Most people who became infected with COVID-19 recovered completely, but approximately 3 to 30% might experience a variety of medium-term to long-term effects after the initial illness (1–3). Post COVID-19 condition, also known as Long COVID (LC), it described by the World Health Organization (WHO) as the persistence or emergence of symptoms 3 months after SARS-CoV-2 infection that persist for at least2 months and cannot be explained by an alternative diagnosis (4). LC can affect anyone exposed to the SARS-CoV-2 virus, regardless of the clinical spectrum of the acute illness or age (5).

Some studies posit that SARS-CoV-2 infection may result in endothelial damage through a pro-inflamatory cytokine storm, oxidative stress, coagulation imbalance, and immune cell response, ultimately leading to chronic low-grade inflammation (6, 7). This can caused a non-specific systemic constellation of persistent symptoms involving different organ systems, including neurological, vascular, musculoskeletal, respiratory and others (8). Recent evidence suggest that the most frequent neuropsychological manifestations are fatigue, brain fog, cognitive decline, sleep disturbances, and anxiety (9, 10). Some symptoms may persist for years (11, 12), and it is unclear if they can be established for life (13). The characteristics significantly impact the individual work performance (14), psychosocial well-being and quality of life (15). In addition, it imposes a burden on the health system (16), economy, and social spheres.

Cognitive sequelae are among the most disabling neurological symptoms that affect a high proportion of people with LC. A meta-analysis of LC patients reported that about 32% suffered from brain fog, 28% had memory disturbances, and 22% had attentional difficulties (17). Many studies that evaluated cognition found widespread cognitive impairment (18, 19). Moreover, imaging studies revealed structural and functional changes associated with cognitive assessments scores due to SARS-CoV-2 infection in the brain (20, 21). Additional research effort are needed to understand neurocognitive function in LC by adopting domain-specific assessment tools.

People with LC often experience ontological/vestibular symptoms such as dizziness, vertigo, and tinnitus (22). It appears that the SARS-CoV-2 virus can affect the systems related to balance (23–25). However, current studies are based on subjective methods such as questionnaires or case reports. Alternative, posturographic tests are an objective assessment to measure balance alterations.

Considering the endothelial dysfunction hypothesis, several reports have shown signs of vascular disorders in different organ systems due to COVID-19. The virus can affect the endothelium through the angiotensin-converting enzyme 2 (26) and cause direct damage to the vascular endothelial cells, and it is possible to detect it in the retina. Therefore, retinal examination by retinography, a valuable tool for studying the clinical effects of COVID-19 in vivo.

The persistence and consequences of LC underscore the need to delineate the areas of involvement and associated factors to formulate enhancements in the therapeutic interventions for individuals with this condition. Therefore, it is important to understand how LC affects cognition, balance, and ocular health. This study examines the cognitive, balance and retinal outcomes and explores the relationship between the duration of LC symptoms and the degree of neurocognitive impairment.

In the APC cohort of people with LC and cognitive complaints, the three most common self-reported symptoms were concentration and memory deficit, asthenia, fatigue. More than 60% presented a cognitive deficit in at least one domain, being the executive functions the most impaired. Additionally, more than half of the participants presented a dysfunctional pattern in balance; and the 9% presented a fundus retina alteration.

The demographic profile of our cohort study is similar to other studies (1, 41). According to several studies, women are more susceptible to developing LC (42, 43). Some papers propose that this may be due to a different expression of angiotensin-converting enzyme 2 (ACE-2) or transmembrane protease serine 2 (TMPRSS2) receptors, or to lower production of proinflammatory cytokines such as interleukin-6 (IL-6) in women after a viral infection (44, 45). The greater frequency of women’s participation in health-related studies may be attributed to various factors, including their tendency to care more for their health. Most people in our study had a mild or moderate clinical course of SARS-CoV-2 infection. Thus, the data from our study corroborate previous research that the morbidity associated with prolonged COVID-19 is not related to the severity of the initial infection (5, 46, 47). In our sample, the most predominant complaints were lack of concentration and memory, asthenia, fatigue, brain fog, insomnia, myalgia, vertigo and dizziness. These findings are consistent with the current literature (48, 49). It is important to consider that high percentage of health professionals in our cohort could be influence a higher detection and reporting of symptoms.

