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. Author manuscript; available in PMC: 2024 Feb 16.
Published in final edited form as: Acta Ophthalmol. 2023 May 18;102(1):e126–e132. doi: 10.1111/aos.15708

Assessment of intraretinal hyperreflective foci using multimodal imaging in eyes with age-related macular degeneration

Deniz Oncel 1,2, Giulia Corradetti 1,2, Ye He 1,2, Maryam Ashrafkhorasani 1,2, Muneeswar Gupta Nittala 1,2, Dwight Stambolian 3, Margaret A Pericak-Vance 4, Jonathan L Haines 5,6, SriniVas R Sadda 1,2
PMCID: PMC10656356  NIHMSID: NIHMS1911841  PMID: 37199278

Abstract

Purpose

This study aimed to investigate the correspondence between intraretinal hyperreflective foci (IHRF) identified on optical coherence tomography (OCT) B-scans with hyperpigmentation on color fundus photography (CFP) or hyperreflectivity on infrared reflectance (IR) images in eyes with age-related macular degeneration (AMD).

Methods

Flash CFP, IR images, and OCT B-scans obtained at the same visit were evaluated. Individual IHRF identified on OCT B-scans were assessed for the qualitative presence or absence of a hypotransmission tail into the choroid. The corresponding IR image obtained at the time of OCT acquisition was analyzed for the presence or absence of hyperreflectivity in this region. The IR images were manually registered to the CFP image, and CFP images were inspected for the presence or absence of hyperpigmentation at the location of IHRF.

Results

From 122 eyes, a total of 494 IHRF were evaluated. For the primary analysis of qualitative presence or absence of hyperpigmentation on CFP and hyperreflectivity on IR at the locations corresponding to IHRF on OCT, 301 (61.0%) of the IHRFs demonstrated evidence of hyperpigmentation on CFP, while only 115 (23.3%) showed evidence of hyperreflectivity on IR. The qualitative determination of the presence or absence of an abnormality on CFP or IR were significantly different (p <0.0001). 327 (66.2%) of the IHRF showed hypotransmission, and 80.4% of these IHRF showed hyperpigmentation on CFP, though only 23.9% (p <0.0001) demonstrated hyperreflectivity on IR.

Conclusions

Less than two-thirds of IHRF evident on OCT manifest as hyperpigmentation on color photos, though IHRF with posterior shadowing are more likely to be evident as pigment. IR imaging appears to be even more poorly sensitive for visualizing IHRF.

Keywords: Intraretinal hyperreflective foci, OCT, color fundus photography, CFP, age-related macular degeneration, AMD

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the United States’ elderly population (Bressler et al. 2003, Congdon et al. 2004, Flaxel et al. 2020). It has been estimated that approximately 288 million people will suffer from AMD by 2040 worldwide (Wong et al. 2014). AMD progresses from early and intermediate stages characterized by drusen, which are characterized by focal extracellular deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane to advanced stages characterized by macular neovascularization (MNV) or geographic atrophy (GA) (Friedman et al. 2004, Wong et al. 2014). Color fundus photography (CFP) was considered the gold standard for assessing AMD stage and biomarkers associated with risk for progression. The broad availability of optical coherence tomography (OCT) and the wide use of pharmacotherapies for the treatment of neovascular AMD has led to OCT surpassing CFP as the key imaging modality for assessing patients with AMD in clinical practice (Oncel et al. 2022). Intraretinal hyperreflective foci (IHRF) have been demonstrated in multiple studies to be a consistent and important OCT risk factor for progression from intermediate to late AMD (Christenbury et al. 2013, Lei et al. 2017, Nassisi et al. 2018, Ouyang et al. 2013, Sleiman et al. 2017). Ho et al. identified IHRF as small, discrete, punctiform hyperreflective lesions in the neurosensory retinal layers with greater reflectivity than the retinal pigment epithelium (RPE) band on OCT (Ho et al. 2011). Corradetti et al. also demonstrated that IHRF were a specific risk factor for conversion from incomplete outer retinal atrophy (iRORA) to complete outer retinal atrophy (cRORA) (Corradetti et al. 2021). IHRF are not only associated with an increased risk for progression to atrophy but have also been identified as precursors to the development of Type 3 macular neovascularization (MNV) (Nagiel et al. 2015). Although the origin of all IHRF in the retina in AMD is not established, at least some are thought to be anteriorly migrated retinal pigment epithelial cells, which may be a reflection of distress in the outer retina (Echols et al. 2020). Curcio et al. classified different RPE morphologies during the progression of AMD and proposed that activated, migrating RPE cells are the typical histologic correlates of IHRF (Curcio et al. 2017).

