
==== Front
Ophthalmol Ther
Ophthalmol Ther
Ophthalmology and Therapy
2193-8245
2193-6528
Springer Healthcare Cheshire

39150604
1012
10.1007/s40123-024-01012-y
Commentary
Predict and Protect: Evaluating the Double-Layer Sign in Age-Related Macular Degeneration
Sivaprasad Sobha sobha.sivaprasad@nhs.net

12
Chandra Shruti 12
Sadda SriniVas 3
Teo Kelvin Y. C. 45
Thottarath Sridevi 1
de Cock Eduard 6
Empeslidis Theo 6
Esmaeelpour Marieh 6
1 https://ror.org/03zaddr67 grid.436474.6 0000 0000 9168 0080 National Institute of Health Research Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London, UK
2 https://ror.org/02jx3x895 grid.83440.3b 0000 0001 2190 1201 University College London Institute of Ophthalmology, London, UK
3 grid.19006.3e 0000 0000 9632 6718 Doheny Imaging Reading Center, Doheny Eye Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA
4 grid.419272.b 0000 0000 9960 1711 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
5 https://ror.org/02j1m6098 grid.428397.3 0000 0004 0385 0924 Duke-NUS Medical School, Singapore, Singapore
6 grid.420061.1 0000 0001 2171 7500 Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
16 8 2024
16 8 2024
10 2024
13 10 25112541
29 5 2024
24 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch’s membrane (BM), which is described by various terms, including double-layer sign (DLS).

Methods

In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy.

Results

The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans.

Conclusions

The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment.

Plain Language Summary

Age-related macular degeneration (AMD) is an eye disease that may develop in older people, usually those aged over 60 years. Early in the disease, people often do not show any symptoms, but as the disease progresses, vision loss may occur. The advanced forms of AMD are called neovascular AMD (also called “wet” AMD) and advanced dry AMD (called geographic atrophy; GA). It is important to identify features and signs on eye scans that can help to predict if someone with AMD will develop an advanced form of the disease because this will help doctors plan the most appropriate treatment. One such feature on eye scans is the double-layer sign (DLS). In this article, we summarise the different names used for DLS, and assess if having a DLS increases the likelihood of someone with early AMD developing wet AMD or GA. We conclude that how DLS looks varies between people, which leads to DLS being called by various names. Someone with early AMD and a DLS containing blood vessels may be more likely to develop wet AMD; whereas someone with early AMD and a DLS without blood vessels may be more likely to develop GA. Taking photos of the eye using optical coherence tomography angiography imaging is the main method of identifying DLS and confirming whether it contains blood vessels.

Keywords

Age-related macular degeneration
Biomarker
Bruch’s membrane
Double-layer sign
Geographic atrophy
Neovascular age-related macular degeneration
Optical coherence tomography
Quiescent choroidal neovascularisation
Retinal pigment epithelium
Shallow irregular RPE elevation
issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
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pmcKey Summary Points

The double-layer sign (DLS) is a shallow separation of the retinal pigment epithelium (RPE) and Bruch’s membrane and is heterogeneously described in the literature as quiescent choroidal neovascularisation, shallow irregular RPE elevation and small RPE elevation.	
Differences in the size and/or characteristics of DLS may reflect its predictive value associated with age-related macular degeneration progression and growth of non-exudative macular neovascularisation, which varies between patients.	
Vascularised DLS appears to protect against atrophy but can progress to exudation, whereas non-vascularised DLS is associated with an increased risk of atrophy.	
Optical coherence tomography (OCT) is required to identify DLS and OCT angiography (OCTA) is the principal method for identifying vascularised DLS.	
If OCTA is unavailable, or not practically possible, simplified clinician-friendly classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated.	

Introduction

In developed countries, age-related macular degeneration (AMD) is one of the most common causes of blindness in individuals aged ≥ 60 years [1–4]. Early forms of AMD are often asymptomatic [5], with vision loss being caused by late or advanced forms of the disease, such as neovascular AMD (nAMD) and geographic atrophy (GA) [1–4]. As there is inter-individual variability in progression from early to advanced AMD [6], there is much interest in precursor lesions that may predict the onset and progression rate of advanced AMD.

Several well-established structural biomarkers, including drusen volume, the presence of pigmentary abnormalities, reticular pseudodrusen (RPD) and fellow eye status, indicate a risk for progression from intermediate AMD to vision-threatening late stages [7–9].

Sub-retinal pigment epithelium (RPE) deposits of lipids and proteins known as drusen are the hallmark of AMD, with evidence showing that increasing drusen volume is strongly associated with disease progression [9, 10]. RPD are located above the RPE [11] and appear to be a highly prevalent and critical sub-phenotype in AMD [9]. RPD are considered to be a risk factor for the development of late AMD and, to a greater extent, for GA (p < 0.0001) [12]. Eyes with RPD have also been reported to have more rapid growth of atrophic lesions compared with eyes without RPD, with lesions growing towards the RPD [13]. Additionally, some people with RPD may be at increased risk of GA but not nAMD progression [7]. Pigmentary abnormalities in the drusen are another traditional risk factor for evaluating severity and risk of progression of AMD, either as regions of hypopigmentation or hyperpigmentation [14]. The Age-Related Eye Disease Study of 95 eyes demonstrated that both hyperpigmentation (96% of eyes) and hypopigmentation (82% of eyes) preceded GA onset, with a mean time to onset of 5.0 years and 2.5 years, respectively [15].

Other features that influence AMD progression include incomplete RPE and outer retinal atrophy which was shown to confer a significantly increased risk of progression to GA (p = 0.021); however, nascent GA may account for this observed association [16]. Hyperreflective foci (HRF) are seen on optical coherence tomography (OCT) as roundish, hyperreflective lesions in any retinal layer. HRF area correlates with an increased 1–2 year risk of AMD progression [17, 18]. Furthermore, intraretinal HRF have been associated with type 3 macular neovascularisation in patients with AMD, suggesting the representation of early stages of intraretinal neovascularisation [19].

Lesions aside, Friberg et al. proposed that the presence of advanced AMD in the fellow eye is the most critical risk factor, compared with drusen size and total drusen area, especially pertaining to the risk of conversion to nAMD [20].

Recent advances in imaging have facilitated greater understanding of early AMD and its progression. One such finding seen with OCT is the shallow separation of the RPE and Bruch’s membrane (BM), which can be a precursor to advanced nAMD [21]. Many different terms have been used to describe this feature, including double-layer sign (DLS), shallow irregular RPE elevation (SIRE) and flat irregular pigment epithelial detachment [22–24]. Although there are differences between term definitions regarding size and/or characteristics, the definitions appear to refer to the same overall feature. In this article, the term DLS is used.

