Late neurological consequences of SARS-CoV-2 infection: New challenges for the neurologist

Abstract

Objective:

In this study, a systematic review of the literature was performed to study the frequency of neurological symptoms and diseases in adult patients with COVID-19 that may be late consequences of SARS-CoV-2 infection.

Methods:

Relevant studies were identified through electronic explorations of Scopus, PubMed, and Google Scholar. We followed PRISMA guidelines. Data were collected from studies where the diagnosis of COVID-19 was confirmed and its late neurological consequences occurred at least 4 weeks after initial SARS-CoV-2 infection. Review articles were excluded from the study. Neurological manifestations were stratified based on frequency (above 5, 10, and 20%), where the number of studies and sample size were significant.

Results:

A total of 497 articles were identified for eligible content. This article provides relevant information from 45 studies involving 9,746 patients. Fatigue, cognitive problems, and smell and taste dysfunctions were the most frequently reported long-term neurological symptoms in patients with COVID-19. Other common neurological issues were paresthesia, headache, and dizziness.

Conclusion:

On a global scale of patients affected with COVID-19, prolonged neurological problems have become increasingly recognized and concerning. Our review might be an additional source of knowledge about potential long-term neurological impacts.

Introduction

There is growing evidence indicating that neurological manifestations occur in patients as sequelae of COVID-19 (Misra et al., 2021). Approximately one-third of positive patients develop neurological and neuropsychiatric symptoms (Rudroff et al., 2020).

SARS-CoV-2 neurotropism has been increasingly recognized by its imaging and clinical manifestations from severe (encephalitis) to mild (hyposmia) in the literature. The neurological symptoms profile associated with COVID-19 covers symptoms of the central nervous system, peripheral nervous system, and neuromuscular disorders. The impact of SARS-CoV-2 on the nervous system is associated with the following issues: olfactory and taste disorders, Guillain–Barre syndrome (GBS), encephalopathy, neurological inflammation (myelitis, encephalitis, and meningitis), cerebrovascular diseases, seizures, cognitive impairment, myalgia, non-specific symptoms such as headache, dizziness, and fatigue, or neuropsychiatric symptoms such as anxiety, depression, psychosis, and sleep disorder (Divani et al., 2020; Collantes et al., 2021; Roy et al., 2021; Yassin et al., 2021). Most infected people develop mild to moderate illness and recover without requiring hospitalization, while others must be hospitalized.

Neurological symptoms are not necessarily correlated with the severity of COVID-19 infection, implying that different mechanisms or timing of mechanisms may be involved (Rogers et al., 2021).

These symptoms can appear in three disease periods, such as acute (parainfectious), post (postinfectious), and late infections (long-term sequelae). Datta et al. (2020) presented a theoretical timeframe for periods of SARS-CoV-2 infection: acute infection (from the onset of symptoms up to 2 weeks), post-acute infection (2 weeks after initial infection), and late sequelae (4 weeks after initial infection) (Datta et al., 2020). According to current knowledge, concerning the duration of neurological manifestation from COVID-19 symptoms onset, neurological issues can be placed in a timeframe.

Regarding cerebrovascular diseases, most manifestations occur within 21 days from COVID-19 onset, and stroke was rarely the first manifestation (Vogrig et al., 2021).

In the literature, neurological inflammation related to COVID-19 is observed as para- or postinfectious disease (Paterson et al., 2020). On average, encephalitis occurred 14.5 days after the diagnosis of COVID-19 infection (range = 10.8–18.2 days) (Siow et al., 2021).

Cases of Guillain–Barre syndrome in patients with COVID-19 have been described as a parainfectious disease (Romoli et al., 2020) or a postinfectious disease with a 2-week interval between SARS-CoV-2 and GBS infection (Palaiodimou et al., 2021).

It is known that severe acute respiratory syndrome coronavirus (SARS) and Middle East respiratory syndrome coronavirus (MERS) may have prolonged neurological impact (Ngai et al., 2010; Hosseiny et al., 2020). Emerging evidence suggests that the neuroinvasive nature of COVID-19 may be the driving force behind late neurological complications.

An increasing number of patients with COVID-19 continue to experience symptoms for months, even after recovering from mild cases of COVID-19 such as muscle pain, dizziness, headaches, fatigue, and anosmia (Wijeratne and Crewther, 2020), as well as signs and symptoms involving cognitive functions (Baig, 2020). Qin et al. (2021) found that the patients with mild- and severe-type COVID-19 with no specific neurological manifestations or obvious lesions on the conventional MRI, although recovered from pneumonia, still exhibited brain microstructure changes and a decrease in cerebral blood flow after a 3-month follow-up (Qin et al., 2021). For healthcare professionals and scientists, the prolonged neurological impact is a new challenge. In the literature, we can find different nomenclature for this phenomenon as Chronic COVID syndrome (CCS) (Baig, 2020), Post-COVID-19 Neurological Syndrome (PCNS) (Wijeratne and Crewther, 2020), Long COVID, and Long hauler COVID (Mendelson et al., 2020).

