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Neurological Manifestations in COVID-19 Population: A Short Review

Neurological Manifestations in COVID-19 Population: A Short Review Background: Coronaviruses (CoVs) have a neuroinvasive potential, which has been discussed in various research papers. During the current pandemic, the novel CoV, i.e., SARS-CoV-2, is causing a considerable number of fatalities and posing a great danger of a recurrent epidemic. COVID-19 has been labeled as a public health emergency of international concern, and the epidemic curves are on the rise. Purpose: Some studies discuss the neurological implications of SARS-CoV-2 but in light of growing number of evidences we cannot ignore the planning of mental health care settings in COVID-19. We are discussing how this novel CoV can affect the human brain directly and indirectly, including psychiatric problems, and how neurological conditions can be explored as a diagnostic tool in COVID-19 by analyzing cohort studies and review papers that discuss the recent neurological findings in COVID-19. Method: Current research and review papers were searched to find out any relation between the COVID-19 disease and the altered mental health. This study attempts to find out neurological symptoms in a large population affected by COVID-19 and thus filtering out individual case reports and cohort studies which have a patient pool of less than 50. Results: This unique observation revealed that SARS-CoV-2 has direct neurological manifestations such as anosmia and gustatory impairment, encephalopathy, and seizures as well as an indirect effect on the psychiatric health such as anxiety, amnesia, etc. because of psychosocial stress. Conclusion: The most commonly reported neurological symptoms should not be ignored and must be tested for COVID-19. More neurological studies like medical imaging and neuropathology should be performed on these COVID-19 patients. Keywords Coronavirus, COVID-19, neuroinvasion, neurology, neuroimaging Received 18 October 2020; accepted 27 October 2020 to many countries. In 2012, Saudi Arabia reported infection Introduction and deaths from a CoV which was was named as MERS-CoV, stands for Middle East respiratory syndrome coronavirus. Coronaviruses (CoVs) were first identified during an infection The novel 2019 CoV is named SARS-COV-2 because it has a in chicks in 1931 and named the avian infectious bronchitis genetic similarity and biochemical resemblance more to virus. Later, such viruses were also reported as human pathogens SARS-CoV. in a common cold infection. Extensive research by T Estola and The transmission and infection of CoVs have been shown many other scientists from years 1930 to 1975 and a growing to infect the cells of the respiratory mucosa; this can occur number of respiratory viruses compelled scientific leaders to constitute a separate group of viruses. Subsequently, after several discussions among virologists a new family of viruses Department of Neurochemistry, Institute of Human Behaviour and Allied Coronaviridae, with one genus, was created in 1975. CoVs Sciences, Delhi, India were further divided into four subtypes, i.e., alpha, beta, gamma, Corresponding author: and delta CoVs. The novel SARS-CoV-2 is a beta CoV. Rachna Agarwal, Department of Neurochemistry, Institute of Human The first case of a CoV disease was notified as cold in Behaviour and Allied Sciences, Delhi 110095, India. 1960. In 2003, China reported the spread of the SARS-CoV E-mail: dr.rachnaneurochem@gmail.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 2 Annals of Neurosciences when virus particles are inhaled or come in a direct contact A neuroinvasion mechanism by SARS-CoV-2 is proposed with a mucosal surface of the mouth, nose, or eyes. It can also through the olfactory bulb and the olfactory nerve. The transmit through a physical contact when someone touches COVID-19 virus’s movement to the brain via the cribriform the infected surface and then touches their nose, eyes, or plate close to the olfactory bulb can be an additional pathway. mouth. Generally, viruses can also spread by the airborne From the olfactory bulb and the olfactory nerve, it would route in small droplet nuclei that can remain suspended for spread to various parts of the brain by a synapse-connected long periods of time and inhaled. Respiratory viruses route and trans-synaptic transfer and infects the pre-Botzinger preferentially bind and infect ciliated or nonciliated epithelial complex in the brainstem, the respiratory center of the brain cells of the respiratory epithelium airways, which are that controls the lungs, shutting down breathing, and causing pneumocytes lining the alveoli in the lungs