Abstract
Objective
To evaluate the sensitivity and specificity of structural optical coherence tomography (OCT) in comparison to fluorescein angiography (FA) and OCT angiography (OCTA) in discerning between macular haemorrhages (MH) due to myopic choroidal neovascularization (m-CNV) and idiopathic macular haemorrhage (IMH) in myopic patients and to suggest a new OCT biomarker to discern these two entities.
Methods and analysis
In this longitudinal retrospective study, patients affected by MH and pathological myopia were included. All patients underwent OCTA and FA to discern bleeding from m-CNV or IMH. Furthermore, all patients underwent a structural OCT and 2 expert graders evaluated the presence of the myopic 2 binary reflective sign as a biomarker to discern between IMH and bleeding from m-CNV.
Results
Forty-seven eyes of 47 patients were enrolled. By means of angiographic examinations, 34 out of 47 eyes with MH (57%) were diagnosed as m-CNV, whereas 13 eyes (43%) as IMH. Using structural OCT, the graders identified the presence of the myopic 2 binary reflective sign in 13 out of 13 eyes with IMH. In 33 out of 34 cases with m-CNV, the 2 graders established the absence of the sign. This accounted for 100% of sensibility and 97% of specificity of structural OCT in discerning between MH from m-CNV and IMH.
Conclusion
Structural OCT can discern with good reliability between IMH and bleeding from m-CNV based on the presence/ absence of the myopic 2 binary reflective sign. This could be of paramount relevance in the clinical setting for the diagnosis and treatment of HM patients.
Subject terms: Retinal diseases, Predictive markers
Introduction
Myopia is a leading cause of visual loss, estimated to affect 1.6 billion people worldwide [1, 2]. Approximately one fifth of the myopic population has high myopia (HM), defined as a refractive error with spherical equivalent exceeding −6 dioptres (D) and/or the axial length (AL) longer than 26.5 mm1. Pathologic myopia (PM) is a major cause of visual impairment worldwide and is characterized by progressive posterior segment elongation and posterior staphyloma and may lead to myopic maculopathy (MM) [3]. The most common findings of MM are chorioretinal and scleral thinning, chorioretinal atrophy, myopic choroidal neovascularization (m-CNV), myopic macular hole, dome-shaped macula, macular haemorrhages (MH), and lacquer cracks (LC) [4].
The development of m-CNV is one of the most frequent MM complications, especially in patients younger than 50 years [5], and affects approximately 10–11% of highly myopic eyes [6, 7]. If left untreated, it can cause scarring with expanding macular atrophy leading to irreversible visual loss [8]. Early diagnosis and anti-VEGF treatment are key elements to avoid this unfavourable outcome [8–10].
On fundoscopy, m-CNV typically appears as a flat, small, greyish subretinal lesion beneath or close to the fovea, often associated with MH [5]. Although the pathogenesis of m-CNV is not well understood, the mechanical tissue strain caused by the progressive elongation of the anteroposterior axis seems to break the retinal pigment epithelium (RPE)-Bruch’s membrane-choriocapillaris complex, resulting in LC [6, 11]. LC promotes the ingrowth of neovascular tissue from the choriocapillaris, causing generally type 2 CNV [5].
However, fresh LC formation may be associated also with spontaneous idiopathic macular haemorrhages (IMH) in the absence of m-CNV [4, 12]. The IMH is caused by the rupture of choriocapillaris with the onset of LC [13]. Curtin et al. reported that these IMH usually resolve with little or no residual effect and the visual prognosis is good without the necessity of treatment, unlike haemorrhages caused by m-CNV [4, 14]. Given their different prognosis and management, the MH due to m-CNV should be carefully distinguished from IMH. Fluorescein angiography (FA) is still considered the gold standard for investigating the origin of MH, showing IMH as blocked fluorescence only, whereas m-CNV as hyperfluorescence within the haemorrhagic area [5]. Recently, Battista et al. reported that optical coherence tomography angiography (OCTA) was comparable to FA to discern these two different causes of MH, avoiding the limitations of FA, including masking effects and adverse events related to dye injections [15, 16]. The optical coherence tomography (OCT) capacity in discerning MH caused by m-CNV from IMH has not been investigated in the literature.