This review focused on the neurological symptoms and diseases that may be late consequences of SARS-CoV-2 infection.

Methods

The databases Scopus, PubMed, and Google Scholar were reviewed before 4 June 2022. An individual database search strategy was adopted with the following variations of keywords: (“COVID-19” OR “COVID19” OR “neuro-covid 19” OR “Sars Cov-2” OR “coronavirus”) AND (“long term” OR “chronic” OR “long haul^*” OR “post-covid^*” OR “post covid^*” OR “long covid^*”) AND (“neurological manifestation” OR “neurological complication” OR “neurolog^*”). The first step was the title screening; the second was the abstract screening, and the third step was a full-text review of the relevant information. We followed PRISMA guidelines.

The inclusion criteria

The time criteria for identifying neurological issues were at least 4 weeks after the initial SARS-CoV-2 infection.

The exclusion criteria

We excluded review articles and publications that relied on the analysis of neurological symptoms associated with previous outbreaks (SARS in 2003; MERS in 2012). In addition, neuropsychiatric symptoms such as anxiety, depression, psychosis, and sleep disturbances were not included. Database searches were combined and duplicates were removed.

The following variables were extracted from included studies: first author, type, year and source of publication, research country, sample size, neurological issues, methods, and time when symptoms were identified. In addition, attention was paid to the severity of the COVID-19 disease course, whose severity was measured by hospitalization status without distinction between hospitalization in the intensive care unit. Descriptive analyses were applied. The incidence of neurological issues was presented as numbers and percentages. If in the analyzed article there were more follow-up visits within the time criterion of our study, the most numerous study group was selected. However, if there was the same sample size at the follow-up visits, the last visit was selected.

Categorization of neurological symptoms

To summarize the neurological issues, we had to define a cluster of cognitive problems. Such a cluster was defined as any subjective reports of concentration, memory and attention difficulty, perceived “brain fog”, disorientation/confusion, word-finding difficulty, inability to effectively multitask, and measurable cognitive impairment confirmed by a test. “Frequent,” “more frequent,” and “the most frequent” neurological consequences were defined to have a frequency above 5, 10, and 20%, respectively, and were reported in at least five different studies including at least 1,000 of all patients studied. The term “possible significant neurological consequences” was used if the frequency of symptoms was reported above 15% in at least three publications, with a total study group of at least 300.

Results

Included types of publications—Short characteristic

A total of 497 articles were identified for eligible content. After excluding duplicates and screening titles and abstracts, which did not meet inclusion criteria, 139 full-text publications were assessed. From full-text publications, 94 were excluded due to the non-relevance of the investigated topic. Our review included data from 45 articles: retrospective studies (2), prospective studies (21), case reports/series (15), and cross-sectional studies (7). PRISMA flow diagram is presented in Figure 1. Features of studies included in our review are summarized in Table 1.

Figure 1

Characteristic of neurological issues

In our study, “the most frequent” neurological consequences were fatigue and cognitive problems. Paresthesia and altered smell/taste were classified as “more frequent” and headache and dizziness were identified as “frequent” neurological symptoms in patients with COVID-19. Myalgia and blurred vision were identified as “possible significant neurological consequences” (Table 2). Figure 2 represents the percentage distribution of neurological symptoms as late sequelae of SARS-CoV-2 infection.

Figure 2

Discussion

Our review presents the neurological issues that may be late consequences of SARS-CoV-2 infection. This article provides relevant information from 45 studies involving 9,746 patients. Pooled evidence showed that fatigue, cognitive problems, altered smell/taste, and paresthesia were very common neurological issues that were identified at least 4 weeks after a positive SARS-CoV-2 polymerase chain reaction (PCR) test and/or symptomatic start of confirmed SARS-CoV-2 infection. Other common neurological issues were headaches and dizziness.

Many studies reported a high rate of post-COVID-19 fatigue (Huang et al., 2020; Townsend et al., 2020; Wang et al., 2020). Fatigue is a non-specific symptom that accompanies many diseases, including infectious diseases. Of more than 6,000 studied patients from 15 different articles, more than 40% reported fatigue. It is worth mentioning that fatigue is reported in 5–45% of the general healthy population (Finsterer and Mahjoub, 2014). However, the studies included in our review did not focus on fatigue as the leading symptom. These studies evaluated various sets of symptoms with a neurological profile that accompanies the patient even for months after recovery from COVID-19. Bearing in mind the above data, it is difficult to conclude whether the problem of fatigue has increased during the pandemic. Therefore, further analysis of this issue is necessary.