and alveolar potential death, similar to what has been proposed by SARS- 4 11 macrophages. CoV-2. There are only a few case reports till the time which The attachment receptor for SARS-CoV and SARS-CoV-2 show SARS-CoV-2 in the cerebrospinal fluid (CSF) of is the human angiotensin-converting enzyme 2 (ACE2). patients; studies of acute SARS-CoV illness in the past have After its attachment to the receptor, the virus is engulfed by demonstrated the presence of the virus in CSF. In the past, the cell and the viral genome either DNA or RNA is uncoated autopsy findings of the SARS-CoV-infected patients have to release the viral genetic material, which is RNA in case of shown strong evidence of the SARS-CoV’s presence in the SARS-CoV-2. The replication cycle of CoVs occurs entirely brain by electron microscopy, immunohistochemistry, and in the cytoplasm and involves the production of a series of real-time reverse transcription-polymerase chain reaction subgenomic RNAs, which further makes proteins for virion (RT-PCR). assembly. Progeny virions are released from the infected cells into the surrounding cells and tissues in the respiratory tract, Methods where they are shed by coughing and sneezing. During the incubation period, the virus attaches to and infects cells, This review’s inclusion criteria were as follows: all studies replicates its genome, and spreads to infect adjacent cells. with any study design that reported the neurological features The incubation period for SARS-CoV-2 is found to be from in a cohort of more than 50 patients with COVID-19 and 4.5 to 5.8 days, with an average of 5.1 days. published on or prior to August 1, 2020 were included. Two From the earliest reports, ACE2 receptors have been electronic databases, namely PubMed and Google Scholar, shown to be present in many organs and tissues of human and one worldwide online search engine Google were body. An immunohistochemistry analysis revealed that searched for the concerned articles. The lists of references in SARS-CoV was predominantly present in the lungs, trachea, the included studies were also screened for any relevant and bronchi and was also detected in many other organs and papers. In this review, we have excluded Chinese studies that tissues, such as the stomach, small intestine, distal convoluted do not have coauthors from other countries except the pioneer renal tubule, sweat gland, parathyroid, pituitary, pancreas, study by Mao et al., which has scored more than 1,000 adrenal, liver, and cerebrum. CoVs have also been detected citations as on August 1, 2020. Also, preprint platforms and in tissues such as endothelial cells of small and large arteries their publications were not considered in this study. and veins, type I and type II alveolar epithelial cells in normal This review analyzed 247 research and reviewed articles lungs, in the basal layer of the nonkeratinizing squamous using the keywords neurological manifestations, epithelium of nasal and oral mucosa and the nasopharynx, neuroinvasion, neuroimaging, coronavirus, COVID-19, basal cell layer of the epidermis extending to the basal cell SARS-CoV-2, cohort, population, analysis in all possible layer of hair follicles, endothelial and smooth muscle cells of combinations. The final list of included articles was generated the brain, etc. on the basis of relevance to the topics covered in this review. Clinical features of COVID-19 ranging from an After removal of duplicate, non-original articles and preprints, asymptomatic state to acute respiratory distress syndrome a total of 102 articles were used for an initial screening based and multi-organ dysfunction. SARS-CoV-2 leads to chronic on titles and abstracts. Out of 102 studies, 48 studies were inflammation of the lungs, severe dyspnea, fever, dry cough, selected for the full-text review. Finally, 5 reviews and 9 cyanosis, and complete lung failure in more vulnerable clinical studies were taken in the present study as they met the patients. The typical clinical features include fever, cough, 14–27 inclusion criteria (Figure 1). sore throat, headache, fatigue, myalgia, and breathlessness. In some patients, the disease can progress to pneumonia, respiratory failure, and ultimately death. The disease Results progression is associated with an increase in inflammatory cytokines including IL2, IL6, IL7, IL10, GCSF, IP10, The study find out that COVID-19 patients do have concurrent MCP1, MIP1A, and TNFα. The disease in neonates, infants, neurological manifestations that are subjected to further study. and children has been reported to be significantly milder We collected 97 reviews through the search strategy described than adults. in this review and finally included 5 