Acute zonal occult outer retinopathy (AZOOR) complex associated with torpedo retinopathy following COVID-19 recombinant mRNA vaccination: a case report of a rare clinical presentation

Abstract

Background

While vaccination remains crucial in mitigating the impact of the COVID-19 pandemic, several ocular adverse events has been reported, including Acute Zonal Occult Outer Retinopathy (AZOOR) complex.

Case presentation

A 31-year-old female presented declined best corrected visual acuity (BCVA) and flashes in both eyes three days following second recombinant mRNA COVID-19 vaccine (Moderna). Fundus autofluorescence (FAF) illustrated speckled hyper-AF lesions surrounding right eye torpedo maculopathy site and hyper-AF lesions in the left macula. The spectral-domain optical coherence tomography delineated inner and outer segment (IS/OS) line disruption; hyperreflective deposits in the outer nuclear layer (ONL); and undetectable interdigitation zone (IDZ). Her BCVA further declined after 3-month observation, thus she received 8-month oral prednisolone and mycophenolate mofetil treatment. Her BCVA recovered; the hype-AF lesions resolved; and the IS/OS line and ONL resumed.

Conclusions

We present a rare case of AZOOR complex following COVID-19 vaccination inciting from torpedo retinopathy where outer-retinal barrier breaks down.

Background

Although vaccine-associated uveitis is relatively rare, a few reports have indicated the importance of adverse ocular effects following severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccines and its booster shots. Singh et al. reported that anterior uveitis being the most common (44.1%) non-infectious uveitis event following second recombinant mRNA vaccine (Moderna), followed by panuveitis (10%) and posterior uveitis (4.1%) [1]. Among the ocular inflammatory events, cases of acute zonal occult outer retinopathy (AZOOR) have been reported in several multicenter studies [2, 3].

The AZOOR complex, first described by Gass in 1992, is usually presented with a trizonal pattern of the ellipsoid zone or interdigitation zone disruption [4], indicating a photoreceptor disease. The exact cause of AZOOR complex remains unclear, but it is possibly linked to prior infections, autoimmune conditions [5], or vaccinations. To our best of knowledge, no other report has described AZOOR being associated with torpedo retinopathy. We herein present a rare case of a patient developing AZOOR complex following second dose of the COVID-19 vaccine from torpedo maculopathy site, where the outer-retinal barrier breakdown was not related to autoimmune disease.

Case presentation

A 31-year-old healthy female with a history of myopia (-6 diopter) and prior Laser Assisted in Situ Keratomileusis surgery, was noted to have a torpedo maculopathy temporal parafoveally in the right eye (Fig. 1a).

Fig. 1

Fundus photography of both eyes. a: Fundus photography 5 years ago before the Laser Assisted in Situ Keratomileusis (LASIK), showing a torpedo maculopathy adjacent to the right fovea. b: Fundus photography of right eye at the first visit. Greyish-white dots are noted around the torpedo maculopathy area (white arrowhead). c: Fundus photography of left eye at the first visit

She noticed a decline in best corrected visual acuity (BCVA), intermittent flashes and a new focal central scotoma in the right eye three days following her second recombinant mRNA vaccine (Moderna). Three months later, she was referred for medical aid. No other ocular symptoms such as tearing, pain, redness, or eye movement problem were noted. The patient was a non-smoker and had no allergy history. She denied having any systemic diseases, including diabetes mellitus, hypertension and cardiovascular diseases. No night sweats, cough, headache, skin rashes, prior viral prodromes, or family history of autoimmune diseases was reported.

