key: cord-1035679-2d4uc4k5
authors: Hawkins, Michael; Sockalingam, Sanjeev; Bonato, Sarah; Rajaratnam, Thiyake; Ravindran, Mithunan; Gosse, Paula; Sheehan, Kathleen Ann
title: A rapid review of the pathoetiology, presentation, and management of delirium in adults with COVID-19
date: 2020-12-25
journal: J Psychosom Res
DOI: 10.1016/j.jpsychores.2020.110350
sha: 02f2f3b462327cd965136ec90ed78989af0f6dad
doc_id: 1035679
cord_uid: 2d4uc4k5

Background COVID-19 causes significant morbidity and mortality. Despite the high prevalence of delirium and delirium-related symptoms in COVID-19 patients, data and evidence-based recommendations on the pathophysiology and management of delirium are limited. Objective We conducted a rapid review of COVID-19-related delirium literature to provide a synthesis of literature on the prevalence, pathoetiology, and management of delirium in these patients. Methods Systematic searches of Medline, Embase, PsycInfo, LitCovid, WHO-COVID-19, and Web of Science electronic databases were conducted. Grey literature was also reviewed, including preprint servers, archives, and websites of relevant organizations. Search results were limited to the English language. We included literature focused on adults with COVID-19 and delirium. Papers were excluded if they did not mention signs or symptoms of delirium. Results 229 studies described prevalence, pathoetiology, and/or management of delirium in adults with COVID-19. Delirium was rarely assessed with validated tools. Delirium affected >50% of all patients with COVID-19 admitted to the ICU. The etiology of COVID-19 delirium is likely multifactorial, with some evidence of direct brain effect. Prevention remains the cornerstone of management in these patients. To date, there is no evidence to suggest specific pharmacological strategies. Discussion Delirium is common in COVID-19 and may manifest from both indirect and direct effects on the central nervous system. Further research is required to investigate contributing mechanisms. As there is limited empirical literature on delirium management in COVID-19, management with non-pharmacological measures and judicious use of pharmacotherapy is suggested.

studies, and only nine of the 40 studies reporting prevalence used a validated tool to screen or diagnose delirium, with the majority relying on review of medical records or subjective patient self-report. The language used to indicate delirium, or its related symptoms, varied across studies ( Table 1) .

Rates of delirium differed substantially depending on the study population and setting.

Prevalence of delirium was highest in those admitted to the ICU, ranging from 65% to 79.5% [31] [32] [33] . In studies which stratified groups by COVID-19 severity, higher rates were reported in those with severe respiratory disease (disorder of consciousness: 7.2% vs. 38.9%; OR 8.18, CI 5.5-12.2; acute confusional syndrome: 3.9% vs. 14.9%; OR 4.31 CI 2.5-7.4; p < .001 [34] ; confusion: 0% vs 18.5%; p<0.01 [35] ; impaired consciousness: 2.4% vs 14.8%; p<0.001 [13] ).

Similarly, studies of older adults found that significant proportions experienced delirium while hospitalized with COVID-19, often associated with age and frailty ranging from 29% to 40% [36] [37] [38] [39] [40] . Nine studies reported delirium motor subtype, agitation or specifically hyper-or hypoactive delirium, with mixed results [31, 37, [41] [42] [43] [44] [45] [46] [47] . Patients admitted to acute medical wards demonstrating hypoactive delirium ranged from 31% to 74.5% [37, 43, 45, 46] . Other studies found substantial proportions of patients with agitation in the palliative setting (69% [31] ; 77% [44] ) and ICU (42.6% [42] ; 86.6% [33] ). In contrast, Khan et al. (2020) found that, on first assessment, most ICU patients (86.8%) had hypoactive delirium [32] . Although few studies included a comparison group, rates of delirium were substantially higher in those with COVID- [72, [89] [90] [91] and can increase the permeability of the blood-brain barrier (BBB) allowing inflammatory cells to enter the brain, where they too can release cytokines causing neuronal damage [22, 71, [92] [93] [94] [95] [96] . One manifestation of this theorized mechanism, illustrated in a case report of a patient presenting with altered mental status, is acute necrotizing encephalopathy [92] . This condition is thought to involve an intracranial cytokine storm mediated by BBB permeabilization rather than direct viral neuronal damage [17, 92, 97, 98] . These hypotheses are supported by a recent study involving CSF analysis in COVID-19 patients with encephalitis, where signs of CSF inflammation were identified in the absence of viral RNA, suggestive of an autoimmune or inflammatory process [46] .