studies that could fit in Singh and Agarwal 3 Figure 1. Flow Chart for Literature Search Results our inclusion criteria ( Table 1 ). Together these studies reported (also known as acute inflammatory demyelinating 14–18 many neurological features either in the cohort analysis or polyneuropathy), coma, seizures, ataxia, and psychosis. case studies. Headache and dizziness were the most common Similarly, to study individual neurological symptoms, we symptoms in COVID-19-positive patients, followed by further analyze the penetration of neurological symptoms in anosmia and ageusia. The other reported clinical features COVID-19 patients as per the inclusion criteria for were confusion, hyposmia, encephalopathy, corticospinal neurological and neuropsychiatric presentations ( Table 2 ). tract signs, acute cerebrovascular problems, acute ischemic Out of 150 research papers, we isolated 9 studies that reported stroke, olfactory disorders, gustatory dysfunction, cerebral neurological symptoms in a cohort of more than 50 COVID- venous sinus thrombosis, hypoxia, Guillain–Barré syndrome 19 patients. Table 1. Selected Review Reports of Neurological Manifestations Associated With COVID-19 S. No. Title Date of Publication No. of Studies/ Patients Conclusion From the Review 1 Neurological manifestations of May 10, 2020 31 studies Anosmia, headache seizures, stroke, and COVID-19: A systematic review Guillain–Barré syndrome and current update 2 A review of neurological compli- May 18, 2020 15 studies Headache, dizziness anosmia, ageusia, cations of COVID-19 Miller Fisher syndrome, olfactory dys- function, and encephalopathy 3 Neuropathogenesis and neuro- May 29, 2020 Not specifi ed Anosmia, ageusia, headache, stroke, logic manifestations of the coro- impairment of consciousness, seizures, naviruses in the age of coronavi- and encephalopathy rus disease 2019: A review 4 Neurological and musculoskeletal June 26, 2020 60 studies Anosmia, ageusia, myalgia, headache, back features of COVID-19: A system- pain, and dizziness atic review and meta-analysis 5 Neurological associations of July 02, 2020 901 patients Encephalopathy, encephalitis, Guillain– COVID-19 Barré syndrome, anosmia, ageusia, acute cerebrovascular disease, and stroke 4 Annals of Neurosciences Table 2. Selected Clinical Studies of Cohort Showing Neurological Manifestations Associated With COVID-19 No. of Neuro- Author, Type of logically Affected SARS-CoV-2 Diag- Major Neurological Clinical S. No. Study, and Country Patients nostic Test Presentation Brain Abnormalities Findings 1. Mao et al., ret- 214 RT-PCR positive Dizziness, headache, hy- Not available rospective study, pogeusia, hyposmia, acute China cerebrovascular diseases, impaired consciousness, and skeletal muscle injury 2. Helms et al., ob- 58 RT-PCR positive Agitation, confusion, dys- MRI showed leptomeningeal servational study, executive syndrome, and enhancement, perfusion abnor- France encephalopathy malities, and cerebral ischemic stroke 3. Varatharaj et al., 125 RT-PCR positive, or Ischemic stroke, intracere- Not available UK-wide surveil- anti-SARS-CoV-2 bral hemorrhage, cerebral lance study, UK IgM, or IgG positive vasculitis, encephalopathy, encephalitis, Guillain–Barré syndrome and variants, neu- rocognitive (dementia-like) syndrome, psychiatric disor- der, psychosis, dementia-like syndrome, and affective disorder 4. Romero-Sánchez 841 RT-PCR positive, or Myalgia, headache, dizziness, Electroencephalogram  et al., ALBACOVID anti-SARS-CoV-2 anosmia, dysgeusia, impaired showed moderate encepha- registry, retrospec- IgM, or IgG positive consciousness, myopathy, lopathy in two patients, one tive, observational dysautonomia, cerebrovascu- patient showed MRI pattern study, Spain lar diseases, seizures, move- resembling posterior revers- ment disorders, encephalitis, ible encephalopathy syndrome, Guillain–Barré syndrome, one patient showed bilateral and optic neuritis temporal hyperintensity in FLAIR sequences of brain MRI 5. Benussi et al., retro- 56 RT-PCR positive, Ischemic attack, ischemic Not available spective study, Italy bronchoalveolar stroke, hemorrhagic stroke, lavage and epilepsy 6. Lu et al., prospec- 60 RT-PCR positive Mood change, fatigue, head- Diffusion tensor imaging and tive study, China ache, vision change, myalgia, 3D high-resolution T1 weight- impaired mobility, memory ed image showed significantly loss, taste loss, limb numb- higher bilateral gray matter ness, tremor, smell loss, and volumes (GMVs) in olfactory hearing loss cortices, hippocampi, insu- las, left Rolandic operculum, left Heschl’s gyrus, and right cingulated gyrus and a general decline of MD, AD, RD accom- panied with an increase of FA in white matter, especially AD in the right CR, EC and SFF and MD in SFF 7. Yan et al., cross- 59 RT-PCR positive Anosmia and ageusia Not available sectional study, USA 8. Lechien et al., Euro- 417 RT-PCR positive Olfactory dysfunction, anos- Not available pean study mia, hyposmia, and gustatory disorders 9. Kandemirli et al., 749 Not specified Not available Cortical, subcortical, and deep observational study, white matter FLAIR signal Turkey abnormality Singh and Agarwal 5 Mao and coworkers reported that 36.4% of the 214 patients positivity in order of descending frequency included fatigue had neurological symptoms. 