October 2013
Volume 54, Issue 10
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Retina  |   October 2013
Functional Characterization and Multimodal Imaging of Treatment-Naïve “Quiescent” Choroidal Neovascularization
Author Affiliations & Notes
  • Giuseppe Querques
    Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France
  • Mayer Srour
    Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France
  • Nathalie Massamba
    Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France
  • Anouk Georges
    Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France
  • Naima Ben Moussa
    Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France
  • Omer Rafaeli
    Notal Vision LTD, Tel Aviv, Israel
  • Eric H. Souied
    Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France
  • Correspondence: Giuseppe Querques, Department of Ophthalmology, University of Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, 40 Avenue de Verdun, 94000 Creteil, France; giuseppe.querques@hotmail.it
Investigative Ophthalmology & Visual Science October 2013, Vol.54, 6886-6892. doi:10.1167/iovs.13-11665
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      Giuseppe Querques, Mayer Srour, Nathalie Massamba, Anouk Georges, Naima Ben Moussa, Omer Rafaeli, Eric H. Souied; Functional Characterization and Multimodal Imaging of Treatment-Naïve “Quiescent” Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(10):6886-6892. doi: 10.1167/iovs.13-11665.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To investigate the multimodal morphological and functional characteristics of treatment-naïve “quiescent” choroidal neovascularization (CNV) secondary to AMD.

Methods.: Eleven patients with treatment-naïve “quiescent” CNV that consecutively presented over a 6-month period, underwent multimodal morphological and functional assessment (including indocyanine green angiography [ICGA], spectral-domain optical coherence tomography [SD-OCT], microperimetry, and preferential hyperacuity perimeter [PHP]). For the purpose of this study, asymptomatic previously untreated CNVs showing absence of intraretinal/subretinal exudation in two consecutive visits (at least 6 months apart) were defined as treatment-naïve “quiescent” CNV.

Results.: Eleven eyes of 11 patients (9 females; mean age 76.5 ± 8.5 years) were included. On fluorescein angiography (FA), “quiescent” CNVs appeared as late speckled hyperfluorescent lesions lacking well-demarcated borders. Mid-late phase ICGA allowed visualizing the hyperfluorescent “quiescent” CNV network and delineating the plaque. Mean lesion area (mid-late phase ICGA) appeared larger compared with earliest previous examination performed 23.8 ± 16.0 months before (3.24 ± 2.51 mm2 vs. 3.52 ± 2.46 mm2, respectively; P = 0.01). SD-OCT revealed, at the site of “quiescent” CNV, an irregularly slightly elevated RPE, without hyporeflective intraretinal/subretinal fluid, showing a major axis in the horizontal plane, which was characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane. Hypergeometric distribution revealed a significant correlation between microperimetry and PHP with respect to locations of “affected areas” (P = 0.001).

Conclusions.: “Quiescent” CNVs are sub-RPE CNVs secondary to AMD, showing absence of intraretinal/subretinal exudation on repeated OCT. “Quiescent” CNVs enlarge over time and may contribute to local reduced retinal sensitivity and metamorphopsia.

