Acute macular neuroretinopathy and COVID-19 infection.

Acute macular neuroretinopathy (AMN) and coronavirus disease 2019 (COVID-19) infection both have been shown to be associated with microvascular ischemia. We present 25 eyes in 15 patients who have coinciding diagnoses of AMN and COVID-19.

Report

Acute macular neuroretinopathy (AMN) is a rare, poorly understood retinal disease that most commonly occurs in young, healthy women. The most commonly proposed pathogenesis is ischemia of the deep capillary plexus, and it is often associated with a preceding respiratory or influenza-like illness.

The novel coronavirus disease 2019 (COVID-19) has been reported to affect various segments of the eye and a report of 12 adults with COVID-19 infection showed subtle cotton wool spots and micro hemorrhages pointing to vascular damage in these patients.

More recently, cases of AMN have been reported to be associated with COVID-19. Fourteen cases of presumed COVID-19-associated AMN have previously been published. A summary of these studies can be found in Table S1 (available at www.ophthalmologyretina.org). We aim to expand upon these cases with our series.

This was an Institutional Review Board approved retrospective case series from eight referral centers from November 2020 to June 2022. Patients were included if they were clinically diagnosed with AMN with concurrent symptomatic COVID-19 infection confirmed by PCR or antigen testing. Multimodal imaging including OCT, optical coherence tomography angiography (OCTA), fluorescein angiography (FA), indocyanine green angiography (ICGA) were obtained at each clinician’s best clinical judgment.

Twenty-five eyes from 15 patients were included. Table 1 summarizes their demographics and clinical presentations. The majority of patients were female (80%) and the mean age was 24 years (SD: 7.7 years). Ten patients (67%) had bilateral disease. All patients presented with paracentral scotomata, and four patients (27%) also presented with headache. All patients were diagnosed with the support of near-infrared reflectance with characteristic perifoveal, petaloid shaped areas of hyporeflectance and/or OCT with disruption of outer retinal architecture. Thirteen patients (87%) had a normal fluorescein angiogram. Of the five patients (33%) who had OCTA, two of them had positive findings consisting of flow voids to the deep capillary plexus (Table 1, Case 10) or choriocapillaris (Table 1, Case 11); the former is displayed in Figure S1 (available at www.ophthalmologyretina.org). Three patients (20%) had ICGA, which were unremarkable. Fourteen patients (93%) had symptoms of COVID-19 within two days of the onset of symptoms of AMN. On presentation, visual acuity on presentation was excellent (better than 20/25) in 21 eyes (84%).

