Relationship between neuropsychiatric signs and symptoms and SARS-CoV-2 infection: an integrative review

Introduction: Several viruses, including CoVs, can affect the nervous system, causing neuropsychiatric signs and symptoms. Because this is an unknown disease widely spread, there are few studies that deal with the effects of the SARS-CoV-2 on the nervous system. Objective: To describe the relationship between neuropsychiatric signs and symptoms and SARS-Cov-2 virus infection. Methods: integrative review conducted in the Pubmed Portal, Virtual Health Library, Cochrane and the academic researcher Science Direct. The works were analyzed qualitatively, with the narrative description divided into four thematic categories. Results: 1024 studies were found and 48 studies selected to compose this integrative review. There is a pathophysiological relationship of SARS-Cov-2 infection and the involvement of the Central Nervous System and Peripheral Nervous System through different pathways and mechanisms. Conclusion: Monitoring patients during and after COVID-19 can minimize the neuropsychiatric sequelae resulting from this disease, especially in elderly patients with comorbidities.


Introduction
In December 2019, in Wuhan, China, an epidemic of cases of atypical pneumonia caused by a new coronavirus emerged, called SARS-CoV-2. Due to the high transmissibility of this virus, the infection quickly took on worldwide proportions and, currently, the Corona Virus Disease 2019 (COVID- 19) pandemic has been an intense public health problem with impacts on all spheres of society (Brito & Silva, 2020).
With the erratic behavior and the rapid spread of the SARS-CoV-2 virus, the problem has become a worldwide public health emergency (WHO, 2020). Currently, it is known that several viruses, including CoVs, can affect the Central Nervous System (CNS) and the Peripheral Nervous System (PNS), causing several neuropsychiatric signs and symptoms. The increasing reports based on clinical data from patients infected with SARS-CoV-2 reveal the presence of signs and symptoms such as headache, delirium, psychosis, altered consciousness, hyposmia or anosmia, dysgeusia, and hypogeusia or ageusia (Parry et al., 2020).
Because this is an unknown disease widely spread, there are few studies that deal with the effects of the SARS-CoV-2 on the Nervous System. It is important that studies are developed to better explain the clinical manifestations and complications of COVID-19, among them, neuropsychiatric signs and symptoms manifested in the acute phase of the disease and/or that persist as sequelae of the infection.
Health professionals who are currently involved in the prevention, early detection and treatment of COVID-19 can use the synthesized knowledge on the subject for decision-making. Furthermore, it can contribute to the creation of multidisciplinary outpatient health services for the follow-up of patients with neuropsychiatric sequelae of  Therefore, the following research question arose: What is the relationship between neuropsychiatric signs and symptoms and SARS-CoV-2 infection? In the context of a SARS-CoV-2 pandemic, evidence-based practice encourages the use of research results into healthcare practices. In view of the aforementioned, the present study aims to describe the relationship between neuropsychiatric signs and symptoms and SARS-CoV-2 infection.