Care should be taken to differentiate DLS from pigment epithelial detachment (PED), which is characterised by the accumulation of fluid and/or fibrovascular tissue under the RPE [25, 26]. Both DLS and PED manifest as separation of the RPE and BM; however, the height of separation and contents vary. While DLS lesions may harbour solely basal laminar deposits or contain macular neovascularisation (MNV) [27], the contents of PEDs may be serous, fibrovascular or drusenoid in nature [26]. An arbitrary RPE and BM separation of > 100 µm in height is frequently used to differentiate PED from DLS [28].

It is also important to distinguish DLS from drusen, which manifest as a localised and often nodular and homogeneous separation of the RPE and BM, with the major axis being vertical rather than horizontal in most cases. Drusen substructures may vary and add to the challenges in identifying DLS. Although drusen or pigmentary changes suggest predominantly RPE dysfunction, DLS may also harbour non-exudative macular neovascularisation (neMNV) [29]. Very rarely, drusen may appear vascularised, too. Since neMNV does not involve any exudation or bleeding, patients are commonly asymptomatic; however, the presence of neMNV may be a precursor of vision-threatening exudative nAMD, necessitating the monitoring of patients with this feature [29].

Alternatively, some evidence indicates that neMNV may protect against the development of GA [29–31], suggesting that patients with DLS may be at lower risk of the onset and progression of GA. As the efficacy of recently approved and emerging therapies for GA is limited to slowing GA lesion progression [32, 33], protection against GA onset and progression by other mechanisms remains an important treatment concept [34]. Indeed, GA therapies may themselves increase the risk of exudation [35], and the presence of DLS may itself suggest an increased risk of exudation (i.e., if DLS ultimately proves to be associated with neMNV growth); DLS may therefore be a useful factor to consider as a guide to treatment and follow-up in patients with nAMD [36].

In this article, we evaluate current evidence on the two facets of DLS in AMD: first, the predictive association with exudative nAMD; and second, the potential protective properties against GA; identifying points of consensus and gaps in the literature. We also investigate current evidence for the added value of DLS as a separate biomarker for nAMD and consider existing biomarkers. We aim to examine and clarify the different terms referring to shallow separation of the RPE and BM, and to explore the use of structural OCT to determine the presence of neMNV. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Define: DLS Definitions

Overall, there is limited published information regarding DLS in AMD. To address this issue, we collated information on the definitions used by studies in which DLS has been assessed (Table 1) [22, 37–42].Table 1 Definitions of DLS in AMD

References	Indication	Study type	OCT scan equipment	OCT scan parameters	OCT scan assessment	DLS definition	Term used	Requires NV to be present?	
Querques et al. 2013 [37]	Treatment-naïve qCNV secondary to AMD	Retrospective case series	SD-OCT (Spectralis; HRA + SD-OCT; Heidelberg Engineering, Heidelberg, Germany)	19 horizontal lines (6 × 6 mm area), 1024 A-scans per line; each line manually corrected for errors

High-resolution 9-mm single B-scans (each composed of up to 100 averaged OCT B-scans) in a subset of eyes with extrafoveal CNV

	Two investigators interpreted SD-OCT changes at the site of qCNV as visualised by ICGA; disagreement resolved by open adjudication	Slightly elevated RPE showing a major axis in the horizontal plane, characterised by collections of moderately reflective material in the sub-RPE space

Clear visualisation of the hyperreflective BM

Absence of subretinal or intraretinal exudation on SD-OCT images for at least 6 months

	qCNV	Yes (ICGA)	
Liu et al. 2016 [38]	Typical nAMD or PCV	Prospective study	EDI SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany)	Detailed raster scans, 30° × 25°, consisting of 651 sections (11 µm between B-scans) performed vertically and horizontally multiple times

When lesion size was larger than the scanning range, the internal fixation target was changed to ensure the lesion frontier was reached; additional raster scans were added in such cases

	2D images built with raster scans analysed for each patient

Two doctors read the SD-OCT images independently to identify DLS

Disagreement resolved via review by a third experienced OCT reader

	Flat gap with moderate reflection between the hyperreflective RPE band and the hyperreflective remainder of the BM and inner choroid	DLS	No	
Narita et al. 2020 [22]	Large drusen (> 125 μm) secondary to AMD in ≥ 1 eye	Cross-sectional observational study	SD-OCT (Spectralis; HRA + OCT)

SS-OCTA (PLEX Elite 9000 prototype device; Carl Zeiss Meditec, Dublin, CA, USA)

	SD-OCT: 20° × 20° region, 49 horizontal B-scans and 1024 A-scans, 25 frames averaged per B-scan

SS-OCTA: broad-spectrum laser (1060 nm central wavelength), rapid scan acquisition rate (up to 100,000 A-scans per second). Raster scans (6 × 6 mm) consisted of horizontal B-scans comprising 500 A-scans with 500 B-scan positions over 6 mm. Two B-scans obtained sequentially at each location; angiographic image produced using the machine’s OCT microangiography algorithm

	SD-OCT cube scans reviewed and graded using inbuilt proprietary viewing software, including the native calliper tool for measurements

SS-OCTA: two slabs used (pre-set ORCC segmentation slab and a custom RPE-to-RPE fit slab). Scans assessed by an internal panel of three experienced OCTA clinicians. De-identified scans sent with control cases to an external panel

	RPE elevations with greatest transverse linear dimension of ≥ 1000 μm

An irregular RPE layer with a height of predominantly < 100 μm

Non-homogeneous internal reflectivity the characteristic feature of DLS when neMNV was present

	SIRE	No	
Fukuyama et al. 2022 [39]	Foveal-sparing GA and AMD	Retrospective, consecutive case series	OCT (Spectralis; HRA + OCT)	OCT volume scans and NIR images (820 nm) acquired with a 30° × 30° field of view	Each eye evaluated for the presence or absence of DLS inside the foveal-sparing area by two independent graders

Disagreement resolved by discussion or by a senior third reviewer

	Irregular low-lying elevation of the RPE from the underlying intact BM with low internal reflectivity

> 250 µm in the horizontal dimension

< 100 µm in height

	DLS	No	
Lee et al. 2022 [40]	Exudative MNV	Retrospective study	EDI SD-OCT (Spectralis)	6-mm horizontal raster scans, 30–60-μm spacing, covering 1500-μm diameter centred on the fovea	ETDRS grid and software tools embedded in the OCT machine used to determine position, length and height of RPE elevations

Three independent examiners reviewed all images and determined the results of all variables

Disagreement resolved by open adjudication with access to original images and data

