Acute macular neuroretinopathy following COVID-19 infection: Three case reports

Abstract

BACKGROUND

During the Coronavirus disease 2019 (COVID-19) pandemic, a notable increase in acute macular neuroretinopathy (AMN) cases was observed. This study aimed to investigate the potential association between AMN and COVID-19 by examining 3 cases in China.

CASE SUMMARY

The first case involved a 30-year-old man who presented with progressive vision loss following a COVID-19 infection. Optical coherence tomography (OCT) and near-infrared imaging identified hallmark AMN lesions, hyperreflective disruptions within the outer plexiform layer, and hyporeflective anomalies in the ellipsoid zone, leading to an AMN diagnosis. Despite partial visual recovery, OCT angiography (OCTA) revealed persistent microvascular changes, specifically a decreased vascular density in the deep capillary plexus. The second case was a 24-year-old woman who experienced blurred vision and exhibited bilateral cotton-wool spots on fundus examination post-COVID-19. Imaging confirmed the presence of AMN along with paracentral acute middle maculopathy (PAMM). Follow-up OCTA found a progressive reduction in vascular density, indicating ongoing microvascular compromise. The third case was a 28-year-old woman who reported sensations of occlusion in her right eye following a COVID-19 infection. Imaging confirmed both AMN and PAMM, revealing similar decreases of microvascular density on OCTA despite a significant improvement in visual acuity. We noted that all 3 patients had received the COVID-19 vaccine prior to the appearance of symptoms.

CONCLUSION

The findings highlight the diagnostic utility of advanced ocular imaging in detecting AMN in COVID-19 patients and the importance of comprehensive eye examinations.

Key Words: Acute macular neuroretinopathy; Paracentral acute middle maculopathy; COVID-19; Optical coherence tomography; Optical coherence tomography angiography; Deep capillary plexus; Case report

Core Tip: Advanced ocular imaging has diagnostic value in identifying neuroretinopathy (AMN) in patients with Coronavirus disease 2019 (COVID-19). The clinical variability of AMN is highlighted by individual differences in the occurrence of symptoms, recovery rate, and the degree of visual improvement after COVID-19.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emerged as a global pandemic starting in late 2019. The disease spread rapidly worldwide, leading to significant morbidity and mortality[1]. COVID-19 manifests with a broad spectrum of clinical symptoms ranging from mild respiratory issues to severe complications including multi-organ failure and death[2]. Since the easing of epidemic control measures for COVID-19 in China in early December 2022, there has been a rapid resurgence of the virus in the country[3].

Acute macular neuroretinopathy (AMN) is a relatively rare ophthalmic disorder characterized by subtle yet potentially significant visual disturbances, with scotoma being the most prominent symptom[4]. The epidemiological profile of AMN shows a distinct predilection toward women and frequently presents bilaterally[5]. AMN is associated with a diverse range of precipitants, including viral infection, use of oral contraceptives, traumatic events, and systemic conditions such as anemia[4]. Although generally considered a self-limiting condition, the long-term effects of AMN, including persistent visual field defects despite a general trend toward recovery, highlight the need for greater clinical attention.

Onset of the COVID-19 pandemic was associated with an increase in cases exhibiting ocular symptoms, with AMN reported with increased frequency. A retrospective analysis conducted in France revealed a marked rise in the incidence of AMN, from 0.66 per 100000 cases in 2019 to 8.97 per 100000 cases in 2020 following the outbreak of COVID-19[5]. This significant increase underscores the potential role of COVID-19 not only as a systemic health emergency but also as a contributing factor to various ocular conditions, including conjunctivitis, uveitis, and glaucoma in addition to AMN. Despite the apparent correlation, the mechanisms underlying the association between COVID-19 and AMN remain unclear, and the current literature provides limited insight into the potential interplay.

This challenge is further increased by the slow development of clinical management strategies for AMN in the midst of COVID-19 co-infection. This uncertainty underscores the reliance on advanced diagnostic and therapeutic approaches, particularly near-infrared (NIR) imaging and optical coherence tomography (OCT). NIR imaging offers superior detection of AMN lesions beyond the capability of traditional fundus examination[6], and OCT provides detailed visualization of lesion changes[7]. These techniques highlight the critical need for specialized ocular information in managing AMN with COVID-19 co-infection. This case report describes the use of NIR and OCT in a series of three instances of AMN that developed after COVID-19 infection.

CASE PRESENTATION

Chief complaints

Case 1: A 30-year-old man who presented with a 2 d history of progressive vision loss in the left eye.

