Atypical presentation of acute macular neuroretinopathy: a case description

Introduction

In 2019, following the identification of the wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in Wuhan, China implemented stringent epidemic prevention measures. After the comprehensive lifting of coronavirus disease 2019 (COVID-19) control policies in December 2022, the Omicron subtypes of the SARS-CoV-2 variant spread rapidly and widely among the population, and the peak of the infection coincided with an increase in visually impaired patients. Existing literature has documented various ocular manifestations following COVID-19 infection, including acute conjunctivitis, epithelial keratitis, scleritis, acute anterior uveitis, reactivation of choroiditis, retinal vasculitis, central retinal artery occlusion (CRAO), central retinal vein occlusion (CRVO), optic neuritis, optic disc edema, acute macular neuroretinopathy (AMN), paracentral acute middle maculopathy (PAMM), ocular muscle paralysis, pupillary changes, and orbital or ocular adnexal inflammation (1).

In this case description, the 12-year-old girl who visited our hospital was experiencing fever accompanied by rapid visual impairment and rare changes in fundus imaging after being infected with the Omicron variant. The initial hospital misdiagnosed her condition as bilateral macular edema and treated her with bilateral intravitreal injections of ranibizumab. Following treatment, the recovery of vision in both eyes varied in speed and degree. We analyzed and discussed the uncommon fundus imaging changes during and after treatment.

Case presentation

The patient was a female aged 12 years and 7 months with no significant medical history. After being infected with SARS-CoV-2, the patient developed a high fever (her temperature was as high as 39.6 ℃) and subsequently experienced a rapid reduction in binocular vision one day later. Ophthalmic examination revealed a visual acuity of 3.20 logarithm of minimal angle resolution (logMAR) in both eyes with no improvement after correction. The intraocular pressure (IOP) was 15 mmHg in both eyes. No abnormalities were observed in the anterior segment of either eye. Ultra-widefield fundus photography showed irregular multifocal patchy grayish lesions in the macular area of both eyes (Figure 1).

Figure 1 Bilateral ultra-wide-angle fundus photography. Multifocal irregular patchy grayish lesions at and around the macular fovea (black square frame).

Near-infrared reflectance (NIR) images from optical coherence tomography (OCT) revealed irregular patchy hyporeflective lesions with well-defined boundaries in the macular region involving the fovea (Figure 2A,2B). OCT B-scan imaging showed medium-to-high reflectivity at the junction of the outer plexiform layer (OPL) and outer nuclear layer (ONL) in the corresponding lesions, interspersed with non-reflective dark areas. The external limiting membrane (ELM) in the corresponding region appeared discontinuous, and the reflectivity of the ellipsoid zone (EZ) and interdigitation zone (IZ) was weakened and interrupted. In the right eye, a cone-shaped bulge was observed in the outer layer of the subfoveal region, whereas in the left eye, a thumb-shaped bulge was noted in the outer layer of the subfovea, along with retinal neuroepithelial elevation and subretinal fluid (SRF) (Figure 2C,2D). Optical coherence tomography angiography (OCTA) of both eyes revealed reduced or absent vascular density in the superficial capillary plexus (SCP) (internal limiting membrane to internal plexiform layer), deep capillary plexus (DCP) (internal plexiform layer to outer plexiform layer), choriocapillaris (CCP) (29–49 µm beneath the retinal pigment epithelium), and deep vascular plexus (DVP) (64–115 µm beneath the retinal pigment epithelium) layers, corresponding to NIR hyporeflective lesions (Figure 2E-2L).

Figure 2 OCT and OCTA of both eyes (6 mm × 6 mm) (Zeiss, Inc.). (A,B) NIR imaging demonstrated irregular patchy hypo-reflective lesions with well-defined boundaries involving the fovea in the macular region (the green line represents the area of the macula scanned by OCTA to obtain the E-L images, whereas the blue line represents the cross-sectional scan passing through the foveal center to obtain the C and D images). (C,D) OCT revealed medium-to-high reflectivity at the junction of the OPL and ONL (white arrows), interspersed with punctate hyporeflective dark areas (blue arrows). The ELM in the corresponding region appeared discontinuous (green arrows), and the reflectivity of the EZ (yellow arrows) and the IZ (orange arrows) was attenuated or disrupted. A cone-shaped elevation of the outer retinal structure was observed beneath the central fovea in the right eye, while a thumb-shaped elevation was noted beneath the central fovea in the left eye (red arrow). In the left eye, there was a protrusion of the retinal neuroepithelial layer under the macular central fovea accompanied by SRF (hexagram). (E-L) OCTA demonstrated reduced or absent vascular density (red-bordered hexagram) in the SCP, DCP, CCP, and DVP, corresponding to the hyporeflective lesion observed in the NIR imaging. CCP, choriocapillaris; DCP, deep capillary plexus; DVP, deep vascular plexus; ELM, external limiting membrane; EZ, ellipsoid zone; IZ, interdigitation zone; NIR, near-infrared reflectance; OCT, optical coherence tomography; OCTA, optical coherence tomography angiography; ONL, outer nuclear layer; OPL, outer plexiform layer; SCP, superficial capillary plexus; SRF, subretinal fluid.