24.8% of these patients exhibited (81%), ageusia (71%), fever (70%), anosmia (68%), myalgia or arthralgia (63%), diarrhea (48%), and nausea (27%). central nervous system (CNS) symptoms, the most common A multicenter European study by Lechien et al. showed of which were dizziness (16.8%) and headache (13.1%) and that 85.6% and 88.8% of a total of 357 patients reported less common were the alteration of mental status, acute olfactory and gustatory dysfunctions, respectively, with the cerebrovascular accident (CVA), ataxia, and seizures. olfactory dysfunction emerging before other symptoms in Helms et al. reported neurological complications in an 11.8% cases. 284 (79.6%) patients were anosmic and 73 observational case series of 58 patients admitted to the (20.4%) were hyposmic. Phantosmia and parosmia were intensive care unit (ICU) for acute respiratory distress reported in 12.6% and 32.4% of patients, respectively. syndrome, in Strasbourg, France. Neurological findings were Structural changes in the brain can provide excellent seen in 14% of patients at admission and 69% of cases were inputs to understand the effect of COVID-19 on the brain and seen when they were weaned off sedation and paralytics. The nervous system. Lu et al. reported cerebral microstructural most frequently observed symptoms were confusion (65%), changes in COVID-19 patients. Neurological symptoms were agitation (69%), upper motor neuron syndrome signs like present in 55% of COVID-19 patients. They further found hyperreflexia with clonus and positive Babinski’s sign (69%) that the recovered COVID-19 patients were more likely to during the ICU stay, and a dysexecutive syndrome (33%) have enlarged olfactory cortices, hippocampi, insulas, after discharge. Magnetic resonance imaging (MRI) of the Heschl’s gyrus, Rolandic operculum and cingulate gyrus, and brain in patients who developed unexplained encephalopathic a general decline of mean diffusivity (MD), axial diffusivity features revealed leptomeningeal enhancement (62%), 20 (AD), radial diffusivity (RD) accompanied by an increase of perfusion abnormalities (100%), and ischemic CVA (23%). fractional anisotropy (FA) in white matter (WM), especially In one UK-wide national surveillance study of 125 patients AD in the right coronal radiata (CR), external capsule (EC) with COVID-19 and neurological or psychiatric disease and superior frontal-occipital fasciculus (SFF), and MD in reported over three weeks showed that 39 (31%) patients had SFF as compared to non-COVID-19 volunteers. Global gray altered mental status, which included 16 (13%) with matter volume (GMV), GMVs in the left Rolandic operculum, encephalopathy [of whom seven (6%) had encephalitis], and right cingulate, bilateral hippocampi, left Heschl’s gyrus, and 23 (18%) with a neuropsychiatric diagnosis, including 10 global MD of WM were found to correlate with memory loss. (8%) with psychosis, 6 (5%) with neurocognitive (dementia- GMVs in the right cingulate gyrus and left hippocampus were like) syndrome, and 4 (3%) with an affective disorder. related to smell loss. Notably, 77 (62%) patients had a cerebrovascular event: 57 Kandemirli et al. showed that COVID-19 patients had (46%) ischemic strokes, 9 (7%) intracerebral hemorrhages, 1 acute findings in brain MRI, which include a cortical, (<1%) had CNS vasculitis, and 10 (8%) presented other subcortical, and deep white matter fluid-attenuated inversion cerebrovascular events. recovery (WM FLAIR) signal abnormality. Abnormalities Romero-Sánchez et al. reported that in 841 patients were also present in the frontal lobe, parietal lobe, occipital hospitalized with COVID-19 in Spain, myalgia (17.2%), lobe, temporal lobe, insular cortex, and cingulated gyrus. headache (14.1%), and dizziness (6.1%) were present mostly We have also analyzed neuropsychiatric conditions in in the early stages of infection. Anosmia (4.9%) and the COVID-19 pandemic and found that many conditions dysgeusia (6.2%) were the next most common symptoms. like anxiety, amnesia, hallucinations, depression, sleep The other symptoms reported were disorders of consciousness disorder, delirium, mood