Now that anosmia and hypogeusia are well-recognized presenting symptoms of COVID-19, numerous papers have considered whether SARS-CoV-2 can directly enter the CNS [21, [99] [100] [101] . There is a well-established precedent of neurotropism among related human coronaviruses such as SARS-CoV, which binds to the same ACE2 receptor as SARS-CoV-2 to gain entry into host cells, including neurons and glial cells, via its spike (S) protein [18, [102] [103] [104] [105] [106] [107] [108] [109] [110] . SARS-CoV-2 has been shown to be capable of infecting neurons of human ACE2 transgenic mice, as well as dopaminergic neurons derived from human pluripotent stem cells [83, 111, 112] .

In addition, there exists some histological, laboratory, and imaging evidence to support the direct involvement of SARS-CoV-2 in the CNS. A case report of a patient with COVID-19, which presented postmortem tissue analysis, demonstrated viral structures in frontal lobe tissue [113] . Furthermore, although the majority of studies published have not identified detectable levels of SARS-CoV-2 in cerebrospinal fluid (CSF) [114] [115] [116] [117] , there have been isolated reports J o u r n a l P r e -p r o o f of SARS-CoV-2 detected in CSF [118] [119] [120] [121] . Additionally, a recent study of patients who died of COVID-19 identified structural brain abnormalities on postmortem brain imaging, with 21% of subjects having asymmetric olfactory bulbs [122] . Taken together, these findings suggest the potential for direct CNS infection by SARS-CoV-2.

Two pathways which would allow for SARS-CoV-2 to directly access the CNS are frequently proposed; namely, the trans-synaptic and hematogenous routes. Mouse models of SARS-CoV have demonstrated that the virus can enter the brain through the olfactory bulb, with significant effects on the thalamus and brainstem [123] [124] [125] [126] . These neurons may provide a refuge for the virus from CD8 T-cells because they cannot present antigens required for T-cell activation [127] . A transcribrial route to the olfactory bulb is also suspected because of anosmia noted clinically [21, [99] [100] [101] . Moreover, a recent autopsy report showed damage to neurons and glial cells that became progressively worse from the olfactory nerve to the brainstem with detection of SARS-CoV-2 virions along this pathway [128] . Other trans-synaptic routes for CNS infection have been hypothesized but have not been as thoroughly investigated, such as those originating in the gastrointestinal (GI) tract or the lungs [103, [129] [130] [131] [132] [133] [134] .

If the virus were to invade the CNS, delirium could manifest either directly due to neuronal damage within the brain or indirectly due to hypoxia caused by disruptions in the function of the medullary respiratory centers [23, 98, 123, 132, [143] [144] [145] . Ultimately, further investigation is required before any conclusions can be drawn regarding deliriogenic pathoetiology and whether direct neuroinvasion by SARS-CoV-2 plays a role.

At the time of this review, no randomized clinical trials have evaluated treatment of delirium in patients with COVID-19. Nevertheless, several articles have described the treatment of delirium in patients infected with SARS-CoV-2 [23, 26, 27, [146] [147] [148] [149] [150] .

Despite the limited literature on delirium management in COVID-19 patients, several hospitals have developed protocols for the treatment of delirium in these patients based on experience with other coronaviruses and expert consensus [26, 27, 71, 95, 146] . The focus of these recommendations is variable, with some concentrating on the management of delirium in the intensive care unit [23] and others discussing the treatment of specific symptoms related to delirium in COVID-19 patients [150, 151] . Most have suggested that treatment decisions be based on symptom presentation, underlying medical comorbidities, and consideration for medication interactions and side effect profiles [26, 152] .