A number of studies including the Age-Related Eye Disease Study (AREDS) study have shown that the presence of macular pigmentary changes in eyes with intermediate is a risk factor for disease progression advanced AMD (Davis et al. 2005, Ferris et al. 2013, Ferris et al. 2005, Klein et al. 2002). Thus, the presence of pigmentary abnormalities lead to a classification of a more advanced stage of intermediate AMD in AMD severity scales (Ferris et al. 2013). Regions of macular hyperpigmentation have been described as gray or black colored lesions within the macula that appear darker than the surrounding fundus on CFP (Age-Related Eye Disease Study Research Group 2001). It remains unclear whether macular hyperpigmentation in AMD represents a single or diverse group of histopathologic abnormalities. Hyperpigmentation in CFP has been attributed to the proliferation of RPE cells and increased concentration of melanin-containing organelles (Cao et al. 2021).

Previous studies (Ho et al. 2011), have demonstrated that IHRF on OCT can correspond to pigment clumping on CFP. Whether this correlation is universal and whether specific subsets of these lesions show better correlation remains to be defined. Furthermore, some areas of hyperpigmentation in the fundus can appear hyperreflective on infrared reflectance (IR) imaging, but it is unclear how these correlate with IHRF on OCT (Kunze et al. 1999, Laiginhas et al. 2022, Ly et al. 2016, Weinberger et al. 2006). Defining these relationships across multiple imaging modalities, however, is essential for the development of future staging systems of AMD which may take advantage of multimodal information. Thus, the purpose of this study is to assess the multimodal imaging characteristics of these lesions by comparing IHRF identified on OCT B-scans with hyperpigmentation on color fundus photographs (CFP) and reflectivity on infrared reflectance (IR) images in eyes with AMD.

Materials and Methods

Data Collection

The Amish Eye Study (AES) is an ongoing NEI-supported clinical research investigation whose aim is to identify phenotypic and genetic biomarkers for the purpose of better characterizing AMD in the elderly population. A total of 1339 (2668 eyes) elderly Amish subjects have been enrolled in this study and the baseline characteristics and OCT features have been described in previous reports (Nittala et al. 2019). OCT imaging was performed on both eyes using the Spectralis (HRA + OCT; Heidelberg Engineering, Inc, Heidelberg, Germany) using a volume cube acquisition protocol (97 B-scans, 512 A-scans per B-scan, ART of nine frames) over a 20 × 20° (~ 6 mm × 6 mm) field centered on the fovea. A 30° infrared reflectance (IR) image was obtained concomitant with the OCT as part of the acquisition protocol and the instrument software automatically registers the B-scans to the IR image. In addition, a 30° flash CFP of the macula was obtained with the Zeiss FF450 (Carl Zeiss Meditec, Germany) fundus camera for all subjects. The data collection and analysis were approved by the institutional review boards of the University of Miami, University of Pennsylvania, Case Western Reserve University, and the University of California – Los Angeles, and all subjects provided written, informed consent. The study was conducted in compliance with the Health Insurance Portability and Accountability Act of 1996, and the Declaration of Helsinki.

Eyes with intermediate AMD (as defined using the Beckman classification (Ferris et al. 2013) with evidence of IHRF were eligible for the study. Images with poor quality interfering with the assessment were excluded. Furthermore, eyes with retinal pathology other than AMD that could interfere with the assessment were also excluded.

Grading Procedure

Flash CFP, IR images, and OCT B-scans (Heidelberg Spectralis) obtained at the same visit were evaluated by trained reading center graders (DO, YH, MA). DO served as the primary grader for all cases, while YH and MA each served as secondary grader for half the cohort to allow detailed assessment of grading reproducibility. IHRF were identified as hyper-reflective lesions within the neurosensory retinal layers (i.e., above the level of the RPE band), at least 3-pixels in size, with a similar brightness as the RPE band. Individual IHRF identified on OCT B-scans were assessed for the qualitative presence or absence of a posterior hypotransmission tail into the choroid. In addition, the axial location of the IHRF was classified as being above or below the inner nuclear layer (INL) – outer plexiform layer (OPL) junction. The local distribution of the IHRF lesion was also assessed and classified as “isolated” if a single lesion had no other lesion within 19 microns (an approximation of the transverse optical resolution of the OCT B-scan) or “clustered” if multiple (≥2) distinct IHRF were observed within 19 microns on the OCT B-scans. Examining the adjacent B-scans was not relevant in making this determination of isolated vs clustered as the spacing between B-scans was ~ 62 microns. The corresponding IR image obtained at the time of OCT acquisition was analyzed for the presence or absence of hyperreflectivity in this region. The IR images were manually registered to the CFP image, and CFP images were inspected for the presence or absence of hyperpigmentation at the location of the IHRF (Figure 1).