There is a growing concern about the cognitive aspect of people who have recovered from COVID-19. Hampshire et al., based on cross-sectional cognitive performance data from 81,337 participants, observed that cognitive impairments were most pronounced in people who had been hospitalized but, importantly, were also observed in non-hospitalized patients with no reported breathing difficulties (Hampshire et al., 2021). Therefore, it is easier to understand the cognitive problems in patients hospitalized for COVID-19, who were more likely to have hypoxia, as well as septic complications. Hypoxia is a common cause of neuropsychological changes observed in acute respiratory distress syndrome (Hopkins et al., 2006). Patients who have required ventilation for multiple reasons may need help with daily tasks due to problems with attention, memory, verbal fluency, and information processing speed (Mikkelsen et al., 2012; Sasannejad et al., 2019). Thus, it is well-known that hypoxia, sepsis, and the accompanying immune hyperstimulation contribute to cognitive deficits.

It is less clear that patients with mild COVID-19 course, who have not been hospitalized, may also have objectively measurable Alzheimer's disease (AD)-like cognitive impairment (Albu et al., 2021b; Boesl et al., 2021; Papri et al., 2021). Although the specific mechanisms remain largely unknown, a recent study based on the use of single nuclear RNA sequencing datasets revealed associations between the pathogenic mechanisms of COVID-19 and AD. Researchers have identified significant similarities in neuronal damage, synaptic dysfunction, and neuroinflammation in both diseases. They presented the role of neural cell adhesion molecule 2 (NCAM2) and ICA1L (AD gene marker) in the process leading to cognitive impairment, which may be a potential target for AD intervention (Fu et al., 2022).

There is still too little information in the literature about baseline (before COVID-19 infection) clinical measures of cognitive-affective alteration. Therefore, it can only be assumed that the cognitive impairment may be either the result of the direct negative effects of the SARS-CoV-2 virus or the acceleration and aggravation of pre-existing cognitive deficits. Hence, advancing medical scientific knowledge through full case reports with included pre-COVID-19 status seems the most appropriate way. A case report of a young “33-year-old woman” with cognitive deficits 149 days after the first COVID-19 symptoms is a good example, as we can find a comparison for cognitive tests from 12 years ago (Hellmuth et al., 2021).

Cognitive decline is often undiagnosed until it is more advanced, leading to impairment of the ability to perform daily activities. The SARS-CoV-2 infection has spread to all continents, affecting particularly hard older people with comorbidities. This group of people often experiences a diminished quality of life resulting from new impairments with accompanying limitations in activities and restrictions to their participation in life. Therefore, it is necessary to focus on the possible cognitive impact of SARS-CoV-2 infection. When analyzing the topic of cognitive problems after SARS-CoV-2 infection, it is worth paying attention to the promising reports on the reversibility of cognitive disorders. Blazhenets et al. (2021) demonstrated essential reversibility of decreased neocortical glucose metabolism assessed by 18F-FDG PET accompanied by an improvement in cognitive functions in patients with COVID-19 (subjective and objective MoCa examination) from the subacute stage to the chronic stage after SARS-CoV-2 infection.

Future work would benefit from systematic cognitive assessments of ambulatory patients with COVID-19.

A complete or partial loss of smell and taste sensations is the most frequent neurological manifestation of COVID-19. Their occurrence can be explained as the expression of SARS-CoV-2 entry receptors in the olfactory epithelium. Then, SARS-CoV-2 via the olfactory nerve can spread to the olfactory bulb (Desforges et al., 2019; Beltrán-Corbellini et al., 2020). Clinicians should be alert regarding olfactory disorders which may mark the onset of some neurodegenerative diseases (Zhu et al., 2021).

Paresthesia is a common non-specific symptom with which patients come to the neurological clinic. There is evidence of changes in nociceptor excitability that COVID-19 could induce through multiple potential mechanisms (McFarland et al., 2021).

Other non-specific symptoms reported in the studies were headaches and dizziness. If they persist for several weeks, it is of concern among symptom-experienced people and physicians. This is often the reason for extended diagnostics procedures. During the COVID-19 pandemic, the incidence of headaches increased 5-fold in the studied region (Lippi et al., 2020). De novo headache is common post-COVID-19 and can persist long after infection resolution. Post-COVID-19 headache has often migraineurs features which may reflect an activation of the trigeminovascular system by inflammation or direct involvement of SARS-CoV-2. This hypothesis can be supported by concomitant anosmia (Caronna et al., 2020; Al-Hashel et al., 2021).

Moreover, Al-Hashel et al. (2021) found in the cohort study that a significant number of patients with primary headaches had worsening of their headaches within 3 months after COVID-19 disease. Headache and dizziness were presented very commonly in relevant studies included in our review.

The frequency was above 8 and 6% for headache and dizziness, respectively, reported in 17 different studies for headache and eight for dizziness.

It is worth keeping in mind that the COVID-19 pandemic may contribute to poor mental health manifested by somatization in the form of mental fatigue, cognitive changes, paresthesia, headaches, or dizziness.

