John Murphy, M.D., M.P.H. D.P.H., President Covid Long-haul Foundation
Abstract
Post‑acute sequelae of SARS‑CoV‑2 infection (long COVID) frequently manifest with systemic, neurologic, and visual symptoms. While neurocognitive and cardiopulmonary sequelae have been extensively described, persistent optic nerve and retinal involvement represent an emerging and clinically significant phenotype. This review integrates current evidence on the etiology, pathology, physiology, and genomics of optic nerve involvement in long COVID, with emphasis on molecular mechanisms, clinical phenotypes, diagnostic modalities, treatment strategies, and prognosis. We propose a working framework for future research and therapeutic trials.
Introduction
Since the onset of the COVID‑19 pandemic, SARS‑CoV‑2 has been recognized as a multi‑system pathogen with both acute and long‑term sequelae. Long COVID — defined by persistent symptoms ≥12 weeks after initial infection — encompasses a spectrum of manifestations, including neurological and ophthalmic disorders. While retinal microvascular changes and optic nerve pathology have been reported, their mechanistic underpinnings, clinical course, and optimal management remain poorly defined.
Etiology of Optic Nerve Damage in Long COVID
Viral Tropism and Receptor Expression
SARS‑CoV‑2 gains cellular entry via the angiotensin‑converting enzyme 2 (ACE2) receptor. ACE2 expression is detectable in ocular tissues, including retinal pigment epithelium, Müller glia, and possibly the optic nerve, suggesting biological plausibility for direct viral interaction with the visual pathway.^[1][2] Binding triggers endothelial dysfunction and inflammatory cascades that may contribute to microvascular compromise.
Immune Modulation and Neuroinflammation
Persistent immune dysregulation is a hallmark of long COVID. Parainfectious optic neuritis — classically immune‑mediated inflammation following infection — has been documented in SARS‑CoV‑2 contexts, characterized by optic disc edema and significant visual loss, with responsiveness to corticosteroids typical of immune‑mediated injury rather than direct viral cytopathy.^[3]
Microvascular Injury and Endothelial Dysfunction
COVID‑19 is associated with systemic endothelial injury, cytokine‑induced microvascular damage, coagulopathy, and thrombotic phenomena. In the retina, altered vessel density and structural changes in capillary plexuses have been observed after acute infection, implicating ischemic processes in visual and optic nerve sequelae.^[1][4]
Viral Reactivation and Secondary Neuropathic Pathways
Large longitudinal analyses suggest elevated risks of optic neuritis following herpes zoster (HZ) reactivation in individuals previously infected with SARS‑CoV‑2, implicating immune exhaustion and reactivation of latent neurotropic viruses in optic nerve vulnerability.^[5]
Pathology and Physiology
Structural and Cellular Alterations
Optic nerve dysfunction can result from inflammation (optic neuritis), ischemia (non‑arteritic anterior ischemic optic neuropathy), or microvascular injury. Microglial activation and retinal microvascular changes have also been identified in postmortem analyses of COVID‑19 eyes, supporting ongoing inflammatory and vascular effects that could extend to optic nerve integrity.^[6]
Physiologic Consequences
Optic nerve damage disrupts axonal conduction in retinal ganglion cell pathways, leading to decreased visual acuity, contrast sensitivity deficits, visual field defects, and dyschromatopsia. Alterations in retinal nerve fiber layer (RNFL) thickness and ganglion cell loss have been reported in COVID‑19–associated retinal studies, supporting neuro‑ophthalmic sequelae with potential optic nerve involvement.^[7]
Genomics and Molecular Factors
Genomic analyses, including network approaches, highlight neuroinflammatory and thromboinflammatory pathways as central to long COVID pathophysiology, with implications for optic nerve susceptibility given its metabolic demands and vascular dependencies. While direct causal gene variants specific to post‑COVID optic nerve pathology have yet to be definitively identified, immune‑regulatory and vascular genes are logical candidates for future study.
Clinical Presentation and Diagnosis
Symptomatology
Patients may present with unilateral or bilateral visual impairments including blurred vision, visual field defects, photopsias, and decreased contrast sensitivity. Optic neuritis may present with pain exacerbated by eye movement and rapid visual decline.
Ophthalmologic and Neurologic Evaluation
Diagnosis hinges on clinical history, visual acuity exam, visual field testing, and neuroimaging. MRI may reveal optic nerve enhancement consistent with inflammatory involvement. Optical coherence tomography (OCT) and OCT angiography can quantify RNFL thickness and microvascular density, aiding in objective characterization of structural and vascular changes.^[1][4]
Clinical Course and Prognosis
Parainfectious optic neuritis associated with SARS‑CoV‑2 often demonstrates an atypical clinical profile compared with idiopathic cases, with severe initial visual loss and high incidence of optic disc edema, but a favorable response to corticosteroid therapy and visual recovery reported in aggregated case series.^[3] The long‑term prognosis outside acute inflammatory cases remains poorly characterized; persistent microvascular changes may contribute to chronic alterations in visual function.
Management
Immunomodulatory Therapy
High‑dose systemic corticosteroids remain the cornerstone of acute optic neuritis management and have shown benefits in SARS‑CoV‑2–associated optic neuropathy, with rapid visual improvement reported.^[3] For refractory or recurrent cases, additional immunomodulation (e.g., plasma exchange or targeted biologics) may be considered, though evidence in long COVID contexts is limited.
Supportive and Neuroprotective Strategies
Addressing systemic inflammation, optimizing vascular health, and considering antithrombotic strategies may be rational in cases with significant microvascular injury. Rehabilitation measures including contrast training and regular monitoring of visual function are recommended.
Conclusion
Optic nerve involvement in long COVID represents a multifaceted clinical entity with contributions from immune dysregulation, endothelial dysfunction, and potentially direct viral effects mediated through ACE2 expression in ocular tissues. Recognition of this phenotype is essential for prompt diagnosis and management. Prospective studies, detailed imaging modalities, and molecular investigations are urgently needed to refine diagnostic criteria, elucidate mechanisms, and develop targeted therapies.
References
- Long‑Term Effects of COVID‑19 on Optic Disc and Retinal Microvasculature Assessed by Optical Coherence Tomography Angiography. Diagnostics (Basel). 2025;15(1):114. DOI:10.xxxx/mdpi. PMID: – ACE2 and microvascular findings in COVID retina.
- Ocular Symptoms Associated with COVID‑19 Are Correlated with the Expression Profile of Mouse SARS‑CoV‑2 Binding Sites. PubMed. – ACE2 ectopic expression, including in optic nerve.
- Gluckstein J et al. SARS‑CoV‑2 Parainfectious Optic Neuropathy: 3 Case Reports and a Review of the Literature. J Neuroophthalmol. 2023;43(4):491–498. – parainfectious optic neuritis profile and steroid response.
- Retinal Microvascular Impairment in COVID‑19 Bilateral Pneumonia Assessed by OCTA. PubMed. – RNFL and GCL changes in COVID patients.
- Increased risk of uveitis and optic neuritis after herpes zoster reactivation in COVID‑19: a TriNetX database study. QJM. – Long‑term COVID and optic neuritis risk with HZ reactivation.
- Microglia activation and neuronal alterations in retinas from COVID‑19 patients. Eye Vis. – microglial and inflammatory changes.
- Alterations in the optic nerve and retina in patients with COVID‑19. A theoretical review. PubMed. – comprehensive review of optic/retinal COVID effects.