Acute Macular Neuroretinopathy (AMN) is a rare retinal disease first reported by Bos and Deutman in 1975. It causes temporary or permanent paracentral visual impairment due to vascular changes in the outer retina.
AMN predominantly affects young women in their 20s to 40s. In the largest series (101 patients, 156 eyes), the majority were white women in their 20s, with bilateral involvement in 54.4% and unilateral in 44.5%. Review data show that 84.2% of patients are women, with a mean age of 29.5 years 3). Prior influenza-like illness or fever is present in 47.5%, and oral contraceptive use in 35.6% 3).
The incidence has increased sharply since the COVID-19 pandemic. A French retrospective study reported that the incidence of AMN rose from 0.66 per 100,000 in 2019 to 8.97 per 100,000 in 2020 4). In a review of 21 cases of AMN after COVID-19 vaccination, 95% were women, 67% were oral contraceptive users, and 90% developed symptoms within 8 days of vaccination 9).
AMN belongs to the group of diseases classified as part of the AZOOR complex, and advances in OCT technology have revealed that the main lesion is located in the outer retina.
Before the COVID-19 pandemic, it was an extremely rare disease. A French study reported an incidence of 0.66 per 100,000 in 2019, but after the COVID-19 outbreak in 2020, it increased approximately 14-fold 4). Case reports continue to be published worldwide, and increased awareness has led to more frequent diagnoses.
The most characteristic symptom of AMN is the sudden onset of a petaloid paracentral scotoma.
In many patients, the paracentral scotoma persists long-term. Partial improvement is observed, but complete resolution is rare. In a long-term follow-up of a 19-year-old male, subjective symptoms and test findings almost completely disappeared 86 days after COVID-19 vaccination, and a good course without recurrence was reported after 366 days 3). On the other hand, in a 70-year-old patient with AMN after dengue fever, severe visual loss persisted even after 5 years 7). Younger patients may recover more easily, but this is not definitive.
Fundus examination often reveals no abnormalities in the early stage. Findings observed at onset are shown below.
Fundus and Anterior Segment
Reddish-brown wedge-shaped or petaloid lesions: Wedge-shaped or petaloid reddish-brown discoloration around the fovea with the tip pointing toward the fovea. Clearly observed under red-free light.
Anterior vitreous inflammation and retinal hemorrhage: Anterior vitreous cell 1+ and perifoveal intraretinal hemorrhage have been reported in post-vaccination AMN cases 8).
Cotton-wool spots: Observed in cases of AMN combined with PAMM after COVID-19 4).
Special examination findings
NIR (near-infrared reflectance) hyporeflective lesions: Wedge-shaped, teardrop-shaped, or petaloid dark gray hyporeflective lesions. One of the most sensitive findings that can detect lesions almost certainly.
SD-OCT outer layer changes: In the acute phase, changes occur in the order of OPL/ONL hyperreflectivity → EZ (ellipsoid zone) disruption → ONL thinning.
VEP abnormalities: Decreased amplitude and prolonged latency have been reported in cases of AMN after COVID-19 1).
In severe cases, visual impairment becomes prominent. In a 70-year-old female patient after dengue fever, best-corrected visual acuity (BCVA) was 20/200 (right eye) and 20/400 (left eye), left eye RAPD positive, and bilateral VEP abnormalities were observed 7). More than 80% of AMN patients maintain visual acuity of 20/40 or better, but exceptionally severe cases exist in elderly patients or after severe systemic infections 7).
The exact etiology of AMN remains unknown. Vascular damage to the deep capillary plexus (DCP) or choriocapillaris is considered the main pathophysiological mechanism.
The main risk factors and triggers are listed below.
Comparative epidemiological data between COVID-19-associated AMN and non-COVID-19 triggers are shown below.
| After COVID-19 infection | After COVID-19 vaccination | |
|---|---|---|
| Number of cases (review) | 36 cases2) | 21 cases9) |
| Mean age | 35.5±15.7 years2) | 24.8±4.8 years |
| Female proportion | 69%2) | 95%9) |
| Bilateral involvement | 72% (26/36 cases)2) | 35.7%3) |
| Time to onset | Mean 12.1 ± 26.6 days2) | Mean 3.1 ± 2.4 days |
Since the COVID-19 pandemic, AMN after infection or vaccination has been reported worldwide, and the incidence has increased dramatically4). However, the absolute risk remains extremely low. In a review of 21 post-vaccination cases, 90% developed symptoms within 8 days after vaccination9). Oral contraceptive users are considered to require particular caution.
AMN is often missed on routine fundus examination or FA, and specialized imaging equipment is essential for diagnosis.
The main imaging modalities are summarized below.
NIR
Features: Clearly depicts wedge-shaped or teardrop-shaped dark gray hyporeflective lesions.
