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.

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.

Retinal angiomatous proliferation: natural history and progression of visual loss.

PURPOSE: To investigate the natural history and visual outcome in eyes with untreated retinal angiomatous proliferation, a neovascular form of age-related macular degeneration. METHODS: Fourteen consecutive white patients (11 women, 78%; mean age, 74 years) with 16 eyes affected by retinal angiomatous proliferation were prospectively followed-up without treatment by means of complete ophthalmologic examinations at regular intervals, including best-corrected visual acuity and dynamic fluorescein and indocyanine green angiography using a scanning laser ophthalmoscope. RESULTS: The patients were observed for a mean of 20 months (range, 6-44 months). Mean visual acuity in the eyes with retinal angiomatous proliferation was 0.48 at the initial examination, decreased to 0.23 after 6 months, and was 0.19 at the final examination, with a mean decrease of 6 lines from baseline. In 13 eyes (81%), visual acuity deteriorated by 2 Early Treatment Diabetic Retinopathy Study lines or worse by the time of the 6-month examination, and 31% of the patients had experienced severe loss of vision; the remaining 3 eyes (19%) showed a relatively stable clinical course and visual acuity. By the time of the final examination, visual acuity had decreased to 0.1 or worse in 11 eyes (69%), and 5 of the 14 patients (36%) were legally blind. At the final examination, 10 eyes (62%) showed a subretinal fibrosis and 9 (56%) showed a retinal choroidal anastomosis. CONCLUSION: Retinal angiomatous proliferation is a distinct form of neovascular age-related macular degeneration with high vasogenic potential, having its own clinical course and visual prognosis. The poor visual outcome is because of the exudative nature of the retinal angiomatous proliferation, and progression to poor vision is common and rapid (within 3 months in faster cases, and within 1 year in slower cases). The treatment options for this type of neovascular lesion should be planned bearing in mind its unfavorable natural history.

The prevalence of retinal angiomatous proliferation in age-related macular degeneration with occult choroidal neovascularization.

BACKGROUND: The purpose of the study was to ascertain the prevalence of retinal angiomatous proliferation (RAP) by means of dynamic indocyanine green angiography (d-ICGA) in patients with newly diagnosed fibrovascular pigment epithelium detachment (type 1) or late leakage of undetermined source (type 2) occult choroidal neovascularization (CNV) on fluorescein angiography. METHODS: We carried out a review of digital fluorescein and ICG angiograms obtained by confocal scanning laser ophthalmoscope (HRA; Heidelberg Engineering GmbH, Dossenheim, Germany) in 253 consecutive patients (270 eyes) with a clinical diagnosis of type 1 or type 2 occult CNV on fluorescein angiography (1998 through 2003). RESULTS: Sixty eyes had type 1 and 210 eyes type 2 occult CNV on fluorescein angiography. Overall, 57 cases of RAP were identified in 54 eyes (20%) with d-ICGA. RAP was present in 6 out of 60 eyes with type 1 (10%) and in 51 out of 210 eyes with type 2 occult CNV (24%). Mean distance of the lesion from the fovea was 682 +/- 304 microm (mean +/- SD). CONCLUSIONS: d-ICGA is invaluable for early diagnosis of RAP in exudative age-related macular degeneration (ARMD). In our series, up to one fourth of type 2 occult CNV were in fact RAP.

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.

Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation.

OBJECTIVE: To report the management of retinal angiomatous proliferation (RAP), a recently described intraretinal neovascular lesion occurring in age-related macular degeneration. METHODS: This was a retrospective review of consecutive patients with age-related macular degeneration who underwent treatment of RAP from January 1, 2000, through January 31, 2003. Inclusion criteria were age 55 years or older, signs of age-related macular degeneration, and diagnosis of RAP based on dynamic indocyanine green angiography. Baseline angiograms were reviewed and RAP was classified into the following 3 stages: stage 1, intraretinal neovascularization, early stage; stage 2, subretinal neovascularization, middle stage; and stage 3, choroidal neovascularization, late stage. Treatment and concomitant treatment results were assessed separately for each RAP stage. The clinical data were statistically analyzed (chi2 test and analysis of variance) for 2 main outcome measures--complete obliteration of the lesion and final visual acuity. RESULTS: Eighty-one patients (99 eyes) with 104 RAPs were identified. Forty-two lesions were at stage 1, 42 at stage 2, and 20 at stage 3. The following 5 treatments were performed: direct laser photocoagulation of the vascular lesion, laser photocoagulation of the feeder retinal arteriole, scatter "gridlike" laser photocoagulation, photodynamic therapy, and transpupillary thermotherapy. Complete obliteration of RAP was achieved in about 24 (57.1%) of the stage 1 lesions (direct laser photocoagulation of the vascular lesion, 73% success rate; photodynamic therapy, 45%), 11 (26.2%) of the stage 2 lesions (scatter gridlike laser photocoagulation, 38% success rate; direct laser photocoagulation of the vascular lesion, 17%), and only 3 (15.0%) of stage 3 lesions (P = .001). Predictive factors with a significant effect on final visual acuity were initial visual acuity (P = .003) and early lesion stage (P = .04). Best final visual acuity was 0.41 (mean, direct laser photocoagulation of the vascular lesion in stage 1) and 0.39 (mean, photodynamic therapy in stage 1), with a mean decrease of 2.5 and 3 lines from baseline, respectively. CONCLUSIONS: Treatment of RAP remains difficult. Early detection of the lesion and subsequent direct conventional laser photocoagulation seems to be associated with better anatomical and functional outcome. Once the vascular complex is well established, anatomical closure is rarely achieved. Further study is warranted to assess the long-term efficacy and the need for re-treatment.

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.

Remodeling of the vascular channels in retinal angiomatous proliferations treated with intravitreal triamcinolone acetonide and photodynamic therapy.

BACKGROUND: The objective was to describe the remodeling of the vascular channels in stage II retinal angiomatous proliferation (RAP) treated by intravitreal injections of triamcinolone acetonide (TA) and subsequent photodynamic therapy (PDT). METHODS: Stage II RAP secondary to age-related macular degeneration was documented by dynamic digital fluorescein and indocyanine green angiography in 3 consecutive patients (3 eyes). All eyes were treated with intravitreal injection of TA (4 mg, 0.1 ml) followed by PDT 5-10 days later. RESULTS: Indocyanine green angiography (ICGA) revealed a complete remodeling of the vascular structure of the three RAPs after treatment. The feeding retinal artery, which shunted a major part of the blood flow from the original arteriole toward the intraretinal neovascular complex before treatment, regained a normal appearance after treatment. With RAP closure, the blood flow was again directed through the original retinal arteriole, and the connection to the RAP was no longer visible. CONCLUSIONS: Stage II RAPs are difficult lesions to treat. A real remodeling of the vascular lesion is achieved with the combined use of intravitreal TA and PDT. This finding corroborates the need for randomized clinical trials currently under way to evaluate this combination treatment in wet, age-related macular degeneration.