Introduction
Exudative AMD is characterized by exudative retinal changes (intraretinal/subretinal) due to an abnormal growth of newly formed vessels (choroidal neovascularization [CNV]) within the macula, and causes severe and irreversible vision loss if untreated. 1 Gass 2,3 used enucleated eyes and classified the neovascular growth pattern as sub-RPE (type 1), subretinal (type 2), or combined. Fluorescein angiography (FA) allows distinguishing occult from classic CNVs (which actually reflects the anatomical classification proposed by Gass) while indocyanine green angiography (ICGA) allows visualizing and delineating occult CNV, the most frequent type of CNV due to AMD. 411 Several clinicopathologic reports, using surgically removed CNV, showed that occult CNVs tend to be composed of tissue that appears to be from the sub-RPE space while classic CNVs tend to exhibit either a subretinal or combined growth pattern. 1214 Hughes and associates, 15 using time-domain optical coherence tomography (OCT), suggested that classic CNVs tend to be subretinal, whereas occult CNVs tend to be sub-RPE. 
Intravitreal ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA) 16 was the first therapy for exudative AMD to show an improvement in mean visual acuity in two phase III clinical studies. 17,18 These results were obtained by a fixed-dosing regimen of ranibizumab 0.5 mg or 0.3 mg monthly injected over 24 and 12 months, respectively. 17,18 The Prospective OCT Imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab (PrONTO) study demonstrated a variable dosing regimen mainly based on time-domain OCT findings to be as effective as a fixed-dosing regimen in improving visual acuity and OCT findings with a far lower number of injections over a period of 24 months. 19,20 It is noteworthy that treatment/retreatment with ranibizumab (0.5 mg/0.05 mL) was performed if any amount of fluid associated with CNV was detected using OCT. This highlights how meaningful, in the era of anti-VEGF drugs, OCT evaluation of intra/subretinal fluid accumulation is in taking the treatment/retreatment decision. In this context, it is generally admitted that, whether uncommon, asymptomatic treatment-naïve “quiescent” CNV (i.e., CNV showing absence of intraretinal/subretinal exudation on OCT, but well detectable on FA and especially on ICGA), may be left untreated until development of intraretinal/subretinal exudation on OCT. 
Spectral-domain optical coherence tomography (SD-OCT) technology improves resolution compared with previous time-domain OCT. Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) is a high-speed OCT system (up to 40,000 axial scans per second) using spectral/Fourier domain detection, with an axial image resolution of 7 μm. Moreover, Spectralis SD-OCT, using confocal scanning laser ophthalmoscopy (cSLO) technology to track the eye and guide OCT to the selected location, gives a real-time reference for locating the SD-OCT scan. Hence, by combining an angiograph (Heidelberg Retina Angiograph HRA; Heidelberg Engineering) with an OCT in Spectralis SD-OCT, an analysis of angiographic lesions by cSLO technology and corresponding SD-OCT (i.e., multimodal analysis) is possible. 
In this study, we investigated the multimodal morphological and functional characteristics of treatment-naïve “quiescent” CNV secondary to AMD. 
Methods
Patient Selection
Eleven consecutive patients presenting with diagnosis of asymptomatic treatment-naïve “quiescent” CNV due to AMD were entered over a 6-month period at the University Eye Clinic of Creteil. Inclusion criteria were: age older than 55 years; diagnosis of “quiescent” CNV at least 6 months before, defined as a CNV showing absence of intraretinal/subretinal exudation on OCT, but well detectable on FA and ICGA; and ophthalmoscopic signs of AMD, including hard and soft drusen, mottling of the RPE, and reticular pseudodrusen. Exclusion criteria were any prior treatment in the study eye (such as laser photocoagulation, photodynamic therapy, intravitreal injections of steroids or anti-VEGF), and “quiescent” CNV due to causes other than AMD (such as pathologic myopia, inherited macular dystrophy). 
Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects. French Society of Ophthalmology Ethics Committee approval was obtained for this study. 
Study Protocol
All patients underwent a complete ophthalmologic examination (which per protocol was performed at study entry and at least 6 months before), including measurement of best-corrected visual acuity (BCVA) using standard early treatment of diabetic retinopathy study (ETDRS) charts, fundus biomicroscopy, FA, ICGA, SD-OCT (Spectralis HRA+SD-OCT; Heidelberg Engineering). Automated central macular thickness (CMT) measurements were generated by Spectralis SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering) using a 19 horizontal lines protocol (6 × 6-mm area), each consisting of 1024 A scans per line (Spectralis Acquisition and Viewing Modules, version 3.2; Heidelberg Engineering); each line was manually corrected for any errors. In a subset of eyes with extrafoveal CNV, further high-resolution 9-mm single B scans (each composed of up to 100 averaged OCT B scans) were guided from the lesion. 