The aim of this study is to evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the OCT in comparison with those of FA and OCTA in discerning between MH from m-CNV and IMH, and to suggest a new OCT biomarker that may help in differential diagnosis of these two entities.
Materials and methods
This longitudinal retrospective study was conducted according to the principles of the Declaration of Helsinki and its later amendments. Informed consent was obtained from all study participants for retrospective studies. We screened patients with MM with a newly diagnosed MH in at least one eye, referred to the Medical Retina and Imaging Unit at the San Raffaele Scientific Institute, Milan, Italy between January 2016 and November 2022. Patients were eligible for study inclusion if they had (1) a diagnosis of MH determined by fundus examination and documented by multicolour imaging or colour fundus image and (2) structural OCT, FA, and/or OCTA scans performed on the same day of the onset visit. They were excluded from the study if they had (1) evidence of myopic traction; (2) evidence of posterior inflammatory disorders (i.e. multifocal choroiditis and punctate inner choroidopathy); (3) history of any ocular surgery 6 months before the onset visit; (4) any previous retinal treatments (e.g., intravitreal injections, photodynamic therapy) excluding peripheral barrage laser; (5) history or evidence of other retinal and optic nerve diseases; (6) poor quality of images acquired. Haemorrhages outside the macular area were excluded from the analysis. Each patient underwent a multimodal imaging and/or true-colour fundus imaging, and a comprehensive ophthalmic examination. Multimodal retinal imaging included FA, multicolour imaging, spectral domain-OCT (Spectralis HRA + OCT, Heidelberg Retina Angiograph+OCT; Heidelberg Engineering, Heidelberg, Germany), swept-source OCT-A (PLEX Elite 9000; Carl Zeiss Meditec Inc., Dublin, CA, USA), and AL measurements (IOLMaster device, Carl Zeiss Meditec AG, Jena, Germany). Best-corrected visual (BCVA) was assessed using Snellen charts and converted the results into the logarithm of the minimal angle of resolution (logMAR) for statistical analysis.
Imaging analysis
Two independent and experienced readers (CM and AS) first reviewed multicolour and/or true colour fundus images, structural OCT, OCTA, and FA images for eligibility, including eyes that met inclusion criteria. Thereafter, the eligible eyes were divided in IMH and haemorrhages related to m-CNV, according to FA and OCTA analysis. They also classified study cases without any prior knowledge of the cases and whether the MH was caused by spontaneous Bruch’s membrane rupture or m-CNV.
A senior grader (GQ), with experience in visualizing MH on OCT imaging, trained two graders (RS and AC) to recognize a new OCT biomarker, the “myopic 2 binary reflective sign”, using a small training set of cases separated from the study cases. This sign consists of a homogeneous hyper reflective lesion (of varying sizes) in the outer retina, corresponding to the haemorrhage, and a hyporeflective line separating the haemorrhage from the RPE, and was used to identify spontaneous haemorrhage (without a m-CNV) (Fig. 1). Each grader independently evaluated structural OCT B-scans of the included eyes in a random order, in order to evaluate the presence or absence of the “myopic 2 binary reflective sign”. When there was disagreement between the two graders, the senior grader was asked to take the decision.
Fig. 1. Myopic 2 binary reflective sign of a patient with idiopathic macular haemorrhage (IMH) in the left eye.
A Structural optical coherence tomography (OCT) passing through the fovea at baseline shows the presence of myopic 2 binary reflective sign. This sign is composed by homogeneous hyperreflective material (yellow arrows) corresponding to the haemorrhage, and by a hyporeflective line (black triangles) which separates the haemorrhage from the RPE. B The OCT image at the 6-month follow-up displays the complete resolution of the IMH with the disappearance of the myopic 2 binary reflective sign.
The primary outcome measure was to assess the sensitivity and specificity of myopic 2 binary reflective sign on OCT in discerning between m-CNV and IMH, in comparison to FA and/or OCTA.
Statistical analysis
Statistical analyses were performed using the open-source software R (R Foundation for Statistical Computing, Vienna, Austria). Results of quantitative variables analyses are expressed as means ± standard deviations, whereas results of categorical variables are expressed as counts and percentages.