Moreover, myalgia and blurred vision were identified as “possible significant neurological consequences”. Most cases of myalgia and blurred vision were self-reported and there was no information about the specificity of the symptoms. Rodriguez et al. (2021) considered whether myopathy is a part of long-COVID-19. They presented Multi Voltage Rule Check (MVRC) recordings 3 weeks after the onset of COVID-19 symptoms showed a marked reduction of early supernormality as a sign of muscle membrane depolarization compared to an earlier recording (Rodriguez et al., 2021).

In addition, it is worth referring to rare late neurological consequences of COVID-19 in our reviews, such as GBS and seizures. Most of the cases of GBS described in the literature are para- or directly postinfectious which is beyond the scope of our review. We found four relevant case reports related to GBS within the timeframe of our review where the interval between GBS and SARS-CoV-2 ranged from 1 month to 53 days. Keddie et al. (2021) compared GBS cases reported during the COVID-19 pandemic to GBS cases from 2016 to 2019. This epidemiological and cohort study investigated the UK population. Based on the comparison, the researchers concluded that GBS incidence has fallen during the pandemic. They assumed it might be caused by a lockdown that reduces transmission of GBS-inducing pathogens such as Campylobacter jejuni and respiratory viruses. There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings, or outcome between the COVID-19 pandemic group and the control groups (Keddie et al., 2021).

There are many descriptions of seizures during the acute infectious period in patients with COVID-19. Even convulsive and nonconvulsive status epilepticus triggered by SARS-CoV-2 virus infection has also been described (Emami et al., 2020; Somani et al., 2020; Asadi-Pooya et al., 2021). In our review, we focused on seizures/status epilepticus as a late consequence of COVID-19. Seizures are not a common late manifestation of COVID-19.

Limitations

The main limitations were reliance on self-report measures in many articles. In some cases, there was a lack of clear information about comorbidities, so some symptoms may be due to pre-existing comorbidities. The same situation was about baseline assessment in the analyzed sources, which makes it impossible to reliably estimate the incidence.

Additionally, in some cases, the grouping of symptoms with an overlapping profile was used, which may have contributed to the fact that the frequency of some of the symptoms found in this review may be incorrectly estimated.

Conclusion

According to data from World Health Organization (WHO) by 3 June 2022, the total number of COVID-19 cases worldwide reaches 528,816,317.00.

Assuming that only a minority percentage of patients with COVID-19 will struggle with late neurological issues when calculated on a global scale of patients affected with COVID-19, the prolonged neurological impact has become increasingly recognized and concerning.

We must remember that symptoms such as fatigue, cognitive problems, smell/taste disturbance, paresthesia or headache, and dizziness may accompany patients for many weeks after infection with SARS-CoV-2. Thus, recognition and familiarity with these neurological issues are imperative in managing these patients.

In our review, the long-term neurological consequences of COVID-19 disease have been collected and categorized in a simple and transparent way. Therefore, our study could be an easily accessible source of knowledge for medical professionals.

References

• 1

  Aasfara J. Hajjij A. Bensouda H. Ouhabi H. Benariba F. (2021). A unique association of bifacial weakness, paresthesia and vestibulocochlear neuritis as post-COVID-19 manifestation in pregnant women: a case report. Pan Afr. Med. J. 38, 30. 10.11604/pamj.2021.38.30.27646

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  Ahmad S. A. Salih K. H. (2021). Post COVID-19 transverse myelitis; a case report with review of literature. Ann. Med. Surg. 69, 102749. 10.1016/j.amsu.2021.102749

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  Albu S. Rivas Zozaya N. Murillo N. (2021b). Multidisciplinary outpatient rehabilitation of physical and neurological sequelae and persistent symptoms of covid-19: a prospective, observational cohort study. Disabil. Rehabil.44, 6833–6840. 10.1080/09638288.2021.1977398

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  Albu S. Zozaya N. R. Murillo N. García-Molina A. Chacón C. A. F. Kumru H. et al . (2021a). What's going on following acute covid-19? Clinical characteristics of patients in an out-patient rehabilitation program. NeuroRehabilitation48, 469–480. 10.3233/NRE-210025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  Alemanno F. Houdayer E. Parma A. (2021). COVID-19 cognitive deficits after respiratory assistance in the subacute phase: A COVID rehabilitation unit experience. PLoS ONE16, 246590. 10.1371/journal.pone.0246590

