Algorithm of the major and minor diagnostic criteria for active myopic choroidal neovascularization.

PURPOSE: To propose an algorithm of the major and minor diagnostic criteria for macular myopic choroidal neovascularization (mCNV). METHODS: This single-center, retrospective, cross-sectional study was based in Istituto Auxologico Italiano, Milan, Italy. Two authors evaluated the clinical and imaging parameters of eyes with high myopia (spherical equivalent of -6D or less) and suspected to have naïve, recurrent, or inactive mCNV. Recordings of the eyes that met the inclusion criteria were then independently evaluated by two other senior retinal specialists. Fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), and OCT angiography were used for multimodal imaging. RESULTS: One-hundred and twenty-two eyes (n = 107; 39 men, 68 women) were included in the study. The mean patient age was 66 years (range, 22-89 years). There were 83 and 39 eyes in the active mCNV and control groups, respectively. The best diagnostic algorithm had positive- and negative-predictive values of 89% and 85%, respectively, and was based on four criteria: leakage/staining on FA, retinal thickening, fuzzy area on SD-OCT, and recent metamorphopsia. When excluding FA-derived findings, retinal pigment epithelium (RPE) features played a diagnostic role in 33 eyes (27%). Twenty-seven eyes with active mCNV (32%) did not have the fuzzy area. Taken singularly, no clinical or imaging parameter had both sensitivity and specificity greater than 78%. Matching of 2 or 3 biomarkers did not yield a sensitivity or specificity greater than 79%. Sensitivities and specificities ≥ 90% were found in ten criteria combinations that included four to five biomarkers. The most frequent were metamorphopsia, fuzzy area, retinal thickening, and leakage. Less frequently, they included hemorrhage, staining, and RPE features such as elevation, flattening, and focal interruption. For all the parameters, the agreement between the investigators was good (Cohen k ≥ 0.66), being the lowest when detecting the ELM interruption within the lesion. CONCLUSIONS: A combination of at least four clinical and biological markers yielded the highest positive- and negative-predictive values. More ("major") and less ("minor") frequent diagnostic criteria are proposed.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF SUBRETINAL FIBROSIS AFTER MYOPIC NEOVASCULARIZATION.

PURPOSE: To describe the optical coherence tomography (OCT) angiography features of subretinal fibrosis in eyes with myopic choroidal neovascularization after natural evolution or secondary to intravitreal anti-vascular endothelial growth factor therapy. METHODS: Retrospective observational case series. All eyes underwent a multimodal imaging examination including fluorescein angiography, spectral domain OCT, OCT angiography, and en face OCT. RESULTS: Twenty-five eyes of 25 patients with mean age of 56.4 ± 14.9 were included in the study. Subretinal fibrosis was diagnosed at mean 30 (range 6-116) months before inclusion. Within the subretinal fibrosis, an abnormal vascular network was observed in 20/25 (80%) eyes, located typically in the outer retina (18/20, 90%) or the choriocapillaris (14/20, 70%) segmentation. The most prevalent patterns were "round tangle" and "tapered tangle." On en face OCT, the subretinal fibrosis was evidenced in 24/25 (96%) eyes, most prevalently in the outer retina (21/25, 84%) and in the choriocapillaris (18/25, 72%), where main feature was white-hyperreflective (20/21, 95%) and dark-hyporeflective (17/18, 94%) appearance, respectively. The presence of subretinal fibrosis on en face OCT was positively correlated with the presence of abnormal vascular network on OCT angiography in 61% of the cases (P = 0.005). CONCLUSION: Subretinal fibrosis secondary to myopic choroidal neovascularization frequently contains blood flow within a persistent abnormal vascular network as assessed by OCT angiography.

Increased soluble urokinase plasminogen activator receptor (suPAR) levels in neovascular age-related macular degeneration: a role for inflammation in the pathogenesis of the disease?