	RPE elevations with the greatest transverse linear dimension of ≥ 1000 μm

Irregular RPE layer with a height of predominantly < 100 μm

Non-homogeneous internal reflectivity with characteristic features of the DLS

Small RPE elevation also used, defined as shallow RPE elevations with longest diameter < 1000 μm

	SIRE	No	
Hirabayashi et al. 2023 [41]	Intermediate AMD in ≥ 1 eye	Retrospective cohort study	OCT (Spectralis)	49 B-scans, 6 × 6 mm area, ART of 6	Two certified graders

Disagreement resolved by senior reading-centre investigator review

	Irregular area of RPE elevation with clear separation between the RPE and BM

Thin DLS: a single zone of low-to-medium reflectivity occupying the region between the RPE and BM

Thick DLS: area of RPE with multiple layers of different reflectivity

	DLS	No	
Wakatsuki et al. 2023 [42]	Intermediate AMD in ≥ 1 eye	Retrospective cohort study	OCT (Spectralis; HRA + OCT)	49 B-scans spaced 122 μm apart, 6 × 6 mm area (fovea centred), ART of 6	Two certified graders	Visible separation of two highly reflective layers (RPE and BM)

Thin DLS: a single zone of low-to-medium reflectivity occupying the area between the RPE and BM

Thick DLS: multiple layers of different reflectivity between the RPE and BM

	DLS	No	
AMD age-related macular degeneration, ART automatic real time, BM Bruch’s membrane, CNV choroidal neovascularisation, DLS double-layer sign, EDI enhanced depth imaging, ETDRS Early Treatment Diabetic Retinopathy Study, GA geographic atrophy, HRA Heidelberg retinal angiography, ICGA indocyanine green angiography, nAMD neovascular age-related macular degeneration, neMNV non-exudative macular neovascularisation, NIR near-infrared reflectance, NV neovascularisation, OCT optical coherence tomography, OCTA optical coherence tomography angiography, ORCC outer retina to choriocapillaris, PCV polypoidal choroidal vasculopathy, qCNV quiescent choroidal neovascularisation, RPE retinal pigment epithelium, SD spectral domain, SIRE shallow irregular RPE elevation, SS swept source

DLS

In its strictest definition, the term DLS was first used in 2007 by Sato et al. who prospectively performed time-domain OCT on 44 eyes from 42 participants with polypoidal choroidal vasculopathy (PCV) [23]. In areas of branching vascular networks, two highly reflective layers were identified on OCT imaging that consisted of the RPE and another layer beneath the RPE (presumed to be BM), which when considered together were termed the “double-layer sign” [23].

Quiescent CNV

Another term consistent with the description of DLS in its strictest form, containing an area of neovascularisation, is “quiescent” choroidal neovascularisation (CNV), proposed by Querques et al. in 2013; this definition required the presence of non-exudative CNV occurring secondary to AMD [37]. Specifically, quiescent CNV was defined as a slightly elevated RPE showing a major axis in the horizontal plane, angiographically characterised by collections of moderately reflective material in the sub-RPE space. This needed to be accompanied by clear visualisation of the hyperreflective BM and an absence of subretinal or intraretinal exudation on subsequent spectral domain (SD)-OCT images for at least 6 months [37]. Querques et al. also reported that areas of quiescent CNV enlarged over time (mean lesion area increased from 3.24 ± 2.51 mm2 to 3.52 ± 2.46 mm2 [p = 0.01] after a mean of 23.8 ± 16.0 months) [37]. Interestingly, the functional impairment due to quiescent CNV was associated with metamorphopsia (p < 0.001) rather than changes in retinal sensitivity (p = 0.05). As such, the researchers concluded that fundus angiography, and in particular indocyanine green angiography (ICGA), remains the gold standard diagnostic test (versus OCT) for quiescent CNV [37]. In another study, OCT angiography (OCTA) detected the features of quiescent CNV secondary to AMD with 81.8% of the sensitivity and 100% of the specificity of ICGA [43]. The most common features of quiescent CNV on OCTA included irregular shape, non-visible core, well-defined margin and foveal sparing [43]. These results suggest that OCTA may be a useful non-invasive tool to guide the frequency of follow-up examinations and treatment decisions [43].

SIRE

Another term describing the DLS feature is SIRE, observed by Narita et al. in 2020 using SD-OCT in individuals with large drusen (> 125 μm) secondary to AMD in at least one eye. SIRE was defined by RPE elevations with a greatest transverse linear dimension of ≥ 1000 μm, an irregular RPE layer with a height of predominantly < 100 μm and non-homogeneous internal reflectivity [22]. The SIRE definition was used in a study of fellow eyes of participants with unilateral exudative MNV, which also defined small RPE elevation as a separate entity characterised by shallow RPE elevations with the longest diameter of < 1000 μm [40].

Quantitative Definitions

In relation to quantitative definitions, DLS has been defined as having a minimum length of > 250–≥ 1000 μm and a height of < 100 μm [22, 39, 40]. For clarity, in this article, we use the term “DLS” to refer to all cases describing an irregular and slightly elevated RPE (with or without neovascularisation), including cases described in source publications as quiescent CNV, SIRE and small RPE elevation. We also use the terms neMNV for non-exudative neovascularisation in AMD and exudative nAMD when describing exudative disease.

DLS Features

Recent studies have returned to using the original term of DLS to signify irregular RPE elevation visible on OCT imaging [39, 41, 42]. One study defined DLS size as > 250 µm in the horizontal dimension and < 100 µm in height [39], which is smaller than the ≥ 1000 μm transverse linear dimension used for the SIRE definition [22]. Studies of participants with central serous chorioretinopathy report more consistent dimensions for DLS (using a minimum length of 1000 µm for RPE elevation and a maximum height of 100 µm or 150 µm) [44–46] compared with study participants with AMD [22, 39].

Histopathological correlation studies showed that DLS lesions may be vascularised (i.e., contain MNV) or non-vascularised (comprising regions of thickened basal laminar deposits); the studies also highlighted the potential value of OCTA in enabling vascularised and non-vascularised DLS lesions to be distinguished [27, 47].

