key: cord-0312256-wfa5fb3r authors: Butardo, N. D.; Coronel, M. F. D.; Dino, A. M. O.; Mendoza, T. R. F.; Sto. Domingo, O. K. D.; Regencia, Z. J. G.; Dominguez, J. C.; Baja, E. S.; Ligsay, A. D. title: Clearing the Fog: A Systematic Review on Cognitive Dysfunction in COVID-19 date: 2022-05-25 journal: nan DOI: 10.1101/2022.05.24.22275552 sha: 1e22a8d0164870ac38c4c3e3a7b1d278d0bd5b29 doc_id: 312256 cord_uid: wfa5fb3r Objective: The systematic review aims to examine the association between COVID-19 and cognitive dysfunction, including the link between the severity of COVID-19 and the occurrence of cognitive impairment and the potential pathophysiological mechanisms related to brain fog among COVID-19 patients. Methods: PubMed, Oxford University Press, ProQuest Health and Medical Complete, ScienceDirect, Ovid, HERDIN, Google Scholar, and Cochrane Library databases were accessed to retrieve literature using the PRISMA guidelines. Results: After critical appraisal, thirteen full journal articles were included in the study. The studies showed the most frequent cognitive impairment are attention, memory, and executive function in COVID-19 patients. Compared with healthy controls (HC) in 3 out of 4 studies, cognitive impairment was only evident in COVID-19 patients. Furthermore, two studies showed no correlation between brain fog and depression, and five studies showed a link between the severity of COVID-19 infection and cognitive impairment. Cases ranging from mild to severe illness presented manifestations of brain fog. However, a disparity in the evidence of the pathophysiology of COVID-19 and cognitive dysfunction exists, prompting the need to investigate further. Additionally, recent studies provide insufficient evidence for direct central nervous system invasion, and there are emerging studies that contrast the presumed pathogenesis of neurological complications from neuroinflammation. Conclusion: There is an association between COVID-19 and cognitive dysfunction. Manifestation of cognitive dysfunction is present regardless of illness severity. Moreover, there are existing pathophysiological mechanisms of the Coronavirus that lead to cognitive dysfunction in COVID-19 patients; however, additional studies are required to substantiate such mechanisms further. 4 is afflicting the nervous system (Iadecola et al., 2020) . The SARS-CoV-2 virus could 76 potentially affect the gustatory system in two different ways-either by directly 77 damaging the mucosal membrane of the oral cavity and the peripheral neuronal 78 trajectory of the gustatory tract or by directly damaging the cranial nerves that are 79 responsible for the sense of taste (Finsterer & Stollberger, 2020) . With the 80 presentation of anosmia in COVID-19 patients, olfactory neurons were at an incredibly 81 high risk of injury due to the high viral load within the nasal cavity (Zou et al., 2020) . 82 The discovery of the brain invasion of mice by the intranasal administration of 83 the novel coronavirus (Kumari et al., 2021) there is an association between the two, research about the extent of the impact on 97 cognition and the affected cognitive domains of brain fog is limited (Zhou et al., 2020) . 98 Therefore, researchers have yet to determine whether cognitive systems are equally 99 affected or some domains are more susceptible to SARS-CoV-2 infection. The primary 100 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint 7 included in this systematic review. Furthermore, English language restriction was 150 imposed. 151 The electronic literature search included the following key terms: COVID-19, 153 SARS-CoV-2, neurocognitive impairment, brain fog, confusion, poor concentration, 154 memory problems, brain fog pathophysiology, neurological mechanism, and cognitive 155 dysfunction. Moreover, the Boolean search strategy ("AND," "NOT," "AND NOT," 156 "OR") was employed to identify studies using the key terms. The search strategy for 157 databases can be found in online Supplemental Appendix A. 158 Authors independently searched for studies that were included in the 160 systematic review. The initial selection of studies consists of the examination of the 161 titles, abstracts, and full-text, if available. Inclusion criteria implemented were 162 observational studies on individuals with COVID-19 who experience cognitive 163 dysfunction. The authors created the final list of included studies. Any disagreements 164 that arose during the appraisal process were settled by discussing with another author. 165 Three authors (MFDC, TRFM, and OKSD) independently evaluated the risk of 167 bias in each study. A fourth (NDB) and fifth (AMOD) author was assigned to resolve 168 disagreements in assessments. To assess bias in included studies, they were 169 segregated into observational studies such as case reports, case series, cross-170 sectional studies, case-control studies, and cohort studies. The risk of bias in the 171 included studies was assessed using the Strengthening the Reporting of 172 Observational Studies in Epidemiology (STROBE) statement (Vandenbroucke et al., 173 2007) . The risk of bias was scored as "low," "moderate," or "high" risk. The overall 174 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint 8 quality of each study was given a rating based on the score from the STROBE 175 statement. Furthermore, only studies with a low-risk rating were included in the study. 176 Formatted according to the extraction tool used to extract the data, an MS Excel 178 spreadsheet was used to tabulate results for representation of results. The 179 characteristics of the included articles were described, which were previously 180 discussed and agreed upon within the study team. 181 A narrative synthesis of overall evidence was undertaken by comparing and 183 contrasting the data to express and synthesize the results of the included studies. authors frequently met to discuss the results and reach a consensus on the findings. 