = 1.15 × 10(-11)) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87 × 10(-6)), higher body mass index (p = 1.00 × 10(-13)), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60 × 10(-6)) in CFH, rs4151667 (p = 1.01 × 10(-5)) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation.

Allergy is a protective factor against age-related macular degeneration.

PURPOSE: To investigate the role of allergy on AMD. METHODS: Age-related macular degeneration staging was performed for 3585 individuals (1878 from Cologne, Germany, and 1707 from Nijmegen, The Netherlands). Interviewer-assisted questionnaires were evaluated for the factors smoking, use of corticosteroids, and history of allergy, including causative allergens. Serum complement component C3d and C3 levels were measured and the C3d:C3 ratio was calculated. Associations of allergy with AMD/late AMD were assessed by logistic regression analysis; C3d:C3 ratio was compared between groups. RESULTS: The discovery cohort from Cologne included 864 AMD patients and 1014 controls; 495 patients had late AMD. Positive history of allergy showed strong protective effects on the phenotype AMD (OR 0.52; P = 3.42 × 10(-9)) and late AMD (OR 0.32; P = 2.57 × 10(-13)). Subclassification in allergy-provoking agents showed significant protective effects in all groups. After adjustment for age, sex, smoking, and corticosteroid use, protective effects for AMD (OR 0.75; P = 0.018) and late AMD (OR 0.49; P = 2.87 × 10(-5)) were confirmed. Although the C3d:C3 ratio was higher in AMD/late AMD patients (both P < 0.001), there was no association with allergy in AMD (P = 0.22). The protective effect of allergy on AMD was confirmed in the replication cohort from Nijmegen (P = 0.002 for AMD; P = 0.0001 for late AMD). CONCLUSIONS: Allergy has a protective effect on the development of AMD independent of the provoking allergen, which cannot be explained by complement activation. Further investigations are necessary to elucidate the molecular mechanisms underlying the protective effect of allergy on AMD.

Relationship between visual acuity and spectral domain optical coherence tomography retinal parameters in neovascular age-related macular degeneration.

PURPOSE: Relationship between spectral domain optical coherence tomography (SD-OCT) and visual acuity (VA) in neovascular age-related macular degeneration (NVAMD). PROCEDURES: VA and SD-OCTs of 64 treatment-naive eyes with NVAMD were retrospectively collected at baseline and 1 year (n = 30). Retinal and subretinal spaces were manually analyzed. Volume and thickness measurements were correlated with VA. RESULTS: At baseline, lower VA correlated with increased volume of subretinal hyperreflective material (R = 0.4, p < 0.001) and with decreased volume of the photoreceptor layer (PRL, R = -0.4, p < 0.01). At 1 year, lower VA correlated with decreased volume of the retina (R = -0.7, p < 0.001), outer nuclear layer (R = -0.6, p < 0.05) and PRL (R = -0.7, p < 0.001). Decrease in VA after 1 year correlated with a decrease in PRL (R = 0.4, p < 0.05). CONCLUSIONS: Quantitative analysis of SD-OCT revealed correlations between VA and retinal and subretinal morphological changes in NVAMD. MESSAGE: Atrophy of the outer retina is an important correlate for lower VA in NVAMD.

Response to anti-VEGF therapy in patients with subretinal fluid and pigment epithelial detachment on spectral-domain optical coherence tomography.

PURPOSE: To analyse the long-term functional and morphological response of a specific choroidal neovascular membrane (CNV) phenotype to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Data from 30 eyes of 30 consecutive patients with subretinal fluid (SRF) and fibrovascular pigment epithelial detachment (PED) due to CNV on spectral-domain optical coherence tomography (SDOCT) with a follow-up of at least 20 months were retrospectively collected. Main outcome measures included change in visual acuity, quantitative and qualitative parameters on SDOCT [photoreceptor layer, outer nuclear layer (ONL), choroid, PED, SRF] and on fluorescein angiography (CNV activity). Subjects were divided into responders and non-responders based on morphological and functional aspects. RESULTS: An average number of 20.23 ± 9.9 anti-VEGF injections were administered during a mean follow-up of 40.25 ± 13.5 months. Fourteen eyes were categorized as morphological non-responders, 12 as functional non-responders and eight as complete non-responders. Complete non-responders were significantly younger than complete responders (68.5 ± 4.5 vs 74.3 ± 6.8 years; p < 0.05) and presented thinner baseline ONL values (68.43 ± 15.2 vs103.5 ± 32.8 µm; p < 0.05). Intermediate or large drusen as typical features for age-related macular degeneration (AMD) were less frequently present in complete non-responders; however, this was not statistically significant (62.5 % vs 91.7 %; p = 0.25). CONCLUSIONS: Our preliminary findings indicate that eyes with the specific SDOCT phenotype with isolated fibrovascular PED and SRF frequently demonstrate non-response to anti-VEGF therapy, and the underlying disease mechanism may be different from AMD. Larger prospective trials are required to validate those results, and to develop strategies to improve the morphological as well as functional outcome.