Methodology
This study is about an integrative review of the literature, with the objective of establishing the relationship between sinus and neuropsychiatric symptoms and infection by SARS-CoV-2. The study was elaborated in the following stages: theme Research, Society andDevelopment, v. 11, n. 2, e17011225460, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i2.25460 3 definition; elaboration of the guiding question; literary search; delimitation of study selection criteria; reading of studies; organization of studies; synthesis of the information found; interpretation of results and presentation of the review (Sousa et al., 2017).
The following libraries and databases were selected for the bibliographic search: the Brazilian Virtual Health Library (BVS in Portuguese), which covers the LILACS, BDENF, WHO-IRIS, PAHO-IRIS, and SCIELO databases; Pubmed, which covers the Medical Literature Analysis and Retrieval System Online (Medline) database; Cochrane; and Science Direct. The use of these different databases was intended to expand the scope of the research and, thus, to minimize possible bias. In order to survey the studies in these databases, different descriptors were initially defined to be used in each database.
The following descriptors from the MeSH vocabulary were used in Pubmed, Science Direct, and Cochrane: "coronavirus", "SARS", and "neurologic symptoms", using "MeSH Terms" as a query. In Science Direct, we limited the search to the year 2020. In the Virtual Health Library, the following descriptors from the Health Sciences Descriptors Vocabulary (DeCS in Portuguese) were used: "SARS Virus" and "Nervous System", using "descriptor" as a query. No other filters were used to search for these articles, as the choice of descriptors based on their operational definitions was enough to make this search adequate.
The inclusion criteria were: (a) full-text studies addressing neuropsychiatric signs and symptoms related to SARS-CoV-2 infection, and (b) studies answering the research question of the integrative review. Duplicate articles were excluded as well as editorials, letters to the editor, and opinion articles. The bibliographic search took place from June to August 2020.
Each database and the respective search engines were accessed in a single day, with a recording of the search retrieved from each database. The selection of studies was carried out in the subsequent days through reading of titles and abstracts. When necessary, full texts were accessed and read for assessment of the pre-established inclusion and exclusion criteria.
Two pairs of independent reviewers extracted information from the studies (1 pair for the Virtual Health Library, Pubmed, and Cochrane searches, and 1 pair for the Science Direct search). These pairs were also responsible for conducting the evaluation of selected studies based on the Joanna Briggs Institute (JBI) (Sousa et al., 2017). Data from the analyzed studies were extracted using an electronic form created in Microsoft Word 2013-2015 with the following variables: name of the database, title of the article, country of origin, study objective, study design, level of evidence, and results about the relationships between neuropsychiatric signs and symptoms and SARS-CoV-2 infection.  The data analysis was done in a qualitative way, with a narrative approach. The researchers opted for this approach because the review included research with different methodological designs, resulting in a high heterogeneity of data and thus it would not be feasible to carry out a meta-analysis. The reading and synthesis of the selected studies allowed the identification of the following thematic categories that describe the results of the integrative review: (1) Neuropsychiatric signs and symptoms: prevalence, types, and relationship with sociodemographic and clinical characteristics; (2) Pathophysiological mechanisms of SARS-CoV-2 associated with CNS and PNS manifestations; (3) Neuroprotective mechanisms that decrease the occurrence of neuropsychiatric signs and symptoms; and (4) Neuropsychiatric signs and symptoms that occur and/or persist after COVID-19.

Neuropsychiatric signs and symptoms: prevalence, types, and relationship with sociodemographic and clinical characteristics
Regarding the prevalence of neurological symptoms in people with COVID-19 infection, it was found that 36.4% had neurological symptoms, including smell and taste disorders. The findings also suggest that patients with the most severe form of the disease were more likely to manifest neurological symptoms, such as acute cerebrovascular diseases (5.7% vs. 0.8%), impaired level of consciousness (14.8% vs. 2.4%), and skeletal muscle injury (19.3% vs. 4.8%) compared to those with the mild form of the disease (Troyer et al., 2020;Rao & Jayabaskaran, 2020;Koralnik & Tyler, 2020;Msigwa et al., 2020;Singh et al., 2020;Pedicelli et al., 2020;Mao et al., 2020).

Identification
Studies selected through title and abstract screening (n = 494)

Screening Eligibility
Full-text articles assessed for eligibility (n = 224)

Included
Studies excluded for not addressing the study subject after full-text reading (n = 141) or Editor Letters (n= 16) Studies included (n = 48) A second study with 58 patients hospitalized with severe acute respiratory syndrome caused by COVID-19 found that 69% of the patients had agitation, 67% had signs of corticospinal compromise, and 36% had dysexecutive syndrome, which is characterized by difficulty in concentration, attention, orientation, and in following commands (Helm et al., 2020). A study reported the first cases of myoclonus related to SARS-CoV-2 neuro invasion (Rábano-Suárez et al., 2020).