PURPOSE: To evaluate the plasma concentration of the soluble form of the urokinase-type plasminogen activator receptor ((s)uPAR), an established biomarker of chronic inflammation, in patients affected by neovascular age-related macular degeneration. METHODS: Forty consecutive patients affected by age-related macular degeneration and 52 subjects with no history of the disease were included in this case-control study. The two groups of individuals considered for the study were matched for age, sex, and class of medications taken. Plasma concentration of suPAR was measured using a specific ELISA assay (suPARnostic, Birkeroed, Denmark). RESULTS: The case and control groups were similar for age, gender distribution, weight, height, and systolic and diastolic blood pressure, as well as for dyslipidemia and high blood pressure medication (P > 0.28). The plasma concentrations of suPAR were significantly increased in patients with neovascular age-related macular degeneration when compared to controls (6.19 ± 2.2 ng/ml, vs 5.21 ± 1.5, respectively, mean ± SD P = 0.01). CONCLUSIONS: Patients with neovascular age-related macular degeneration display increased plasma levels of suPAR, suggesting that chronic inflammation may be involved in the pathogenesis of the disease.

Is ellipsoid zone integrity essential for visual recovery in myopic neovascularization after anti-VEGF therapy?

PURPOSE: To evaluate functional prognostic factors and neuroretinal changes after anti-vascular endothelial growth factor (VEGF) treatment in patients with naïve, recent myopic neovascularization (mCNV), as assessed by spectral-domain optical coherence tomography (SD-OCT). METHODS: Specific changes in tomographic features between baseline and final follow-up were retrospectively evaluated by two examiners independently. Imaging was obtained by a multi-modal imaging system which combines fluorescein angiography and SD-OCT. RESULTS: Twenty-two eyes (male, six; female, 16; mean age, 65 ± 14 years) were considered. Mean follow-up was 21.5 ± 14 months. Best-corrected visual acuity (BCVA) improved from 0.38 ± 0.26 to 0.16 ± 0.20 logMAR (p < 0.001). The ellipsoid zone and the external limiting membrane (ELM) were disrupted in 21 (95.5%) and 15 (68.2%) eyes at baseline, and in 16 (72.7%) and nine (40.9%) eyes after therapy respectively. The ellipsoid zone and ELM were typically intact at lesion margins in 13 (59.1%) and 19 eyes (86.5%) respectively at baseline. The inner retina was intact in 20 eyes (91%). Six eyes (27.3%) exhibited complete regression without fibrosis. Absence of hemorrhage and integrity of lesion-adjacent ELM and of lesion-adjacent ellipsoid zone at baseline were factors for better final BCVA (p ≤ 0.05) CONCLUSION: Vision gain might occur despite ellipsoid zone or ELM restoration. Hemorrhage could be considered a negative prognostic factor, integrity of lesion-adjacent ELM and of lesion-adjacent ellipsoid zone as positive prognostic factors. Myopic CNV can also resolve completely without fibrosis.

Endothelial progenitor cells and response to ranibizumab in age-related macular degeneration.

BACKGROUND: Choroidal neovascularization (CNV) is the main cause of vision loss in age-related macular degeneration (AMD). In experimental CNV, endothelial progenitor cells (EPCs) contribute to the formation of new vessels. The aim of this study was to investigate whether the behavior of EPCs in patients with AMD supports a role for EPCs in human CNV. METHODS: The number of circulating EPCs that are considered pure endothelial precursors and EPCs with monocytic characteristics, and the plasma levels of regulatory cytokines were evaluated in 23 patients with AMD with active CNV and 20 matched controls. In the patients, this profile was re-evaluated after ranibizumab. RESULTS: When compared with controls, the patients with AMD showed a lower number of both EPC types (P = 0.03) and higher plasma levels (P = 0.03) of stromal cell-derived factor 1. Three monthly injections of ranibizumab returned to control levels the number of circulating EPCs considered pure endothelial precursors and of stromal cell-derived factor 1, but not of monocytic EPCs. CONCLUSION: The observations indicate responsiveness of circulating EPCs to the CNV process in AMD. They suggest the hypothesis that increased stromal cell-derived factor 1 production at the CNV site (reflected in higher plasma levels) recruits EPCs from the circulation, and that antivascular endothelial growth factor therapy selectively decreases the recruitment of cells to be incorporated into new vessels.