189 Two hundred eighty-nine studies were identified after a comprehensive search 193 through databases (PubMed, ProQuest, Oxford University Press, ScienceDirect, 194 Cochrane Library, Google Scholar, JSTOR, and Herdin). Duplicate records (n=12) 195 were removed based on their titles. After initial screening, 177 studies were excluded 196 due to differences in study design (e.g., review paper, narrative review, 197 hypothesis/theory article and chart review) based on the title and abstract. In addition, 198 15 articles were not retrieved because the study is ongoing. A total of 85 full-text 199 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Systematic Reviews and Meta-Analyses) flow chart of the study selection is presented 202 in Fig. 1 . 203 Characteristics of the included studies are tabulated in Table 1 . The age of the 205 study participants in the included studies was greater than 16 years old. All study 206 participants were diagnosed with COVID-19 through various diagnostic tests such as 207 SARS-CoV-2 RT-PCR of a nasopharyngeal swab, SARS-CoV-2 antibody testing (e.g., 208 SARS-CoV-2-specific IgG in serum), rapid antigen test, and polymerase chain 209 reaction (PCR) test for SARS-CoV-2 in upper and/or lower airway samples. 210 Participants in 4 included studies were assessed during COVID-19 infection, seven 211 during post-COVID-19 infection, 4 had follow-ups, and one examined patients post-212 mortem. The duration of the follow-ups in the included studies ranges from 2 to 4 213 months. Out of the 13 included observational studies, 1 is a case series, 1 is a case 214 report, 6 were cross-sectional studies, and 5 were cohort studies. 215 A total of 276 studies were excluded from the list of included studies due to the 217 following reasons: different study design (n=179), irrelevance to the systematic review 218 (n=59), unavailability of the full-text article (n=16), duplications (n=13), and focused on 219 the psychological aspect (n=9). 220 Observational studies were evaluated based on ten domains: Introduction -(1) 222 Objectives; Methods -(2) Participants; Results -(3) Participants, (4) Descriptive Data, 223 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint 10 (9) Interpretation, and (10) Generalizability. Of the 13 included observational studies, 225 all were assessed as low risk of bias. 226 Eleven studies focused on the association between COVID-19 and brain fog, five 228 (5) studies identified the link between the severity of COVID-19 and the occurrence of 229 cognitive dysfunction, and seven (7) studies described the possible pathophysiological 230 mechanisms related to brain fog in COVID-19 patients. 231 The prospective cohort study conducted two MoCA tests with mean scores of whereas 15% (4/26) were severely impaired (see Table 2 for details). (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint patients and healthy controls; however, it did not show any significant difference 275 between the Toolbox T-scores of the two groups. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 3 ). In the cross-sectional study examining Post-Acute COVID-19 Team (PACT) Pulmonary Clinic reveals that out of 82 patients 320 classified for critical illness, 67% (54) demonstrated abnormally low cognitive scores 321 (≥1 deviation from published age-adjustive normative means) and is correlated to 322 mild/moderate or severe range of cognitive impairment (Vannorsdall et al., 2022) . In 323 addition, the prospective-single center study involved 19 patients with a distribution of 324 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint 11% (2) having a mild illness, 21% (4) having a moderate illness, another 21% (4) 325 having a severe illness, and 47% (9) having critical illness severity (2021) were 326 reported (Virhammar et al., 2021) . Report also showed that 2 out of 9 critically ill 327 patients manifested cognitive dysfunction, 2 out of 4 severely ill patients showed 328 patients showed a trend of significant difference for lower reaction time in the first and 348 second parts of CPT and a lower correct number in the second part of CPT than the 349 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. the observer, 10 of the subjects had cortical hypometabolism, with 2 cases having 374 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In a case study, the CSF analysis through lumbar puncture is unremarkable. 383 The N-acetylaspartate (NAA), glutamate, and glutamate/glutamine ratio were 384 measured using MR-spectroscopy and bilateral DLPFC. A week and three months 385 following the initial diagnosis of SARS-CoV-2 infection, substantial increases in 386 glutamate, glutamine, and NAA levels were discovered during follow-up, suggesting 387 that the glutamatergic pathway might be implicated in the pathogenesis of cognitive 388 impairment (Yesilkaya et al., 2021) . 389 All studies that utilized the MoCA test showed MCI following COVID-19 391 infection. An included study reported a more severe global cognitive impairment 392 among COVID-19 patients than healthy controls (Ortelli et al., 2021) . Among the 393 cognitive domains, attention, executive function, and memory are most likely to be 394 impaired. These were also the domains that frequently showed significant differences 395 between COVID-19 and non-COVID-19 patients in a recent study (Crivelli et al., 2022) . 