The Gaussian distribution of continuous variables was verified with the Shapiro-Wilks test. The agreement between ratings was quantified with percent agreement and Cohen’s Kappa statistic. Kappa adjusts percent agreement for marginal prevalence and a guide to its interpretation is: <0.40, poor agreement; >0.75, excellent agreement; 0.40 to 0.75, fair to a good agreement [17].
Association between categorical variables was assessed using Fisher’s exact test. In all analyses, p values less than 0.05 were considered statistically significant.
Results
Fifty-two eyes with MH from 52 patients were graded according to the cause of the haemorrhage, based on FA/OCTA. However, 5 eyes were excluded by senior graders from the OCT analysis due to low quality OCT images. Demographics and main clinical features of the included patients are reported in Table 1. Of 47 eyes enrolled, 13 were classified as IMH and 34 as m-CNV haemorrhages, based on FA/OCTA. In all eyes of m-CNV, subretinal hyperreflective material (SHRM) was observed (100%). Among these cases, 22 eyes (65%) were affected by only SHRM, while 12 eyes (35%) presented also subretinal and/or intraretinal fluid.
Table 1.
Main clinical features of patients affected by macular haemorrhages (MH) due to myopic choroidal neovascularization (m-CNV) or by idiopathic MH (IMH).
| IMH GROUP | m-CNV GROUP | p | |
|---|---|---|---|
| (13 eyes) | (34 eyes) | ||
| Age (years) | 63.01 ± 21.42 | 71.12 ± 16.86 | 0.19 |
| Sex | Male 2/13 (15.38 %) | Male 9/34 (26.47%) | 0.89 |
| Female 11/13 (84.62 %) | Female 25/34 (73.53) | ||
| SE (D) | −11.6 ± 4.31 | −11.91 ± 5.43 | 0.73 |
| BCVA (logMar) | 0.30 ± 0.42 | 0.48 ± 0.43 | 0.66 |
| MH height (μm) | 184.32 ± 73.53 | 196.82 ± 88.91 | 0.67 |
| Distance from MH to the fovea (μm) | 310.74 ± 106.51 | 295.13 ± 112.87 | 0.74 |
| Intraretinal infiltration level (layers) | No infiltration=6/13 (46.15%) | No infiltration=11/34 (32.35%) | 0.84 |
| ONL = 4/13 (30.77%) | ONL = 16/34 (47.05%) | ||
| IPL = 3/13 (23.08%) | IPL = 7/34 (20.59%) |
BCVA best corrected visual acuity, SE spherical equivalent, ONL outer nuclear layer, INL inner nuclear layer.
The two graders agreed with the presence of a myopic 2 binary reflective sign in all eyes with IMH (Fig. 2). In 1 out of 34 eyes with bleeding from m-CNV, both readers graded the presence of a myopic 2 binary reflective sign (Fig. 4A–C). In 28 out of 34 eyes with m-CNV haemorrhage, both graders agreed with the absence of the myopic 2 binary reflective sign (Fig. 3). In 5 out of 34 eyes with bleeding from m-CNV, a disagreement on its presence/absence between the two graders was observed. Consequently, the senior grader established the presence/absence of myopic 2 binary reflective sign (Figs. 4D–G). In short, in 33 out of 34 eyes with m-CNV bleeding, no myopic 2 binary reflective sign was detected.
Fig. 2. Multimodal retinal imaging of a patient with idiopathic macular haemorrhage (IMH) in the left eye.
Multicolour imaging (B) displays the presence of a macular haemorrhage (blue arrow). Fluorescein angiography (D) illustrates a hypofluorescent area (red arrow) due to a masking effect at the site of the IMH. Structural optical coherence tomography (OCT) (A) shows the presence of myopic 2 binary reflective signs (yellow arrows). OCT-angiography image (C, E) excludes the presence of anomalous vascular network in correspondence of the myopic 2 binary reflective sign (green arrows).
Fig. 4. Multimodal retinal imaging of doubtful cases regarding presence/absence of the “myopic 2 binary reflective sign”.