swings, and suicidal thoughts (19.6%), myopathy (3.1%), dysautonomia (2.5%), were also present in the general population because of cerebrovascular diseases (1.7%), seizures (0.7%), movement increased psychosocial stress, psychotropic drugs usage, disorders (0.7%), encephalitis (n = 1), Guillain–Barré etc., during the pandemic. Thus, neurological and syndrome (n = 1), and optic neuritis (n = 1). Neurological neuropsychiatric manifestations can become a more complications were the main cause of death in 4.1% of all pressing concern as the pandemic spreads and has longer- deceased study subjects. term effects on the general population. Benussi et al. from Italy observed a significant increase in cerebrovascular disease rates in the COVID-19 group (n = 43, 76.8% vs. n = 68, 58.1%, P = .02), with a similar Discussion distribution between transient ischemic attack (n = 5, 11.6% vs. n = 8, 11.9%), ischemic stroke (n = 35, 81.4% vs. n = 50, There are only a few studies that have shown the relation 74.6%), and hemorrhagic stroke (n = 3, 7.0% vs. n = 9, between the SARS-CoV-2 infection and neurological 13.4%) within groups. complications in COVID-19 patient cohorts. The human Smell and taste loss showed the largest magnitudes of brain has been reported to express ACE2 receptors that have association with COVID‐19 positivity reported in 68% been detected in glial cells and neurons in mice, which makes (40/59) and 71% (42/59) of COVID-19-positive subjects by them a potential target of SARS-CoV-2. Neurologists Yan et al. Self‐reported symptoms associated with COVID‐19 categorized neurological manifestations into nonspecific 6 Annals of Neurosciences symptoms (headache, dizziness, or myalgia), neuropsychiatric changes in the brain after the SARS-CoV-2 infection. disorders (insomnia, depression, anxiety, or psychosis), CNS Restrictions imposed during pandemic like lockdown have shown number of psychosocial effects in the community. disorders (direct viral infection, encephalitis, disorders of Symptoms such as anxiety, amnesia, hallucinations, consciousness, seizures, and stroke), peripheral nervous depression, sleep disorder, delirium, mood swings, and system disorders (cranial neuropathies, anosmia/dysgeusia, suicidal thoughts were observed in COVID-19 patients as and peripheral neuropathy), myopathy, demyelinating events, well as in the general population. and cerebrovascular manifestations. This study is based on the findings of neurological symptoms in the COVID-19 population, which further Conclusion discusses present and future implications in the COVID-19 management. By reviewing cohort-based studies, we have Neurological manifestations of COVID-19 have not been analyzed common as well as other neurological symptoms studied in detail yet. It is possible that patients having severe that need attention in health care settings. These findings also illness, developed CNS and neurological manifestations. have relevance for follow-up studies as many of the patients The most commonly reported neurological symptoms such showed up psychiatric problems that do not involve any as anosmia, gustatory impairment along with altered mental underlying pathology but were occurred because of a status should not be ignored and the patients in these cases psychosocial effect on the brain and behavior. It has been must be tested for COVID-19. Based on the available pieces established that CoVs have a potential to reach brain receptors of evidence, it is suggested that health care units taking care through the ACE2 receptor which is present in many tissues of infected patients must now include neurologists to gain of the brain and is proposed through two routes, i.e., olfactory more perspective into the nature of the infections, which can bulb and cribriform plate. be neurological. More autopsies on brains of the COVID-19 First, we analyzed the review papers that reported patients with neurological symptoms need to be performed neurological symptoms in COVID-19 patients. Based on the to establish the neuroinfection track of the disease. A through inclusion criteria, five studies came out to be most neurological assessment should be performed to note appropriate, which show that neurological symptoms such as neurological symptoms (e.g., headache, dizziness, etc.) and anosmia and ageusia were the most common and were noted signs (e.g., change in mental status, meningeal signs, etc.), in all five studies (5/5). It was followed by headache (4/5), detailed clinical, neurological, and electrophysiological stroke (3/5), encephalopathy (3/5), seizures (2/5), encephalitis investigations (e.g., electroencephalogram) of the patients (1/5), Guillain–Barré syndrome (1/5), and Miller