Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, is well-documented for inducing significant pulmonary complications, including pneumonia and acute respiratory distress syndrome (ARDS). In addition to its pulmonary ramifications, clinicians have observed a spectrum of extrapulmonary manifestations associated with COVID-19. Notably, ocular manifestations, ranging from conjunctival congestion and conjunctivitis to more severe conditions such as keratoconjunctivitis, retinal changes, uveitis, and optic neuritis, have been reported in individuals with COVID-19 (1–11). However, the existing literature on optic neuritis associated with COVID-19 (COVID-19 ON) predominantly comprises case reports, lacking a comprehensive examination of its clinical characteristics.

Optic neuritis (ON), characterized by inflammation of the optic nerve, presents in various forms—autoimmune, infectious, or systemic. Autoimmune optic neuritis includes distinct subtypes such as neuromyelitis optica-related optic neuritis (NMO-ON), collapsin response mediator protein 5 optic neuritis (CRMP5-ON), myelin oligodendrocyte glycoprotein ON (MOG-ON), multiple sclerosis ON (MS-ON), single isolated optic neuritis (SION), relapsing isolated optic neuritis (RION), and chronic relapsing inflammatory optic neuropathy (CRION). Antibody-negative optic neuritis (antibody-negative ON) is classified into SION and RION based on the course of the disease. Systemic disorders causing optic neuritis include allergic granulomatous angiitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, ankylosing spondylitis, Behçet's disease, Churg–Strauss disease, Cogan syndrome, giant cell arteritis, granulomatosis with polyangiitis, IgG 4 disease, Kawasaki disease, microscopic polyangiitis, polyarteritis nodosa, primary antiphospholipid syndrome, rheumatic disease, sarcoidosis, Sjögren syndrome, systemic lupus erythematosus, Susac's syndrome, systemic sclerosis, Takayasu arteritis, treatment side-effects, ulcerative colitis, and Wegener granulomatosis. COVID-19 infections can directly affect the optic nerve and may also trigger optic neuritis as a post-infectious or post-vaccination phenomenon. This trigger can result in infectious optic neuropathies, which is a less common but diverse group with varied and non-specific clinical presentations (12). Infectious optic neuropathies are less common and may present with varied, overlapping, and non-specific clinical appearances (13). COVID-19 ON falls within the category of infectious optic neuropathies. This retrospective study aims to comprehensively explore and compare the clinical features of COVID-19 ON with those of NMO-ON, MOG-ON, and antibody-negative ON.

Our study investigated the clinical features of COVID-19 ON, categorizing it as an infectious optic neuropathy. The etiology of bacterial infectious optic neuropathies includes Bartonella, Brucella, Coxiella burnetii, leprosy, Mycoplasma pneumoniae, ocular cat-scratch disease, Streptococcus, syphilis, tuberculosis, Whipple disease, and typhus. Fungal infectious optic neuropathies are mainly associated with histoplasmosis, while parasitic infectious optic neuropathies are primarily linked to toxoplasmosis and neurotoxocarosis. The etiology of viral infectious optic neuropathies encompasses Chikungunya fever, cytomegalovirus, coronavirus, dengue, Epstein–Barr virus, echovirus, hepatitis B and C, herpes simplex, human immunodeficiency virus (HIV), human herpesvirus 6, Inoue-Melnick virus, measles, mumps, rubella, varicella-zoster virus (VZV), tick-borne encephalitis, West Nile virus, and Zika virus (12). COVID-19 belongs to the category of coronaviruses within the viral class.

Optic neuritis induced by cytomegalovirus, dengue, echovirus, hepatitis B, herpes simplex, human herpesvirus 6, measles, mumps, rubella, West Nile virus, and Zika virus is primarily reported in individual case studies, lacking a systematic summary of clinical presentations, MRI characteristics, and treatment efficacy. Limited reports on optic neuritis caused by HIV suggest that patients may experience unilateral or bilateral onset, often with the manifestation of optic disk swelling. The recommended treatment is directed toward addressing the underlying primary condition. Optic neuropathy related to HIV demonstrates axonal degeneration, possibly mediated by infected macrophages and increased expression of proinflammatory cytokines (16, 17). Another small number of reports on varicella-zoster virus-induced optic neuritis indicate that patients may experience the condition unilaterally or bilaterally, with some presenting optic disk swelling. MRI findings suggest abnormalities in the optic nerve and/or the myelin sheath. The recommended treatment involves antiviral therapy combined with corticosteroid treatment, and the prognosis is uncertain, possibly associated with timely administration of medication. The pathological mechanism may be attributed to direct damage by VZV or optic nerve demyelination caused by an immune response (18). Infectious optic neuropathy induced by viruses has been extensively reported, with documented cases linked to the Chikungunya virus (CHIKV) infection during a short epidemic in 2006–2007 in Southern India. Patients may experience the condition unilaterally or bilaterally, both accompanied by optic disk swelling. Corticosteroids have been found to expedite recovery when initiated early in the disease. The possible causes may include direct viral involvement and a delayed immune response after a viral infection. A good response to corticosteroid therapy indicates the possibility of an autoimmune mechanism in the pathogenesis of the disease (18, 19).