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  Al-Hashel J. Y. Abokalawa F. Alenzi M. Alroughani R. Ahmed S. F. J. (2021). Coronavirus disease-19 and headache; impact on pre-existing and characteristics of de novo: a cross-sectional study. Headache Pain22, 97. 10.1186/s10194-021-01314-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  Ali S. T. Kang A. K. Patel T. R. Clark J. R. Perez-Giraldo G. S. Orban Z. S. et al . (2022). Evolution of neurologic symptoms in non-hospitalized COVID-19 “long haulers”. Ann. Clin. Transl. Neurol. 9, 950–961. 10.1002/acn3.51570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  Alvare A. Amirianfar E. Mason M. C. Huang L. Jose J. Tiu T. et al . (2021). Extended neuralgic amyotrophy syndrome in a confirmed COVID-19 patient after intensive care unit and inpatient rehabilitation stay. Am. J. Phys. Med. Rehabil. 100, 733–736. 10.1097/PHM.0000000000001795

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  Anaya J. M. Rojas M. Salinas M. L. Rodríguez Y. Roa G. Lozano M. et al . (2021). Post-COVID syndrome. A case series and comprehensive review. Post-COVID study group. Autoimmun Rev. 20, 102947. 10.1101/2021.07.17.21260655

  • CrossRef
  • Google Scholar

• 10

  Asadi-Pooya A. A. Simani L. Shahisavandi M. Barzegar Z. (2021). COVID-19, de novo seizures, and epilepsy: a systematic review. Neurol. Sci.42, 415–431. 10.1007/s10072-020-04932-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  Baig A. M. (2020). Deleterious outcomes in long-Hauler COVID-19: the effects of SARS-CoV-2 on the CNS in chronic COVID syndrome. ACS Chem. Neurosci. 11, 4017–4020. 10.1021/acschemneuro.0c00725

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  Beltrán-Corbellini Á. Chico-García J. L. Martínez-Poles J. Rodríguez-Jorge F. Natera-Villalba E. Gómez-Corral J. et al . (2020). Acute-onset smell and taste disorders in the context ofCovid-19: a pilot multicenter PCR-based case-control study. Eur J Neurol.27, 1738–1741. 10.1111/ene.14359

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  Blazhenets G. Schroeter N. Bormann T. (2021). Slow but evident recovery from neocortical dysfunction and cognitive impairment in a series of chronic COVID-19 patients. J. Nucl. Med. 62, 910–915. 10.2967/jnumed.121.262128

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  Boesl F. Audebert H. Endres M. Prüss H. Franke C. A. (2021). Neurological outpatient clinic for patients with post-COVID-19 syndrome — A report on the clinical presentations of the first 100 patients. Front. Neurol. 12, 738405. 10.3389/fneur.2021.738405

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  Bozzali M. Grassini A. Morana G. (2021). Focal seizures with impaired awareness as long-term neurological complication of COVID-19: a case report. Neurol. Sci. 42, 2619–2623. 10.1007/s10072-021-05233-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  Bungenberg J. Humkamp K. (2022). Long COVID-19: objectifying most self-reported neurological symptoms. Ann. Clin. Transl. Neurol.9, 141–154. 10.1002/acn3.51496

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  Carfi A. Bernabei R. Landi F. (2020). Gemelli against C-P-ACSG. Persistent symptoms in patients after acute COVID-19. JAMA324, 603–605. 10.1001/jama.2020.12603

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  Caronna E. Ballvé A. Llauradó A. Gallardo V. J. (2020). Headache: a striking prodromal and persistent symptom, predictive of COVID-19 clinical evolutionCephalalgia40, 1410–1421. 10.1177/0333102420965157

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  Carroll E. Neumann H. Aguero-Rosenfeld M. E. Lighter J. Czeisler B. M. Melmed K. et al . (2020). Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus. Epilepsia61, 135–139. 10.1111/epi.16683

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  Carvalho-Schneider C. Laurent E. Lemaignen A. Beaufils E. Bourbao-Tournois C. Laribi S. et al . (2020). Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin. Microbiol. Infect.27, 258–263. 10.1016/j.cmi.2020.09.052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  Collantes M. E. V. Espiritu A. I. Sy M. C. C. Anlacan V. M. M. Jamora R. D. G. (2021). Neurological manifestations in COVID-19 infection: a systematic review and meta-analysis. Can. J. Neurol. Sci. 48, 66–76. 10.1017/cjn.2020.146

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  Datta S. D. Talwar A. Lee J. T. A. (2020). Proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA324, 2251–2252. 10.1001/jama.2020.22717

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  Desforges M. Le Coupanec A. Dubeau P. Bourgouin A. Lajoie L. Dubé M. et al . (2019). Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system?Viruses12, 14. 10.3390/v12010014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  Divani A. A. Andalib S. Biller J. Di Napoli M. Moghimi M. Rubinos C. A. et al . (2020). Central nervous system manifestations associated with COVID-19. Curr. Neurol. Neurosci. Rep. 20:60. 10.1007/s11910-020-01079-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  Emami A. Fadakar N. Akbari A. Lotfi M. Farazdaghi M. Javanmardi F. et al . (2020). Seizure in patients with COVID-19. Neurol. Sci.41, 3057–3061. 10.1007/s10072-020-04731-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  Finsterer J. Mahjoub S. Z. (2014). Fatigue in healthy and diseased individuals. Am. J. Hosp. Palliat. Med. 31, 562–575. 10.1177/1049909113494748