Table 1

Cases of acute macular neuroretinopathy

Case	Age (years)	Sex	Symptoms	Timing of ocular symptoms*	Past medical history	Laterality	VA OD	VA OS	Imaging obtained	Notes
1	24	Female	Blurry vision, scotomas	2 days after	Undifferentiated connective tissue disease on hydroxychloroquine	OS	20/20	20/20	OCT, OCTA, FA	Persistent scotomas after 1 year
2	11	Female	Blurry vision, redness, photophobia	Same day	None	OU	20/40	20/50	OCT, FA	Concurrent undifferentiated panuveitis with negative work-up; resolved with systemic steroids and immunosuppression‡
3	19	Female	Bilateral central gray scotomas	14 days after	Ovarian cyst on oral contraceptive pills	OU	20/125	20/450	OCT, OCTA, FA, ICGA	Treated with systemic steroids
4	20	Female	Blurry vision, scotomas	Same day	None	OU	20/20	20/20	OCT
5	22	Female	Scotoma, photopsias	1 day before	Type 1 diabetes mellitus	OU	20/20	20/25	OCT, FA	Persistent scotomas
6	32	Female	Scotomas	Same day	None	OS	20/20	20/20	OCT, FA
7	30	Male	Scotomas	Same day	None	OD	20/20	20/20	OCT, FA, ICGA
8	23	Female	Headache, scotomas	2 days after	None	OU	20/20	20/20	OCT, FA,
9	41	Female	Headache, scotomas	Same day	Migraines	OS	20/20	20/20	OCT, FA
10	20	Male	Scotomas	Same day	Seasonal allergies	OU	20/20	20/20	OCT, OCTA, FA	Subjective and OCT improvement after 3 months
11	13	Female	Headache, scotomas	Same day	Sensory processing disorder	OU	20/20	20/20	OCT, OCTA, FA, ICGA	Resolved scotomas within 1 month
12	32	Male	Scotomas	Same day	None	OU	20/20	20/20	OCT, FA
13	21	Female	Scotomas	1 day before	Oral contraceptive pills	OU	20/20	20/20	OCT, FA
14	21	Female	Vomiting, scotomas	1 day after	Oral contraceptive pills	OU	20/25	20/25	OCT, OCTA, FA
15	26	Female	Headache, scotomas	Same day	None	OS	20/20	20/20	OCT	Subjective improvement after 2 months
Average	24 (SD: 7.7)	80% female		1 day after (SD: 4 days)		67% bilateral
Previously reported cases
Azar et al7	28	Female	Scotomas	Not reported	Not reported	OU	20/20	20/20	OCT, OCTA	OCTA showed slight deep capillary plexus attenuation
	27	Female	Scotomas	Not reported	Not reported	OU	20/16	20/16	OCT, OCTA
	22	Female	Scotomas	Not reported	Not reported	OD	20/20	20/20	OCT, OCTA
	21	Male	Central scotomas	Not reported	Not reported	OD	20/2000	20/20	OCT, OCTA
Aidar et al8	71	Female	Blurry vision	14 days before	None	OS		20/63	OCT, FA	Persistent scotomas after 2 months
David et al9	22	Female	Scotomas, headache	Same day	Oral contraceptive pills	OU	20/20	20/20	OCT, OCTA, FA, ICGA	Subjective and OCT improvement after 6 months
Gascon et al10	53	Male	Scotomas	Not reported	None	OS		20/63	OCT, VF	Improved to 20/32 after 2 weeks
Giacuzzo et al11	23	Female	Scotomas, photopsias	2 weeks after	None	OU	20/20	20/20	OCT, FA	Concomitant Herpes Simplex infection
Jalink et al12	29	Female	Scotomas	5 months after	Hormonal intrauterine device	OS			OCT, VF	2 vaccine doses
	21	Female	Scotomas, photopsias	6 weeks after	Oral contraceptive pills	OD			OCT, VF
Masjedi et al13	29	Female	Scotomas	2 weeks after	None	OS			OCT
Preti et al14	70	Male	Scotomas, diaphoresis	4 days after	None	OS	20/20	20/100	OCT	Near complete recovery on OCT
Virgo et al15	32	Male	Scotomas	16 days after	Acephalgic visual migraine aura	OD			OCT
Zamani et al16	35	Female	Scotomas	9 days before	Acute myeloid leukemia on chemotherapy	OD	20/20	20/20	OCT
Average of previously reported cases	35 (SD: 17)	71% female		33 days after (SD: 54 days)		29% bilateral
Composite†	39 (SD: 14)	76% female		10 days after (SD: 32 days)		48% bilateral

* Timing refers to ophthalmologic onset of symptoms relative to positive COVID-19 symptoms.

† The composite row combines this case series with previously reported cases.

‡ Infectious and inflammatory work-up included negative lab work for the following: fluorescent treponemal antibody test absorption test, rapid plasma reagin, QuantiFERON gold, angiotensin converting enzyme, lysozyme, Bartonella immunoglobulin (Ig) G and IgM, toxoplasmosis IgG, human leukocyte antigen-B27, antineutrophil cytoplasmic antibodies, and urine beta 2 macroglobulin. This patient’s visual acuity improved to 20/25 OU after therapy with one milligram per kilogram transitioned to methotrexate.

VA: Visual acuity, OD: Right eye, OS: Left eye, OU: Both eyes, OCT: Optical coherence tomography, OCTA: Optical coherence tomography angiography, FA: Fluorescein angiography, ICGA: Indocyanine green angiography, VF: Visual field.