Pathophysiological mechanisms of SARS-CoV-2 associated with CNS and PNS manifestations
The following pathophysiological mechanisms are described in the literature: hematogenous invasion of the CNS

Neuroprotective mechanisms that decrease the occurrence of neuropsychiatric signs and symptoms
Authors describe that specific monoclonal antibodies that bind to the SARS-CoV-2 receptor and antibodies that block the action of inflammatory interleukins, such as tocilizumab, seem to offer a neuroprotective effect in people with COVID-19 (Carod-Artal et al., 2020). A follow-up study of people with severe cases of COVID-19 shows that the use of the anti-epileptic medication levetiracetam via intravenous injection can prevent compromise of the Central Nervous System (Afshar et al., 2020).
Another study on the therapeutic use of botulinum toxin in people with COVID-19 shows the following benefits: (1) increased immune cell count such as platelet count (improvement of macrophage-mediated phagocytosis); (2) improved blood circulation and oxygen supply, which improves the survival rate of people with ischemic conditions, in particular, neuroprotection in ischemic brain; and (3) suppression of the angiotensin-converting enzyme 2 (ACE2) receptor expression (Sousa et al., 2017). It is important to highlight that there is a need for further investigation and development of clinical research on drugs that may offer neuroprotective effects in people with COVID-19. CNS and PNS compromise are concerning and should be considered as essential elements in the treatment of SARS-CoV-2 infection.