Figure 1.

Figure 1.

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The optical coherence tomography (OCT) B-scan (C, right panel) shows the intraretinal hyperreflective foci (IHRF) that have evidence of shadowing or hypotransmission selected. The infrared reflective (IR; B) image of the left eye with AMD has an absence of hyperreflectivity. The IR image was manually registered to the color fundus photography (CFP) by aligning vessel crossings. CFP image (A) of a left eye with AMD shows hyperpigmentation (black arrow). The OCT B-scan (F, right panel) shows the intraretinal hyperreflective foci selected. The IR (E) image of the left eye with AMD has presence of hyperreflectivity. The IR image was manually registered to the CFP by aligning vessel crossings. CFP image (D) of a right eye with AMD shows hyperpigmentation (black arrow).

Statistical Methods

For statistical analysis and comparison, a chi-square test was used for the qualitative determination of the presence or absence of an abnormality on CFP or IR. A p-value of ≤ 0.05 was considered to be statistically significant. A column chart was created to better compare the differences between IR and CFP detection of the OCT IHRF lesions. These comparisons were performed using SPSS 18 statistical software (SPSS version 18.0, IBM, Chicago, IL).

Cohen’s kappa was used to assess inter-grader agreement between the two graders for each case. Kappa values of 0.4 to 0.8 indicate moderate agreement, while kappa values greater than 0.8 indicate excellent agreement.

Results

A total of 122 eyes from 77 patients with intermediate AMD and IHRF were included in this analysis. The mean age of the included patients was 78.5±8.6. Forty-one of the patients included in our analysis were women and 36 were men. From these eyes, a total of 494 IHRF were identified on OCT. Among the 494 distinct IHRF lesions, 399 were classified as isolated on the OCT B-scans, while 95 were graded as clustered. 430 (87.0%) IHRF were located below the INL-OPL junction, while 59 (12.0%) were above the INL-OPL junction, and five (1.0%) appeared to straddle the junction.

Comparison of the sensitivity of visualizing IHRF on Color Fundus Photography and Infrared Reflectance Imaging

Figure 2 shows the primary analysis of qualitative presence or absence of hyperpigmentation on CFP and hyperreflectivity on IR at the locations corresponding to IHRF on OCT. 301 (61.0%) of the IHRFs demonstrated evidence of hyperpigmentation on CFP, while only 115 (23.3%) showed evidence of hyperreflectivity on IR (Figure 2). In CFP locations where hyperpigmentation could not be detected, fundus pigmentation similar to the background was observed in all cases. Within IR locations with absence of hyperreflectivity on IR, the reflectivity was either isoreflective (N= 274) or slightly hyporeflective (N=105) relative to the background. The qualitative determination of the presence or absence of an abnormality at corresponding location on CFP or IR were significantly different (p <0.001) from OCT.

Figure 2.

Figure 2.

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Qualitative assessment of the presence or absence of hyperpigmentation on color fundus photography (CFP) or hyperreflectivity on infrared reflectance (IR) that corresponds to intraretinal hyperreflective foci (IHRF) (n=494) on OCT

The correspondence among specific subsets of IHRF based on their characteristics was also assessed. 327 (66.2%) of the IHRF showed evidence of shadowing or a hypotransmission tail (Figure 1). When considering only this subset of IHRF, 80.4% showed hyperpigmentation on CFP, though only 23.9% (p <0.001) demonstrated hyperreflectivity on IR (Table 1).

Table 1.