OCTA is not always available or practically possible, and measurement of DLS and size/thickness criteria do not enable accurate differentiation between vascularised and non-vascularised DLS lesions. Addressing this challenge, studies in participants with intermediate AMD have classified DLS lesions as “thin” (a single layer of reflectivity between the RPE and BM) or “thick” (two or more layers with differing reflectivity between the RPE and BM) [41, 42]. In these studies, thin DLS was associated with the development of complete RPE and outer retinal atrophy (cRORA) [41] and basal laminar deposits [42]. On the other hand, thick DLS has been purported to be an independent predictor for the development of exudative MNV [42]. Case studies showing the progression of atrophy in patients with DLS at baseline and the conversion of DLS to exudative MNV can be seen in Figs. 1, 2, and 3.Fig. 1 Case study showing the 1-year progression of atrophy in a patient with DLS at baseline. Patches of atrophy are indicated by yellow arrowheads. Areas of DLS have been magnified on the right-hand side. DLS double layer sign, OCT optical coherence tomography

Fig. 2 A case study showing the conversion of DLS to exudative MNV on infrared reflectance and OCT in a patient with DLS at baseline. Areas of DLS have been magnified on the right-hand side. DLS double layer sign, MNV macular neovascularisation, OCT optical coherence tomography

Fig. 3 A case study showing the conversion of DLS to exudative MNV on infrared reflectance and OCT in a patient with DLS at baseline. DLS double layer sign, MNV macular neovascularisation, OCT optical coherence tomography, OCTA optical coherence tomography angiography

However, as a relatively newly identified biomarker, the impact of DLS thickness on the progression of AMD is not yet fully understood, and other studies suggest that DLS thickness may play a more complex role as a prognostic biomarker. A 2020 study [27] identified a biphasic trend in the behaviour of thick DLS, whereby thicker DLS may exacerbate RPE ischaemia and dysfunction, basal laminar deposits and, ultimately, foveal atrophy. Cicinnelli et al. reported that thin DLS could play a role as a protective factor against foveal involvement, with the authors contending that a thickness subclassification of DLS was less critical than grading and definitions of DLS [48].

The requirement for multiple layers of reflectivity ensures that “thick DLS” will invariably be thicker than “thin DLS” without the need to specify an absolute thickness value.

Predict: DLS in MNV

Non-exudative MNV lesions are frequently detected in the fellow eyes of patients with exudative MNV [49]. In one study of 24 eyes, 37% displayed baseline neMNV that developed exudation after approximately 9 months, and 21% of eyes without baseline neMNV showed neMNV after approximately 13 months and subsequent exudation after approximately 8 months [50]. In total, MNV in the fellow eye accounted for 79% of exudation over a 3-year follow-up [50]. Another study reported significantly higher proportion of fellow eyes developing exudation in patients presenting with neMNV (18 eyes, 22.2%) than those without neMNV (two eyes, 2.6%) (p = 0.01) [49]. The risk of exudation is particularly high in eyes with subclinical, actively growing MNV and within the first year of detection [36, 51–54]. Furthermore, lesion growth rate and baseline lesion density may affect the rate of exudation [55]. As such, identification and characterisation of neMNV may assist in the selection of patients at increased risk of exudation and who may benefit from additional monitoring.

One possible biomarker for neMNV is DLS, which reportedly correlated with type 1 neMNV (growth of neovascularisation below the RPE) in studies of participants with intermediate and advanced AMD (Table 2) [22, 37, 43, 51, 56, 57]. In 2019, Shi et al. reported a significant association between the presence of DLS on structural OCT B-scans and the presence of type 1 MNV on OCTA (p < 0.001) [58]. Approximately 30% of eyes with treatment-naïve DLS developed exudation within 2 years of follow-up [59]. Furthermore, studies in participants with exudative MNV in one eye found that the presence of DLS was associated with a higher risk of exudative MNV developing in the fellow eye [40, 60]. However, the prevalence of DLS in fellow eyes increases from the date of onset of unilateral nAMD and, therefore, the prevalence of DLS varies between studies. Moreover, not all DLS lesions harbour neMNV, and it is unclear whether exudative MNV can occur spontaneously without DLS.Table 2 Predictive value of DLS in MNV

References	Indication	N	Study type	Predictive value of DLS	
Querques et al. 2013 [37]	Treatment-naïve qCNV secondary to AMD	11 participants; 11 eyes	Retrospective case series	SD-OCT identified sites of qCNV—irregular slightly elevated RPE characterised by collections of moderately reflective material in the sub-RPE space and clear visualisation of the hyperreflective BM

qCNVs similar to non-quiescent occult type 1 CNVs

qCNVs enlarged over time (mean lesion area increased from 3.24 ± 2.51 to 3.52 ± 2.46 mm2; p = 0.01)

Despite sharing similarities with qCNV, some lesions progressed to typical exudative nAMD

7/11 fellow eyes were treated with anti-VEGF for leaking CNV

	
Carnevali et al. 2016 [43]	Treatment-naïve qCNV secondary to AMD	20 participants; 22 eyes	Observational case series	OCTA allows identification of non-invasive treatment-naïve qCNV

OCTA detected flow beneath qCNV in 21/22 participants

OCTA features were evaluated in 18/22 eyes

o Shape was circular in 8/18 eyes and irregular in 10/18 eyes

o Core was visible in 2/18 eyes (1 central and 1 eccentric position) and not visible in 16/18 eyes

o Margin was well defined in 15/18 eyes and poorly defined in 3/18 eyes

o Margin loops were small in 9/18 eyes and large in 6/18 eyes

o Location was foveal sparing in 12/18 eyes and foveal involving in 6/18 eyes

The most common features (irregular, non-visible core, well-defined margin, foveal sparing) were observed in 6/18 eyes each

	
Roisman et al. 2016 [56]	Asymptomatic intermediate AMD in one eye and symptomatic nAMD in the second eye	3 participants; 3 eyes	Retrospective, observational, consecutive case series	In asymptomatic eyes with intermediate AMD, ICGA identified the presence of central macular plaques

SS-OCT revealed subclinical type 1 neovascularisation corresponding to the plaques

Type 1 neovascularisation extended from the border of the outer retina to the choriocapillaris, 8 µm beneath BM

	
Capuano et al. 2017 [57]	qCNV in GA secondary to nAMD	19 participants; 19 eyes	Retrospective, observational case series	OCTA revealed flow signal beneath the small irregular elevation of the RPE at the site of qCNV

During the study period, 5/19 CNVs (26.3%) developed exudation with the rest displaying specific alterations in structural OCT and OCTA imaging

	
de Oliveira Dias et al. 2018 [51]	Intermediate AMD or GA secondary to nAMD in one eye and exudative nAMD in the second eye	160 participants	Prospective, observational, consecutive case series	SS-OCTA identified subclinical MNV in 23/160 eyes (14.4%) and in a further 6 eyes during follow-up

Of the 134 eyes with follow-up completed, 13 demonstrated exudation; and 10 of these 13 eyes had pre-existing subclinical MNV

At 12 months, risk of exudation was greater for eyes with subclinical MNV (21.1%) versus those without (3.6%)

Risk of exudation was 15.2 times greater in eyes with subclinical MNV (95% CI 4.2–55.5) versus those without