A, B, C (left panel): Multimodal retinal imaging of a patient with a misdiagnosis of type 2 choroidal neovascularization (CNV) on OCT image in the right eye. Multicolour imaging (A) displays the presence of a macular haemorrhage (white arrow). Structural optical coherence tomography (OCT) (C) seems to show the myopic binary reflective sign (green arrow). However, fluorescein angiography (B) reveals the presence of type 2 CNV (red arrow). D, E, F, G (right panel): Multimodal retinal imaging of a patient with a type 2 choroidal neovascularization (CNV) on OCT image in the left eye. Multicolour imaging (D) displays the presence of a macular haemorrhage (blue arrow). In the structural optical coherence tomography (OCT) image (F) the two graders disagree about the sign, but the senior grader establishes the absence of the myopic binary reflective sign (yellow arrow). OCT-angiography images (E, G) confirm the presence of type 2 CNV (black arrows).
Fig. 3. Multimodal retinal imaging of a patient with macular haemorrhage due to type 2 choroidal neovascularization (CNV) in the left eye.
Multicolour imaging (B) displays the presence of a macular haemorrhage (blue arrow). Fluorescein angiography (D) illustrates a hyperfluorescent lesion corresponding to a type 2 CNV in the site of the macular haemorrhage. Structural optical coherence tomography (OCT) passing through the lesion (A) shows the presence of subretinal hyperreflective material above the retinal pigment epithelium (yellow arrows). OCT-angiography images (C, E) confirm the presence of a neovascular network (green arrows).
Thus, the agreement between the two graders was excellent (agreement = 89%, Kappa = 0.779).
The sensitivity, specificity, PPV, and NPV were 100%, 97%, 93% and 100%, respectively. The OCT sensitivity and specificity were not significantly different from those of FA and OCTA (p < 0.001). Overall, the association between the underlying cause of the bleeding and the presence/absence of myopic 2 binary reflective sign and IMH was found to be highly statistically significant (P < 0.001).
Discussion
In this study we found a high sensitivity and specificity of structural OCT in discerning between IMH and haemorrhage related to m-CNV, without significant differences with FA and OCTA. Particularly, we observed that all IMH eyes showed the presence of a “myopic 2 binary reflective sign” at the structural OCT and thus this sign could be considered as a potential new OCT biomarker to distinguish between these two entities.
One of the most frequent findings on fundus examination in PM eyes is MH, whose treatment is strictly related to its cause. Indeed, LC in the absence of m-CNV could cause simple macular bleeding (i.e. IMH), which generally has a good visual prognosis. On the other hand, haemorrhages from m-CNVs require prompt anti-VEGF treatment in order to improve visual outcomes [5].
The gold standard in identifying the cause of MH is still FA [18]. M-CNVs are mostly type 2, appearing on FA as well‐defined areas of hyperfluorescence in the early phase with progressive leakage of dye in the late phases of the angiogram [4]. Conversely, IMH appears as a hypofluorescent area due to a masking effect at the site of MH in both the early and late phases of FA [18]. However, the hypofluorescence of the MH could mask the underlying CNV fluorescence, thus causing failure in the diagnostic process [4, 18]. In addition, FA has potential adverse events ranging from mild (e.g., nausea, vomiting, and skin eruptions) to severe (e.g., syncope, laryngeal oedema, and anaphylaxis) [19]. These limitations have been overcome with the introduction of the clinical practice of OCTA. Battista et al. demonstrated that OCTA is as reliable as FA in discerning between m-CNV haemorrhage and IMH [15]. However, OCTA acquisition could be difficult in myopic patients due to the increasing of artefacts (blinks, movement, vessel ghosting) [20]. For these reasons, structural OCT biomarkers could be of paramount relevance in the clinical setting [21, 22].
We used FA and OCTA to classify the cause of MH, spontaneous (IMH) or m-CNV related. We found that all the eyes with IMH showed the “myopic 2 binary reflective sign”, and the graders correctly identified the IMH based on the presence of this finding on OCT in most of these eyes. This reflects the real-world scenarios in which the real cause of the MH is not known and the clinician wants to evaluate if the presence or absence of this sign predicts the origin of the bleeding, i.e. spontaneous or from m-CNV.