Among ON cases caused by coronaviruses, COVID-19 ON has been most frequently documented, predominantly in the form of individual cases or case series, lacking systematic clinical presentations and treatment outcomes (5–11). In our study, all patients presented with bilateral involvement, differing from optic neuropathy induced by HIV, VZV, and CHIKV, which can affect either one or both eyes. Patients exhibited optic disk swelling similar to that observed in optic neuritis caused by CHIKV. The unique characteristics of MRI examinations in this context have not been systematically summarized in previous research. A 14-day follow-up of patients with COVID-19 ON revealed no significant difference in BCVA compared to that in the MOG-ON group; however, there was a notable improvement in the COVID-19 ON group compared to the NMO-ON group and antibody-negative ON group. At the last follow-up, BCVA in the COVID-19 ON group significantly differed from the NMO-ON group. This study suggests that patients with COVID-19 ON respond well to glucocorticoid therapy, akin to the effects observed in previous studies on corticosteroid treatment for optic neuropathy induced by CHIKV. The treatment of optic neuritis caused by HIV primarily focuses on addressing the underlying primary disease. For optic neuritis caused by VZV, the recommended approach involves a combination of antiviral therapy and corticosteroid treatment, and the prognosis remains uncertain.

Efforts to delve deeper into understanding the pathogenesis of COVID-19 ON demand heightened attention. The coronavirus, an enveloped virus with a diameter of ~120 nanometers, exhibits distinctive crown-shaped projections on its surface (20). Its genome comprises an exceptionally lengthy positive-stranded RNA. The infection process relies on the angiotensin-converting enzyme 2 (ACE2) receptor, which is present in severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 and is mediated through the ACE2 receptor (21, 22). The neuropathological characteristics of COVID-19 arise from SARS-CoV-2′s direct invasion into the brain via the nasopharyngeal region. ACE2 receptors are identified in the nervous system, including glial cells and the basal ganglia (23). Inflammatory mediators disrupt the blood–brain barrier, activate glial cells, and induce demyelination of nerve fibers (24). In a previous study, it was revealed that molecular mimicry and the production of autoantibodies may contribute to immune-mediated damage to nervous tissues (23, 24). In our study, patients exhibited a favorable response to steroid treatment, suggesting that the pathological mechanism may be primarily attributed to molecular mimicry and the production of autoantibodies, contributing to immune-mediated damage to nervous tissues. This mechanism is similar to the pathogenesis of optic neuropathy induced by CHIKV. However, optic neuropathy caused by HIV and VZV may involve direct damage to the optic nerve, with or without demyelination, triggered by an immune response.

Among NMO-ON patients, 47% had a history of viral infection (25), while among MOG-ON patients, 37.5–60% had a history of previous infections (26). However, these patients were diagnosed with NMO-ON or MOG-ON rather than infectious optic neuropathy. Extensive research has been conducted on NMO-ON and MOG-ON, with standardized diagnostic and treatment guidelines and systematic summaries of clinical manifestations and MRI examinations. In alignment with this finding, we have summarized the clinical characteristics of COVID-19 ON. In comparison to NMO-ON and MOG-ON, COVID-19 ON mainly presents with bilateral onset and is more prone to optic disc edema. Previous studies have indicated that NMO-ON often involves the posterior and frequently longitudinally extensive optic nerve, with a tendency to affect the chiasmal region (14); MOG-ON is frequently longitudinally extensive and involves the optic nerve sheath (15). Our study corroborates these findings but uniquely identifies COVID-19 ON as presenting with long-segment enhancement without involvement of the intracranial segment of the optic nerve in T1-enhanced images, which is a novel observation (Figure 1).

Unfortunately, due to the retrospective nature of this relatively small sample size and short-term follow-up, our statistical conclusions lack the strongest evidence support.

Our investigation highlights the favorable impact of glucocorticoid therapy on COVID-19 ON. Notably, our orbital MRI observations unveiled a unique long-segment enhancement in T1-enhanced images, excluding the involvement of the intracranial optic nerve segment. These distinctive features identified in COVID-19 ON contribute significantly to advancing our comprehension of infectious optic neuropathies, offering valuable insights for future research and clinical considerations.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients/participants or patients/participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

F-FZ: Writing – original draft, Writing – review & editing. YW: Writing – review & editing. T-PL: Writing – review & editing. SH: Writing – review & editing. X-SY: Writing – review & editing. XL: Writing – review & editing. JC: Writing – review & editing. KH: Writing – review & editing. HL: Writing – review & editing. J-FY: Writing – review & editing. LC: Writing – review & editing. L-PC: Writing – review & editing.