At study entry, all patients also underwent microperimetry (Spectral OCT/SLO; OPKO-OTI, Miami, FL) and preferential hyperacuity perimeter (PHP) (Reichert Technologies, Depew, NY). All examinations were performed under the supervision of a trained physician (GQ). Spectral OCT/SLO and MP techniques have been previously described elsewhere. 21 In brief, the Spectral OCT/SLO (OPKO-OTI) combines simultaneous high-resolution cross-sectional OCT imaging of retinal layers with en face fundus imaging of the retina using the scanning laser ophthalmoscope. During the microperimetry, the patient was instructed to maintain fixation on the central target and to push the handheld button every time a stimulus was seen. Once the patient's fundus was aligned and focused properly, the operator designated which vessel to track and adjusted the location of the stimulus pattern to the area of interest. A square test pattern, the “square 7 × 7” (49 dots), was used to test the patients (14 degrees from edge to edge [∼4.15 mm on the retina], with 2.33 degrees spacing between dots [∼0.7 mm on the retina]). It incorporates the following features: Goldman III stimulus size (0.43°; 2.26 mm), 200-ms stimulus duration, and a 1500-ms interval between stimuli presentation and a 4-2 strategy. The system automatically tracks fundus localization according to the retinal vessel alignment to ensure accurate stimuli placement, and testing pauses automatically if the patient was unable to maintain good fixation. At the end of the test, each of the 49 tested retinal points receives a numerical value, representing the threshold sensitivity at that point on the retina. The MP values are expressed in numerical units, ranging from 0 to 20 (low to high sensitivity, respectively). The PHP technology has been described in detail elsewhere. 22 In brief, the PHP is a macular perimetry device using a method based on the human visual function of hyperacuity, which gives it the capability of detecting functional changes. Hyperacuity (also termed “Vernier acuity”) is defined as the ability to perceive a difference in the relative spatial localization of two or more visual stimuli. During the test, the patient's visual attention is drawn to a fixation cue displayed at the center of a touch screen. When the device automatically recognizes that the patient is ready to respond, a stimulus is briefly presented on the display. Each stimulus consists of a dotted line (white dots on a black background), in which few dots are misaligned relatively to the main axis of the stimulus (artificial distortion). The patient's task is to identify where the distortion appears, and to mark this location on the display. A succession of such stimuli is flashed on various locations of the display, such as to cover the entire macular field (12.5 degrees of the central visual field). When a stimulus is flashed on a location that corresponds to a healthy portion of the retina, the artificial distortion is readily detected. If the stimulus is flashed on a location that corresponds to a CNV lesion, RPE elevation may create the perception of a pathological distortion. In the patient's perception, competition for visual attention takes place between the artificial and pathological distortions. If the pathological distortion is more prominent than the artificial distortion, the patient is more likely to perceive the former and ignore the latter. During the test, varying sizes of artificial distortions are displayed, allowing quantification of the degree of the pathological distortion, as well as assessment of reliability of performance. The patient's responses are recorded and automatically analyzed by a predesigned algorithm. Therefore, a compilation of the errors performed during the test enables location of the visual dysfunction as well as estimation of their severity. For severity measurements, we have used the “PHP test score” (a continuous, global score, between −30 and +600, which represents the log [Probability(Responses pattern\CNV)/Probability(Responses pattern\Intermediate)]). This score is basically the same score that has been used in the PHP and has been validated as a classifier to discriminate between intermediate non-neovascular AMD patients and neovascular AMD (CNV) patients. Usually this score is normalized to P values between 0 and 1 (which indicates the probability of non-neovascular AMD eyes to have such a visual field defect). Because in the current study all patients have CNV (and the question had changed from “what is the likelihood of this eye to have CNV” to “what is the activity level of the CNV”) we had used this score in its non-normalized manner to prevent “ceiling effect.” 
Informed consent was obtained, as required by the French bioethical legislation, in agreement with the Declaration of Helsinki for research involving human subjects. French Society of Ophthalmology Institutional Review Board approval was obtained for this study. 
Multimodal Morphological and Functional Analysis
Two investigators (GQ, EHS) reviewed the multimodal imaging of the study eyes, and interpreted the SD-OCT changes at the site of “quiescent” CNV as visualized by ICGA; disagreement between readers was resolved by open adjudication. For each study eye, the entire lesion area was measured on mid-late phase ICGA frames, at both study entry and earliest previous (at least 6 months before) examination, using the Heidelberg software (Spectralis Acquisition and Viewing Modules, version 3.2; Heidelberg Engineering) by two independent observers (MS, NM). Mean observed values were considered. Functional correlates (both microperimetry and PHP) of the ICGA extension of “quiescent” CNVs were investigated by means of hypergeometric distribution, which allows correlation between locations of “affected areas,” derived from two different sources of spatial information (http://stattrek.com/online-calculator/hypergeometric.aspx). The investigators provided, for each eye, a 7 × 7 grid with marked affected cells (area of abnormality according to the Gold Standard - ICGA) (Fig. 1). The total area represented by the grid is central 12 × 12 degrees (3600 × 3600 μm); therefore, each cell represents 1.7 × 1.7 degrees (514 × 514 μm), and the center of the grid (4,4) represents the fovea location. According to the “background normative color” of the microperimetry, red cells (P < 1%) were taken as abnormal (x ≤ 6). Maps of the PHP were produce by AlgViewer (in-house research tool; PHP abnormal cells = red [distortion]). 
Figure 1
 