Case 2: A 24-year-old woman who presented with a complaint of blurred vision in her left eye persisting for 10 d.

Case 3: A 28-year-old woman presenting a sensation of occlusion in her right eye persisting for 1 wk (Table 1).

Table 1 Summary of 3 cases of acute macular neuroretinopathy following coronavirus disease 2019 infection.

Characteristic	Case 1	Case 2	Case 3
Chief complaint	Progressive vision loss in left eye for 2 d	Blurring vision in left eye for 10 d	Sensation of occlusion in right eye for 1 wk
History of present illness	Fever for 3 d 1 wk ago, confirmed COVID-19 infection via throat swab	Fever 2 wk prior, confirmed COVID-19 infection via throat swab, not pregnant	Confirmed COVID-19 infection via nucleic acid test 2 wk prior, not pregnant
Vaccine	Inactivated COVID-19 vaccine (Vero cell, Beijing Institute of Biological Products Co., Ltd.)
BCVA	0.6 (left eye), 1.0 (right eye)	1.0 (right eye), 0.5 (left eye)	0.3 (right eye), 1.0 (left eye)
Fundus exam	Rugby ball-like lesion over macula	Scattered cotton-wool spots in both eyes
NIR	Hyporeflective lesion oriented towards fovea in left eye	Hyporeflective lesions in both eyes, pronounced in left eye	Hyporeflective lesions in right eye
OCT/ OCTA	Hyporeflective ELM, hyperreflective MZ, diminished EZ; No initial abnormalities in SCP/DCP	Hyperreflective foci in OPL, hyporeflective foci in EZ/IZ in both eyes, hyperreflective foci in INL in right eye	Hyperreflective lesions in OPL, hyporeflective lesions in EZ/IZ, hyperreflective lesions in INL
Treatment	Ibuprofen (0.2 g three times a day)	Acetaminophen (0.3 g three times a day)	Acetaminophen (0.3 g three times a day)
Final diagnosis	AMN	AMN and PAMM	AMN and PAMM

AMN: Acute macular neuroretinopathy; BCVA: Best-corrected visual acuity; COVID-19: Coronavirus disease 2019; DCP: Deep capillary plexus; ELM: External limiting membrane; EZ: Ellipsoid zone; INL: Inner nuclear layer; MZ: Myoid zone; NIR: Near-infrared reflectance imaging; OCT: Optical coherence tomography; OCTA: Optical coherence tomography angiography; PAMM: Paracentral acute middle maculopathy; SCP: Superficial capillary plexus.

History of present illness

Case 1: The patient had a fever for 3 d in the previous week. COVID-19 infection was subsequently confirmed by a throat swab.

Case 2: The patient experienced a fever approximately 2 wk before her visit. COVID-19 was confirmed by a throat swab.

Case 3: The patient had a COVID-19 infection that was confirmed by nucleic acid testing 2 wk before her visit.

History of past illness

None of the patients had a previous history of myopia or other ophthalmologic disease. Their medical history was otherwise unremarkable.

Personal and family history

All 3 patients had received an inactivated COVID-19 vaccine (Vero cell, Beijing Institute of Biological Products Co., Ltd.) 3, 4, and 3 mon before their visit, respectively.

Physical examination

Case 1: Initial ophthalmologic assessment revealed a best-corrected visual acuity (BCVA) of 0.6 in the affected eye and 1.0 in the contralateral eye. Fundus examination identified a distinctive rugby ball-like lesion over the macular region of the left eye (Figure 1A). The blood pressure was 120/80 mmHg.

Figure 1 Multimodal imaging of the evolution of an acute macular neuroretinopathy lesion in the left eye of Case 1. A: Ultra widefield pseudocolor fundus photography (Optos PLC, Dunfermline, Scotland, United Kingdom) shows a rugby ball-like lesion within the macular region; B: Near-infrared reflectance imaging of a hyporeflective lesion directed towards the macula; C, F and I: Sequential optical coherence tomography (OCT) B-scans shows the progression of the lesion. Initially, the images show a hyporeflective external limiting membrane, a hyperreflective myoid zone, and a hyporeflective ellipsoid zone (EZ), alongside the collapse of the outer plexiform layer with hyperreflective Henle's fiber layer and loss of the interdigitation zone (IZ). Follow-up at 1 mon reveals persistence of the hyporeflective EZ and deterioration in the IZ, which remains the sole impairment after 6 mon; D, G and J: Tracked OCT-angiography (OCTA) (Plex Elite 9000; Carl Zeiss Meditec, Inc., Dublin, CA, United States), targeting the superficial capillary plexus, indicating no observable flow signal deficits throughout the follow-up period; E, H and K: Tracked OCTA (Plex Elite 9000; Carl Zeiss Meditec, Inc.) at the deep capillary plexus level, showing an emergence and subsequent exacerbation of flow signal deficits (indicated by orange arrow) at 1 mo and 6 mo.