VIDEO COLOR OCT ANGIOGRAPHY FOR MYOPIC CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To investigate the myopic macular neovascularization (mMNV) features on dynamic video-color optical coherence tomography (OCT) angiography (OCTA) and the diagnostic rate versus the static, four-segmentations visualization mode. DESIGN: Retrospective cohort study PARTICIPANTS: Fifty-four patients with mMNV METHODS: Sixty-two eyes with high myopia complicated by mMNV were included. Clinical charts, fluorescein angiography and structural OCT were used as standard reference to assess lesion activity. Static and video-color OCTA were then analysed and compared by two independent reviewers. MAIN OUTCOME MEASURES: Morphology description of mMNV on video-color OCTA and differences in the proportion of diagnosis between video-colour and static OCTA. RESULTS: 62 eyes from 54 patients (mean age 63,22 years) were enrolled. Thirty-four (55%) mMNV were active and 28 (45%) inactive. Twenty-two (65%) active mMNV presented on video-color OCTA as an interlacing vascular network in the outer retina and the choriocapillaris. A tapered form was the prevalent size (72,7%). In 3 eyes (9%) an abnormal and irregular vascular network (AVN) was disclosed and in 5 (15%) only some blood flow alteration. All the lesions extended both in the outer retinal and the choriocapillaris. Eleven (39%) inactive mMNV presented on video-color OCTA as an interlacing vascular network too, in the outer retina and the choriocapillaris. Eight (29%) had some AVN and 6 (21%) only some blood flow alteration. The diagnostic rate of video-color vs static OCTA was 95% (IC 95% 86% to 99%) vs 77% (IC 95% 86% to 99%, p= 0.0009), and shows an advantage in favour of video-colour OCTA of 15% (CI 95%, 3%-27%) and 22% (CI 95%, 7%-38%) in active and inactive lesions, respectively (p<0.026). Lesion extension within both the outer retina and the choriocapillaris was present in 90% and 69% of cases on dynamic OCTA and static OCTA, respectively, with a proportion difference of 20% (CI 95%, 10%-31%, p= 0.0005). Concordance between the two examiners was high: 0.95 (95%, CI 0.88 to 1.00) and 0.96 (0.91 to 1.00) for active and inactive lesions, respectively. CONCLUSIONS: Video color-enhanced OCTA may help in diagnosing mMNV and should be considered by clinicians in addition to structural OCT and static OCTA.

Sensitivity of fluorescein angiography alone or with SD-OCT for the diagnosis of myopic choroidal neovascularization.

BACKGROUND: Myopic choroidal neovascularization (mCNV) has certain characteristics and features that distinguish it from choroidal neovascularization secondary to age-related macular degeneration. There may be angiographic diagnostic difficulties even when using the scanning laser ophthalmoscope, which gives more contrast and better definition than traditional angiography. The aim of the study is to compare the sensitivity of fluorescein angiography (FA) alone or combined with Spectral Domain Optical Coherence Tomography (SD-OCT) for assessing the incidence of mCNV. METHODS: In this retrospective study, two authors reviewed the charts and images of patients with recent (<30 days) vision deterioration, pathologic myopia, axial length >26 mm, documentation or suspicion of mCNV or macular exudative pathologies at FA and OCT. They only examined the images at first presentation obtained by the multi-modal imaging system that combines Infrared reflectance, FA, and SD-OCT, (Spectralis, Heidelberg Engineering, Germany). The images selected were then evaluated by three other investigators in blinded, independent conditions, in order to make their diagnosis, which was noted or rated as doubtful if it could not be decided on the basis of FA alone. SD-OCT images were then shown and compared to IR and FA by each of the three investigators individually to formulate a conclusive diagnosis. RESULTS: A total of 71 eyes of 69 patients were suitable for the study, mean age 65.97±14.57 years, spherical equivalent refraction -8.82 ± 2.51 diopters. Concordance between the three examiners' interpretations of FA features and FA-guided SD-OCT was 50/71 (70.4 %) and 67/71 (94 %) respectively. Total agreement on diagnosis between the three examiners was achieved in 55 % of cases for FA (κ = 0.53, p < 0.001), and 94 % for FA-guided SD-OCT (k = -0.01, p = 0.5). The final diagnosis with FA and FA-guided SD-OCT differed in 29 cases (40 %; 95 % C.I. 29-42 %), whereas 12 (17 %) mCNV were overlooked at FA, and in 11 (15 %) cases none of the examiners reached a diagnosis based on FA alone. CONCLUSIONS: On the basis of FA alone, active mCNV can be misdiagnosed. The use of SD-OCT combined with FA should therefore be strongly considered.