Our results show that many patients in the sample demonstrated cognitive deficits in at least one domain. This overall result supports subjective cognitive complaints with objective neuropsychological measurements. Several articles assess cognitive functioning in people with LC, and most point to lower functioning compared to healthy subjects (17, 19, 50). In our study, patients showed impairments in several cognitive domains, including executive functions, attention, speed processing, and memory. These findings are in line with recent reviews (8, 49, 51). Linguistic and visuospatial abilities appear to be more preserved, whereas memory, executive function and attention seem to be the most affected capacities in these patients (52–54). This may be because attention, memory, and executive functions are high-level cognitive processes that integrate multiple brain regions. In contrast, language and visuospatial skills are more specific modular functions that are localized to specific brain areas. Considering that, COVID-19 affects the central nervous system (CNS), several hypotheses that try to explain the cognitive impairment. The immune response induced by the SARS-CoV-2 infection resulted in inflammation of CNS through systemic chemokines and other possible mechanisms (55). Persistent elevation of cytokines, chemokines and reactive microglia in cerebrospinal fluid can dysregulate multiple neural cell types. Such as altering homeostasis and plasticity (56), impairing neurogenesis (57) and inducing neurotoxic reactivity (58), all of which can affect neural circuit function and thus cognition (59).

To our knowledge, this is the first study to examine differences in cognitive impairment in relation to the duration of cognitive symptoms such as lack of concentration and memory, brain fog, and non-specific disorientation. It should be noted that most of the comparisons were not significant, making it difficult to draw conclusions. In the domain of executive functions, it seems that more time with the symptoms (lack of concentration and memory, brain fog and non-specific disorientation) is related to greater deficits. Nevertheless, there is some dispersion in the results for the other domains. This may be because it behaves differently depending on each symptom and cognitive domain. These discrepancies may also be caused by the intervention of other factors that have not been considered, such as comorbidities, severity of LC symptoms, and cognitive reserve. Thus, the results are inconclusive; therefore, we cannot assume that the persistence of symptomatology affects the progression of cognitive deficits. According to the PHOSP-COVID research group (60), a small improvement was found at 1 year, indicating that part of this deficit was not pre-existing and is potentially modifiable; however, some persisted after 1 year in susceptible individuals. In contrast, other studies showed a lower rate of improvement after 2 years of follow-up (61).

Results of the posturography test showed a wide variety of patterns in our sample, with the most predominant being somatosensory and vestibular dysfunction. These results cannot be strictly attributed to LC due to limited evidence in the literature. Even so, Yilmaz et al. (62) proved that balance in patients undergoing COVID-19 was impaired compared to healthy individuals. The mechanisms for reduced postural control remain unclear. It is not known whether the virus causes dysfunction of the vestibular system or whether such dysfunction is the result of an infectious process within the neural structures (25). Our findings suggest that the dysfunction is not due to a specific system; but is a more generalized affectation in the different systems involved in balance. The results obtained in the study by Gervasoni et al. (63) suggest the LC balance test performances were away from normality when integrating vision, somatosensory and vestibular information. It is therefore postulated that the alterations induced by SARS-CoV-2 infection result in a failure to integrate the various sensory inputs. Nevertheless, more specific complementary tests, such as nerve conduction, nuclear resonance, sensory, and organizational tests, are required to corroborate this hypothesis.

Retinal vascular involvement following SARS-CoV-2 infection has been little studied. Nevertheless, some studies indicate that SARS-CoV-2 infection causes retinal manifestations. Vavvas et al. (64) reported that the diameter of arteries and vessels in the retina was larger in patients with COVID-19 than in healthy individuals. This could be because when the inflammatory response begins, blood supply increases and vasodilation occurs (65). Some of the fundus findings in people with recent COVID-19 infection included retinitis patches, hard exudates, cotton wool spots, and superficial hemorrhages (66, 67). In a longitudinal study conducted by Invernizzi et al. (68), they found that most of the retinal vasculature alterations regress with time after acute COVID-19. However, those who suffer from severe COVID-19 may have long-lasting retinal vessel dilation persisting. In absence of previous information, we cannot be sure that the retinal lesions are due to SARS-CoV-2. There are also no studies on the prevalence of retinal vascular lesions in the general population. Although some retinal damage has been reported in the literature, the percentage of retinal damage observed in our sample is low, suggesting that retinography may not be a sensitive instrument for detecting the type of lesions produced by SARS-CoV-2. Therefore, it may be more advisable to use other techniques such as optical coherence tomography (69).