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  Frontera J. A. Yang D. Lewis A. A. (2021). prospective study of long-term outcomes among hospitalized COVID-19 patients with and without neurological complications. J. Neurol. Sci. 426, 117486. 10.1016/j.jns.2021.117486

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  Fu Y. Guo Z. Wang Y. Zhang H. Zhang F. Xu Z. et al . (2022). Single-nucleus RNA sequencing reveals the shared mechanisms inducing cognitive impairment between COVID-19 and Alzheimer's disease. Front. Immunol. 13, 967356. 10.3389/fimmu.2022.967356

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  Garg A. Goyal S. Comellas A. P. (2021). Post-acute COVID-19 functional movement disorder. SAGE Open Med. Case Rep.9. 10.1177/2050313X211039377

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  Garrigues E. Janvier P. Kherabi Y. Le Bot A. Hamon A. Gouze H. et al . (2020). Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. Dec. 81, 4–6. 10.1016/j.jinf.2020.08.029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  Graham E. L. Clark J. R. Orban Z. S. Lim P. H. Szymanski A. L. Taylor C. et al . (2021). Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers”. Ann. Clin. Transl. Neurol. 8, 1073–1085. 10.1002/acn3.51350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  Halpin S. J. McIvor C. Whyatt G. Adams A. Harvey O. McLean L. et al . (2021). Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J. Med. Virol.93, 1013–1022. 10.1002/jmv.26368

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  Hampshire A. Trender W. Chamberlain S. R. Jolly A. E. (2021). Cognitive deficits in people who have recovered from COVID-.19. EClin. Med. 39, 101044. 10.1016/j.eclinm.2021.101044

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  Hellmuth J. Barnett T. A. Asken B. M. Kelly J. D. Torres L. Stephens M. L. et al . (2021). Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients. Neurovirology27, 191–195. 10.1007/s13365-021-00954-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  Hopkins R. O. Gale S. D. Weaver L. K. (2006). Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj.20, 263–271. 10.1080/02699050500488199

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  Hosseiny M. Kooraki S. Gholamrezanezhad A. Reddy S. Myers L. (2020). Radiology perspective of coronavirus disease 2019 (COVID-19): lessons from severe acute respiratory syndrome and Middle East respiratory syndrome. Am. J. Roentgenol. 214, 1078–1082. 10.2214/AJR.20.22969

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  Huang C. Huang L. Wang Y. Li X. Ren L. Gu X. et al . (2021). 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet397, 220–232. 10.1016/S0140-6736(20)32656-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. et al . (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet395, 497–506. 10.1016/S0140-6736(20)30183-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  Iqbal A. Iqbal K. Arshad A. S. Azim D. Farid E. Baig M. D. et al . (2021). The COVID-19 sequelae: a cross-sectional evaluation of post-recovery symptoms and the need for rehabilitation of COVID-19 survivors. Cureus.13. 10.7759/cureus.13080

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  Kanberg N. Simrén J. Edén A. Andersson L. M. Nilsson S. Ashton N. J. et al . (2021). Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. Biomedicine70, 103512. 10.1016/j.ebiom.2021.103512

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  Kayaaslan B. Eser F. Kalem A. K. Kaya G. Kaplan B. Kacar D. et al . (2021). Post-COVID syndrome: a single-center questionnaire study on 1007 participants recovered from COVID-19. Med. Virol. 93, 6566–6574. 10.1002/jmv.27198

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  Keddie S. Pakpoor J. Mousele C. Pipis M. Machado P. M. Foster M. et al . (2021). Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barre syndrome. Brain144, 682–693. 10.1093/brain/awaa433

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  Leth S. Gunst J. D. Mathiasen V. Hansen K. Søgaard O. Østergaard L. et al . (2021). Persistent symptoms in patients recovering from COVID-19 in Denmark. Open Forum Infect. Dis.8. 10.1093/ofid/ofab042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  Lippi G. Mattiuzzi C. Bovo C. Henry B. M. (2020). Headache is an important symptom in patients with coronavirus disease 2019 (COVID-19)Diagnosis7, 409–411. 10.1515/dx-2020-0048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  McFarland A. J. Yousuf M. S. Shiers S. Price T. J. (2021). Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain. Pain Rep. 6, 885. 10.1097/PR9.0000000000000885

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  Mendelson M. Nel J. Blumberg L. Madhi S. A. Dryden M. Stevens W. et al . (2020). Long-COVID: An evolving problem with an extensive impact. S. Afr. Med. J. 111, 10–12. 10.7196/SAMJ.2020.v111i11.15433