Atypical outer retinal fluid accumulation in choroidal neovascularization: a novel OCT finding.

BACKGROUND AND OBJECTIVE: To report a novel optical coherence tomography (OCT) finding in choroidal neovascularization (CNV). PATIENTS AND METHODS: The authors identified seven eyes with CNV demonstrating the atypical pattern of fluid accumulation within the outer retina on OCT. Patient demographics, best corrected visual acuity and spectral-domain OCT (SD-OCT) images were collected for all available follow-up visits. Volume and area of the fluid were measured on SD-OCT. Microperimetry was performed in one case. RESULTS: The outer retinal fluid was located between the external limiting membrane (ELM) and the outer photoreceptor band on SD-OCT. Within this area, the outer segments of the photoreceptors were visualized as a continuous band, which appeared to split from the retina, dropping down toward the retinal pigment epithelium (mean area: 2.53 ± 1.23 mm(2); mean volume: 0.19 ± 0.20 mm(3)). All cases demonstrated the finding only at one time point during follow-up. Recovery of the outer retina and retinal function could be detected. CONCLUSION: Atypical intraretinal fluid accumulation externally to the ELM may be detected on SD-OCT in eyes with CNV. This finding may be transient and may not preclude subsequent improvement in visual function. The frequency of the presumed photoreceptor delamination and its full clinical significance remain to be defined.

SDOCT thickness measurements of various retinal layers in patients with autosomal dominant optic atrophy due to OPA1 mutations.

PURPOSE: To specify thickness values of various retinal layers on macular spectral domain Optical Coherence Tomography (SDOCT) scans in patients with autosomal dominant optic atrophy (ADOA) compared to healthy controls. METHODS: SDOCT volume scans of 7 patients with ADOA (OPA-1 mutation) and 14 healthy controls were quantitatively analyzed using manual grading software. Mean thickness values for the ETDRS grid subfields 5-8 were calculated for the spaces neurosensory retina, retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), a combined space of inner plexiform layer/outer plexiform layer/inner nuclear layer (IPL+INL+OPL), and a combined space of outer nuclear layer/photoreceptor layers (ONL+PL). RESULTS: ADOA patients showed statistically significant lower retinal thickness values than controls (P < 0.01). RNFL (P < 0.001) and GCL thicknesses (P < 0.001) were significantly lower in ADOA patients. There was no difference in IPL+INL+OPL and in ONL+PL thickness. CONCLUSION: Manual subanalysis of macular SDOCT volume scans allowed detailed subanalysis of various retinal layers. Not only RNFL but also GCL thicknesses are reduced in the macular area of ADOA patients whereas subjacent layers are not involved. Together with clinical findings, macular SDOCT helps to identify patients with suspicion for hereditary optic neuropathy before genetic analysis confirms the diagnosis.

A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.

Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

Grading of Age-Related Macular Degeneration: Comparison between Color Fundus Photography, Fluorescein Angiography, and Spectral Domain Optical Coherence Tomography.