In all eyes that demonstrated exudation without detection of subclinical MNV, a drusen-like elevation was identified at the site of exudation where the MNV developed; RPE elevations were the first sign of type 1 MNV

	
Shi et al. 2019 [58]	nAMD	94 participants; 100 eyes	Prospective, observational study	DLS identified in 24/33 eyes with subclinical MNV and not detected in 56/67 eyes without MNV on SS-OCTA by two junior graders

o Sensitivity, specificity, PPV and NPV were 73, 84, 69, and 86%, respectively

DLS was identified in 29/33 eyes with subclinical MNV, and not detected in 58/67 eyes without MNV, on SS-OCTA by a senior grader

o Sensitivity, specificity, PPV and NPV were 88, 87, 76, and 94%, respectively

All graders reported significant associations between type 1 MNV and DLS ( p < 0.001)

	
Forte et al. 2020 [74]	qCNV with AMD or pachychoroid disease	65 participants; 67 eyes	Retrospective study	Of the 28 eyes with DLS, the 12 eyes with pachychoroid disease had more choroidal thinning and less vision loss than the 16 eyes with AMD

Eyes with pachychoroid-associated MNV were more responsive to treatment

	
Narita et al. 2020 [22]	Asymptomatic AMD with large drusen (> 125 µm) in at least one eye	132 participants; 233 eyes	Cross-sectional observational study	24 (10.3%) eyes were identified with SIRE

On SS-OCTA, 6/233 eyes had definite subclinical neMNV; all 6 (100%) had SIRE correlating directly with the area of neMNV

Absence of SIRE was observed in 209/227 eyes without neMNV (specificity 92.1%)

PPV and NPV of SIRE were 25% and 100%, respectively

Features of SIRE significantly associated with neMNV included height of the RPE elevation, overall flat or variable morphological features, RPE layer irregularity and non-homogeneous reflectivity

	
Serra et al. 2020 [72]	Treatment-naïve qCNV secondary to AMD	68 participants; 68 eyes	Retrospective study	Progression to exudation in eyes with DLS was associated with increased PED height (p < 0.0001 vs. non-exudative eyes)

Progression to exudation in eyes with DLS was associated with a smaller increase in PED diameter (p = 0.009 vs. non-exudative eyes)

	
Fukushima et al. 2021 [59]	Treatment-naïve qCNV	37 participants; 38 eyes	Longitudinal study	DLS progressed to exudation in 12 (31.6%) eyes over a mean follow-up period of > 2 years

Eyes that developed exudation tended to have larger CNV at baseline than eyes that did not progress (difference not significant)

	
Ghanchi et al. 2021 [76]	Treatment-naïve nAMD	26 participants; 43 eyes	Retrospective study	DLS was identified in 28/43 eyes (65%) using SD-OCT and OCTA

DLS was observed in 96% of true-positive MNV cases

Sensitivity and specificity of DLS alone for detecting the presence of CNV was 96 and 78%, respectively, compared with fluorescein angiography findings

	
Solecki et al. 2021 [73]	Treatment-naïve nAMD	144 participants; 144 eyes	Prospective observational study	DLS was present in 15.9% of treatment-naïve eyes

There was a higher risk of exudation in eyes with DLS than in eyes without

Exudation was preceded by a significant increase in central macular thickness (OR 116; 95% CI 4.74–50,530; p = 0.038), PED height (OR 1.76; 95% CI 1.17–3.18; p = 0.021) and width (OR 1.53; 95% CI 1.12–2.62; p = 0.042), lesion surface area (OR 6.32; 95% CI 1.62–51.0; p = 0.033), vessel branching (OR 7.50; 95% CI 1.37–61.5; p = 0.032) and the appearance of a hypointense halo around the lesion (OR 10.00; 95% CI 1.41–206; p = 0.048)

	
Wykoff et al. 2021 [77]	GA secondary to AMD	246 participants	Post hoc analysis of the FILLY trial	Exudation was reported in 26 study eyes over 18 months

A higher proportion of participants with DLS in the study eye demonstrated exudative nAMD versus participants without DLS in the study eye (p = 0.0001)

Among eyes that developed exudative nAMD, 19/26 (73.1%) had DLS at baseline, whereas DLS was only present at baseline in 70/215 (32.5%) study eyes that did not develop exudative nAMD (p < 0.0001)

	
Lee et al. 2022 [40]	Unilateral treatment-naïve exudative MNV	241 participants	Retrospective study	5-year incidence of fellow eye exudative MNV was 55.0 and 15.6% in participants with SIRE and small RPE elevation on OCT imaging, respectively, which was significantly higher than in participants with no RPE elevation (0.0%; p < 0.001 for both)

There was an increased risk of exudative MNV in the fellow eye in participants with SIRE (HR 132.589; 95% CI 16.562–1061.463; p < 0.001) and small RPE elevation (HR 41.823; 95% CI 4.711–371.261; p < 0.001) on OCT imaging versus no RPE elevations

	
Csincsik et al. 2024 [60]	Unilateral exudative nAMD	459 participants	Retrospective analysis of EDNA study data	In fellow eyes, conversion to exudative nAMD was significantly higher (p < 0.001) in eyes with DLS (41 vs. 18%) and SIRE (37 vs. 21%) versus those without DLS or SIRE

Adjusted HRs indicated the increased risk of developing exudative nAMD in the second eye: i.e., associated with the presence of DLS (HR 3.41; 95% CI 2.26–5.14; p < 0.001) and SIRE (HR 2.83; 95% CI 1.68–4.75; p < 0.001) at baseline (on SD-OCT imaging) versus no DLS or SIRE present at baseline

	
Stattin et al. 2023 [78]	Unilateral treatment-naïve exudative nAMD	33 participants; 33 eyes	Retrospective, observational, cross-sectional study	35 ICGA plaques were identified in the non-exudative fellow eyes of participants

27 plaques (77.1%) had a DLS on OCT B-scans

When they were present, hyperreflective dots (22.9% of plaques) were almost always detected above the DLS

SS-OCTA confirmed type 1 MNV in 28 plaques (80.0%)

	
Wakatsuki et al. 2023 [42]	Intermediate AMD in at least one eye	458 participants; 458 eyes	Retrospective cohort study	At baseline, thin and thick DLS lesions were observed in 11.4 and 9.6% of participants, respectively

83 eyes (18.1%) progressed to exudative MNV over 2 years

Thick DLS was an independent predictor of exudative MNV development within 2 years (OR 4.339; 95% CI 2.178–8.644; p < 0.001)

Among the biomarkers, thick DLS was the strongest predictor of exudative MNV development

	
Yaghy et al. 2023 [79]	Intermediate AMD	751 participants	Single-centre cohort study	130 participants (17%) progressed to MNV, 120 progressed (16%) to GA and 501 (67%) did not progress to advanced AMD

