# On the Quest for Ophthalmological Biomarkers for Long COVID: A Scoping Review
## 1 Introduction  
COVID-19 is a respiratory infection caused by the SARS-CoV-2 virus for which, as of February 2025, over 777 million cases have been reported, and has contributed to 7 million deaths worldwide [1]. Frequently reported symptoms include fever, cough, fatigue, and dyspnoea [2]; however, many patients also experience neurological symptoms, such as headaches, cognitive impairment ('brain fog'), and anosmia [3, 4]. Despite widespread neurological symptoms, currently, there is little evidence for direct invasion of neuronal tissue or cerebrospinal fluid (CSF) by the virus [5]. Alternative hypotheses have been proposed to explain these neurological symptoms, including the expression of angiotensin-converting enzyme 2 (ACE-2) by neural cells [6], indirect encephalitis, thrombosis or hypoxia, and immune system hyperactivation [3]. Although mild COVID-19 cases typically resolve within two weeks of onset [7], sometimes symptoms persist beyond the acute phase of the disease, often lasting months. Thiscondition, referred to as long COVID, post-acute sequelae of COVID-19 syndrome (PASC), or post COVID-19 syndrome, is defined by signs and symptoms consistent with COVID-19 infection over a period of 12 or more weeks that cannot be explained by an alternative diagnosis as outlined by the National Institute for Health and Care Excellence (NICE) [8]. Long COVID is estimated to have affected over 2 million people in the UK alone [9], causing significant long-term socio-economic implications [10]. Risk factors for long COVID include demographic characteristics (female sex and age), comorbidities (such as anxiety and depression), and severity of COVID infection, while vaccination may act as a protective factor [11]. Psychological and neuropsychiatric issues associated with long COVID, such as anxiety and depression, are commonly reported, with some researchers suggesting that these elements may be predominant in long COVID, akin to post-traumatic stress disorder (PTSD) [12]. The psychosocial burden is further intensified by unemployment, income loss, and increased reliance on social support. Long COVID arises from a complicated interaction of different persisting immune processes. Often, there is also overlap with predisposing conditions with multi-system involvement (e.g., mast cell activation syndrome and perimenopausal syndrome). This results in a syndrome with varying combinations of hundreds of symptoms (the Centers for Disease Control and Prevention (CDC) refers to \(>\)200 symptoms). Amid this complexity, clinicians working with the long COVID population recognise patterns of symptom reporting among patients where symptoms have a nervous system basis (pain, fatigue, brain fog, headache, vision, balance, and hearing disturbance). Direct evidence of the pathological basis for central nervous system involvement is limited. There is evidence from postmortem studies [13], structural imaging [14], and functional imaging [15]. Ophthalmic signals provide a means of monitoring various aspects of brain function. We have taken an approach that structures information from ophthalmic signals according to impacts on brain function from long COVID pathology: altered resting state (e.g., visual cortical excitability); altered neuromodulation state (e.g., pupillary light reflex); and altered network connectivity (e.g., saccadic control). Until the pathophysiology of the neurological symptoms of long COVID is fully understood, diagnosis and management remain challenging. NICE recommends early neurorehabilitation for patients with neurological sequelae, which affects over 80% of those hospitalised with COVID-19 [9; 16]. However, many symptoms are non-specific, may not elicit any abnormal findings upon clinical examination, and may not be a direct result of COVID-19 infection. Additionally, examinations may also be subjective and rely on self-reported information and are, therefore, subject to bias. In contrast, automated eye feature evaluation can be used as an objective and non-invasive biomarker of neurocognitive status.