Case 2: Fundus examination disclosed the presence of scattered cotton-wool spots in both eyes (Figure 2A and B). The BCVA was 1.0 in the right eye and 0.5 in the left eye. The blood pressure was 125/80 mmHg.

Figure 2 Multimodal imaging and deep capillary plexus flow signal evolution in acute macular neuroretinopathy in Case 2. A and B: Ultrawide field pseudocolor fundus photography (Optos PLC, Dunfermline, Scotland, United Kingdom) shows scattered cotton-wool spots in both eyes; C and D. Near-infrared reflectance imaging shows hyporeflective lesions within the macular region; E and F. Optical coherence tomography (OCT) B-scans provide detailed visualization of hyperreflective foci within the outer plexiform layer and hyporeflective foci in the ellipsoid zone/interdigitation zone in both eyes, with additional hyperreflective foci observed in the inner nuclear layer of the right eye; G-I: Tracked OCT angiography (OCTA) (Plex Elite 9000; Carl Zeiss Meditec, Inc., Dublin, CA, United States), focused on the deep capillary plexus, reveals a gradual decrease in the flow signal (orange arrow) in the right eye in the follow-up period; J-L: Similar OCTA imaging of the deep capillary plexus for the left eye also shows progressive reduction in flow signal (orange arrow), underscoring the bilateral impact on vascular density over time.

Case 3: The BCVA was 0.3 in the affected eye and 1.0 in the unaffected eye. The blood pressure was 128/78 mmHg.

Laboratory examination

The patients self-tested with COVID-19 rapid antigen detection kits and a throat swab.

Imaging examination

Case 1: NIR imaging delineated a hyporeflective lesion oriented toward the fovea (Figure 1A and B). In addition to the collapse of the outer plexiform layer (OPL), marked by hyper-reflectivity in Henle's fiber layer and the vanishing of the interdigitation zone (IZ), OCT revealed a hyporeflective external limiting membrane, a conspicuously hyperreflective myoid zone, and diminished reflectivity within the ellipsoid zone (EZ), supporting the diagnosis of AMN. OCT angiography (OCTA) initially showed no significant abnormality of the superficial or deep capillary plexus (DCP) (Figure 1C-E).

Case 2: NIR imaging identified hyporeflective lesions within the macular regions of both eyes with a pronounced manifestation in the left eye (Figure 2C and D). OCT imaging provided a more detailed view, revealing hyperreflective foci within the OPL and hyporeflective foci in the EZ/IZ affecting the fovea in both eyes, plus hyperreflective foci in the inner nuclear layer (INL) of the right eye. The observations indicated AMN coexisting with paracentral acute middle maculopathy (PAMM) (Figure 2E and F).

Case 3: Diagnostic imaging revealed hyporeflective lesions within the macular region of the right eye on NIR imaging (Figure 3A), indicative of AMN. OCT findings showed hyperreflective lesions in the OPL, hyporeflective lesions in the EZ/IZ, and hyperreflective lesions in the INL (Figure 3B), suggesting concurrent presentation of PAMM.

Figure 3 Multimodal imaging evolution of acute macular neuroretinopathy with paracentral acute middle maculopathy in the right eye of Case 3. A: Near-infrared imaging shows hyporeflective lesions within the macular area, indicative of the interplay between acute macular neuroretinopathy and paracentral acute middle maculopathy; B-D: Sequential optical coherence tomography (OCT) B-scans detail the progression of the lesion. Initially, hyperreflective lesions in the outer plexiform layer coexist with hyporeflective lesions in the ellipsoid zone/interdigitation zone (IZ) and hyperreflective lesions in the inner nuclear layer within the macular region. By 2 mon, the lesions in the IZ transition to hyporeflective foci, a change that persisted in subsequent follow-up evaluations; E-G: Tracked OCT angiography (OCTA) (Plex Elite 9000; Carl Zeiss Meditec, Inc., Dublin, CA, United States), targeting the deep capillary plexus, illustrates a gradual reduction in the flow signal (indicated by orange arrow), signifying a decrease in vascular density over the course of the follow-up.