396 This observation is congruent with another study reporting that the exact cognitive 397 domains, except for memory, seem prone to impairments (Daroische et al., 2021) . On 398 the other hand, results on language, orientation, and visuospatial function varied in 399 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Emerging reports indicate that a large population suffers from cognitive 441 dysfunction due to COVID-19 infection. Results from the selected studies (Table 3 ) 442 showed that cognitive dysfunction is present among patients characterized by mild, 443 moderate, severe, and critical illnesses. According to a report, cognitive impairments (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. normal and mild cognitive impairment groups, suggesting its significance as a marker 474 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint of cognitive impairment and early cognitive impairment changes (Hall et al., 2020) . In 475 a previous study that used a community-based population of non-cognitive impairment 476 participants, CSF NfL is a better predictor of cognitive deterioration than other CSF 477 markers of neurodegeneration (Mielke et al., 2021) . Another study elaborates on the 478 association of biomarkers such as t-tau with cognitive decline (Chen et al., 2021) . The 479 findings showed that higher levels of plasma biomarkers (i.e., Aβ42, t-tau, and Aβ42 480 × t-tau) were found in participants who showed a cognitive decline (the declined group) 481 compared to those who did not (the stable group) and were associated with lower 482 episodic verbal memory performance at baseline and a more significant annual 483 have been published in languages other than English (e.g., Chinese). We also did not 499 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint have access to some other databases that may store some articles on COVID-19 and 500 cognitive dysfunctions. And lastly, there could be some other studies on this theme in 501 the literature that skipped our attention and analyses. However, a comprehensive 502 search strategy that covers a broad range of evidence was implemented. 503 This systematic review gathered evidence that could provide clarity on the 504 association between brain fog and COVID-19 infection. The information acquired in 505 this study may help re-evaluate the impact of the virus. Furthermore, the use of the 506 data gleaned from this analysis may assist in earlier treatment, allowing physicians 507 and clinicians to manage the neurological manifestation effectively. Additionally, this 508 will aid in the development of various therapeutic strategies to support COVID-19 509 patients in recovering from impaired cognitive capacity. Finally, the analysis of such 510 data could provide an insight into the challenges that this virus could cause people in 511 their prime years, particularly those in the workforce. 512 Attention, memory, and executive function were the most frequently affected 514 cognitive domains in COVID-19 patients. There was also a significant difference in the 515 neuropsychological assessment scores between COVID-19 patients and HC. 516 Interestingly, results from the included studies showed no correlation between 517 cognitive dysfunction and depression. Increasing evidence suggests that cognitive 518 dysfunction due to COVID-19 is manifested across disease severity ranging from 519 asymptomatic to critical illness. The interplay of physical and cognitive impairments 520 may lead to functional problems inhibiting health-related standards of life. The 521 knowledge gained from this study may be used to improve the implementation of 522 comprehensive treatment modalities and rehabilitation throughout the COVID-19 care 523 continuum to remove such barriers and restore the meaningful lives of patients brought 524 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. ; https://doi.org/10.1101/2022.05.24.22275552 doi: medRxiv preprint about by brain fog. The findings from this systematic review indicate multiple potential 525 pathophysiological mechanisms related to cognitive dysfunction in COVID-positive 526 individuals. Neuroinflammation is one of the mechanisms that have led to cognitive 527 dysfunction based on the studies obtained. Neuroinflammation in the NFL protein and 528 inflammatory levels indicated by CRP provide further insight into the pathophysiology 529 that could lead to cognitive dysfunction. The evidence appears to be contrasting; 530 however, from what was gathered, the CNS invasion is not the primary pathological 531 mechanism due to the lack of studies that portray the presence of SARS-COV-2 532 concerning said mechanism. It is also suggested that neuroinflammation is not 533 substantial enough even with the rising levels of pro-inflammatory markers due to the 534 lack of value in numbers. Therefore, more studies are needed to substantiate these 535 pathophysiological mechanisms further. 536 The authors acknowledge the University of Santo Tomas College of Science, 538 especially the Department of Biological Sciences, for the support and assistance. accepts full responsibility for the finished article has access to any data and controlled 547 the decision to publish. The corresponding author attests that all listed authors meet 548 the authorship criteria and that no others meeting the criteria have been omitted. 549 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Register for Systematic Reviews) as CRD42022325669. 557 Author Note: If there is a need to amend the study protocol or results, the date of 558 each amendment and the reason for the change will be described. 559 Patient consent for publication 561 Not applicable. 562 Ethical approval was not required for this systematic review, since all data came from 564 information freely available in the public domain (i.e., published articles or conference 565 abstracts). This study does not involve human participants. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. becoming a long-hauler: looking for clarity in the haze of the pandemic. 671 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 25, 2022. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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