Study of FTMT and ABCA4 genes in a patient affected by age-related macular degeneration: identification and analysis of new mutations.

BACKGROUND: Age-related macular degeneration (AMD) is a multifactorial disease for which an involvement of alterations in the retinal ABC transporter gene (ABCA4) is still debated. Oxidative stress in retinal pigment epithelial cells has been postulated to contribute to the pathogenesis of the disease. Mitochondrial ferritin (FtMt), an iron-sequestering protein, is expressed in cell types characterized by high metabolic activity and oxygen consumption, including human retina, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. Based on these findings we wanted to investigate whether mutations in this gene could be found in AMD patients. METHODS: Mutational scanning of the FTMTgene was performed in a cohort of 50 patients affected by age-related macular degeneration. The ABCA4 gene was also scanned in one patient carrying an FtMt mutation. In silico analyses were carried out on the identified variants. The recombinant form of FtMt variant was expressed in Escherichia coli and biochemically characterized. RESULTS: One patient was found to be heterozygous for two previously unreported genetic changes: a complex FtMt mutation (c.437_450delinsCT: delAGGACATCAAGAAGinsCT) and a missense p.Leu973Phe (c.2919G>T) mutation in exon 20 of ABCA4. Computational analyses predicted a severe structural impairment for FtMt variant and a mild destabilizing effect for ABCA4. E. coli expression of recombinant FtMt variant yielded a highly insoluble protein that could not be renatured under in vitro conditions suitable for wild-type ferritins. CONCLUSIONS: Our findings suggest that the FtMt mutation may determine a condition similar to haploinsufficiency resulting in a reduced protection from iron-dependent oxidative stress in mitochondria.

Vascularized retinal pigment epithelial detachment in age-related macular degeneration: treatment and RPE tear incidence.

BACKGROUND: To review vascularized-pigment epithelial detachment (V-PED) treatment visual outcome, and to assess acute retinal pigment epithelium (RPE) tear incidence. METHODS: One hundred and thirty-two eyes of 125 consecutive patients with age-related macular degeneration and V-PED were included. Ninety-four eyes (71.2%) were associated with choroidal new vessels (CNV), 38 (28.8%) with retinal angiomatous proliferation (RAP). Patients, treated over a 10-year period with the time-current therapy, received: verteporfin photodynamic therapy (PDT) (group 1, 38 eyes), combined intravitreal triamcinolone acetonide (IVTA) and PDT (group 2, 44 eyes) or intravitreal anti-VEGF injection (bevacizumab or ranibizumab) (group 3, 50 eyes). RESULTS: Mean follow-up was 20.5 months. At month 12, all eyes treated with PDT or with IVTA and PDT showed a mean significant severe visual decrease. Eyes with CNV lost -0.67 and -0.37 logMAR (p < 0.01 and p < 0.01 respectively), and eyes with RAP -0.55 and -0.31 logMAR (p < 0.01 and p = 0.01 respectively). RPE tear occurred in 14 eyes (36.8%) and in six eyes (13.6%) in groups 1 and 2 respectively. Eyes treated with anti-VEGF therapy showed slight mean visual acuity decrease at month 12. Those with CNV had a mean baseline best-corrected visual acuity (BCVA) of 0.36 ± 0.24 logMAR, final of 0.44 ± 0.30 logMAR (-0.08 logMAR, n.s.). In eyes with RAP, mean baseline BCVA was 0.58 ± 0.39 logMAR, final was 0.78 ± 0.47 logMAR (-0.20 logMAR, n.s.). RPE tear occurred in 14 eyes (36.8%). Patients with either V-PED with CNV or a better baseline BCVA showed greater risk of acute RPE tear (p = 0.01 and p = 0.003 respectively). CONCLUSIONS: Effective treatment for vascularized PED is still lacking. Until now, only stabilization of the disease has been achieved using anti-VEGF therapy, but the risk of RPE tear can further hamper our expectations. Baseline characteristics are helpful for prognosis, but patients must be informed of the uncertain response. New therapeutic strategies are needed.