DLS was associated with progression to GA (HR 7.7; p < 0.001) and MNV (HR 3.4; p = 0.04)

	
Teo et al. 2023 [70]	nAMD and PCV	488 participants	Prospective cohort study	Five-year incidence of progression to exudation in the fellow eye was 16.2% (95% CI 12.0–20.2)

SIRE was associated with an increased risk of fellow-eye progression to exudation over 5 years (OR 2.86; 95% CI 1.58–5.18)

	
Terminology in the table has been taken directly from the source papers, but for the purposes of our review, quiescent CNV corresponds to DLS

AMD age-related macular degeneration, BM Bruch’s membrane, CI confidence interval, CNV choroidal neovascularisation, DLS double-layer sign, GA geographic atrophy, HR hazard ratio, ICGA indocyanine green angiography, MNV macular neovascularisation, nAMD neovascular age-related macular degeneration, neAMD non-exudative macular neovascularisation, NPV negative predictive value, OCT optical coherence tomography, OCTA optical coherence tomography angiography, OR odds ratio, PCV polypoidal choroidal vasculopathy, PED pigment epithelium detachment, PPV positive predictive value, qCNV quiescent choroidal neovascularisation, RPE retinal pigment epithelium, SD spectral domain, SIRE shallow irregular retinal pigment epithelium elevation, SS swept source, VEGF vascular endothelial growth factor

In PCV, a subtype of nAMD, DLS on OCT was reported in high proportions of study participants (59.1–91.4%) [23, 61, 62]. In the first study to use the term DLS in participants with PCV, serous retinal detachment was reported in 88% of eyes with DLS compared with only 6% of eyes without DLS [23]. This DLS essentially harbours the branching vascular network. In one study, the boundaries of DLS features on OCT and near-infrared images accurately covered most of the polypoidal lesions and branching neovascular network for the photodynamic therapy spot [63]. As such, in the context of PCV, DLS is an important clinical sign that could help to accurately guide photodynamic therapy [63].

In pachychoroid disease and central serous chorioretinopathy, DLS was reportedly present in 31.4–75.9% of patients with associated MNV [44, 46, 61, 64–67]. The presence of MNV with a background of pachychoroid disease has been termed pachychoroid neovasculopathy [68, 69]. DLS is an important feature in this spectrum of conditions and has been identified as an independent risk factor for MNV [64]. Certain qualitative characteristic features of DLS on OCT imaging have also been associated with the presence of MNV. These features include a non-homogeneous hyperreflective sub-RPE space, which has a higher probability of the presence of MNV [44]; and serous PED, which appears to protect against the development of MNV [45]. Furthermore, in a large study of patients with nAMD and PCV, the presence of SIRE was associated with an almost threefold increased risk of fellow-eye progression to exudation over 5 years (odds ratio [OR] 2.86; 95% confidence interval [CI] 1.58–5.18) [70].

Overall, further research is needed to help identify which DLS lesions are likely to harbour neMNV. The answer to this question may be provided, in part, by data from the EYE NEON study, an ongoing, 2-year, multicentre study that will enrol approximately 800 participants with new-onset nAMD in one eye [71]. Primary outcomes of the study are to estimate the prevalence and incidence of subclinical neMNV in the fellow eye. Secondary outcomes include estimating the rate of conversion of neMNV to exudative nAMD; the diagnostic accuracy of DLS to detect neMNV; and survival analyses of times to the occurrence of DLS, the conversion of DLS to neMNV and the conversion of neMNV to exudative MNV [71]. Predictive models of conversion will be developed using the study data [71].

To date, the features of DLS associated with neMNV include increased RPE detachment height, overall flat or variable morphological features, RPE layer irregularity and heterogeneous internal reflectivity [22, 72]. Consistently, exudation has been associated with a statistically significant increase in central macular thickness (p = 0.038), PED height (p = 0.021), PED width (p = 0.042), lesion surface area (p = 0.033), vessel branching of the neMNV (p = 0.032) and the appearance of a hypointense halo around the neMNV (p = 0.048) [73]. One long-term retrospective study also reported that, in eyes with DLS, the presence of pachychoroid MNV was associated with a greater treatment response than in eyes with non-pachychoroid MNV [74]. As such, characterisation of DLS lesions may assist in prognostic decisions and the appropriate allocation of resources for AMD management.

Another important consideration is that in individuals with GA, DLS lesions may have a co-existent neovascular membrane with or without exudation [57]. In a small sample of 19 eyes of 19 patients with GA and neMNV, five DLS lesions with neMNV developed exudation over 2 years, with the rest displaying specific alterations on OCT or OCTA imaging, including significantly increased maximal horizontal diameter and central macular thickness, with a clearly visible external limiting membrane [57]. Importantly, the presence of a DLS may also indicate thickened extracellular matrix material or basal laminar deposits without neMNV [27, 47, 75]. Consequently, distinguishing a DLS from thick basal laminar deposits, in the absence of fundus angiography to confirm MNV, is crucial in evaluating the risk of an eye progressing to exudative MNV [27].

OCT is an important, non-invasive imaging modality to help make this distinction. In a retrospective study, 18.1% of eyes with intermediate AMD progressed to exudative MNV, with a thick DLS identified as the strongest independent predictor for the development of exudative MNV within 2 years after the first visit (OR 4.339; 95% CI 2.178–8.644; p < 0.001) [42]. In treatment-naïve suspected nAMD, the sensitivity and specificity of DLS alone on SD-OCT imaging for detecting the presence of MNV was 96% and 78%, respectively, compared with fluorescein angiography [76]. Although OCT can be used to exclude the presence of MNV in eyes without a hyperreflective core within a DLS lesion, OCTA is needed to provide a definitive diagnosis of MNV in eyes in which these features are present [44]. However, as OCT is more widely available than OCTA, it may be of use for identifying eyes at an increased risk of disease progression that require monitoring using OCTA. Moreover, the blood flow within areas of neMNV may be too slow to be detected by OCTA.

There are some suggestions of an association between DLS and non-exudative neovascularisation in AMD and pachychoroid spectrum disease. In AMD, DLS lesions reportedly developed exudation and were significantly associated with progression to exudative MNV. As such, DLS lesion identification and characterisation may lead to better risk stratification and treatment approaches for patients likely to progress from neMNV to exudative MNV as well as enhanced risk-based screening in nAMD.