Expert consensus articles suggest that in conjunction with daily screening, implementing non-pharmacological preventative interventions be implemented whenever possible in COVID-19 patients [23, 146, 147, 153, 154] . Numerous papers have commented on COVID-19 specific considerations that may limit the implementation of preventative measures to reduce delirium J o u r n a l P r e -p r o o f rates [23, 155] . These include increased social isolation for patients (e.g. lack of family involvement and reduced staff care time with patients due to infection risk), stressful work environments, and increased healthcare demands on staff, which may limit the accuracy and speed of identifying emerging delirium [156, 157] .

Once delirium presents, investigation to determine the underlying and contributory etiologies, and a combination of non-pharmacological and pharmacological interventions, are recommended [26, 71, 146, 147] . Table 2 summarizes proposed prevention, assessment and pharmacological management strategies for COVID-19 delirious patients. It is important to note that the utility of the electroencephalogram (EEG) remains unclear. In a study of patients with COVID-19 and completed CT or MRI brain, altered mental status was the most common indication for brain imaging but few of these patients demonstrated acute pathology [158] . As highlighted by the case reports noted in this review, LP and EEG are being used to assess for and rule out different etiologies potentially contributing to delirium in COVID-19, although the test for detecting the SARS-CoV-2 virus in the CSF is not yet available in the US and EEG findings tend to be non-specific. Authors advocate a judicious symptom-directed approach, using these tests when there is evidence of seizure or focal neurological deficit.

A recent rapid review of the pharmacological treatment of hyperactive delirium in people with COVID-19 underscored the lack of data on the management of delirium in these patients [159] . To date, the literature on the psychopharmacological management of patients with delirium has focused on prevention and a symptom-based treatment approach, such as insomnia and symptoms of agitation and psychosis [26] . In the absence of randomized clinical trials, guidance on delirium psychopharmacology, including dosing, is driven by expert consensus and J o u r n a l P r e -p r o o f generalization of delirium management principles from before COVID-19.

Despite the lack of research and evidence in this area, the National Institute for Health and Care Excellence (NICE) has issued guidelines for managing COVID-19 symptoms in the community [151] . These guidelines highlight, and distinguish between delirium, anxiety, and agitation in COVID-19 patients. A distinction between patients with and without dysphagia was also made ( Table 2 ). Anxiety treatment is not discussed here as it is out of scope for this review.

Two articles propose an algorithm for the pharmacological treatment of delirium in patients with COVID-19 [26, 95] . Sher et al. (2020) recommends considering dexmedetomidine for acute agitation at nighttime and to consider guanfacine to wean other sedation [95] . Valproic acid is suggested for the management of hyperactive and/or mixed (i.e., fluctuating between agitation and hypoactivity) delirium. Valproic acid has been described as having unique qualities including being potentially anti-inflammatory, neuroprotective and antioxidant; it may potentially decrease the transcription of interleukin-6 (implicated in cytokine storm) [95] and may assist in reducing the need for sedative agents in delirious and/or agitated patients in the ICU [95, 160, 161] . Several authors propose using melatonin as a first-line agent in the management of delirium in COVID-19 patients given its safety compared to other agents (e.g. antipsychotics) [26, 95, 150] . Melatonin has also been recommended to optimize sleep in the context of COVID-19 delirium [147] . It has been found to have anti-inflammatory, antioxidative, and immune-enhancing features [95, 162, 163] , which may reduce or interrupt the development of a cytokine storm for some patients [150] . It has also been proposed that melatonin can be advantageous for critically ill patients, reducing vascular permeability, agitation, and improving J o u r n a l P r e -p r o o f quality of sleep [162] . However, no studies have examined the efficacy of melatonin in delirium treatment or prevention in COVID-19 patient populations.