Qualitative assessment of the presence or absence of hyperpigmentation on color fundus photography (CFP) and hyperreflectivity on infrared reflective (IR) images that corresponds to intraretinal hyperreflective foci (IHRF) for all analyzed subsets

CFP Hyperpigmentation IR Hyperreflectivity p-value*
Frequency Percentages
(%)		 Frequency Percentages
(%)
All IHRF (n=494) 301 61.0 115 23.3 <0.001
IHRF with hypotransmission tail (n=327) 263 80.4 78 23.9 <0.001
Isolated IHRF (n=399) 227 56.9 85 21.3 <0.001
Clustered IHRF (n=95) 74 77.9 30 31.6 <0.001
IHRF above INL-OPL junction (n=59) 41 69.5 6 10.2 <0.001
IHRF below INL-OPL junction (n=430) 257 59.8 107 24.9 <0.001
IHRF straddling the junction (n=5) 3 60.0 2 40.0 0.58
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*

Chi-square test was performed to obtain the p-values for these qualitative assessments shown in Table 1.

Regarding the axial locations of IHRF on OCT, the IHRF that were above the INL-OPL junction demonstrated hyperpigmentation on 69.5% of CFP, while only 10.2% (p <0.001) showed hyperreflectivity on IR. IHRF that were below the INL-OPL junction showed hyperpigmentation on 59.8% of CFP, while 24.9% (p <0.001) showed hyperreflectivity on IR. Lastly, the few IHRF that appeared to straddle the junction showed hyperpigmentation on 60% of CFP, though only 40% (p=0.58) demonstrated hyperreflectivity on IR (Table 1).

Clustered IHRF demonstrated hyperpigmentation on 77.9% of CFP and hyperreflectivity on 31.6% (p <0.001) of IR images. Isolated IHRF showed hyperpigmentation on 56.9% of CFP, but hyperreflectivity on only 21.3% (p <0.001) of IR images (Table 1).

The inter-grader reproducibility assessment revealed a high degree of agreement with Cohen’s κ= 0.97 for hyperreflectivity on IR and κ= 0.96 for hyperpigmentation on CFP. Furthermore, it showed a high degree of agreement with Cohen’s κ= 0.99 for IHRF classifying IHRF as isolated or clustered on OCT and κ= 0.97 for the determination of axial location.

Discussion

This study aimed to investigate the correspondence between IHRF identified on OCT B-scans with hyperpigmentation on CFP or hyperreflectivity on IR images in eyes with AMD. We observed that IHRF on OCT were correlated with hyperpigmentation on CFP in less than 2/3 of cases and with hyperreflectivity on IR images in less than a ¼ of cases, with IR imaging thus being significantly less sensitive than CFP for detecting these lesions. Importantly, the CFP without hyperpigmentation at the location of OCT-IHRF demonstrated a normal pigmentation relative to background. In contrast, the IR images without hyperreflectivity at the location of OCT-IHRF demonstrated hyporeflectivity in 21% of the cases. Even if one considers both hyperreflectivity and hyporeflectivity, however, IR images would appear to remain less sensitive than CFP for detecting OCT-IHRF. It should be noted, however, that our analysis was not designed to assess the specificity of hyperpigmentation on CFP or hyperreflectivity on IR for detection if OCT-IHRF, as our primary objective was to assess the CFP and IR correlates of IHRF on OCT. In this regard, Laiginhas et al. used en face OCT images in eyes with intermediate AMD and concluded that hypotransmission defects associated with regions of thickened RPE that block penetration of light into the choroid were an important component of the macular hyperpigmentation (Laiginhas et al. 2022).

Our analysis also demonstrated that most but not all IHRF (66.2%) showed evidence of shadowing or hypotransmission tail into the choroid. Such IHRF lesions were more likely to be evident as hyperpigmentation on CFP imaging (~80%), but they were not seen at a significantly higher frequency on IR imaging (still ~ 23-24%). Post-hoc review of CFP images did not reveal any difference in the CFP characteristics of hyperpigmentation among OCT-IHRF with or without hypotransmission tails. There were also no significant differences in other OCT characteristics among IHRF with and without hypotransmission tails, though most clustered IHRF (76.8%) had hypotransmission tails. On post hoc inspection, IHRF with hypotransmission tails did tend to be larger, but we were not able to precisely segment or quantify the IHRF lesion size. We also observed that IHRF overlying a drusen or drusenoid PED appeared to more frequently demonstrate a hypotransmission tail. However, this could be an confounded by hypotransmission resulting from the drusenoid material itself (Zhou et al. 2022). Previous studies have also noted hypotransmission beneath calcified drusen (Liu et al. 2022, Suzuki et al. 2015).