On examination, her BCVA was hand motion in the right eye and 30/50 in the left eye. Fundus examination revealed a few greyish-white dots confluent at the level of retinal pigment epithelium (RPE) around the torpedo maculopathy in the right eye (Fig. 1b), and normal in the left eye (Fig. 1c). The spectral-domain optical coherence tomography (SD-OCT) showed normal retinal layers of the left eye (Fig. 2a-c), whilst the right eye illustrated inner and outer segment (IS/OS) line disruption with hyperreflective deposits in the outer nuclear layer (ONL), hazy and disrupted external limiting membrane (ELM), and undetectable interdigitation zone (IDZ) (Fig. 2d-f). Fluorescein angiography (FAG) showed RPE staining with subtle mid-phase leakage at torpedo maculopathy site in the right eye (Fig. 3a), and it was surrounded by hypo-fluorescent spots in late phase on indocyanine green angiography (ICGA) exam (Fig. 3b). Fundus autofluorescence (FAF) illustrated speckled hyper-AF lesions around the torpedo maculopathy in the right eye (Fig. 3c) and normal in the left (Fig. 3d).

Fig. 2

Infrared (IR) fundus image and Spectral-domain optical coherence tomographic (SD-OCT) exam of left eye (a-c) and right eye (d-f). a, d: IR fundus images at the first visit. b: Magnified view of the area in the image of (c) outlined by yellowish dashed line. c.f: Spectral-domain optical coherence tomographic (SD-OCT) exam in the left (c) and right eye (f) at the first visit. e: Magnified view of the area in the image of (f) outlined by yellowish dashed line, revealing columnar inflammatory deposits in outer retinal area (red arrow), fuzzy and disrupted External limiting membrane (ELM, yellow arrow), and disrupted ellipsoid zone (EZ) and interdigitation zone (IDZ), blue arrow

Fig. 3

Fundus fluorescein angiography (FAG), indocyanine green angiography (ICGA) and fundus autofluorescence (FAF) images at initial visit (a, b, c, d) and at 7-month follow-up (e.f). a, f: FAG at 3 min illustrated a window defect and subtle leakage at the old macular scar (a) which resolved 7 months later (f). b: ICGA at 15 min at the first visit showed hypocyanine spots around torpedo maculopathy site. c: FAF image of the right eye at the first visit (c), and at seven months later (e). The hypo-autofluorescence lesions at torpedo maculopathy site were surrounded by blue arrowhead. The speckled hyper-autofluorescence around the torpedo maculopathy area (surrounded by yellow arrowhead) shrunk 7 months later (e). However, the hypo-AF areas were slightly enlarged (blue arrowhead). d: FAF image of the left eye at the first visit (d)

Laboratory surveys including hematology test, biochemistry examination, autoimmune workup (ANA and rheumatic factor), QuantiFERON gold test and rapid plasma regain (RPR), ESR and CRP were within normal range. Thus, syphilis, Mycobacterium tuberculosis uveitis, and autoimmune retinopathy were ruled out. Although the image didn’t present the typical trizonal appearance of AZOOR, there were no wreath-like hyperfluorescence dots characteristic of MEWDS. In addition, there were also no punched-out multifocal choroiditis lesions presented on ICGA images. The diagnosis of AZOOR complex was established by exclusion. Initially, we kept the patient under observation. However, after three months of observation, the patient reported a further decline in visual acuity. Thus, she was treated with 8-month of oral prednisolone and mycophenolate mofetil. Her BCVA recovered to 40/50 in the right eye. The speckled hyper-AF area was shrunk by 79%, which was calculated with ImageJ (Fig. 2e). FAG at 3 min showed resolved window defect (Fig. 3f). On FAF images, the hyper-AF lesions faded, but the hypo-AF spots persisted with slightly enlarged in size and encroaching fovea in the right eye (Fig. 2d). The hyper-reflective dots in ONL resolved. The ELM and IDZ were partially recovered, but slightly hazy (Fig. 4a-c).