FINAL DIAGNOSIS

AMN.

TREATMENT

The 3 patients received ibuprofen (0.2 g three times a day), acetaminophen (0.3 g three times a day), and acetaminophen (0.3 g three times a day) for symptomatic therapy of COVID-19.

OUTCOME AND FOLLOW-UP

Case 1: The patient was COVID-19 negative 2 wk after diagnosis. Follow-up examination 1 mon after diagnosis revealed partial recovery of the BCVA to 1.0/0.8. Despite this improvement, OCTA detected a reduction in vascular density within the DCP together with persistent hyporeflective changes in the EZ and impairment of the IZ (Figure 1F-H). At 6 mon, the BCVA was fully restored at 1.0/1.0, reflecting significant clinical improvement. However, OCT imaging continued to show residual impairment in the IZ, with further decreased vascular density in the DCP observed on OCTA (Figure 1I-K).

Case 2: The patient was COVID-19 negative within 15 d after diagnosis. Subsequent follow-up showed an improvement of the BCVA to 1.0/0.8 within 2 wk, which was maintained 1 mon later. However, OCTA revealed a progressive decrease in vascular density within the DCP of both eyes on follow-up. (Figure 2G-L).

Case 3: The fever resolved within 5 d, and though initially testing positive for COVID-19 after experiencing fever, the patient was found to be negative at the time of her visit. Remarkably, within 2 mon, the patient's BCVA improved to 1.0/1.0, with OCT showing near restoration of the macular structure, albeit with lingering hyporeflective foci in the IZ (Figure 3C). The improvement stabilized over the following month (Figure 3D). Nonetheless, OCTA demonstrated a progressive decline in the vascular density within the DCP at the site of the lesions during the follow-up period (Figure 3E-G).

DISCUSSION

In our case series, the common characteristics observed across all three cases of AMN following COVID-19 infection included visual symptoms and specific imaging signatures on OCT and NIR imaging. Each case exhibited hyporeflective lesions in the macular region and alterations in the DCP, indicative of ischemic changes. Individual differences in symptom onset post-COVID-19, variable recovery rates, and degree of visual acuity improvement were noted, underscoring the clinical variability of AMN.

The etiology of AMN remains under investigation, as current theories cannot fully account for its diverse clinical manifestations. It is hypothesized that the development of AMN may be linked to ischemic disturbance of the choroidal circulation, particularly within the DCP[7-10]. A review of the literature indicates that AMN may have pathological features similar to conditions that show angular signs of Henle’s fiber layer hyperreflectivity on OCT, such as trauma, central retinal vein occlusion, acute posterior multifocal placoid pigment epitheliopathy, cancer-associated retinopathy, and laser-related retinal damage[11]. Similar to AMN, these conditions are believed to damage photoreceptors and Müller cells through ischemic impact on the choroid or DCP. Taken together, the evidence underscores the complex pathogenesis of AMN. And highlights the need for further study of its ischemic mechanism and the potential influence of systemic conditions such as COVID-19.

Pathological studies have detected the presence of SARS-CoV-2 in the optic nerve, choroid, and retinal tissues, with particular impact on ganglion cells, the IPL, and the OPL[12]. These findings suggest specific tissue affinities, or tropisms of the virus, that may influence the pathogenesis of acute macular AMN commonly associated with viral infection. These tropisms could lead to distinct pathological pathways that result in the retinal impairment observed in AMN. Furthermore, COVID-19 has been associated with microcirculatory disturbance within the retina, characterized by a reduction in microvessel density near the optic nerve and veins, venous occlusion, and preceding hemorrhage linked to venous constriction[12]. The incidence of AMN during the COVID-19 pandemic highlights the adverse effects of the virus on retinal vasculature, and the need for further investigation of the vascular effects of COVID-19 within the ocular sphere to increase our understanding of its role in AMN pathogenesis.