Purpose. To compare color fundus photography (FP), fluorescein angiography (FA), and spectral domain optical coherence tomography (SDOCT) for the detection of age-related macular degeneration (AMD), choroidal neovascularisation (CNV), and CNV activity. Methods. FPs, FAs, and SDOCT volume scans from 120 eyes of 66 AMD and control patients were randomly collected. Control eyes were required to show no AMD, but other retinal pathology was allowed. The presence of drusen, pigmentary changes, CNV, and signs for CNV activity was independently analyzed for all imaging modalities. Results. AMD was diagnosed based on FP in 75 eyes. SDOCT and FA showed sensitivity (specificity) of 89% (76%) and 92% (82%), respectively. CNV was present on FA in 68 eyes. Sensitivity (specificity) was 78% (100%) for FP and 94% (98%) for SDOCT. CNV activity was detected by SDOCT or FA in 60 eyes with an agreement in 46 eyes. Sensitivity was 88% for SDOCT and 88% for FA. FP showed sensitivity of 38% and specificity of 98%. Conclusions. CNV lesions and activity may be missed by FP alone, but FP may help identifying drusen and pigmentary changes. SDOCT is highly sensitive for the detection of AMD, CNV, and CNV activity; however, it cannot fully replace FA.

A functional variant in the CFI gene confers a high risk of age-related macular degeneration.

Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 × 10⁻6; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.

Aqueous flare is increased in patients with clinically significant cystoid macular oedema after cataract surgery.

BACKGROUND: To analyse the relationship of clinically significant cystoid macular oedema (CME after phacoemulsification to blood-aqueous barrier breakdown as determined by aqueous flare, visual acuity and retinal thickness in optical coherence tomography (OCT). MATERIALS AND METHODS: 30 eyes of 30 consecutive patients with clinically significant CME and vision loss were included. 46 pseudophakic and 45 phakic eyes without CME served as controls. Clinical data included age, gender, best-corrected visual acuity (BCVA) and spectral domain OCT volume scans. Retinal thickness measuring of the foveal central subfield was determined. Aqueous flare was measured quantitatively with the Kowa FM-500 Laser Flare-Cell Meter. RESULTS: Patients with CME had significantly higher flare values compared with pseudophakic patients (p<0.0001). For patients with CME, aqueous flare values correlated significantly with BCVA (Spearman rs=0.4, p=0.041), while there was no correlation with retinal thickness. Using flare values to predict CME, receiver operating characteristic analysis returned an area under the curve of 0.976. CONCLUSIONS: Aqueous flare as a marker for inflammation and breakdown of the blood-retinal barrier is increased in patients with CME after cataract surgery.

Individual recurrence intervals after anti-VEGF therapy for age-related macular degeneration.

BACKGROUND: To assess the time interval to recurrent choroidal neovascular membrane (CNV) activity in eyes with neovascular age-related macular degeneration (AMD) after intravitreal anti-VEGF therapy. METHODS: Data from all patients who received intravitreal ranibizumab injections for neovascular AMD at the University of Cologne prior to February 2009 were retrospectively reviewed. Patients were treated on a pro re nata (PRN) basis and eyes with active CNV received three consecutive monthly injections. Recurrence of CNV activity was defined as recurrence of intra- or subretinal fluid on optical coherence tomography (OCT) or leakage on fluorescein angiography (FA) after initial resolution of fluid and leakage following anti-VEGF therapy. All eyes showing at least two documented recurrences of CNV activity during follow-up were included in this analysis. Recurrence intervals were calculated and were deemed to be regular or periodical if the difference between recurrence interval times was less than 50 days. RESULTS: Twenty-nine eyes of 28 patients met the inclusion criteria. Two to six recurrences were detected per case (mean 2.8 ± 1.1 recurrences). Recurrence intervals ranged from 41 days to 523 days (mean 5.5 ± 3.4 months, median 4.5 months). Twenty-two eyes (76%) showed at least two periodical recurrence intervals. In 12 eyes (41%), all recurrences occurred at regular intervals (2-4 recurrences, mean 2.3 ± 0.6 recurrences). Seven eyes (24%) showed irregular recurrence intervals (2-3 recurrences, mean 2.1 ± 0.4 recurrences). All 11 eyes with a classic CNV lesion component showed at least two periodical recurrence intervals. Eyes with occult CNV lesions showed periodical recurrence intervals in 11 out of 18 cases (61%). CONCLUSIONS: Preliminary data indicate that periodical recurrences of CNV activity may be seen in eyes with neovascular AMD undergoing anti-VEGF therapy. Knowledge of individual recurrence interval times may allow for the development of an individualized treatment plan and prophylactic therapy.