Antipsychotics are considered for the management of delirium, ongoing agitation, and end-of-life care in patients with COVID-19 [26, 151, 164] . However, only one study has explored this, using intramuscular aripiprazole for the management of hyperactive delirium in a series of patients with COVID-19 [165] . Aripiprazole appears to effectively reduce symptoms of delirium and agitation, and it was well tolerated. Otherwise, no other antipsychotic has been studied in patients with COVID-19.

In general, antipsychotics should not be used unless there is a safety risk to the patient or others [23, 95, 146, 147, 159] . However, some anecdotal reports suggest using antipsychotic medications earlier in the treatment of COVID-19 patients with hyperactive delirium [95] . When antipsychotics are required, consideration for dosing should be made based on the patient population being treated. Sanders et al. (2020) propose using higher doses of antipsychotics when managing risky behaviors, which put the patient and others at risk of harm secondary to spreading infection, after accounting for the risks and benefits of such interventions [27] . In contrast, for the elderly and for people with neurological conditions, other guidelines suggest conservative dosing when treating delirium in patients with COVID-19 [27, 146, 151] . Experts cautioned the use of antipsychotics in the elderly and those with neurological conditions such as Parkinson's disease [146] . Specific antipsychotic use varies among studies that described the pharmacological management of these patients. Quetiapine has been suggested as an option for the management of delirium in the elderly and in patients with neurological conditions based on J o u r n a l P r e -p r o o f its tolerability and wide therapeutic range [146] . Olanzapine appears to be a preferred agent in the management of agitation in delirious patients with COVID-19 due to its sedative capacity and lower drug-drug-interaction potential with antiviral medications, as noted by one author [166] . In a recent review, Ostuzzi et al. suggests not using haloperidol, quetiapine, or lorazepam for the management of delirium in patients with COVID-19 due to the potential for drug-drug interaction with COVID-19 drugs [159] . At least two authors suggest close monitoring for respiratory depression in delirious patients treated with antipsychotics, based on a theoretical potential for antipsychotic related respiratory depression [159, 166] . It is important to also monitor for QTc prolongation in these patients if antipsychotics are prescribed [159] . Whether antipsychotics have other benefits beyond assisting in the management of behaviors and/or neuropsychiatric symptoms associated with delirium is yet to be determined. However, haloperidol appears to offer some possible immunological benefits. It has been found to be an effective antagonist of sigma-1 receptors, which, in theory, might potently protect against oxidative stress-related cell death [95] . No papers recommend using medications to prevent delirium [27] .

Finally, although benzodiazepines have been found to worsen delirium, experts highlighted the use of benzodiazepines in COVID-19 patients with suspected alcohol-withdrawal delirium [146] .

Based on the current literature on patients with COVID-19, delirium is common in patients affected by SARS-CoV-2 across the severity spectrum. It can be a core symptom at presentation, even in the absence of respiratory symptoms. Similar to pre-COVID-19 pandemic, delirium may be under-recognized and under-diagnosed which limits clinicians' ability to J o u r n a l P r e -p r o o f manage its underlying causes and symptoms, as well as appreciate its short-and long-term impact on patients [45, 167, 168] . The current literature investigating rates and course of delirium in COVID-19 is limited by the lack of systematic screening and diagnosis, as well as the challenges in controlling for other factors when comparing to groups without COVID-19. In this review, validated delirium screening tools were seldomly used and many papers referred to terms such as encephalopathy, confusion, or altered mental status rather than delirium [167] . Rates of delirium were often determined by positive scores on screening tests, rather than clinical assessment, which may reflect the challenges of conducting research and in-person assessments during COVID-19. There is a need for greater focus on delirium in individuals with COVID-19

given its association with poor outcomes, including prolonged cognitive difficulties, increased length of stay, and increased mortality [14] .