Protect: DLS in GA

Evidence for the protective effects of DLS against atrophy is limited. A distinction should be made between atrophy occurring de novo, described as GA in the context of advanced AMD [80] and macular atrophy (atrophy in the presence of neovascularisation). This distinction is difficult in the case of non-exudative, incidentally detected neovascularisation within areas of DLS. Nonetheless, there is evidence that some DLS lesions that harbour neovascularisation may prevent further atrophy and the development of GA. In a retrospective, observational study of 19 individuals with GA, DLS lesions appeared to cover areas spared from atrophy [57]. The borders of most of the DLS lesions were “sharp” compared with areas characterised by an enhanced choroidal signal due to RPE loss in areas of atrophy [57]. DLS in foveal-sparing areas may protect against the foveal progression of GA [39].

Other recent studies demonstrated that the presence of a thin DLS on OCT imaging is associated with a significant risk of developing cRORA (a term that includes GA) [81] at that location (Table 3) [41, 82]. Specifically, a thick DLS is significantly associated with the risk of exudative MNV within 2 years after the first visit (baseline frequency 9.6%, OR 4.339; 95% CI 2.178–8.644; p < 0.001), and a thin DLS is significantly associated with the risk of cRORA at 2 years after the first visit (baseline frequency 11.8%, OR 4.517; 95% CI 1.555–13.126; p = 0.006) [41, 42]. Notably, although the presence of cRORA in one eye is a risk factor for development of cRORA in the fellow eye, exudative MNV does not increase the risk of cRORA [41]. Thin DLS lesions are perceived as less likely to harbour MNV, meaning a reduced likelihood of protection against GA. However, it is unknown if thin DLS can become thick over time.Table 3 Protective value of DLS in GA

References	Indication	N	Study type	Predictive value of DLS	
Capuano et al. 2017 [57]	qCNV in GA secondary to nAMD in at least one eye	19 participants; 19 eyes	Retrospective, observational case series	At last follow-up, 13/14 qCNVs (92%) covered the area spared from atrophy

In 12/14 qCNVs (85%), the border was “sharp” with respect to the area characterised by an enhanced choroidal signal due to RPE loss where atrophy was present

	
Fukuyama et al. 2022 [39]	Foveal-sparing GA secondary to AMD	23 participants; 26 eyes	Retrospective, consecutive case series	17 eyes had DLS in the foveal-sparing area on OCT imaging

Progression of GA towards the fovea was significantly faster in eyes without DLS (square root centripetal progression 0.149 ± 0.078 mm/year) versus eyes with DLS (0.088 ± 0.052 mm/year; p = 0.04)

	
Caplash et al. 2023 [85]	Newly nAMD in one eye and dry AMD in the fellow eye	57 participants	Retrospective study	On SD-OCT, DLS was more common in participants with dry AMD (64%) rather than newly nAMD (45%)

There was no significant correlation between DLS and participant demographics or visual acuity

	
Hirabayashi et al. 2023 [41]	Intermediate AMD	330 participants; 330 eyes	Retrospective cohort study	Thick and thin DLS lesions were observed in 11.5% and 11.8%, respectively, of all 330 eyes at baseline

At month 24, 16.4% of eyes (54/330) had developed cRORA

Presence of thin DLS on OCT imaging was associated with a significant risk of developing cRORA at 2 years (OR 4.517; 95% CI 1.555–13.126; p = 0.006)

	
Manafi et al. 2023 [82]	Dry AMD with cRORA	41 participants; 57 eyes	Retrospective, case–control study	Thin DLS at baseline was associated with an increased risk of cRORA development at that location within 4 years, and was an independent predictor of cRORA (OR 3.483; p = 0.021)

Thick DLS at baseline was not associated with an increased risk of cRORA development

	
Yaghy et al. 2023 [79]	Intermediate AMD	751 participants	Retrospective study	130 participants (17%) progressed to MNV, 120 (16%) progressed to GA and 501 (67%) did not progress to advanced AMD

DLS was associated with progression to GA (HR 3.4; p = 0.04)

	
Corvi et al. 2023 [83]	Type 1 MNV	44 participants	Prospective, observational case series	A choriocapillaris-like structure (“neo-CC”) at the anterior surface was less likely to be present in eyes that progressed to cRORA MNV than in those that did not

The risk of progression to cRORA was significantly higher in eyes with reduced neo-CC coverage of the MNV

	
Terminology in the table has been taken directly from the source papers, but for the purposes of our review, quiescent CNV corresponds to DLS. cRORA is a term that includes GA

AMD age-related macular degeneration, CI confidence interval, cRORA complete retinal pigment epithelium and outer retinal atrophy, DLS double-layer sign, GA geographic atrophy, HR hazard ratio, MNV macular neovascularisation, nAMD neovascular age-related macular degeneration, OCT optical coherence tomography, OR odds ratio, qCNV quiescent choroidal neovascularisation, RPE retinal pigment epithelium, SD spectral domain

Chen et al. showed that MNV lesions can develop small-vessel circulation at the anterior surface of the neovascular complex, with morphological properties similar to the native choriocapillaris, and the term “neo-choriocapillaris” was proposed for this feature [31]. Corvi et al. demonstrated that MNV lesions with more extensive neo-choriocapillaris were less likely to demonstrate atrophy or atrophy progression, showing a potential mechanism by which MNV lesions could be protective against atrophy [83]. In a recent review, it was posited that if a region of neMNV has been stable for a period of years, it is unlikely to have a high risk of conversion [84]. Such “stable neMNVs” may be protective against atrophy, with a lower risk of the subsequent exudation usually associated with neMNV. However, further research is needed to confirm this hypothesis.

Identify: DLS in AMD

In studies in which DLS in AMD was defined (Table 1), the most common type of scan was SD-OCT using the Spectralis platform [22, 37–42]. The field of view choices included 20° × 20°, 30° × 25° and 30° × 30° [22, 38, 39]. In most studies, OCT scans were assessed by two independent graders, with disagreements reconciled by discussion or by a senior third reviewer [37–39, 41].

Manual identification and quantification of DLS from OCT scans is time-consuming and requires expertise [86, 87]. Detailed quantification may include measuring the maximum width and height of the DLS and qualitative assessment of the internal reflectivity of DLS. These complex measurements and assessments may be reserved for research use by reading centres, while simplified definitions such as “thick” and “thin” DLS [41, 42] have been designed to assist clinicians without the time or expertise to precisely measure lesion thickness, or without ready access to OCTA. The presumption is that thick DLS lesions will be more likely to be vascularised than thin DLS lesions, although the distinction will not be 100% specific. Furthermore, efforts are taking place to automate the detection of DLS by applying deep-learning algorithms to OCT scans [86, 87]. Accuracy and sensitivity rates within the ranges of 75.2–94.3% and 82.0–95.1%, respectively, indicate the potential viability of this approach [86, 88, 89]. The application of deep-learning technology to large datasets of OCT images also has the potential to help identify novel, exploratory biomarkers in AMD [90].