Multimodal imaging and diagnosis of myopic choroidal neovascularization in Caucasians.

PURPOSE: To investigate myopic choroidal neovascularization (mCNV) by fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), near-infrared (NIR) reflectance, and autofluorescence (AF). METHODS: This retrospective study included 65 eyes of 62 Caucasian patients with a mean age of 66.72 years (95% confidence interval [CI] 63-70 years) and a mean refraction of -9.72 diopters (95% CI -8.74 to -10.70 diopters). RESULTS: Most of the mCNV cases were foveal-juxtafoveal (60/65, 92.3%), with thickening of the corresponding retina (62/65, 95.3%) and leakage on FA (44/65, 67.6%). No retinal fluid was detectable in 32 (49.2%) eyes and there was no hemorrhage in 25 (38.4%) eyes. Papillary chorioretinal atrophy was evident in 58 (89.2%), a shadowing effect in 48 (73.8%), and an epiretinal membrane in 38 (58.4%) eyes. If an area of macular chorioretinal atrophy was present, mCNV frequently developed adjacent to it and was hyperfluorescent rather than with leakage (P⩽0.001). In eyes with edema or hemorrhage, hyper-reflective foci were more frequent (P⩽0.005). NIR and AF features were indeterminable in 19 (29.2%) and 27 (41.5%) eyes, respectively. The predominant feature was black or grayish on NIR (34/65, 52.3%) and patchy (hypo- and hyperfluorescence was observed) on AF (25/65, 38.4%). FA and SD-OCT correctly detected mCNV in 49 (75.3%) and 48 (73.8%) eyes, respectively, whereas NIR and AF exhibited limited diagnostic sensitivity. Doubtful diagnosis was associated with hyperfluorescent mCNV (P⩽0.001), absence of retinal fluid and epiretinal membrane (P⩽0.05), and presence of macular chorioretinal atrophy (P⩽0.01). CONCLUSION: Tomographic, angiographic, AF, and NIR features of mCNV are described in this study. Combination of SD-OCT and FA is recommendable for diagnosis.

Only first intravitreal bevacizumab injection achieves statistically significant visual improvement in naïve myopic choroidal neovascularization.

BACKGROUND: The aim of this study was to evaluate the efficacy of intravitreal bevacizumab when administered on an as-needed basis for the treatment of myopic choroidal neovascularization (CNV), and to assess visual changes upon treatment. METHODS: This study was designed as a retrospective, interventional case series, for which the inclusion criteria were pathologic myopia, and documentation of untreated active macular CNV on fluorescein angiography and optical coherence tomography. Monthly changes in best-corrected visual acuity (BCVA), visual gain after each treatment, and correlation with refraction, age, location, and dimension of CNV were considered. The data were analyzed using the one-tailed, paired Wilcoxon test. RESULTS: Nineteen naive eyes were found suitable for the study. The mean number of treatments was 3.32 ± 2.36 (confidence interval 2.25-4.37) during a mean follow-up period of 18.95 ± 8.3 months. At baseline, mean BCVA was 0.58 ± 0.37 logarithm of the minimum angle of resolution (logMAR) units. At 12 months, mean BCVA was 0.39 ± 0.35 logMAR and at 24 months was 0.39 ± 0.40. Mean improvement in BCVA from baseline was +0.17 ± 0.25 logMAR (P < 0.05) at month 12, +0.14 ± 0.25 logMAR (P = 0.1) at month 18, and +0.09 ± 0.32 logMAR (P = 0.5) at month 24. Improvement on pretreatment BCVA was significant (+0.16 logMAR, P < 0.01) after the first injection, but not after the second (-0.01 logMAR, P = 0.5) or third (+0.02 logMAR, P = 0.5) injections. There was a statistically significant correlation between age and number of treatments, and between improvement in BCVA of foveal versus extrafoveal location of CNV. CONCLUSION: The use of intravitreal bevacizumab "as needed" is an effective treatment for myopic CNV, but visual gain is statistically significant only after the first injection and decreases in the second year.