Individuals who are older, have dementia, and more severe illness, appear to be more susceptible to developing delirium, similarly to delirium from other causes. Identification of well-recognized risk factors for delirium in COVID-19 patients remains central to preventing and managing delirium [78, 79, 169] . The policies designed to prevent the spread of COVID-19 present logistical challenges in the prevention of delirium through disorienting PPE or lack of inperson support from caregivers [23, 70] .

There currently remains insufficient evidence to definitively elucidate the pathophysiological role of SARS-CoV-2 in the development of delirium; however, the literature suggests that development of delirium in individuals with COVID-19 is likely multifactorial, and may include systemic inflammation due to COVID-19-related pneumonia or ARDS [22, 92] . It should be noted, however, that the use of the term -cytokine storm‖ in the context of COVID-19 has been controversial [170] . Indeed, the levels of IL-6 in patients with severe COVID-19, are 10 J o u r n a l P r e -p r o o f to 40 times lower than the median values recorded by trials conducted by the National Heart, Lung and Blood Institute's ARDS Network [170, 171] . This may point to an entity involving lower levels of cytokine release, distinct from what is traditionally thought of as cytokine storm associated with ARDS.

The neurological symptoms associated with COVID-19 may suggest a role for SARS-CoV-2 directly injuring the CNS [21, 99] . Trans-synaptic transport of the virus from peripheral nerves [123] and/or hematogenous spread either through direct infection of the BBB endothelial cells or permeabilization of the BBB have been suggested. However, it remains a subject of debate. Furthermore, direct neuronal damage, particularly within the respiratory structures of the medulla oblongata has also been proposed [145] . There is no evidence to suggest that the routes of entry or mechanisms of viral damage discussed in this review are mutually exclusive, indeed these processes may all be occurring simultaneously. The myriad of plausible deliriogenic mechanisms in patients with COVID-19, both indirectly and directly mediated by SARS-CoV-2, suggests the need for a multifactorial hybrid model to explain the clinical picture of delirium reported during the pandemic [71] . A nuanced approach addressing the many variables precipitating delirium is necessary to prevent and manage COVID-19 delirium.

The management of delirium in patients with COVID-19 is in its infancy with no randomized clinical trials published to date. Reviewed literature on the management of delirium in COVID-19 patients was difficult to analyze due to heterogeneity of the article type (e.g., case report(s), anecdotal/experiential) and variable treatment settings (e.g. ICU vs. medical ward).

Despite the limited literature, expert consensus articles suggest that the primary management of delirium in COVID-19 patients is the implementation of preventative measures whenever possible [23, 146, 147] .

Once delirium presents, experts recommend investigating for underlying and contributory etiologies, while concomitantly implementing non-pharmacological and pharmacological interventions [71] . These strategies align with the broader delirium literature [168, 172] .

Notwithstanding the many similarities in the management of delirium in patients with COVID-19 to patients without this condition, there seem to be some peculiarities in the pharmacological and non-pharmacological management of COVID-19 delirious patients. Recommendations on pharmacological symptom management from the literature reviewed were sometimes conflicting.

For example, some authors noted that higher dosages of medications may be required [27] , while others suggested their use at lower dosages for the management of agitation, as these patients appear to commonly present with catatonic features [26, 71] . Alpha-2 agonists may be particularly useful in these patients because they do not cause respiratory depression. Valproate was considered a good option for those who did not respond to antipsychotics and for those who are at increased risk of cardiac morbidity and QTc prolongation because of specific medications used in the treatment of SARS-CoV-2 infected patients, with some early promising anecdotal data in the treatment of hyperactive delirium in patients with COVID-19 [95] . Although there is no rigorous evidence to date to suggest that these pharmacological agents are safe and effective in these patients, these agents have been found to be safe in the broader delirium literature [173] .