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  Mikkelsen M. E. Christie J. D. Lanken P. N. Biester R. C. Thompson B. T. Bellamy S. L. et al . (2012). The adult respiratory distress syndrome cognitive outcomes study. Am. J. Respir. Crit. Care Med.185, 1307–1315. 10.1164/rccm.201111-2025OC

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  Miskowiak K. W. Johnsen S. Sattler S. M. (2021). Cognitive impairments four months after COVID-19 hospital discharge: Pattern, severity and association with illness variables. Eur. Neuropsychopharmacol. 46, 39–48. 10.1016/j.euroneuro.2021.03.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  Misra S. Kolappa K. Prasad M. Radhakrishnan D. Thakur K. T. Solomon T. et al . (2021). Frequency of neurological manifestations in COVID-19: a systematic review and meta-analysis of 350 studies. medRxiv.97, 2269–2281.

  • Pubmed Abstract
  • Google Scholar

• 50

  Nakamura I. Itoi T. Inoue T. (2021). Case report of restless anal syndrome as restless legs syndrome variant after COVID-19. BMC Infect. Dis. 21, 993. 10.1186/s12879-021-06683-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  Ngai J. C. Ko F. W. Ng S. S. To K. W. Tong M. Hui D. S. et al . (2010). The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology15, 543–550. 10.1111/j.1440-1843.2010.01720.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  Orr,ù G. Bertelloni D. Diolaiuti F. (2021). Long-covid syndrome? A study on the persistence of neurological, psychological and physiological symptoms. Healthcare9, 575. 10.3390/healthcare9050575

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  Palaiodimou L. Stefanou M. I. Katsanos A. H. Fragkou P. C. (2021). Prevalence, clinical characteristics and outcomes of Guillain-Barré syndrome spectrum associated with COVID-19: a systematic review and meta-analysis. Eur. J. Neurol.28, 3517–3529. 10.1111/ene.14860

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  Papri N. Hayat S. Mohammed A. Afsar M. N. A. Hasan I. Rahman A. et al . (2021). Guillain-Barre syndrome associated with SARS-CoV-2 infection: a case report with long term follow up. Neuroimmunology356, 577590. 10.1016/j.jneuroim.2021.577590

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  Park S. Majoka H. Sheikh A. Ali I. (2021). A presumed case of new-onset focal seizures as a delayed complication of COVID-19 infection. Epilep. Behav. Rep. Int. Dev. Res. Cent. Can.16, 100447. 10.1016/j.ebr.2021.100447

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  Paterson R. W. Brown R. L. Benjamin L. Nortley R. Sarah W. Bharucha T. et al . (2020). The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain143, 3104–3120. 10.1093/brain/awaa240

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  Pilotto A. Cristillo V. (2021). Long-term neurological manifestations of COVID-19: prevalence and predictive factors. Neurol. Sci. 42, 4903–4907. 10.1007/s10072-021-05586-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  Pistarini C. Fiabane E. Houdayer E. (2021). Cognitive and emotional disturbances due to COVID-19: an exploratory study in the rehabilitation setting. Front. Neurol. 12, 643646. 10.3389/fneur.2021.643646

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  Poletti S. Palladini M. Mazza M. G. (2021). Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life. Eur. Arch. Psychiatry Clin. Neurosci. 272, 773–782. 10.1007/s00406-021-01346-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  Qin Y. Wu J. Chen T. Li J. Zhang G. Wu D. et al . (2021). Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations. J. Clin. Invastig.131, 147329. 10.1172/JCI147329

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  Raahimi M. M. Kane A. Moore C. E. Alareed A. W. (2021). Late onset of Guillain-Barre syndrome following SARS-CoV-2 infection: part of ‘long COVID-19 syndrome’?BMJ Case Rep. (2021) 14:240178. 10.1136/bcr-2020-240178

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  Rass V. Beer R. Schiefecker A. J. (2022). Neurological outcomes 1 year after COVID-19 diagnosis: a prospective longitudinal cohort study. Eur. J. Neurol. 29, 1685–1696. 10.1111/ene.15307

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  Rivera-Izquierdo M. Láinez-Ramos-Bossini A. J. Alba de Long I. G. F. (2022). COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes—a multicentre cohort study. BMC Med. 20, 92. 10.1186/s12916-022-02292-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  Rodriguez B. Nansoz S. Cameron D. R. Z'Graggen W.J. (2021). Is myopathy part of long-Covid?Clin. Neurophysiol. 132, 1241–1242. 10.1016/j.clinph.2021.03.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  Rogers J. P. Watson C. J. Badenoch J. Cross B. Butler M. Song J. et al . (2021). Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives. J. Neurol. Neurosurg. Psychiatry92, 932–941. 10.1136/jnnp-2021-326405

