Since the COVID-19 pandemic in November 2019, over 757 million confirmed cases and over 6.8 million deaths have been reported around the world12. SARS-CoV-2 infects host cells through the transmembrane spike protein (S protein), which in turn infects human endothelial cells with ACE2 as its receptor, so tissues with ACE2 receptors are susceptible to SARS-CoV-2 infection13. ACE2 is widely expressed in endothelial cells of the lung, blood vessels, heart, kidney, small intestine and other tissues and organs, with a small amount of expression in the liver and nose. The above organs are vulnerable to damage after infection with SARS-CoV-214, 15. Moreover, ACE2 is a major converting enzyme in the vascular protective axis of the renin-angiotensin system in the retina, and its downregulation may lead to retinal ischemia, which is related to microangiopathy, retinitis, and retinal degeneration15–17.
Previous literature has reported retinal and choroidal manifestations that may be associated with SARS-CoV-2 as shown in Table 2. Depending on the pathological mechanism, we classify it as noninfectious or infectious. Noninfectious manifestations may be related to ischemia or inflammation. RVO and RAO are common diseases in ophthalmology, and patients often have underlying diseases such as diabetes and hypertension18, 19. Therefore, these diseases were not included in our case series as fundus lesions related to SARS-CoV-2. However, uncommon eye diseases such as AMN and ROCM have increased in incidence alongside the rise in SARS-CoV-2 infection rates20, 21.
Tabel.2 Retinal and choroidal manifestations in patients after SARS-CoV-2 infection
Type of the manifestations | Clinical findings / Disease |
No-infectious | Retinal vein occlusion (RVO)14, 15 Retinal artery occlusion (RAO)16 Purtscher-like retinopathy17 Cotton-wool spots18 Isolated hemorrhages19 | |
| Acute macular neuroretinopathy (AMN)20 Paracentral acute middle maculopathy (PAMM)21 Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)22 Multiple evanescent white-dot syndrome (MEWDS)* Serpiginous choroiditis (SC)23 Optic neuritis (ON)24 Vogt-Koyanagi-Harada syndrome-like uveitis25 Central serous chorioretinopathy (CSCR)26 | |
Infectious | Endogenous endophthalmitis (Bacterial / Fungal)27 Acute retinal necrosis (ARN)28 Rhino-orbital-cerebral mucormycosis (ROCM)29 | |
4. 1 Acute macular neuroretinopathy (AMN) and Purtscher or Purtscher-like retinopathy
We observed this case series with SARS-CoV-2-related retinal and choroidal manifestations. Typically, the patient was a young woman who developed visual impairment two days following the onset of infection symptoms. As the standard, with the relationship of cause, trigger and disease, our results suggested a close relationship between the emergence of AMN or Purtscher or Purtscher-like retinopathy and SARS-CoV-2 infection.
AMN is a relatively rare disorder involving transient or permanent central or paracentral scotomas39. It is characterized by dark, reddish-brown macular lesions and corresponds precisely to visual field abnormalities40. AMN has been reported to occur in several different clinical settings. The majority of patients are women in their reproductive years who develop symptoms in association with oral contraceptives, hypotension, viral illness, intravitreous injection, vaccination and sympathomimetic agents (epinephrine, caffeine).3, 41–47. Since the syndrome was initially characterized by Bos and Deutmann48 in 1975, the pathophysiology of AMN has been the subject of intense discussion, especially in light of the disorder's diverse causes.
Acute retinal lesions are characterized by faint retinal translucency on bio microscopy and hyperreflectivity in the outer plexiform and outer nuclear layers on OCT. FFA and ICGA do not reveal any retinal or choroidal vascular leakage, perfusion deficits or transmission defects. mfERG testing shows reduced amplitudes within the scotomatous areas49. Evolution of macular lesions is characterized by resolution within several days of the initial retinal translucency and hyperreflectivity, followed by the development of reddish-brown lesions that appear dark on IR and show thinning of the outer nuclear layer and attenuation or loss of the ellipsoid and interdigitation zones on OCT. Compared to FFA, ICGA and FAF, OCT and IR images display the lesions of AMN more effectively. The cSSO fundus photography used in this study is a laser with a wavelength of 820 nm; it is also an IR imaging approach in essence. Due to the destruction of the elliptical zone, the laser is absorbed by the deeper and stronger retinal epithelium, demonstrating the essence of shadow and OCT is optical coherence imaging, and the areas with mixed or dense tissue structure will show high reflection50. From the perspective of imaging alone, the morphology of hyper reflex in the early stage of the onset of AMN was consistent with that of the fiber of the cone and rod cells, which indicates the affected site (Fig. 1A)40, 47. At present, the generation of AMN is mainly dominated by two theories: the inflammation-related immune theory and the vascular-related ischemia and hypoxia theory49, 51. This needs to be discussed in combination with vascular parameters, and our research team will explore in future research.
4. 2 VKH-like uveitis and Multiple Evanescent White-Dot Syndrome (MEWDS)
VKH disease is an immune-mediated disorder characterized by bilateral uveitis frequently associated with neurological (meningeal), auditory, and integumentary symptoms. Auditory manifestations (tinnitus, hearing loss and vertigo) and others (including headache, neck and back stiffness) usually occur before or concurrently with ocular involvement52. A previous study linked VKH to SARS-CoV-2 Vaccines 53. The VKH-like patients in this series responded favorably to corticosteroid therapy. Whether SARS-CoV-2 is a precipitating factor or a disease inducer will require longer-term observation. MWDES is related to colds and viral infections. Both patients in this study developed symptoms five days after experiencing SARS-CoV-2-related fever, which is considered a cause.
4.3 Rhino-orbital-cerebral Mucormycosis (ROCM)
ROCM can be a serious complication of severe SARS-CoV-2 infection, particularly in patients with uncontrolled diabetes. The risk factors predisposing patients to ROCM are uncontrolled diabetes, neutropenia, hematological malignancies, organ transplantation, trauma and burn, and use of immunosuppressants such as corticosteroids37, 38. Patients were often blinded by mucormycosis invasion of the orbital apex leading to orbital apex syndrome forming retinal artery obstruction. This disease is easily misdiagnosed due to its reputation as a difficult-to-treat mold infection and its high mortality in patients with SARS-CoV-2 infection, particularly those with pulmonary disease. A careful management plan can be successful for rhino-orbital cerebral disease if there is early diagnosis of infection and control of infection54.
In conclusion, the retinal and choroidal conditions after SARS-CoV-2 infection are diverse, including AMN, MEWDS, VKH-like uveitis, and ROCM. Multimodal imaging may be used to evaluate the lesions from the anatomical and functional levels, and an appropriate examination with multimodal imaging is beneficial for patient management and follow-up.