Nevertheless, higher quality research and evidence are needed before any evidence-based recommendation can be made for the pharmacological management of delirium in patients with COVID-19. Non-pharmacological interventions remain the cornerstone of delirium management in any setting. However, patients with COVID-19 are isolated, and interventions such as reorientation, provision of sensory aids, and early mobilization can be extremely challenging with staff minimizing contact, visitor limitations, and use of PPE which can impair communication. It is important to consider how best to adapt recommended these non-pharmacological delirium interventions to those with COVID-19. For example, using technology to promote contact with family and staff, and taking into account PPE when developing strategies to orient and communicate with patients.

This rapid review used a systematic literature review approach to identify and evaluate the most current literature on the pathoetiology, prevalence, and management of delirium in people with COVID-19. An experienced librarian collaborated with clinicians to develop the broad search strategy, including grey literature, multiple databases, and preprints. The evidence for studies examining delirium management in the context of COVID-19 was appraised.

Limitations of this review include the focus on peer-reviewed publications and literature published in English, which could limit generalizability.

This review suggests that delirium in COVID-19 infected patients is highly prevalent and likely a result of multiple factors including purported direct effects of SARS-CoV-2 on the CNS. Regular assessment with validated delirium screening tools and implementation of prevention interventions are widely recommended. Ensuring that delirium is documented as such, rather than using terms such as acute confusional state and disorder of consciousness, will help strengthen the literature in this area. Given the rapidly evolving pandemic and the lack of studies J o u r n a l P r e -p r o o f regarding management of delirium in general, it is important to acknowledge that there is a role for consensus and expert opinion as well as extrapolation from delirium management approaches in other medically ill populations for the management of these patients. Further research is needed to elucidate specific patient risk factors for and to determine the effectiveness of prevention and management approaches to COVID-19 delirium.

Ethical approval was not required as it is a systematic review with anonymous data.

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Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2, Inflammatory Bowel Diseases

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Letter to the Editor Regarding the Viewpoint -Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanism

COVID-19, Angiotensin Receptor Blockers, and the Brain

Comment on -Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2)

Comment on -The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients

Updates on What ACS Reported: Emerging Evidences of COVID-19 with Nervous System Involvement

Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science

Novel Coronavirus Disease (COVID-19) and Central Nervous System Complications: What Neurologist Need to Know

Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease

SARS-CoV-2-mediated encephalitis: Role of AT2R receptors in the bloodbrain barrier

Does SARS-Cov-2 invade the brain? Translational lessons from animal models

Neurological Impact of Coronavirus Disease of 2019: Practical Considerations for the Neuroscience Community

The brain, another potential target organ, needs early protection from SARS-CoV-2 neuroinvasion

COVID-19: what if the brain had a role in causing the deaths?

Management of older people during the COVID-19 outbreak: Recommendations from an Italian experience

Collaborative Delirium Prevention in the Age of COVID -19

More advice on the use of ibuprofen for COVID-19

Rehabilitation following critical illness in people with COVID-19 infection

Delirium and sleep disturbances in COVID-19: a possible role for melatonin in hospitalized patients?

Improvement, National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement, Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines

Psychopharmacology of COVID-19

Delirium in Older People with COVID-19: Clinical Scenario and Literature Review

The Primary Care Companion For CNS Disorders

Management of Agitation During the COVID-19 Pandemic

COVID-19 Pandemic and Care of Older Adults at Risk for Delirium and Cognitive Vulnerability

Brain Imaging Use and Findings in COVID-19: A Single Academic Center Experience in the Epicenter of Disease in the United States

Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations

Valproic Acid for the Management of Agitation and Delirium in the Intensive Care Setting: A Retrospective Analysis

Valproate for agitation in critically ill patients: A retrospective study

Melatonin potentials against viral infections including COVID-19: Current evidence and new findings

Melatonin's Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease

An audit of end-of-life symptom control in patients with corona virus disease 2019 (COVID-19) dying in a hospital in the United Kingdom

Psychomotor agitation and hyperactive delirium in COVID-19 patients treated with aripiprazole 9.75 mg/1.3 ml immediate release

COVID-19 inpatients with psychiatric disorders: Real-world clinical recommendations from an expert team in consultation-liaison psychiatry

Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies

Delirium in Hospitalized Older Adults

APOE E4 GENOTYPE PREDICTS SEVERE COVID-19 IN THE UK BIOBANK COMMUNITY COHORT

Is a -Cytokine Storm‖ Relevant to COVID-19?