Discussion
SARS-CoV-2 has the ability to selectively bind to ACE2 receptors, which are highly expressed in the epithelial cells of the respiratory and intestinal systems and also in the CNS, both in glial cells and neurons, which makes the CNS a potential target for the virus. The presence of the virus in the systemic circulation is proven and, consequently, in the brain. The slow movement of blood within the microcirculation may be one of the factors that can facilitate the interaction of the virus with the ACE2 receptor expressed in the brain capillary endothelium Serrano-Castro et al., 2020).
Authors present a detailed summary of the physiological mechanisms that explain the CNS and PNS compromise related to the SARS-CoV-2 virus, as follows (Sousa et al., 2020): (a) hypercoagulabity -coagulation dysfunction increasingly reported in severe cases of COVID-19, which can precipitate major bleeding, venous thrombosis, or intracranial hemorrhage; (b) vascular endothelial injury -resulting from tropism of the virus to endothelial cells that express ACE2. Endothelial damage induced by SARS-CoV-2 can predispose to cerebral vascular thrombosis in situ or can lead to the rupture of the blood-brain barrier; (c) hypoxia -acute hypoxemia can result in hypoxic ischemic encephalopathy. Prolonged hypoxia can induce demyelination or produce micro-hemorrhages in the white matter. Prolonged hypoxemia leads to oligodendroglial cell damage.
Oligodendroglial cells form the myelin sheath on CNS axons, and their death causes demyelination of cerebral white matter; (d) neurotropism -SARS-CoV-2 S1 protein has an avid affinity for ACE2 receptors in humans, which are expressed in Research, Society andDevelopment, v. 11, n. 2, e17011225460, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i2.25460 Regarding the predominance of women with neurological symptoms, several authors explain that women were proportionally more affected by hyposmia or anosmia than men. Although more data are needed to determine whether sex is a predisposing factor for the development of anosmia, the predisposition of women to this symptom can be explained by sexual dimorphisms in the olfactory bulb (Rao & Jayabaskaran, 2020;Kosugi et al., 2020). In this context, it is important to highlight that elderly patients are more likely to develop severe forms of COVID-19, with neurological/neuropsychiatric manifestations and complications.
Prolonged hospitalizations in Intensive Care Units associated with severe pathological conditions, such as the cytokine storm, are related to the occurrence of persistent neurocognitive deficits up to 18 months after hospital discharge (Troyer et al., 2020). So the hospitalization itself combined with COVID-19 related complications and the invasion of the virus in the CNS and PNS increase the chances of neuropsychiatric sequelae.
Systemic inflammation triggered by the SARS-CoV-2 infection can further contribute to neuroinflammatory processes and increase susceptibility to neurological syndromes. CNS infections can thus promote the development of neurodegenerative diseases in individuals who are already at risk. Specifically, the impact of SARS-CoV-2 on the CNS can: (1) directly lead to neurological changes, (2) worsen pre-existing neurological conditions, and/or (3) increase susceptibility or aggravate the damage caused by other conditions (Felice et al., 2020).
It is worth noting that the SARS-CoV-2 infection is recently recognized and its long-term neurological consequences are still unknown, although there are indications that they do occur. Long-term monitoring of patients who survived COVID-19 is necessary to determine if there are any permanent neurological effects after the infection. Therefore, patients must be closely monitored, and future studies must consider late neurological complications including demyelinating and degenerative disorders in these patients (Abboud et al., 2020).
The studies included in this integrative review have lower levels of evidence. Therefore, the thematic categories that involve neuroprotective mechanisms and the persistence of neuropsychiatric signs and symptoms after COVID-19 must be further investigated, preferably by cohort studies and well-designed clinical trials.
This integrative review has the following implications: (a) it provides an in-depth and up-to-date synthesis of the knowledge produced by worldwide researchers about serious complications from the SARS-CoV-2 virus, such as neuropsychiatric signs and symptoms; (b) it can assist in the decision-making of health professionals when monitoring and treating patients with COVID-19; (c) it describes knowledge gaps and research questions that need to be investigated in further studies for the advancement of knowledge and improved practice in the area; (d) it can alert health professionals and managers about the need to implement monitoring services for people who have had and (e) in the context of this pandemic, studies involving the theme of SARS-CoV-2 infection are very important, regardless of the approaches used, because this is a new disease and the knowledge that has been produced and disseminated has reduced serious impacts caused by the virus.
The recommendation for health professionals is to monitor patients with COVID-19 during and after the disease for the neuropsychiatric signs and symptoms, especially elderly patients, people with comorbidities (including cardiovascular and pulmonary disorders, diabetes mellitus, and obesity), and patients with pre-existing neurological and psychiatric diseases. Such a situation can allow decision-making for the implementation of an early rehabilitation treatment, minimizing the sequels resulting from COVID-19.
This integrative review points out several questions that need to be investigated in future studies such as the existence of clinical, laboratory, or pharmacological neuroprotective factors that would decrease the chances of developing neuropsychiatric signs and symptoms; follow-up studies with people who had COVID-19, to ascertain the incidence of neuropsychiatric signs and symptoms at a later stage; and investigations on the recurrence of neuropsychiatric signs and symptoms or occurrence of new manifestations in patients who had had those in the early stage of the infection.
The limitations of this study are related to the number of studies listed, the few databases used, and the non-use of methods to assess the methodological quality of these studies. In addition, SARS-CoV-2 infection and its relationship with short, medium and long-term neuropsychiatric symptoms and symptoms are still under study, and its pathology  during and after infection  is not yet fully clarified. It is also worth remembering that at the time, many studies with preliminary results were published, which may interfere with the quality of the reviews carried out on the subject.

Final Considerations
The studies included in this integrative review indicate that there is a pathophysiological relationship between SARS-CoV-2 infection and CNS and PNS compromise. Mechanisms underlying this relationship include the hematogenous pathway, the lymphatic pathway, immunological and inflammatory mechanisms, neuronal invasion in the cribriform plate close to the olfactory bulb (ethmoid bone), hypoxia, trans-synaptic transmission from the lung to the CNS, and through nerve cells present in the gastrointestinal tract and sympathetic afferents.
The chances of nervous system compromise increase in elderly patients, people with associated comorbidities such as obesity, diabetes mellitus, and chronic obstructive pulmonary disease, and in patients with pre-existing neurological/psychiatric diseases. The most cited neuropsychiatric signs and symptoms were headache, delirium, smell and taste disorders, and stroke. The evaluation and monitoring of patients with COVID-19 during and after the disease is important for the early detection and treatment of neuropsychiatric signs and symptoms.