Case 7: Microperimetry and PHP at study entry. A 7 × 7 grid, used to mark affected cells (area of abnormality according to the Gold Standard - ICGA), has been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (left). PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (center and right, respectively).
Figure 1
 
Case 7: Microperimetry and PHP at study entry. A 7 × 7 grid, used to mark affected cells (area of abnormality according to the Gold Standard - ICGA), has been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (left). PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (center and right, respectively).
Statistical Analysis
Statistical calculations were performed using Statistical Package for Social Sciences (version 17.0; SPSS, Inc., Chicago, IL. Paired t-test was used to evaluate changes of mean BCVA (logarithm of the minimum angle of resolution [LogMAR]), mean lesion area on ICGA, and mean CMT at study entry compared with earliest previous (at least 6 months before) examinations. Correlation between modalities (ICGA, microperimetry, and PHP) was calculated by means of hypergeometric distribution. The chosen level of statistical significance was P less than 0.05. 
Results
Patient Demographics and Main Clinical Findings
Eleven eyes of 11 patients (9 females, 2 males; mean age 76.5 ± 8.5 years [range, 64–90 years]) diagnosed with “quiescent” CNV due to AMD were included for analysis. CNVs were followed for a mean 23.8 ± 16.0 months (median 28 months; earliest previous examination ranged 6–51 months) without developing intraretinal/subretinal exudation on repeated (1 visit/2.8 months, range 1 visit/1.5–5.0 months) OCT examinations (mean 8.4 ± 5.2 examinations; median 9 examinations; range 2–17 examinations). Mean BCVA in the study eyes was 0.1 ± 0.1 LogMAR at study entry, and did not significantly differ compared with earliest previous examination (0.07 ± 0.1 LogMAR; P = 0.05). Mean CMT (automated measurements generated by Spectralis SD-OCT) also did not differ significantly compared with earliest previous examination (294 ± 49 μm vs. 290 ± 47 μm, respectively; P = 0.1). Interestingly, mean lesion area, as evaluated on mid-late phase ICGA frames, appeared significantly larger compared with earliest previous examination (3.24 ± 2.51 mm2 vs. 3.52 ± 2.46 mm2, respectively; P = 0.01) (agreement for the two independent observers, intraclass correlation [ICC] 0.97–0.99 95% confidence interval [CI]). Seven of 11 fellow eyes were treated with intravitreal anti-VEGF for actively leaking CNV detected on the basis of FA, ICGA, and OCT; 4 of 11 fellow eyes were diagnosed with early AMD (drusen and pigmentary changes) at study entry. 
Morphological and Functional Characteristics of “Quiescent” CNV
On FA, “quiescent” CNVs appeared as late speckled hyperfluorescent lesions lacking well-demarcated borders (without late-phase leakage of undetermined source or pooling of dye in the subretinal space, which defines typical occult type 1 CNVs). In all patients, mid-late phase ICGA frames (similarly to typical “nonquiescent” occult type 1 CNV) allowed visualizing the hyperfluorescent “quiescent” CNV network and delineating the plaque (Figs. 2A, 3A, 4A). 23 SD-OCT revealed, at the site of “quiescent” CNV (Figs. 2B, 3B, 4B), an irregularly slightly elevated RPE (without hyporeflective fluid accumulation in the intraretinal/subretinal space), showing a major axis in the horizontal plane, which was characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (Figs. 2B, 3B, 4B). In all patients, SD-OCT revealed the absence of other CNV activity signs (such as intraretinal hyperreflective flecks, midreflective exudative material, low lesion optical reflectivity/poorly defined boundaries of the lesion). 24  
Figure 2
 
(A) Case 3: FA and ICGA frames at study entry (right) and 14 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 1.54 mm2–2.31 mm2) (bottom). (B) Case 3: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 2
 
(A) Case 3: FA and ICGA frames at study entry (right) and 14 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 1.54 mm2–2.31 mm2) (bottom). (B) Case 3: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 3
 