IHRF have been shown to be a consistent and strong risk factor for progression to late AMD (Lei et al. 2017) in multiple studies. Previous studies including Lei at al. have linked macular atrophy progression with IHRF, subretinal drusenoid deposits and higher central drusen volume (Lei et al. 2017, Paavo et al. 2017). However, even when accounting for these other features, IHRF was the strongest independent predictor of progression to atrophy (Lei et al. 2017, Nassisi et al. 2018, Sleiman et al. 2017). Furthermore, an increasing number of IHRF lesions has also been demonstrated to further add to the risk of progression to atrophy (Christenbury et al. 2013, Schuman et al. 2009). Previous histopathological studies in eyes with intermediate AMD have demonstrated that IHRF may represent activated RPE cells migrating into the inner nuclear and plexiform layers, which may be associated with complement activation, oxidative damage, and other factors inducing RPE cell injury (Christenbury et al. 2013, Ho et al. 2011). Consequently, Curcio et al. supported the finding that activated and migrating RPE manifest as IHRF in SD-OCT as part of a comprehensive study of 15 phenotypes of RPE and RPE-derived cells in advancing stages of AMD (Curcio et al. 2017). As a result of these studies, IHRF have emerged as an important factor for risk-stratifying patients with intermediate AMD, and potentially selecting patients for enrollment in early intervention trials. The present study highlights that while these OCT-defined IHRF can be observed on CFP and IR images, the sensitivity is modest for CFP and generally poor for IR images. It is uncertain, however, whether the risk for progression to advanced AMD differs between IHRF visible on other imaging modalities versus those that can only be observed on OCT. This question can be evaluated in future longitudinal studies.

Our study has some limitations that should be considered when interpreting our findings. First, we have considered IHRF as at least 3-pixels in size based on conventions from previous studies that have defined the risks for AMD progression associated with these lesions. Ultimately, however, this definition is somewhat arbitrary. It is unclear whether smaller hyperreflective lesions carry a similar risk for AMD progression or are similarly detected on CFP or IR, though one might anticipate that the sensitivity for detecting these smaller lesions on other imaging modalities might be even lower. A second limitation of our study is that we are not able to assess the specificity of the CFP and IR findings. For example, it is also already established that hyperpigmentation on color may correspond to thickening of the RPE band without evidence of IHRF, thus hyperpigmentation is clearly not specific for IHRF. On the other hand, this was not the purpose of our study, as we sought to better define the CFP and IR correlates of OCT-IHRF which are a well-established and reliable biomarker of AMD progression risk Third, our study only assessed IHRF in the context of AMD, and thus our findings cannot be extrapolated to many other diseases where IHRF may be observed including Stargardt’s disease, retinitis pigmentosa, and diabetic retinopathy (Battaglia Parodi et al. 2019, Huang et al. 2022, Midena et al. 2021, Yamaguchi et al. 2022). Finally, we should note that while IHRF may have a uniform appearance on OCT, individual IHRF may reflect different pathological entities and may arise from different pathophysiological processes. It is possible, that although CFP and IR seemed to have a lower sensitivity for detection of IHRF overall, they may be preferentially detecting specific subtypes of IHRF, and their actual sensitivities may vary depending on the specific subtype and relevant underlying pathophysiology. Our study also has a number of strengths including the use of images collected according to a standardized acquisition protocol and the use of trained graders with a demonstrated high level of reproducibility.

In summary, less than two-thirds of IHRF evident on OCT manifest as hyperpigmentation on color photos, though IHRF with posterior shadowing are more likely to manifest this finding on CFP. IHRF are even less well-seen on IR images, highlighting that this imaging modality is likely insufficient for detecting these biomarkers. These findings may be of value in the design of imaging acquisition and analysis protocols in studies of AMD.

Funding

Research reported in this publication was supported by the National Eye Institute of the National Institutes of Health under Award Number RO1EY023164 and R01EY030614. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Disclosure statement

Dr. Sadda has served as consultant for Amgen, Allergan, Genentech/Roche, Iveric, Oxurion, Novartis, Regeneron, Pfizer, 4DMT, Centervue, Heidelberg, Optos, Nanoscope, Apellis, and Jannsen. He has received speaker fees from Carl Zeiss Meditec, Nidek, and Novartis. He has received research instruments from Nidek, Topcon, Heidelberg, Carl Zeiss Meditec, Optos and Centervue. The remaining authors have no conflict of interest to disclose.

Data availability statement

The data used to support these findings of this study are available from the corresponding author upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data used to support these findings of this study are available from the corresponding author upon request.

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