The myopic 2 binary reflective sign appears on structural OCT as a homogeneous hyper-reflective lesion in the outer retina, corresponding to the haemorrhage, distinctly separated from RPE by a hypo-reflective linear layer. This latter helps us distinguish IMH from CNV, which appears on OCT as a highly reflective heterogeneous area above the RPE (type 2 CNV) without any demarcation between the two structures. This sign seems to be in accordance with the previous description of IMH by Asai et al. [23], in which IMH appears on OCT scans as a hyper reflective lesion, which extended beneath the neural retina [23]. However, we underline that the myopic 2 binary reflective sign also includes a clear separation between the haemorrhage and the RPE (hyporeflective linear layer), which is essential for the differential diagnosis. Furthermore, the myopic 2 binary reflective sign characterized all the MH and not only haemorrhages with an intraretinal extension.
In clinical practice, a structural OCT biomarker would be very useful in identifying the underlying cause of bleeding. The myopic 2 binary reflective sign may be considered an objective and cost-effective diagnostic sign for the earlier detection and correct management of MH, especially when FA or OCTA are not available. Furthermore, OCTA imaging in myopic eyes is severely impaired by the frequent fixation instability, the high axial length and the fundus abnormalities, which could lead to low quality and an improperly segmented image [24]. In these cases, the OCT advantages in the differential diagnosis are undeniable.
This study presented several limitations, such as the retrospective design and the relatively small number of included eyes. However, the small cohort was mainly due to the extensive multi-modal imaging applied for all these patients at the baseline. However, the great accordance between OCT and both FA and OCTA and the presence of the “myopic 2 binary reflective sign” in all eyes with IMH suggest a high reliability of the study.
In conclusion, we reported a high sensitivity and specificity of the structural OCT in identifying the cause of MH (i.e. IMH or m-CNV) in comparison with FA and OCTA. In particular, we described the “myopic 2 binary reflective sign”, a new OCT biomarker observed in all the included eyes affected by IMH. If confirmed by larger cohort future studies, the “myopic 2 binary reflective sign” will be a reliable biomarker to identify the cause of MH, driving the treatment decision for myopic patients with MH.
Summary
What was known before
Fluorescein angiography (FA) is still considered the gold standard for investigating the origin of macular haemorrhage (MH) in patients with pathological myopia. A recent study reported that optical coherence tomography angiography (OCTA) was comparable to FA to discern the causes of MH, avoiding the limits of FA.
What this study adds
The optical coherence tomography (OCT) capacity in discerning MH caused by myopic choroidal neovascularization (m-CNV) from idiopathic macular haemorrhage (IMH) has not been investigated in the literature. This study suggests a new OCT biomarker, the myopic 2 binary reflective sign, helpful to distinguish between these two entities.
How this study might affect research, practice, or policy
The myopic 2 binary reflective sign may be considered as an objective and cost-effective diagnostic sign for the earlier detection and correct management of MH, especially when FA or OCTA are not available. Other structural OCT biomarkers could be very useful in clinical practice in the management of the main retinal diseases.
Supplementary information
Author contributions
Conception or design of the work: GQ, FB, RS, MB. Acquisition, analysis, or interpretation of data: RS, MB, CM, AS, AC. Drafted the work or substantively revised it: GQ, FB, RS, LQ, EC, CM, AS, MB, AC.
Data availability
The datasets generated and/or analysed during the current study, which were used for all statistical analyses and for the creation of all figures, as well as the Table 1, are available from the corresponding author upon reasonable request.
Competing interests
RS is consultant for Allergan Inc, Bayer Shering-Pharma, Medivis, Novartis, and Zeiss. FB is consultant for Alcon, Alimera Sciences, Allergan Inc, Farmila-Thea, Bayer Shering-Pharma, Baush and Lomb, Genentech, Hoffmann-La-Roche, Novagali Pharma, Novartis, Sanofi-Aventis, Thrombogenics, and Zeiss. GQ is consultant for Alimera Sciences, Allergan Inc, Amgen, Bayer Shering-Pharma, Heidelberg, KBH, LEH Pharma, Lumithera, Novartis, Sandoz, Sifi, Sooft-Fidea, and Zeiss. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Cecilia Mularoni, Andrea Servillo.
Supplementary information
The online version contains supplementary material available at 10.1038/s41433-023-02780-w.
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Associated Data
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Supplementary Materials
Data Availability Statement
The datasets generated and/or analysed during the current study, which were used for all statistical analyses and for the creation of all figures, as well as the Table 1, are available from the corresponding author upon reasonable request.