Fisher particularly those with a change in mental status should be syndrome (1/5). Other less common neurological symptoms followed. Attempts to isolate SARS-CoV-2 from CSF may that were reported in review studies were impaired clarify the roles played by this virus in causing neurological consciousness, acute cerebrovascular disease, myalgia, back manifestations. Medical imaging and neuropathology will pain, and dizziness. undoubtedly play an essential role in detecting abnormalities To further study the prevalence of each neurological in the olfactory bulb, cranial nerves, and brains of COVID- symptom, we analyzed clinical research studies which have 19 patients. recruited a large number of COVID-19 patients. We analyzed studies from different countries across the globe to see if Author Contribution these symptoms are emerging from all over or have Dr Rachna Agarwal designed the study and approved the final geographical restrictions, because lockdown conditions in manuscript. Kamal Pratap Singh performed the literature analysis different countries can give rise to different neurological and wrote the manuscript. manifestations. A more detailed examination of symptoms revealed that apart from the findings from review studies Declaration of Conflicting Interests there are many more neurological symptoms that are emerging The authors declared no potential conflicts of interest with respect to out after the critical examination of patients. These symptoms the research, authorship, and/or publication of this article are hearing loss, skeletal muscle injury, agitation, confusion, dysexecutive syndrome, intracerebral hemorrhage, cerebral Ethical Statement vasculitis, psychosis, myopathy, dysautonomia, optic neuritis, No ethical consent was required from the Institutional Ethics epilepsy, mood change, fatigue, memory loss, limb numbness, Committee. tremor, etc. In some cases, these findings were very well substantiated by examining structural changes in the brain by Funding performing brain MRI, diffusion tensor imaging, and 3D high-resolution T1 weighted image, which shows that these The authors received no financial support for the research, kinds of studies should be performed in future to see the exact authorship, and/or publication of this article. Singh and Agarwal 7 ORCID iD 16. Zubair AS, McAlpine LS, et al. 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Neurological Manifestations in COVID-19 Population: A Short Review

Annals of Neurosciences , Volume OnlineFirst: 1 – Jan 1, 2021

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Abstract

Background: Coronaviruses (CoVs) have a neuroinvasive potential, which has been discussed in various research papers. During the current pandemic, the novel CoV, i.e., SARS-CoV-2, is causing a considerable number of fatalities and posing a great danger of a recurrent epidemic. COVID-19 has been labeled as a public health emergency of international concern, and the epidemic curves are on the rise. Purpose: Some studies discuss the neurological implications of SARS-CoV-2 but in light of growing number of evidences we cannot ignore the planning of mental health care settings in COVID-19. We are discussing how this novel CoV can affect the human brain directly and indirectly, including psychiatric problems, and how neurological conditions can be explored as a diagnostic tool in COVID-19 by analyzing cohort studies and review papers that discuss the recent neurological findings in COVID-19. Method: Current research and review papers were searched to find out any relation between the COVID-19 disease and the altered mental health. This study attempts to find out neurological symptoms in a large population affected by COVID-19 and thus filtering out individual case reports and cohort studies which have a patient pool of less than 50. Results: This unique observation revealed that SARS-CoV-2 has direct neurological manifestations such as anosmia and gustatory impairment, encephalopathy, and seizures as well as an indirect effect on the psychiatric health such as anxiety, amnesia, etc. because of psychosocial stress. Conclusion: The most commonly reported neurological symptoms should not be ignored and must be tested for COVID-19. More neurological studies like medical imaging and neuropathology should be performed on these COVID-19 patients. Keywords Coronavirus, COVID-19, neuroinvasion, neurology, neuroimaging Received 18 October 2020; accepted 27 October 2020 to many countries. In 2012, Saudi Arabia reported infection Introduction and deaths from a CoV which was was named as MERS-CoV, stands for Middle East respiratory syndrome coronavirus. Coronaviruses (CoVs) were first identified during an infection The