(A) Case 5: FA and ICGA frames at study entry (right) and 39 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 4.45 mm2–5.28 mm2). (B) Case 5: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 3
 
(A) Case 5: FA and ICGA frames at study entry (right) and 39 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 4.45 mm2–5.28 mm2). (B) Case 5: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 4
 
(A) Case 4: FA and ICGA frames at study entry (right) and 6 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 6.53 mm2–6.58 mm2). (B) Case 4: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 4
 
(A) Case 4: FA and ICGA frames at study entry (right) and 6 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 6.53 mm2–6.58 mm2). (B) Case 4: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Retinal sensitivity as evaluated by microperimetry (dB) and metamorphopsia severity as evaluated by PHP (test score) are reported in Table 1
Table 1
 
Retinal Sensitivity as Evaluated by Microperimetry (dB) and Metamorphopsia Severity as Evaluated by PHP (Test Score)
Table 1
 
Retinal Sensitivity as Evaluated by Microperimetry (dB) and Metamorphopsia Severity as Evaluated by PHP (Test Score)
Cases Study Eye Microperimetry, dB Test Score PHP
Case 1 OD 9.00 –10.31
Case 2 OD 8.20 –15.00
Case 3 OD 10.10 –16.16
Case 4 OD 10.00 –10.36
Case 5 OD 7.80 –5.43
Case 6 OS 10.10 –10.00
Case 7 OS 10.80 –15.49
Case 8 OD 10.20 –11.36
Case 9 OS 8.10 –14.58
Case 10 OS 11.80 –10.27
Case 11 OD 6.30 –11.53
Average 9.31 –11.86
Hypergeometric distribution revealed a significant correlation between microperimetry and PHP with respect to locations of “affected areas” (P = 0.001) (Table 2). Interestingly, functional impairment was significantly correlated to the ICGA extension of “quiescent” CNVs in terms of metamorphopsia severity as evaluated by PHP (P < 0.001), but not in terms of retinal sensitivity as evaluated by microperimetry (P = 0.05) (Table 2). 
Table 2
 