AMN is most easily identified by wedge-shaped parafoveal lesions on near-infrared imaging. It may be unilateral or bilateral. There are characteristic OCT findings of outer layer hyperreflectivity that start in the outer plexiform layer. , These classic findings may be found in Figure S2 (available at www.ophthalmologyretina.org). Over time, the outer retinal layers thin, and disruption occurs to the outer segments and retinal pigment epithelium. There are also thought to be OCTA findings consistent with flow voids in the choriocapillaris or the deep capillary plexus. When present, these flow voids on OCTA correspond to the wedge-shaped lesions on near infrared imaging, but OCTA changes are not always detected. In our series, half of the patients who received OCTA had positive flow voids in the deep capillary plexus or choriocapillaris. Clinical associations with AMN include preceding flu-like illness, hormonal oral contraceptive pills (OCPs), antecedent trauma, caffeine, injection of epinephrine and pseudoephedrine, hypovolemia, and pregnancy induced hypertension. The disease course usually lasts weeks to months with diverse outcomes, ranging from persistent scotomas to complete visual recovery.

In our series, two patients presented with decreased visual acuity. One 11-year-old patient (Table 1, Case 2) presented with decreased visual acuity to 20/125 in both eyes and was concurrently diagnosed with panuveitis. Because this patient had 4+ anterior chamber cell and her AMN lesions spared the fovea, it is more likely that the initial decreased visual acuity was due to panuveitis rather than the AMN component. The second patient with decreased visual acuity was a 19-year-old (Table 1, Case 3) female who was taking OCPs. She presented two weeks after positive COVID-19 testing with central scotomas. Her visual acuity was 20/125 in the right eye and 20/450 in the left eye. After stopping her OCPs, she was managed with 30 milligrams of prednisone. By one week, her visual acuity had improved several lines, and by three months, her visual acuity was 20/25 in both eyes. Multimodal imaging can be found in Figure 1 . These images display a partial reconstitution of the outer retinal architecture.

Figure 1

Multimodal imaging of the right eye from a 19-year-old female (Table 1, Case 3). A) NIR showing superior and inferior wedge-shaped lesions. B) OCT showing subfoveal outer retinal layer disruption. C) OCTA without any apparent regions of flow void. D) NIR at 3 months after presentation. E) OCT at 3 months after presentation with reconstitution of areas of previous ellipsoid zone disruption.

Bilateral disease occurred in 67% of patients at presentation. This is in contrast to a large review of 156 eyes with AMN from 2016, which found 54% of cases to be bilateral. The higher rate of bilateral disease in COVID associated cases relative to previously reported cases could point to a greater predisposition for AMN in COVID patients than in other conditions.

The etiology of AMN is unconfirmed. One theory is that microvascular ischemia of the choriocapillaris leads to hypoxic insult to the middle and outer retinal layers. This mechanism is particularly pertinent with recent reports of microthrombi found in COVID-19 patients. Nearly 50% of patients in a Dutch intensive care unit with COVID-19 had computed tomography confirmed thrombotic complications. It is possible that COVID-19 thromboses along with vasoconstriction due to cell mediated stressors contributed to the pathophysiology of microvascular ischemia.

This case series is limited by the number of patients as well as the presence of concurrent risk factors for AMN. However, the association is strengthened by the short time frame between onset of ocular symptoms and diagnosis of COVID-19 in these cases. Because of the rarity of AMN, it is difficult to assess whether the incidence of AMN has truly increased during the COVID-19 pandemic. Azar et al. noted an increase in diagnosis of AMN from 0.66 per 100,000 visits in 2019 to 8.97 per 100,000 visits in 2020 during the height of the pandemic. This finding in addition to the increasing number of case reports citing an association between AMN and COVID-19 both support the association.

This is the largest case series to date and certainly suggests a possible association between AMN and COVID-19 infection. Further investigation will be important to determine if there is a causative link between AMN and COVID-19.

Figure Supplement 1. Multimodal imaging of the left eye in a 13-year-old male (Table 1, Case 11). A) NIR showing superior and inferonasal lesions. B) OCT showing outer layer disruption corresponding to lesions on NIR. C,D) OCTA of the superficial and deep inner retina with no apparent flow voids. E,F) OCTA of the outer retina and choriocapillaris with flow voids in areas corresponding to NIR lesions.

Figure Supplement 2: Near infrared (NIR) and OCT imaging of the right (A) and left (C) eyes at presentation and two-month follow-up (B,D) in a 22-year-old female (Table 1, Case 5). A,C) NIR reveals dark petaloid lesions surrounding the fovea in both eyes, corresponding with areas of ellipsoid zone disruption and outer nuclear layer thinning on the OCT (green arrows). B,D) Repeat OCT scans 2 months later show only a slight reduction in these findings.