The study’s strengths include extensive follow-up of a population with a newly established disease. Our study uses various infrequent assessments such as posturography and retinography, and extensive battery of neurocognitive tests adopting domain-specific assessment tools to provide comprehensive monitoring. Furthermore, we have endeavored to collect all the symptoms reviewed in the literature and their duration, which may aid in the delimitation of the clinical spectrum.

However, our study has several limitations. First, the limited sample size may make it difficult to find significant relationships in the data. Second, there may be a sampling bias considering that most volunteers may have wanted to participate in the study because they had considerable impairment. Third, it should be noted that the measurement of clinical symptoms depended on the participants’ recall accuracy. Lastly, the lack of a control group without LC makes it challenging to definitively attribute the observed effects to LC specifically. For this reason, future lines of research should include a control group in each clinical test. It would also be interesting to re-evaluate the same sample after some time to see the progression of the conditions.

This study describes retinal, balance and cognition status in individuals with LC and cognitive complaints. It provides a framework for addressing patient and family expectations regarding their anticipated health. It also provides a better understanding of the LC syndrome and facilitates awareness of the importance of clinical management in primary care. It is important to maintain and increase the sensitivity of the health system around this pathology, both at the level of health professionals and managers and the general population. Knowing the health status of these individuals can help healthcare professionals distinguish LC symptoms from pre-existing conditions, helping to formalize diagnosis and treatment. Considering that, the majority in our sample present a cognitive deficit, it is convenient to monitor the progression of cognitive deterioration. As well as implementing, a pattern of postural balance exercises as rehabilitation training for vestibular problems. From this perspective, the main objective of clinicians and researchers is to create interventions that promote cognitive stimulation and balance training. Also, that ophthalmologists or retina specialists make a proper diagnosis and, if necessary, implement a personalized treatment plan. In conclusion, it is important to follow up with these patients to control their affectations and to find an adequate multidisciplinary treatment that contemplates physical and psychological aspects.

The original contributions presented in the study are included in the article or the Supplementary material, further inquiries can be directed to the corresponding authors.

The ethics committee of the Foundation University Institute for Primary Health Care Research Jordi Gol I Gurina (IDIAPJGol) has approved the study protocol (ref. 21/220-P). This study adheres to guidelines established in the Declaration of Helsinki. All participants recruited were fully informed about study and signed informed consent to participate. They consented to use their collected data for research and agreed to the applicable regulations, privacy policies, and terms of use. Participant data has been anonymized according to a numerical coding system and stored securely in the REDCap database.

MC-C: Formal analysis, Writing – original draft, Writing – review & editing, Data curation, Validation, Visualization. BL-G: Data curation, Formal analysis, Writing – original draft, Writing – review & editing, Validation, Visualization. RD-A: Writing – review & editing, Investigation, Visualization. NL-V: Writing – review & editing, Investigation, Funding acquisition, Resources, Visualization. PM-A: Writing – review & editing, Investigation, Visualization. GM: Formal analysis, Visualization, Writing – review & editing, Data curation. AA: Writing – review & editing, Investigation, Visualization. CC: Writing – review & editing, Investigation, Funding acquisition, Resources, Visualization. AC-G: Formal analysis, Writing – review & editing, Data curation, Visualization. VL-L: Writing – review & editing, Investigation, Visualization. VZ-P: Writing – review & editing, Investigation, Visualization. LL: Writing – review & editing, Methodology, Visualization. RG-S: Writing – review & editing, Methodology, Funding acquisition, Resources, Software, Visualization. AF: Writing – review & editing, Investigation, Visualization. EM-G: Writing – review & editing, Methodology, Visualization. MMas: Writing – review & editing, Funding acquisition, Project administration, Resources, Supervision, Visualization. JM-M: Writing – review & editing, Methodology, Visualization. MR-P: Writing – review & editing, Investigation, Visualization. LM: Writing – review & editing, Investigation, Funding acquisition, Resources, Visualization. AP: Writing – review & editing, Methodology, Visualization. MMat: Writing – review & editing, Methodology, Visualization. MB: Writing – review & editing, Investigation, Visualization. BQ: Writing – review & editing, Investigation, Visualization. JP: Supervision, Writing – review & editing, Funding acquisition, Project administration, Resources, Visualization. EM-C: Supervision, Writing – review & editing, Funding acquisition, Project administration, Resources, Visualization. CV: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Funding acquisition, Project administration, Resources, Visualization. PT-M: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Funding acquisition, Project administration, Resources, Visualization.

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