Hypergeometric Distribution Correlation Between Modalities (P Value)
Table 2
 
Hypergeometric Distribution Correlation Between Modalities (P Value)
Cases Study Eye Imaging Interpretation vs. PHP Imaging Interpretation vs. Microperimetry Microperimetry vs. PHP
Case 1 OD 0.01659 0.20277 0.33668
Case 2 OD 0.02209 0.25555 0.26062
Case 3 OD 0.08561 0.24490 0.83673
Case 4 OD 0.00106 0.12074 0.19898
Case 5 OD 0.10385 0.00246 0.21838
Case 6 OS 0.43809 0.21494 0.01552
Case 7 OS 0.12057 0.10468 0.00016
Case 8 OD 0.00066 0.29614 0.45674
Case 9 OS 0.32154 0.17037 0.26202
Case 10 OS 0.14176 0.23355 0.19771
Case 11 OD 0.01382 0.12456 0.07513
Average 0.00008 0.05454 0.00180
Discussion
The abnormal growth of newly formed vessels in the sub-RPE space (type 1 CNV), or in the subretinal space (type 2 CNV), 2,3 accompanied by exudative retinal changes (intraretina/subretinal) within the macula, characterizes exudative AMD. 1 In the era of anti-VEGF drugs for the treatment of exudative AMD, OCT evaluation of intra/subretinal fluid accumulation is fundamental in taking the treatment decision. 19,20 Patients undergoing anti-VEGF injections for CNVs on an as-needed basis and showing absence of retinal exudation on posttreatment OCT examinations may skip retreatment until recurrence of intraretinal/subretinal fluid. 19,20,25,26 Similarly, it is generally admitted that, whether uncommon, asymptomatic treatment-naïve CNVs showing absence of intraretinal/subretinal exudation on OCT, but well detectable on FA and especially on ICGA, may be left untreated until development of intraretinal/subretinal exudation on OCT. Such approach gave us the opportunity to investigate, in this study, the multimodal morphological and functional characteristics of this peculiar entity secondary to AMD that we named “quiescent” CNVs. For the purpose of the study, “quiescent” CNV was defined as an angiographically (both FA and ICG) detected CNV showing absence of intraretinal/subretinal exudation on repeated OCT during follow-up (at least two examinations, 6 months apart). 
In all patients meeting the inclusion criteria (n = 11) “quiescent” CNVs appeared as late ICGA plaques, actually not distinguishable from typical “nonquiescent” occult type 1 CNVs. 23 Interestingly, by retrospectively comparing the mean lesion area measured on late ICGA frames at study entry to that of the earliest previous examinations, “quiescent” CNVs appeared to enlarge over time (from 3.24 ± 2.51 mm2–3.52 ± 2.46 mm2 [P = 0.01] after a mean of 23.8 ± 16.0 months). At the site of “quiescent” CNV, SD-OCT revealed an irregularly slightly elevated RPE, showing a major axis in the horizontal plane, which was characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane. These SD-OCT characteristics allow somehow differentiate “quiescent” CNV form soft drusen. 27 In fact, soft drusen are formed by mounds of deposit under the RPE, and typically appear on SD-OCT as multiple dome-shaped RPE elevations. However, because soft drusen may become confluent without development of intra/subretinal fluid, thus mimicking the aspect of a sub-RPE “quiescent” CNV on SD-OCT (even though in most cases drusen coalescence still shows a dome-shaped RPE elevation [i.e., drusenoid PED], rather than an irregularly slightly elevated RPE with major axis in the horizontal plane), we believe that fundus angiographies, and particularly ICGA, still remain the main tools to correctly diagnose the different forms (including this unusual neovascular form) of AMD. It is noteworthy that in the study eyes, mean CMT (automated measurements generated by Spectralis SD-OCT) did not appear to increase significantly over time (from 290 ± 47 μm at earliest previous examination to 294 ± 49 μm at study entry [retrospective analysis, P = 0.1]). On the basis of these findings, it seems that in “quiescent” CNV the apparent lesion growth is characterized by enlargement without thickening of the overlying retina. Enlargement of the CNV plaque over time is not a new ICGA finding. 28 The new finding is that in treatment-naïve “quiescent” CNVs, this happens without intraretina/subretinal fluid accumulation or other CNV activity SD-OCT signs. The multimodal imaging findings in the current series are in agreement with histopathology, showing the presence of clinically quiescent fibrovascular tissue under the RPE in eyes with AMD. 2932  
The functional analysis of “quiescent” CNVs was performed by means of microperimetry (which allows the evaluation of retinal sensitivity, mainly driven by photoreceptors) and PHP (which allows evaluation of metamorphopsia severity). Areas of retinal dysfunction (hypergeometric distribution of “affected areas” with respect to ICGA identification of “quiescent” CNV location) appeared to significantly correlate between the two functional examinations. Of note, retinal dysfunction was significantly correlated to the ICGA extension of “quiescent” CNVs in the PHP functional evaluation, but not in the microperimetry functional evaluation. On the other hand, mean BCVA in the study eyes did not appear to change significantly over time (from 0.07 ± 0.1 LogMAR at earliest previous examination to 0.1 ± 0.1 LogMAR at study [retrospective analysis, P = 0.05]). Taken together, these data suggest that retinal function is affected by “quiescent” CNVs more in terms of metamorphopsia than in terms of retinal sensitivity. 
Our study has several limitations. The series presented here is relatively small, and minimal CNV activity may have been missed during follow-up due to the relatively long time between repeated examinations. Moreover, the specificity of signs here described for “quiescent” CNVs is limited by the retrospective nature of the follow-up analysis, and by the lack of multimodal analysis for the lesions that, despite sharing similitudes with the “quiescent” CNVs, did progress to typical exudative AMD. However, this study was not designed to assess the specificity of signs but rather to describe the characteristics of this unusual entity that we named “quiescent” CNV. Finally, 7 of 11 fellow eyes have been treated by anti-VEGF for actively leaking CNV, and this may have influenced the “quiescent” CNV progression (and the development of intraretinal/subretinal exudation) in the study eyes. Considering all these limitations, as well as the absence of similar descriptions in the current literature, further studies are needed to better understand the different morphological and functional aspects of this peculiar form of AMD. 
In conclusion, we described the multimodal morphological and functional characteristics of an unusual entity that we named “quiescent” CNVs. “Quiescent” CNVs are sub-RPE CNVs secondary to AMD, showing absence of intraretinal/subretinal exudation on repeated OCT. “Quiescent” CNVs enlarge over time without determining retinal thickening, and may contribute to (but not be solely responsible for) local reduced retinal sensitivity and metamorphopsia. Future studies should investigate whether closer follow-up examinations might allow detection of minimal CNV activity (i.e., development of intraretinal/subretinal exudation) between momentary unactive stages, and properly treat “quiescent” CNV activations. 
Acknowledgments
The authors have no proprietary interest in the materials used in this study. 
Disclosure: G. Querques, None; M. Srour, None; N. Massamba, None; A. Georges, None; N. Ben Moussa, None; O. Rafaeli, None; E.H. Souied, None 
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Figure 1
 
