Long COVID's Hidden Eye Syndrome Explained

New research from Linköping University identifies objective clinical and biomarker signatures behind a debilitating post-COVID ocular syndrome that routine eye exams miss entirely and proposes two diagnostic models eye clinics could eventually adopt.

For eyecare professionals who have seen patients present with unexplained light sensitivity, eye pain, blurred vision and reading difficulties following COVID-19, only for standard examinations to come back clean, a newly published study offers the first objective explanation.

The research, led by Professor Neil Lagali at Linköping University and published in Nature Communications, examined 100 non-hospitalised Swedish adults and children who developed persistent ocular symptoms (POS) after mild COVID-19, comparing them against 32 controls who recovered without ocular complaints. Symptoms had lasted anywhere from three months to three years, and a third of the POS group were on part- or full-time sick leave, yet only 39% of those had a formal long-COVID diagnosis.

Why standard tests come up empty

The study's central finding will resonate with clinicians who have struggled to validate these patients' complaints. Conventional anterior eye exams, uncorrected and best-corrected distance visual acuity, refraction, corneal thickness, endothelial cell density, tear film production and stability, bulbar redness and stereoacuity, showed no significant differences between POS and control groups.

The abnormalities only emerged under specialised testing. Near vision assessment revealed reduced best-corrected binocular near acuity and a measurable esophoric shift in near ocular alignment, alongside depleted fusional reserve together pointing to a form of adult-onset strabismus, a condition the authors note is otherwise almost exclusive to young children.

In vivo confocal microscopy of the corneal subbasal nerve plexus showed reduced nerve density and a weakened corneal blink reflex on esthesiometry, alongside a significantly elevated density of mature, antigen-presenting dendritic/T cells indicative of chronic low-grade neuroinflammation rather than acute infection.

Dynamic pupillometry added a further piece: an upward-shifted pupil response curve, with larger resting and constricted pupil sizes, slower constriction, and faster dilation recovery consistent with autonomic pupillary dysfunction. This correlated with patient-reported light sensitivity, headaches and reduced focusing ability.

A tear film signature echoing severe COVID-19

Targeted proteomic analysis of tear fluid (Olink Explore panels, 768 proteins) found 178 dysregulated proteins in the POS group, with five reaching significance after FDR correction: ITGB6, neurofascin (NFASC), CKMT1A-CKMT1B, CCN2 (CTGF) and TPSAB1. Notably, this dysregulated network overlapped substantially with published blood and tissue proteomic and transcriptomic signatures from severe and fatal COVID-19 cohorts suggesting these patients experienced a disproportionately severe systemic immune response that manifested locally in the eye.

"Our findings suggest that these people have suffered a severe reaction to COVID-19 manifested in the eyes, with long-term inflammation and an impact on the nerves that control multiple eye functions," said lead author Petros Moustardas, senior research associate at Linköping University.

Elevated JUN correlated with pupil dysfunction, while ANGPTL2, SKAP2 and DAPP1 correlated with dendritic/T cell activation, findings the authors say point towards demyelination-associated peripheral nerve injury and dendritic cell-mediated T cell maturation as drivers of the corneal inflammatory picture.

Towards a diagnostic pathway

Perhaps most relevant for practice: the team built two penalised logistic regression models to objectively classify POS. A clinical-only model, combining subbasal nerve density, corneal esthesiometry, pupillometry constriction time and dilation velocity, and mature dendritic/T cell density from three instruments (IVCM, esthesiometer, pupillometer), achieved 77% cross-validated AUC. Adding six tear protein markers lifted accuracy to 91% cross-validated AUC.

"I think it's very important that the problem is recognised and that we show that it can be measured by objective testing. Patients don't have access to that today," Professor Lagali said. "We've studied people in Sweden, but believe that many people around the world are experiencing these problems."

What this means for clinicians

For optometrists and ophthalmologists fielding patients with vague post-viral visual complaints, the study offers a reminder that a normal slit-lamp and refraction result doesn't rule out genuine ocular pathology. The authors suggest near vision testing, IVCM, esthesiometry and dynamic pupillometry, tools more common in specialist and academic settings, may be needed to detect the underlying neuroinflammatory and dysautonomic changes.

The authors caution the cohort was self-selected and modest in size, and that tear proteomics remains a research tool rather than a clinic-ready test. Whether the condition resolves over time, and how it should be managed, remain open questions.

"These people are really struggling in their daily lives," Professor Lagali said. "Now we know what's wrong with their eyes, and have several clues as to how COVID-19 may have caused these problems. We hope that the findings can lead to effective treatment... but unfortunately we don't know yet."

The study was funded by the Swedish Research Council and conducted with Linköping University Hospital's Eye Clinic and Linnaeus University, Kalmar.