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  Romero-Duarte A. Rivera-Izquierdo M. de Alba Guerrero-Fernández I. (2021). Sequelae, persistent symptomatology and outcomes after COVID-19 hospitalization: the ANCOHVID multicentre 6-month follow-up study. BMC Med. 19, 129. 10.1186/s12916-021-02003-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  Romoli M. Jelcic I. Bernard-Valnet R. Garcia A. D. (2020). A systematic review of neurological manifestations of SARS-CoV-2 infection: the devil is hidden in the details. Eur. J. Neurol.27, 1712–1726. 10.1111/ene.14382

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  Roy D. Ghosh R. Dubey S. Dubey M. J. Benito-León J. Kanti Ray B. et al . (2021). Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic. Can. J. Neurol. Sci.48, 9–24. 10.1017/cjn.2020.173

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  Rudroff T. Fietsam A. C. Deters J. R. Bryant A. D. Kamholz J. (2020). Post-COVID-19 fatigue: potential contributing factors. Brain Sci. 10, 1012. 10.3390/brainsci10121012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  Santis L. V. D. Sobrino B. González G. E. Ruíz-Mesa J. D. Plata A. Márquez-Gómez I. et al . (2020). Clinical and immunoserological status 12 weeks after infection with COVID-19: prospective observational study. MedRxiv.10.1101/2020.10.06.20206060

  • CrossRef
  • Google Scholar

• 71

  Sasannejad C. Ely E. W. Lahiri S. (2019). Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms. Crit Care23, 352. 10.1186/s13054-019-2626-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  Siow I. Lee K. S. Zhang J. J. Saffari S. E. Ng A. (2021). Encephalitis as a neurological complication of COVID-19: a systematic review and meta-analysis of incidence, outcomes, and predictors. Eur. J. Neurol. 28, 3491–3502. 10.1111/ene.14913

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  Somani S. Pati S. Gaston T. Chitlangia A. Agnihotri S. (2020). De novo status epilepticus in patients with COVID-19. Ann Clin Transl Neurol. 7, 1240–1244. 10.1002/acn3.51071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  Stuby J. Roth R. Strecker N. Teubner J. Rudiger A. (2021). Post-COVID-19 bifacial weakness and paraesthesia: a case report. Swiss Med. Wkly. 21, 151. 10.4414/SMW.2021.w30066

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  Sykes D. L. Holdsworth L. Jawad N. Gunasekera P. Morice A. H. Crooks M. G. (2021). Post-COVID-19 symptom burden: what is long-COVID and how should we manage it?Lung199, 113–119. 10.1183/13993003.congress-2021.OA4189

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  Townsend L. Dyer A. H. Jones K. Dunne J. (2020). Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS ONE15, 20164293. 10.1101/2020.07.29.20164293

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  Vanichkachorn G. Newcomb R. Cowl C. T. (2021). Post–COVID-19 syndrome (Long Haul Syndrome): description of a multidisciplinary clinic at mayo clinic and characteristics of the initial patient cohort. Mayo Clin. Proc. 96, 1782–1791. 10.1016/j.mayocp.2021.04.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  Vogrig A. Gigli G. L. Bnà C. Morassi M. (2021). Stroke in patients with COVID-19: clinical and neuroimaging characteristics. Neurosci. Lett. 743, 135564. 10.1016/j.neulet.2020.135564

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  Wang D. Hu B. Hu C. Zhu F. Liu X. ' Zhang J. et al . (2020). Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA323, 1061–1069. 10.1001/jama.2020.1585

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  Wijeratne T. Crewther S. (2020). Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community. J. Neurol. Sci. 419, 117179. 10.1016/j.jns.2020.117179

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  Wong-Chew R. M. Rodríguez Cabrera E. X. Rodríguez Valdez C. A. Tapia-Conyer R. Valdez-Vázquez R. R. (2022). Symptom cluster analysis of long COVID-19 in patients discharged from the temporary COVID-19 hospital in Mexico City, Ther. Adv. Infect. Dis. 910.1177/20499361211069264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  Woo M. S. Malsy J. Pöttgen J. Seddiq Z. S. Ufer F. Hadjilaou A. et al . (2020). Frequent neurocognitive deficits after recovery from mild COVID-19. Brain Commun.2. 10.1093/braincomms/fcaa205

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  Yassin A. Nawaiseh M. Shaban A. Alsherbini K. El-Salem K. Soudah O. et al . (2021). Neurological manifestations and complications of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. BMC Neurol.21, 138. 10.1186/s12883-021-02161-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  Zhang X. Wang F. Shen Y. Zhang X. Cen Y. Wang B. et al . (2021). Symptoms and health outcomes among survivors of COVID-19 infection 1 year after discharge from hospitals in Wuhan, China. JAMA Netw. Open. 1, 4. 10.1001/jamanetworkopen.2021.27403

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  Zhu Y. Cao M. Zheng P. Shen W. (2021). Residual olfactory dysfunction in coronavirus disease 2019 patients after long term recovery. J. Clin. Neurosci. 93, 31–35. 10.1016/j.jocn.2021.07.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar