The present study provided a comprehensive review examining the link between post-acute COVID-19 syndrome and neuropsychological manifestations after infection recovery. Twenty-five different studies were identified and reviewed that reported data on the post-disease neuropsychological characteristics of COVID-19 infection, of which six were analyzed in this meta-analysis43,44,46,47,48.
The main findings of this systematic review and meta-analysis showed an increased likelihood of exhibiting cognitive deficits in patients who recovered from COVID-1943,44,46,47,48. Furthermore, the evidence indicated that the prevalence of cognitive deficits was high in patients who, after recovery from COVID, continued to suffer from disease symptoms. However, it should be noted that the lack of a standard protocol for baseline cognitive assessment of patients' cognitive performance may complicate the comparison of the results obtained by different studies. Also, failure to report or assess psychological (e.g., stress, anxiety, etc.), socioeconomic (e.g., unemployment, few resources, lack of support networks, etc.), and contextual (e.g., specific COVID-19 measures such as social distancing) factors possibly affected by the pandemic may complicate the distinction between the effects on cognition of infection and the overall impact of the pandemic. Furthermore, another important variable that has not considered is the role of cognitive reserve (CR). CR is a protective factor against possible neuropsychological deficits49, in addition to being associated with neurobiological structures (brain reserve)50 that could make individuals less susceptible to brain alterations caused by the virus. On the other hand, stress or anxiety disorders, among others, can affect cognitive functioning51,52, and it has been reported that psychological problems have increased since the pandemic53. It would therefore be advisable to report such data for a better understanding of the consequences of the infection. Regarding severity, mean scores of cognitive deficits were below clinical cut-offs43,44,46,47,48. Nevertheless, studies such as Alemanno et al.17 concluded that scores on assessment scales improved relative to patients with the virus at the time of assessment, although cognitive deficits in patients with persistent COVID were lower than in healthy controls.
The main results obtained from the meta-analysis showed moderate differences in global cognitive status (g = −0.70) between recovered coronavirus patients with persistent symptomatology and healthy controls. These results support the information reported by other studies that conducted follow-ups on patients with persistent COVID symptoms. They found that approximately 30–80% of these patients developed long-term COVID symptoms lasting one to 6 months, with the most frequent symptoms being fatigue and neuropsychological deficits in executive functions26,31,32; working memory24,44,47,54; processing speed19,21,24; and attention19,31,32,44,47,48.
On the other hand, it should be noted that the scientific literature reviewed in this study reported data from both hospitalized and non-hospitalized patients (i.e., home isolation) depending on the studies. Therefore, it is important to highlight that the patients evaluated in the different studies analysed experienced different levels of severity of the disease in the acute phase. Some studies evaluate patients with mild COVID-19 symptoms that mostly did not require hospitalization or the intensive care unit43,44,48, while others evaluate patients with more severe COVID-19 symptoms that required hospitalization45,46. In particular, a worse cognitive performance could be observed in hospitalized patients compared to non-hospitalized patients19,24,45,55,56,57,58. This could be due to a more severe alteration of brain structures vulnerable to COVID-1959, and as a consequence a worse cognitive performance. Therefore, when interpreting the results obtained in this meta-analysis, it is necessary to consider the variability in the cognitive performance of individuals.
Moreover, not all studies report extensive details of the characteristics of the matched healthy controls. And among the studies that do so, differences can be observed among the healthy participants: in some studies, the healthy participants have lived with the virus at home but have not been infected55, others have not been previously exposed to the virus43,45,47 and others can not to ensure it44,48. Therefore, caution must be taken when interpreting the results and generalizing the findings regarding the long-term side effects of COVID-19, especially for all patients who did not require hospital admission and therefore underwent different levels of symptomatology severity.
The information available so far suggests that, in the acute stage of the infection, cognitive deficits are a common feature17,18,19,22, so it is probably considered a major clinical problem. However, conclusions should be made with caution since the information available on the acute consequences of pathology is limited and there is no specific data on the pathogenesis of the post-acute phase caused by the virus. The etiology of the neuropsychological consequences of coronavirus could be multifactorial. Several causes could affect cognition, such as the direct effects of the virus, the extent of symptoms such as hypoxia, cerebrovascular disease, the immunological response, medical resources and treatments, social isolation and psychological impact of the pandemic, or the concern of infecting others21,26. There is also a link between inflammation and cognitive dysfunction that could explain some of the neuropsychological morbidity16,60,61,62.
In line with the results obtained in the studies included in this review and meta-analysis, the research by Rogers and colleagues16 concluded that, following recovery from pre-COVID-19 coronavirus infections (e.g., MERS and SARS) and during a follow-up period of between six weeks and 39 months, sleep disturbance, emotional lability, reduced concentration levels, memory deficits, and fatigue were reported in more than 15% of patients16. Therefore, further research and monitoring of the health consequences of the current pandemic are needed.
Limitations and future studies
This study has several limitations that offer opportunities for future research. The main limitations of this meta-analysis include the use of non-peer-reviewed preprint papers, the exclusion of manuscripts published in a language other than English or Spanish, as well as the selection of studies with small sample sizes. In addition, few studies included healthy comparison groups, since a large majority compared the results of patients with post-acute COVID-19 syndrome with the standardized mean score of the test itself in the general population. Another significant limitation that may have affected the research conducted has been the mobility restriction measures applied worldwide, which have reduced the possibilities for data collection to online and/or remote formats (e.g., telephone assessment, online questionnaires, etc.). At the same time, the need, timing and process of publishing information about COVID-19 to facilitate the development of guidelines for clinicians may have affected the methodological quality of some studies. Jung et al.63 assessed the methodological quality of 686 COVID-19 articles and compared them with control articles published before the pandemic. The authors observed that COVID-19 articles were associated with lower methodological quality scores when published within a short time period63.
Another limitation was that there was considerable variation in the follow-up period (between approximately 1 and 5 months) in the studies that evaluated the long-term impact of the virus, which made comparability difficult. These may have also contributed to the heterogeneity present in this study. In addition, different studies used tests such as the Montreal Cognitive Assessment Test (MoCA) to assess cognitive impairment in these patients. The test is a cognitive screening scale validated in different populations and ages but mainly used in people older than 50 years and in the context of possible dementia. Although its purpose is to detect cognitive impairment, more sensitive neuropsychological tests such as the Mini-Mental State Examination (MMSE) (which has been shown to have a high sensitivity in neurocognitive diseases) would be needed64,65. Related to this, another limitation of the present study is to have placed the focus of analysis on global cognitive function, rather than on specific cognitive domains. Although this decision was due to a lack of resources (e.g., insufficient studies when the review was initiated), the analysis of data from extensive (domain-specific) neuropsychological assessments is recommended for future research in order to obtain more detailed data. Finally, although statistical methods were used to standardize the scores of all the studies, the different scales used by the included studies may have also contributed to the heterogeneity shown in this meta-analysis.
Future prospective studies on the subject are urgently needed. It is highly encourage that future studies systematically evaluate the prevalence of neuropsychological symptoms in patients with post-acute COVID-19 syndrome. It would be ideal to assess mental health prior to infection; as well as other relevant factors such as cognitive reserve, lifestyle or socioeconomic status, among others. In addition, it would be interesting if most of the studies used a common or similar, comprehensive psychological assessment test that could detect more specific cognitive deficits.
The long-term effect of the coronavirus infection on quality of life and eventual return to normalcy due to productivity loss and persistent cognitive impairment may be significant as the pandemic continues to escalate. Future longitudinal studies are needed to further investigate the cognitive impact of the infection on non-hospitalized people, as they constitute the majority of patients with COVID-19 and may have a significant impact on workforce productivity.
Conclusion and clinical implications
The main objective of this study was to shed light on a scarcely examined issue and to provide some structure to the growing evidence supporting the importance of assessing cognitive deficits in patients with persistent COVID symptoms19,31,32,44,47,48.
COVID-19 disease is a serious and increasingly widespread social and mental health problem and is becoming the focus of empirical research by investigators worldwide. The current findings support previous results by demonstrating significant relationships between persistent COVID symptoms and neuropsychological deficits. Importantly, the findings of the current study extend those of previous research by providing initial evidence that COVID-19 may affect the CNS increasing the likelihood of neuropsychological deficits even weeks after the infection. In summary, the current study makes an important contribution to understanding the relationship between post-acute COVID-19 syndrome and neuropsychological deficits.
Furthermore, it is very important to take into account the strong relationship between neurological and psychiatric symptoms and cognitive deficits in the study of COVID-19 and its consequences. This relationship is crucial to consideration when treating the disease and subsequent rehabilitation of COVID-19 patients, especially in the clinical setting. Therefore, it is important to take these factors into account for future studies and their impact on clinical practice.
While these findings may provide relevant information for the prevention and treatment of such cognitive dysfunctions, additional research is required to further investigate and define the possible mechanisms that could produce the virus-related cognitive alterations.
In conclusion, although there are multiple potential ways in which this pandemic could affect mental health, the present review suggests, firstly, that a high percentage of recovered COVID-19 individuals suffer from neuropsychological deficits in the aftermath of coronavirus infection and, secondly, that there are few existing studies to suggest that common neuropsychological difficulties are a feature of post-acute COVID-19 syndrome. Nevertheless, the present systematic review emphasizes that professionals treating patients with persistent COVID symptoms should be aware of this phenomenon and incorporate standard tests assessing cognitive function (e.g., MoCA) in their routine evaluation, to avoid the adverse consequences already reported in several studies. Furthermore, collecting all the results obtained in the different investigations reviewed in this study, months after hospital discharge, increased fatigue and problems in concentration, memory and cognitive speed are reported, which could disrupt daily life. Therefore, patients and essential workers could benefit from early neuropsychological testing to evaluate the impairment degree after COVID-19 hospitalization and its potential impact on their return to everyday activities. Future studies should carefully assess the long-term overall course of cognitive deficits in patients with post-acute COVID-19 syndrome as well as the effectiveness of rehabilitation treatments, particularly in younger patients. As research on neuropsychological symptoms in patients with post-acute COVID-19 syndrome advances, the need to examine this symptomatology in a multidisciplinary manner to achieve greater scientific evidence to corroborate the incidence and prevalence of COVID is increasingly clear.