Case 7: Microperimetry and PHP at study entry. A 7 × 7 grid, used to mark affected cells (area of abnormality according to the Gold Standard - ICGA), has been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (left). PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (center and right, respectively).
Figure 1
 
Case 7: Microperimetry and PHP at study entry. A 7 × 7 grid, used to mark affected cells (area of abnormality according to the Gold Standard - ICGA), has been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (left). PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (center and right, respectively).
Figure 2
 
(A) Case 3: FA and ICGA frames at study entry (right) and 14 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 1.54 mm2–2.31 mm2) (bottom). (B) Case 3: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 2
 
(A) Case 3: FA and ICGA frames at study entry (right) and 14 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 1.54 mm2–2.31 mm2) (bottom). (B) Case 3: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 3
 
(A) Case 5: FA and ICGA frames at study entry (right) and 39 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 4.45 mm2–5.28 mm2). (B) Case 5: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 3
 
(A) Case 5: FA and ICGA frames at study entry (right) and 39 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 4.45 mm2–5.28 mm2). (B) Case 5: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 4
 
(A) Case 4: FA and ICGA frames at study entry (right) and 6 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 6.53 mm2–6.58 mm2). (B) Case 4: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Figure 4
 
(A) Case 4: FA and ICGA frames at study entry (right) and 6 months before (earliest previous examination) (left). FA showing “quiescent” CNVs as late speckled hyperfluorescent lesions (top). Mid-late phase ICGA frames allow visualizing the hyperfluorescent “quiescent” CNV that enlarges over time (from 6.53 mm2–6.58 mm2). (B) Case 4: Microperimetry, PHP, and SD-OCT at study entry. PHP severity map (metamorphopsia) and microperimetry (retinal sensitivity) have been overlaid on a late ICGA frame showing the “quiescent” CNV plaque (top left and right, respectively). SD-OCT showing an irregularly slightly elevated RPE with a major axis in the horizontal plane, characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane (bottom).
Table 1
 
Retinal Sensitivity as Evaluated by Microperimetry (dB) and Metamorphopsia Severity as Evaluated by PHP (Test Score)
Table 1
 
Retinal Sensitivity as Evaluated by Microperimetry (dB) and Metamorphopsia Severity as Evaluated by PHP (Test Score)
Cases Study Eye Microperimetry, dB Test Score PHP
Case 1 OD 9.00 –10.31
Case 2 OD 8.20 –15.00
Case 3 OD 10.10 –16.16
Case 4 OD 10.00 –10.36
Case 5 OD 7.80 –5.43
Case 6 OS 10.10 –10.00
Case 7 OS 10.80 –15.49
Case 8 OD 10.20 –11.36
Case 9 OS 8.10 –14.58
Case 10 OS 11.80 –10.27
Case 11 OD 6.30 –11.53
Average 9.31 –11.86
Table 2
 
Hypergeometric Distribution Correlation Between Modalities (P Value)
Table 2
 
Hypergeometric Distribution Correlation Between Modalities (P Value)
Cases Study Eye Imaging Interpretation vs. PHP Imaging Interpretation vs. Microperimetry Microperimetry vs. PHP
Case 1 OD 0.01659 0.20277 0.33668
Case 2 OD 0.02209 0.25555 0.26062
Case 3 OD 0.08561 0.24490 0.83673
Case 4 OD 0.00106 0.12074 0.19898
Case 5 OD 0.10385 0.00246 0.21838
Case 6 OS 0.43809 0.21494 0.01552
Case 7 OS 0.12057 0.10468 0.00016
Case 8 OD 0.00066 0.29614 0.45674
Case 9 OS 0.32154 0.17037 0.26202
Case 10 OS 0.14176 0.23355 0.19771
Case 11 OD 0.01382 0.12456 0.07513
Average 0.00008 0.05454 0.00180
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