Fundus fluorescein angiography (FFA) revealed mild dilation and tortuosity of the retinal vessels in both eyes. During the angiography, no abnormal fluorescein leakage was observed in the retinal vessels. In the early phase of the angiography, the optic discs show slightly increased fluorescence, whereas in the late phase, both optic discs demonstrated marked hyperfluorescence. No abnormal fluorescein leakage was seen in the macula of the right eye, whereas the fovea of the left eye displayed weak, spot-like reflective fluorescence (Figure 3A-3H).

Figure 3 FFA of both eyes (Heidelberg Engineering, Inc.) (A-H) FFA revealed slightly tortuous and dilated retinal vessels in both eyes (white arrows). In the late phase of angiography, there was prominent hyperfluorescence of the optic discs in both eyes (red arrows) and mild punctate fluorescein leakage at the central fovea of the left eye (yellow arrows). FFA, fundus fluorescein angiography.

The misdiagnosis was bilateral macular edema and the patient was treated by a bilateral intravitreal injection of ranibizumab. Two days later, the best corrected visual acuity (BCVA) was 1.40 logMAR in the right eye and 1.70 logMAR in the left eye, with normal IOP. No abnormalities were detected during the examination of the anterior segment and fundus. Heidelberg multicolor imaging (MCI) revealed irregular, well-defined dark gray lesions in the macular area of both eyes (Figure 4A-4D). Heidelberg NIR imaging showed irregular hyporeflective lesions with well-defined boundaries in the foveae of both eye (Figure 4E,4F). OCT revealed medium-to-high reflectivity at the junction of the outer plexiform layer and ONL in both eyes, interspersed with hyporeflective signals. The ELM in the corresponding area appeared continuous, whereas the EZ and IZ showed attenuation and disruption of the reflectivity signals. In the left eye, nodular hyperreflective signals were observed in the damaged EZ/IZ region beneath the macular central fovea. Additionally, SRF in the left eye had been absorbed, and the central foveal thickness was significantly reduced (Figure 4G-4H). Transverse structural OCT (from ILM to BM) showed non-reflective cavities at the junction of the OPL and the ONL in the right eye, whereas no such changes were observed in the left eye (Figure 4I,4J).

Figure 4 MCI (Heidelberg Engineering, Inc.). (A-F) MCI revealed irregularly demarcated dark gray lesions in the macular region of both eyes (black square frame). (G,H) OCT revealed medium-to-high reflectivity at the junction of the OPL and ONL in both eyes (white arrows), interspersed with hyporeflective signals (blue arrows). In the corresponding regions, the ELM band appeared blurred (green arrows), while the EZ (yellow arrows) and IZ (orange arrows) showed attenuation and disruption of the reflectivity signals. In the left eye, nodular hyperreflective signals (red arrow) were observed in the damaged EZ/IZ region beneath the macular central fovea. Additionally, SRF in the left eye had been absorbed, and the central foveal thickness was significantly reduced (red arrow). (I,J) Transverse structural OCT (from ILM to BM) showed non-reflective cavities at the junction of the OPL and the ONL in the right eye, whereas no such changes were observed in the left eye (yellow triangle). BM, Bruch membrane; ELM, external limiting membrane; EZ, ellipsoid zone; ILM, internal limiting membrane; IZ, interdigitation zone; MCI, multicolor imaging; OCT, optical coherence tomography; ONL, outer nuclear layer; OPL, outer plexiform layer; SRF, subretinal fluid.

Follow-up examinations using OCT were performed on days 5, 23, 44, and 72 after treatment. On day 5 postoperatively, the retinal thickness of the macular fovea in both eyes had decreased significantly compared to day 2, whereas the thickness of the subfoveal choroid had increased. Compared to days 2 and 5 postoperatively, the macular foveal retinal thickness slowed a gradual increase on days 23, 44, and 72. Additionally, the thickness of the subfoveal choroid showed a gradual reduction. Throughout the follow-up period, the macular foveal retinal thickness and subfoveal choroidal thickness in the left eye were consistently lower than those in the right eye. The recovery rate and degree of visual acuity in the left eye were consistently lower than those in the right eye. The dark grey lesions in NIR images became more distinct over time. On day 72, the final assessment revealed that the visual acuity had recovered to 0 logMAR in the right eye and −0.30 logMAR in the left eye. Additionally, the continuity of the ELM had been restored; however, the reflectivity of the EZ remained weak, and the integrity of the interdigitation IZ band had not yet recovered in either eye (Figure 5).