Fig. 4

Infrared (IR) fundus image and Spectral-domain optical coherence tomographic (SD-OCT) exam (a, b, c) in the right eye at seven months of follow-up and Humphrey visual field 30 − 2 examination (d, e). a: Infrared (IR) fundus image at seven months later. b: Magnified view of the area in the image of (c) outlined by yellowish dashed line. At 7 months of follow-up, the ELM was continuous and prominent, the EZ line was slightly disrupted (blue arrow), and the IDZ line was still not prominent. c: SD-OCT image at seven months later. d: Humphrey visual field 30 − 2 examination at the first visit. e: Humphrey visual field 30 − 2 examination at 7 months later. The mean visual field loss improved from − 4.42 ± 5.87 dB at initial visits (d) to -3.38 ± 2.36 dB at the final visit (e). The nasal superior visual defect was improved at 7 months later

Despite BCVA recovery, the patient described a persistent central scotoma in her right eye (Fig. 4d-e). The initial visual field defect demonstrated on Humphrey visual field (HVF) 30 − 2 test was presented over the superior nasal quadrant with central scotoma in the right eye (Fig. 4d). After treatment, the visual field defect was improved but some central VF defect remained (Fig. 4e), which was compatible to the FAF findings (Fig. 3e). The mean visual field loss improved from − 4.42 ± 5.87 dB at the initial visit to -3.38 ± 2.36 dB at the final visit.

Discussion

While most individuals experience no significant ocular complications after COVID-19 vaccination, there have been sporadic reports of ocular inflammatory adverse events [1]. The possible mechanisms include molecular mimicry between vaccine peptide fragments and uveal self-peptides, delayed-type hypersensitivity with immune complexes deposition, and an immune reaction to vaccination adjuvants [6]. The onset of AZOOR in our patient aligned with the time frame identified for potential vaccine side effects. Moreover, the patient did not have a history of these ocular conditions before vaccination, which further implies a possible cause-and-effect relationship.

It has been reported that AZOOR could be precipitated by previous uveitis episode, such as multiple evanescent white dot syndrome (MEWDS) and punctate inner choroidopathy (PIC) [7, 8]. Fine et al. reported a case of AZOOR inciting from prior MEWDS scar area [8]. This may be resulted from common genetic susceptibility and/or pathogenetic factor of these two entities. Aside from MEWDS, PIC is also hypothesized to share common genetic or immunologic background with AZOOR [7]. Similar to AZOOR, both PIC and MEWDS occur predominantly in young women and may be associated with zones of unexplained visual field loss and reduced electroretinographic amplitudes. Due to the overlap of the features of these entities, Gass hypothesized them to be part of the spectrum of a single disorder, naming it as AZOOR complex [9]. Uveitis is usually the first diagnosis of exclusion from torpedo maculopathy [10]. However, incidental reports of torpedo maculopathy have been reported in patients with keratoconus and tuberous sclerosis [11, 12]. The peculiar instance in our presented case, where the AZOOR complex incited from a previous non-inflammatory scar at the torpedo maculopathy site, further unveils the intricate connections between AZOOR and outer retinal-barrier defect.

In considering the natural course of AZOOR, 73% patients had spontaneous remission within 6 months, while a few patients (4%) may experience gradual deterioration with the progression of the disease. Furthermore, 31% patients had recurrent episodes with a median time of 39 months from the first onset in Gass’ study [5]. There is currently no optimal treatment guideline for AZOOR, but for mild instances where central visual acuity or visual field remains unaffected, it is reasonable to consider observation with frequent follow-ups to assess disease progression. On the other hand, If AZOOR threatens central visual acuity or visual field, steroid therapy should be considered [13]. Saito et al. reported good vision outcome in patients with progressive visual impairment after systemic corticosteroid therapy (P = 0.007) [14]. In our case, the outer retinal disorganization progressed within the first 3 months of onset. Despite our patient demonstrating a fair recovery following oral prednisolone and mycophenolate mofetil treatment, the torpedo maculopathy scar area was enlarged at the final visit comparing to before this AZOOR episode. Close monitoring and prompt intervention may be beneficial for such cases.

Conclusions

AZOOR complex is possibly associated with outer blood-retinal barrier breakdown related to autoimmune disease and viral infection. The case demonstrated that the mRNA vaccine could also trigger an immune response by initiating AZOOR from RPE defect area irrespective to immunogenic, further emphasizing the importance of awareness in ophthalmologic evaluation of individuals reporting ocular disturbances post-vaccination.