In this study, we observed cases of AMN co-occurring with PAMM, a combination rarely reported in previous literature[13,14]. During the course of the disease, OCT imaging demonstrated recovery of both PAMM and AMN lesions, yet persistent defects in the IZ were noted. This lingering abnormality suggests that the lesions may represent an immune-mediated inflammatory response. The retinal vasculature, with its distinctive hammock-like arrangement and the direct flow of arterial vessels returning to the main veins, plays a crucial role[15]. Specifically, the DCP, which is known to have a low oxygen partial pressure and high hydrostatic pressure, appears especially vulnerable to the initial effects of venous constriction or obstruction, potentially aggravating intermediate capillary plexus. These observations, highlighted by the varied ocular manifestations seen in COVID-19 patients, indicate a diverse immune response to infection. Notably, in some patients who reported monocular visual impairment, comprehensive examination disclosed bilateral lesions, consistent with previous reports of occult infections[16]. This emphasizes the vital importance of performing careful ophthalmological evaluations of patients with COVID-19, even in the absence of ocular symptoms. Such assessments are indispensable for a full understanding of the impact of the virus on ocular health and for the early detection and management of potential complications.

In our cases, initial OCT imaging identified AMN lesions on presentation, but OCTA did not show any concurrent alterations of blood flow in the affected regions. This discrepancy suggests that AMN pathogenesis in COVID-19 infection may involve not only changes in vascular density, but also a direct viral impact on photoreceptors as well as induction of inflammatory vasoreaction. Following the resolution of AMN, we noted reductions in vessel density within the lesion areas that coincided with improvement of vision. These changes persisted in cases of mild infection or for several months after the infection onset. Such findings underscore the enduring impact of COVID-19, consistent with studies that have reported microvascular occlusion without significant dysfunction of major organs like the lungs and kidneys in COVID-19 patients[17]. Microvascular angiopathy, presumed to be triggered by acute endothelial dysfunction and proinflammatory cytokines, might increase the risk of microvascular thrombosis that could lead to multiorgan dysfunction[18]. In addition, postmortem analysis has revealed direct viral damage in organs such as the brain, liver, and kidneys[19-21]. Intriguingly, neurological changes persist for months after recovery from COVID-19 in some patients despite the absence of initial neurological symptoms[22]. This suggests that SARS-CoV-2 infection may impact the metabolism of the outer retina, with reduced energy demands potentially leading to vascular atrophy and similar to changes seen in inherited metabolic disorders like Leber’s hereditary optic neuropathy. The possibility of recurrent infection raises questions about the long-term clinical implications of these findings and emphasizes the need for ongoing monitoring of retinal microvascular changes.

Recent studies have reported an association between COVID-19 vaccination and the onset of AMN, particularly in young women shortly after vaccination[23,24]. The three patients in this report developed AMN symptoms after receiving a COVID-19 vaccine, which supporting an association of AMN with vaccination. The pathogenesis of vaccine-associated AMN is elusive, but it is thought to be related to inflammatory responses that precipitate vascular or thromboembolic events that lead to ischemia in the deep retinal capillary plexus[25]. The proposed mechanism includes molecular mimicry and hypersensitivity reactions that induce microvascular pathology akin to that observed in AMN[26]. Increasing evidence underscores the importance of further investigation of the ocular ramifications of COVID-19 vaccination.

In our case series, the time from COVID-19 infection to the onset of AMN varied, with symptoms appearing from a few days to 1 wk after infection. This variability is in line with the findings of other studies. Masjedi et al[27] reported a 29-year-old woman with AMN symptoms that appeared 2 wk after the initial COVID-19 symptoms and 5 d after a positive SARS-CoV-2 test[27]. Similarly, Macé and Pipelart[28] described a case of AMN that appeared in a 39-year-old woman 2 d after COVID-19 infection was diagnosed[28]. Kovalchuk et al[29] reported a case involving 16-year-old girl who noticed paracentral scotomas about 10 d after experiencing mild COVID-19 symptoms. Giacuzzo et al[30] reported a case involving a 23-year-old woman with AMN following a positive PCR test and systemic symptoms of 2 wk duration[30]. Our cases reported vision loss 1 wk after confirmed COVID-19 in case 1, blurred vision 2 wk after fever and COVID-19 diagnosis in case 2, and ocular symptoms 2 wk after a positive COVID-19 test in case 3. These observations show that AMN can occur at different times during COVID-19 infection, from the acute phase to post-symptomatic recovery, and can involve direct viral effects or an immune-mediated response.

CONCLUSION

In summary, this case series highlights the clinical importance of diagnosing and understanding AMN in the context of COVID-19 infection and vaccination. The observed correlation between COVID-19 and increased incidence of AMN, particularly following vaccination, underscores the need for increased vigilance and diagnostic precision, using imaging modalities such as OCT and NIR. These techniques are invaluable for detecting characteristic lesions and vascular alterations associated with AMN. They are essential for adding to our insight into the pathophysiology and the overarching impact of COVID-19.