Figure 5 OCT follow-up images after anti-VEGF treatment (Heidelberg Engineering, Inc.). (A,B) On day 5 postoperatively, the retinal thickness of the binocular macular fovea had decreased significantly when compared to day 2, although the thickness of the subfoveal choroid had increased (C-E). Compared with days 2 and 5, the macular foveal retinal thickness had increased slowly when tested on days 23, 44, and 72 postoperatively. (E) The thickness of the subfoveal choroid had slowly reduced. The continuity of the ELM had been restored, although the EZ band reflection was still weak and the integrity of the IZ band had not yet recovered in either eye. ELM, external limiting membrane; EZ, ellipsoid zone; logMAR, logarithm of minimal angle resolution; OCT, optical coherence tomography; VEGF, vascular endothelial growth factor.

All procedures performed in this study were in accordance with the ethical standards of the Institutional Review Board of Ganzhou People’s Hospital (protocol code TY-ZKY2021-002-01; date of approval: 30 March, 2021) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient and her parent for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The child presented with an atypical form of AMN. AMN is a microvascular neuroretinal disorder first described by Bos and Deutman (2). Prior to the COVID-19 pandemic, it was considered a relatively rare ocular condition (3). AMN is closely associated with vascular factors such as hypotension or hypertension, the use of sympathomimetic drugs, anaphylactic shock, thrombocytopenia, anemia, hyperlipidemia, hypovolemia, and dehydration. It is also linked to viral infections such as dengue fever and influenza (4,5). Notably, during the global COVID-19 pandemic, the incidence of AMN has significantly increased, indicating a strong correlation between COVID-19 and AMN (3). Previous studies have demonstrated that angiotensin-converting enzyme 2 (ACE2), the key entry receptor for both SARS-CoV and SARS-CoV-2, plays a central role in the COVID-19 pandemic (6), and is closely associated with acute lung injury and its most severe form, acute respiratory distress syndrome (7). This receptor is widely distributed in the eye and retina (8).

The 12-year-old female patient had a confirmed history of SARS-CoV-2 infection. After developing a high fever, she presented with significant visual dysfunction in both eyes. NIR imaging revealed irregular, well-defined hyporeflective lesions involving the fovea in the macular region. Corresponding B-scan imaging showed medium-to-high reflectivity lesions at the junction of the OPL and ONL. Additionally, EZ and IZ in the affected area exhibited weakened or disrupted reflectivity. Based on the findings from IR and OCT imaging, the patient’s condition aligns with the typical clinical features of AMN (9). In this patient, a notable difference from the typical OCT findings of AMN was the presence of SRF beneath the fovea in both eyes during the early stage of disease onset. The SRF demonstrated relatively high reflectivity, with the right eye showing a cone-shaped elevation of the EZ under the fovea, whereas the left eye exhibited a thumb-like elevation of the EZ under the fovea. These findings are rare in current reports of OCT characteristics associated with AMN. It has been reported that SRF can also appear in cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) caused by COVID-19 infection (10). APMPPE is primarily characterized by acute inflammation of the retinal pigment epithelium, with its hallmark clinical feature being multiple yellow-white placoid lesions located at the posterior pole of the retina. NIR imaging in APMPPE typically shows no specific changes. OCT findings in APMPPE demonstrate hyperreflective lesions extending from the OPL to the RPE, often accompanied by disruption of the outer retina and RPE, as well as loss of the EZ at the sites of the placoid lesions (11). These clinical features are entirely distinct from those observed in AMN.