Swept source (SS)-OCTA scans were acquired in one study using the PLEX Elite 9000 prototype device [22]. A total of 1024 A-scans and 49 B-scans with an area of 6 × 6 mm have been commonly selected [22, 37, 41, 42]. SS-OCTA has been reported to identify significantly larger areas of MNV than SD-OCTA, with field of view having no significant effect on the measured MNV area [91]. Potentially, SS-OCTA may be more effective in assessing the full extent of MNV than SD-OCTA. The deeper penetration of SS-OCTA may also provide better visualisation of the MNV microvasculature. However, features on B-scans such as subretinal fluid, intraretinal fluid, subretinal hyperreflective material and PED may appear the same in SS-OCTA and SD-OCTA images [91].

As discussed in the PREDICT and PROTECT sections, DLS can be vascularised or non-vascularised with each appearing to confer different risk and protective effects on either exudation or atrophy in the context of AMD. Therefore, when planning the treatment of a patient, it is beneficial to confirm if DLS is present and whether it is vascularised or non-vascularised. A general proposed assessment flow is outlined in Fig. 4. The optimal method for this assessment is OCTA; however, this method is not always available and so, in this situation, the likelihood of vascularisation or atrophy may be characterised by using the more simplified terms of thick or thin DLS.Fig. 4 General assessment flow for vascularised and non-vascularised DLS in patients with AMD. AMD age-related macular degeneration, DLS double-layer sign, GA geographic atrophy, ICGA indocyanine green angiography, OCT optical coherence tomography, OCTA optical coherence tomography angiography

Moreover, the identification and grading of DLS is particularly challenging in eyes with multiple large or confluent drusen. Therefore, Csincsik et al. coined the term irregular elevation of the RPE to classify such eyes according to the presence or absence of DLS [60]. Reflectivity of the DLS is also challenging to grade if the core of the DLS appears homogeneous, especially in thin DLS.

Conclusions

In AMD, there is currently no single established definition for DLS, and it is referred to using several terms including quiescent CNV, SIRE and small RPE elevation. These terms reflect the fact that DLS can present with different characteristics, and distinct definitions for thin and thick DLS are emerging.

DLS can be categorised into vascularised and non-vascularised forms. These forms appear to confer different levels of protective effect and risk of exudation or atrophy in the context of AMD. Vascularised DLS is associated with the presence of type 1 neMNV and carries a higher risk of progression to exudative MNV. DLS lesions with neMNV may be protective against foveal progression of GA. In contrast to the vascularised form, the presence of non-vascularised DLS (i.e., thick basal laminar deposits without other features) increases the risk of GA but does not increase the risk of exudation. Therefore, it is important to ascertain whether DLS is vascularised and associated with active MNV, as early exudation detectable (by OCTA) as intraretinal or subretinal fluid or haemorrhage can facilitate treatment planning. However, OCTA is not always available or practically possible and, in these circumstances, the likelihood of vascularisation or atrophy may be approximated by classifying the DLS as thick or thin. These simplified definitions have been designed to be readily understood and accepted by clinicians. Thick DLS has been identified as an independent predictor for progression to exudative MNV, whereas the presence of thin DLS on OCT imaging is associated with a significant risk of developing cRORA. Efforts are taking place to automate the detection of DLS by applying deep-learning algorithms to OCT scans.

The value of DLS for predicting progression of neMNV to exudative disease holds promise for nAMD management. Identification and close monitoring of patients with DLS may aid in optimising the treatment of AMD.

Further research is warranted to fully elucidate the value of DLS in the real world, including whether thin versus thick DLS can be differentiated in routine ophthalmology clinical practice and whether a PED (harbouring active disease) can be differentiated from DLS with OCT and/or OCTA. Nevertheless, the ability to detect and classify DLS has the potential to provide valuable information regarding the risk of progression to advanced AMD.

Medical Writing, Editorial, or Other Assistance

Medical writing support was provided by Terri Penfold, BSc, and Ania Wydra, MSc, of Callisto, OPEN Health Communications (London, UK), and funded by Boehringer Ingelheim, in accordance with Good Publication Practice guidelines (www.ismpp.org/gpp-2022).

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Sobha Sivaprasad, Shruti Chandra, SriniVas Sadda, Kelvin YC Teo, Sridevi Thottarath, Eduard de Cock, Theo Empeslidis, and Marieh Esmaeelpour were involved in the conception, drafting, reviewing and approval of this commentary article.

Funding

No funding or sponsorship was received for this study or the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of Interest

Sobha Sivaprasad reports receiving financial support from AbbVie, Amgen, Apellis, Bayer, Biogen, Boehringer Ingelheim, Novartis, EyeBio, EyePoint Pharmaceuticals, Janssen Pharmaceuticals, Novo Nordisk, Optos, Ocular Therapeutix, Kriya Therapeutics, OcuTerra, Roche, Stealth BioTherapeutics, Sanofi. Shruti Chandra: None. SriniVas Sadda reports consulting fees from AbbVie, Alexion, Allergan Inc., Amgen Inc., Apellis Pharmaceuticals Inc., Astellas, Bayer HealthCare Pharmaceuticals, Biogen MA Inc., Boehringer Ingelheim, Centervue Inc., Character Bio., EyePoint Pharmaceuticals, Hoffman La Roche Ltd., Iveric Bio, Janssen Pharmaceuticals Inc., Nanoscope, Neurotech Pharmaceuticals Inc., Notal Vision Inc., Ocular Therapeutix, Inc., Optos Inc., Pfizer Inc., Regeneron Pharmaceuticals Inc., Samsung Bioepis, Heidelberg Engineering, Novartis Pharma AG, and Topcon Medical Systems Inc.; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Heidelberg Engineering, Hoffman La Roche Ltd., Nidek Incorporated, Novartis Pharma AG, and Optos Inc.; participation on a data safety monitoring board or advisory board for Regeneron Pharmaceuticals Inc., and REGENXBIO; leadership or fiduciary role in other board, society, committee or advocacy group for the Association for Research in Vision and Ophthalmology (unpaid: president/board of trustees) and Macula Society (unpaid: president); and receipt of equipment from Carl Zeiss Meditec AG, Heidelberg Engineering, iCare, Nidek Incorporated, Optos Inc., and Topcon Medical Systems Inc. Kelvin YC Teo reports consultancy fees, honoraria, travel support and speaker fees from Bayer, Roche, TopCon, Carl Zeiss, Boehringer Ingelheim and Novartis. Sridevi Thottarath: None. Eduard de Cock, Theo Empeslidis and Marieh Esmaeelpour are employees of Boehringer Ingelheim.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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