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

Delirium and antipsychotics: a systematic review of epidemiology and somatic treatment options

COVID-19)-Associated Encephalopathies and Cerebrovascular Disease: The New Orleans Experience

Is delirium a specific complication of viral acute respiratory distress syndrome?

Neurological Manifestations in Critically Ill Patients With COVID-19: A Retrospective Study

The role of extracorporeal life support for patients with COVID-19: Preliminary results from a statewide experience

Subjective neurological symptoms frequently occur in patients with SARS-CoV2 infection

GEMELLI AGAINST COVID-19 group, Assessment of neurological manifestations in hospitalized patients with COVID-19

Frequency of Neurological Presentations of Coronavirus Disease in Patients Presenting to a Tertiary Care Hospital During the 2019 Coronavirus Disease Pandemic

New onset neurologic events in people with COVID-19 in 3 regions in China

Prevalence and Impact of Hyponatremia in Patients With Coronavirus Disease

A prospective clinical study of detailed neurological manifestations in patients with COVID-19

Frailty and Mortality in Hospitalized Older Adults With COVID-19: Retrospective Observational Study

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Neurological and Musculoskeletal Features of COVID-19: A Systematic Review and Meta-Analysis

Challenges and management of neurological and psychiatric manifestations in SARS-CoV-2 (COVID-19) patients

Hemorrhagic Posterior Reversible Encephalopathy Syndrome as a Manifestation of COVID-19 Infection

Cough and Dyspnea: The Neurology of COVID-19

Neurological Consequences of 2019-nCoV Infection: A Comprehensive Literature Review

Neuropsychiatric aspects of COVID-19 pandemic: A selective review

Potential neurological effects of severe COVID-19 infection

Neurological complications of COVID-19: a systematic review

Neurological manifestations of COVID-19: a systematic review

Neurological manifestations and implications of COVID-19 pandemic

Report on Electroencephalographic Findings in Critically Ill Patients with COVID -19

Delirium: A suggestive sign of COVID-19 in dementia

Frontal encephalopathy related to hyperinflammation in COVID-19

Considerations around the SARS-CoV-2 Spike Protein with Particular Attention to COVID-19 Brain Infection and Neurological Symptoms

Neurological manifestations of COVID-19, SARS and MERS

What HIV in the Brain Can Teach Us About SARS-CoV-2 Neurological Complications?

Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: A case series

Neurological symptoms as a clinical manifestation of COVID-19: implications for internists

SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

Neurological complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic

Neurological Manifestations in COVID-19 Infection: A Systematic Review and Meta-Analysis, Can

Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology

COVID-19 PANDEMIA: NEUROPSYCHIATRIC COMORBIDITY AND CONSEQUENCES

Neurologic complications of COVID-19

Encephalopathy in patients with COVID-19: A review

Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis

COVID-19 and the central nervous system

Imaging Features of Acute Encephalopathy in Patients with COVID-19: A Case Series

Nervous system: subclinical target of SARS-CoV-2 infection

COVID-19 and its impact on neurological manifestations and mental health: the present scenario

COVID-19-associated encephalopathy: Neurological manifestation of COVID-19

A systematic review of neurological symptoms and complications of COVID-19

Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients

The authors have no conflicts of interest to declare.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

 Figure 1 . Literature search and study selection process for systematic review of the literature, published between 2019-2020, on individuals with COVID-19 who exhibit signs or symptoms suggestive of COVID-19. Study followed the PRISMA guidelines for conducting systematic review.Records identified through database searching (n =12,079)

Additional records identified through other sources (n = 40 )Records after duplicates removed (n = 10,108)Titles/Abstracts screened (n = 10,108) Excluded (n = 9634)