Diagnostic sensitivity: The most important initial test that can detect lesions even in eyes with normal fundus.
Course: Lesions shrink and disappear with healing3).
SD-OCT
Initial findings: Hyperreflectivity in OPL/ONL, disruption of EZ/IZ.
Chronic findings: Thinning of ONL, often residual indistinct EZ/IZ.
Significance: Allows objective assessment of the degree of outer retinal damage and its recovery over time3).
OCTA
Acute phase: Detects decreased DCP flow signal. Some cases show normal initial findings but later progression of decrease4).
Significance: Noninvasively visualizes microcirculatory disturbances in the DCP. Also useful for differentiation from PAMM.
The main diseases that require differentiation from AMN are as follows.
| Disease | Key differentiating features |
|---|---|
| PAMM | INL damage, intermediate DCP occlusion. Concurrent cases are increasing4) |
| MEWDS | Multiple white dots. Garland staining on FA |
| APMPPE | RPE and choriocapillaris lesions. Early hypofluorescence on FA |
| CSCR | Neuroepithelial detachment. Serous exudation on FA |
| Optic neuritis | RAPD positive. Characteristic changes on VEP and visual field |
NIR and SD-OCT are the most important tests. Lesions are often not visible on routine fundus examination or FA, so evaluation at a facility capable of these imaging studies is essential. In some cases, OCTA may be normal initially but later show progressive decrease in DCP vessel density4), so longitudinal assessment is recommended.
There is no established treatment for AMN, and observation is the mainstay. Many cases show partial improvement with natural course.
Outer retinal lesions often persist as ONL thinning and EZ/IZ disruption, and paracentral scotoma persists long-term in most cases. In a 19-year-old male case, improvement of EZ discontinuity began 30 days after COVID-19 vaccination, almost disappeared by day 86, and complete normalization was confirmed at day 3663).
There is no established indication, but use has been reported in some cases. It may be considered when exudative findings or inflammation are prominent.
Reported administration examples are shown below.
None of these provide definitive evidence of steroid efficacy, and it is difficult to distinguish from spontaneous recovery.
Because oral contraceptives may contribute to microvascular endothelial dysfunction, discontinuation is recommended after AMN onset6)8).
There is no established treatment, and observation is the mainstay. Several cases of steroid administration have been reported, but it is difficult to distinguish from spontaneous recovery, and efficacy has not been proven. If oral contraceptives are being used, discontinuation is recommended6)8). In young patients, spontaneous recovery may occur within a few months3).
The pathophysiology of AMN centers on microcirculatory disturbance of the choriocapillaris (DCP), which supplies nutrients to the outer retina.
SD-OCT findings show a stepwise progression: acute OPL/ONL hyperreflectivity, followed by disruption of the EZ (IS/OS boundary) and IZ (COST line), and finally ONL thinning and photoreceptor loss. OCTA analysis reveals decreased blood flow signal in the DCP, while the intermediate capillary plexus (ICP/SCP) is usually preserved, showing a distribution opposite to that of PAMM (paracentral acute middle maculopathy). The DCP is thought to supply about 10% of the nutrition to the photoreceptor layer, and DCP microcirculatory impairment is directly involved in the onset of AMN.
SARS-CoV-2 binds to ACE2 receptors on the choroidal medium and large vessels and the choriocapillaris, causing direct vascular damage 2). This is thought to lead to acute choroidal blood flow stasis followed by outer retinal ischemia. Studies using LSFG (laser speckle flowgraphy) have measured decreases in macular blood flow velocity (MBR), choroidal thickness (CCT), luminal area (LA), and stromal area (SA) in the acute phase, with gradual increases in the chronic phase 2).
Mitamura et al. (2023) quantitatively evaluated choroidal circulation changes from the acute to chronic phase (20 weeks later) in a case of post-COVID-19 AMN (24-year-old female) using LSFG and choroidal OCT binarization. MBR recovered by 20.4% in the right eye and 29.6% in the left eye; CCT increased by 13.6% in the right eye and 16.1% in the left eye. Luminal area (LA) also showed marked improvement, increasing by 12.6% in the right eye and 14.2% in the left eye 2). This is the first report of quantitative evaluation of choroidal circulation in post-COVID-19 AMN.
Furthermore, SARS-CoV-2 has been detected histologically in the optic nerve, choroid, and retinal tissue (especially in the ganglion cell layer, IPL, and OPL), suggesting that direct viral invasion of photoreceptors and inflammatory vascular reactions may also contribute to the onset 4).
A mechanism involving immune complex deposition due to dengue virus, leading to capillary endothelial defects and collecting venule occlusion, followed by choriocapillaris ischemia has been proposed 6). The prevalence of dengue maculopathy is reported to be 10% among hospitalized patients, and more than half of these cases show AMN findings 6).