Due to treatment at different hospitals, the patient underwent OCT examinations using different devices. After intravitreal anti-vascular endothelial growth factor (VEGF) injection therapy, the SRF was rapidly absorbed. Follow-up using Heidelberg OCT revealed a low-reflectivity lesion area on en face OCT in the left eye, corresponding to a nodular medium-to-high reflectivity signal in the outer retinal structures beneath the fovea on B-scan imaging. In contrast, the right eye showed no hyporeflective lesion but demonstrated IRF between retinal layers in the OCT structure corresponding to the lesion. This finding is also uncommon in cases of AMN. As early as 2005, Chan et al. observed that in the early stages of AMN, there was an increased distance between the photoreceptor outer segments and the RPE, containing hyperreflective material suggestive of retinal edema or SRF (12). In 2016, Groat et al. reported a case of AMN in a 15-year-old girl of unclear etiology who developed symptoms following a high fever. Fundus examination revealed cotton wool spots and IRF (13). In the same year, Wubben et al. described the first non-traumatic case of AMN with transient IRF and SRF, which were fully absorbed 2 days after onset without treatment (14). This suggested that the presence of transient IRF in AMN is common and supports the theory that ischemia causes disruption of the blood-retina barrier and the development of IRF. The hypothesis that transient IRF and SRF are common signs in the early course of AMN has not been further confirmed by animal experiments. However, from a pathological mechanism perspective, this hypothesis is reasonable. As mentioned earlier, SARS-CoV-2 enters host cells via the ACE2 receptor, which is highly expressed on endothelial cells, resulting in direct endothelial cell damage (15). Endothelial injury leads to platelet activation, leukocyte recruitment, and dysregulated release of von Willebrand factor, which promotes microvascular thrombosis and large-vessel events (16). The release of inflammatory cytokines exacerbates endothelial dysfunction and coagulation activation, creating a vicious cycle of thromboinflammation. The ACE2 receptor is abundantly expressed in both the retina and choroid (17). SARS-CoV-2, through ACE2, may trigger intense thromboinflammation in the retina and choroid, leading to reduced blood flow density in the SCP, DCP, CCP, and DVP, as well as the appearance of SRF and IRF. These manifestations may not be rare signs but are likely overlooked in most SARS-CoV-2-infected patients due to mild visual impact, subtle symptoms, or ocular conditions being overshadowed by systemic manifestations, thereby missing the early signs of AMN. We also observed prominent late-stage fluorescein leakage from the optic disc in this patient during FFA, a relatively rare finding in clinical reports of AMN. In a series of AMN cases induced by COVID-19 infection reported by Premi et al., one case showed optic disc staining on FFA (18). However, Feng et al. (4) reported no abnormalities on FFA in their study of AMN cases associated with COVID-19 infection.

Following anti-VEGF treatment, the patient exhibited changes in choroidal and retinal thickness. It remains uncertain whether these changes are part of the natural disease course or a result of anti-VEGF therapy. Although there are case reports suggesting that anti-VEGF intravitreal injections may induce AMN (19,20), no prior cases of AMN patients receiving anti-VEGF treatment have been reported. Previous studies have demonstrated that persistent inflammation can lead to upregulation of VEGF levels (21,22), which increases vascular permeability (22,23). Currently, there are no clinical studies examining changes in intraocular cytokines in AMN patients. In this patient, rapid absorption of SRF was observed in both eyes following intravitreal anti-VEGF therapy, accompanied by changes in retinal and choroidal thickness. Notably, after the early resolution of SRF in the left eye, there was significant thinning of the retina and marked thickening of the choroid. Subsequent follow-up showed that retinal thickness gradually increased, whereas choroidal thickness slowly decreased. However, retinal and choroidal thickness in the left eye remained consistently lower than those in the right eye, and the recovery of visual acuity in the left eye was slower and less complete compared to the right. Prior studies have shown that monoclonal anti-VEGF drugs can penetrate all retinal layers, reach the choroid, and accumulate in the walls of choroidal vessels (24-26). In research on diabetic macular edema, anti-VEGF treatment has been associated with reduced choroidal and macular thickness (27,28). However, if choroidal thickening is observed following anti-VEGF therapy, it might indicate a predominant inflammatory component in the submacular fluid (29). For AMN, Hashimoto et al. proposed that photoreceptor damage might stem from choroidal involvement, suggesting that inflammatory circulatory disturbances in the thickened choroid play a role in the pathogenesis of AMN (30).

Conclusions

We report a case of AMN in a child associated with SARS-CoV-2 infection with unusual clinical features. Multifocal intraretinal fluid and highly reflective SRF were associated with an intense inflammatory response and circulatory disturbance. The influence of the vasculature in the corresponding lesion area was not limited to the DCP layer; it was also evident in the SCP, CCP, and DVP layers. Following anti-VEGF treatment, changes in the retinal choroidal thickness occurred in both eyes. We hypothesize that anti-VEGF drugs may have an impact on the entire intraocular vasculature of AMN patients caused by SARS-CoV-2.

Acknowledgments

We acknowledge the use of imaging equipment from Carl Zeiss, Inc. (Ganzhou Aier Eye Hospital) and Heidelberg Engineering, Inc. (Ganzhou People’s Hospital) for image acquisition in this study.

Footnote

Funding: This study was granted by Jiangxi Province “ShuangQian plan” Innovation Talents Project (No. S2021CQKJ2297) and Jiangxi Provincial Department of Science and Technology Key Research and Development Plan Projects (No. 20203BBGL73133).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2092/coif). All authors report that this study was granted by Jiangxi Province “ShuangQian plan” Innovation Talents Project (No. S2021CQKJ2297) and Jiangxi Provincial Department of Science and Technology Key Research and Development Plan Projects (No. 20203BBGL73133). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Institutional Review Board of Ganzhou People’s Hospital (protocol code TY-ZKY2021-002-01; date of approval: 30 March, 2021) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient and her parent for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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