In post-COVID-19 AMN, cases with combined AMN and PAMM, presenting with OPL hyperreflectivity, EZ/IZ hyporeflectivity, and INL hyperreflectivity, are increasing 4). This suggests a broader panretinal circulatory impairment caused by SARS-CoV-2.
The COVID-19 pandemic dramatically changed the epidemiology of AMN. According to a French retrospective study, the incidence of AMN increased approximately 14-fold from 0.66 per 100,000 in 2019 to 8.97 per 100,000 in 2020 4). In a review of 36 post-COVID-19 cases (mean age 35.5±15.7 years, 69% female), about 72% were bilateral 2), and the proportion of severe cases was higher compared to non-COVID-19-related AMN.
Conventionally, OCTA in the acute phase of AMN was often considered within normal limits. However, in multiple post-COVID-19 AMN cases, even when initial OCTA was normal, a progressive decrease in DCP vessel density was confirmed 1 to 6 months later 4). This indicates the limitations of OCTA alone for acute-phase evaluation and suggests the need for regular long-term follow-up.
Bi et al. (2024) reported three cases of post-COVID-19 AMN in which DCP vessel density progressively decreased at 1 month and 6 months after onset, even though OCTA was normal at onset 4). On the other hand, visual acuity (VA) normalized in 2 to 6 months in some cases, indicating that visual improvement does not necessarily correlate with OCTA findings of the outer retina.
The combination of LSFG (laser speckle flowgraphy) and OCT binarization method is attracting attention as a new technique for quantitative evaluation of choroidal circulation in AMN. Mitamura et al. (2023) applied these methods longitudinally in a single case of post-COVID-19 AMN and succeeded for the first time in quantifying choroidal circulatory impairment in the acute phase and its recovery process in the chronic phase 2).
Regarding the causality of post-COVID-19 vaccine AMN, evaluation using the Naranjo adverse drug reaction probability scale yielded a score of 7 (probable) 9), indicating progress in objective causality assessment.
In a literature review by Fekri et al. (2023) (21 cases), the breakdown by vaccine type was 57% recombinant (AstraZeneca, J&J), 29% mRNA (Pfizer, Moderna), and 9% inactivated (Sinopharm), suggesting that AMN can occur with all vaccine types 9). The time to symptom resolution ranged from 4 to 15 weeks or more.
In a 19-year-old male with post-COVID-19 vaccine AMN, complete clinical recovery at 86 days and no recurrence at 366 days were confirmed 3), indicating that good long-term prognosis can be achieved even in young males. However, in a 70-year-old patient with post-dengue AMN, severe visual impairment remained after 5 years 7), highlighting the challenge of large differences in prognosis depending on age, underlying disease, and pathogenesis.
Vu TA, Schillerstrom M, Mancha S, Sponsel WE. COVID-19 Related Acute Macular Neuroretinopathy (AMN): A Case Series. Int Med Case Rep J. 2023;16:491-496.
Mitamura M, Kase S, Hirooka K, Endo H, Ito Y, Ishida S. Choroidal Circulatory and Vascular Morphological Changes in Acute Macular Neuroretinopathy After Infection With Severe Acute Respiratory Syndrome Coronavirus 2: A Case Report With Literature Review. In Vivo. 2023;37(6):2869-2876.
Ikema S, Miura G, Shimizu D, Baba T. Long-term follow-up of a young male who developed acute macular neuroretinopathy following COVID-19 vaccination. Clin Case Rep. 2023;11(11):e8181.
Bi C, Huang CM, Shi YQ, Huang C, Yu T. Acute macular neuroretinopathy following COVID-19 infection: Three case reports. World J Clin Cases. 2024;12(25):5775-5783.
Dröke D, Pleyer U, Hoerauf H, Feltgen N, Bemme S. Acute macular neuroretinopathy (AMN) following COVID-19 vaccination. Am J Ophthalmol Case Rep. 2021;24:101207.
Guardiola GA, Villegas VM, Cruz-Villegas V, Schwartz SG. Acute macular neuroretinopathy in dengue virus serotype 1. Am J Ophthalmol Case Rep. 2022;25:101250.
Translateur A, Perez-Rueda M. Acute macular neuroretinopathy associated to dengue disease. Am J Ophthalmol Case Rep. 2022;26:101474.
Rennie AT, DeWeerd AJ, Martinez MG, Kay CN. Acute Macular Neuroretinopathy Following COVID-19 mRNA Vaccination. Cureus. 2022;14(7):e27502.
Fekri S, Khorshidifar M, Dehghani MS, Nouri H, Abtahi SH. Acute macular neuroretinopathy and COVID-19 vaccination: Case report and literature review. J Fr Ophtalmol. 2023;46(1):72-82.