novel 2019 CoV is named SARS-COV-2 because it has a in chicks in 1931 and named the avian infectious bronchitis genetic similarity and biochemical resemblance more to virus. Later, such viruses were also reported as human pathogens SARS-CoV. in a common cold infection. Extensive research by T Estola and The transmission and infection of CoVs have been shown many other scientists from years 1930 to 1975 and a growing to infect the cells of the respiratory mucosa; this can occur number of respiratory viruses compelled scientific leaders to constitute a separate group of viruses. Subsequently, after several discussions among virologists a new family of viruses Department of Neurochemistry, Institute of Human Behaviour and Allied Coronaviridae, with one genus, was created in 1975. CoVs Sciences, Delhi, India were further divided into four subtypes, i.e., alpha, beta, gamma, Corresponding author: and delta CoVs. The novel SARS-CoV-2 is a beta CoV. Rachna Agarwal, Department of Neurochemistry, Institute of Human The first case of a CoV disease was notified as cold in Behaviour and Allied Sciences, Delhi 110095, India. 1960. In 2003, China reported the spread of the SARS-CoV E-mail: dr.rachnaneurochem@gmail.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 2 Annals of Neurosciences when virus particles are inhaled or come in a direct contact A neuroinvasion mechanism by SARS-CoV-2 is proposed with a mucosal surface of the mouth, nose, or eyes. It can also through the olfactory bulb and the olfactory nerve. The transmit through a physical contact when someone touches COVID-19 virus’s movement to the brain via the cribriform the infected surface and then touches their nose, eyes, or plate close to the olfactory bulb can be an additional pathway. mouth. Generally, viruses can also spread by the airborne From the olfactory bulb and the olfactory nerve, it would route in small droplet nuclei that can remain suspended for spread to various parts of the brain by a synapse-connected long periods of time and inhaled. Respiratory viruses route and trans-synaptic transfer and infects the pre-Botzinger preferentially bind and infect ciliated or nonciliated epithelial complex in the brainstem, the respiratory center of the brain cells of the respiratory epithelium airways, which are that controls the lungs, shutting down breathing, and causing pneumocytes lining the alveoli in the lungs and alveolar potential death, similar to what has been proposed by SARS- 4 11 macrophages. CoV-2. There are only a few case reports till the time which The attachment receptor for SARS-CoV and SARS-CoV-2 show SARS-CoV-2 in the cerebrospinal fluid (CSF) of is the human angiotensin-converting enzyme 2 (ACE2). patients; studies of acute SARS-CoV illness in the past have After its attachment to the receptor, the virus is engulfed by demonstrated the presence of the virus in CSF. In the past, the cell and the viral genome either DNA or RNA is uncoated autopsy findings of the SARS-CoV-infected patients have to release the viral genetic material, which is RNA in case of shown strong evidence of the SARS-CoV’s presence in the SARS-CoV-2. The replication cycle of CoVs occurs entirely brain by electron microscopy, immunohistochemistry, and in the cytoplasm and involves the production of a series of real-time reverse transcription-polymerase chain reaction subgenomic RNAs, which further makes proteins for virion (RT-PCR). assembly. Progeny virions are released from the infected cells into the surrounding cells and tissues in the respiratory tract, Methods where they are shed by coughing and sneezing. During the incubation period, the virus attaches to and infects cells, This review’s inclusion criteria were as follows: all studies replicates its genome, and spreads to infect adjacent cells. with any study design that reported the neurological features The incubation period for SARS-CoV-2 is found to be from in a cohort of more than 50 patients with COVID-19 and 4.5 to 5.8 days, with an average of 5.1 days. published on or prior to August 1, 2020 were included. Two From the earliest reports, ACE2 receptors have been electronic databases, namely PubMed and Google Scholar, shown to be present in many organs and tissues of human and one worldwide online search engine Google were body. An immunohistochemistry analysis revealed that searched for the concerned articles. The lists of references in SARS-CoV was predominantly present in the lungs, trachea, the included studies were also screened for any relevant and bronchi and was also detected in many other organs and papers. In this review, we have excluded Chinese studies that tissues, such as the stomach, small intestine, distal convoluted do not have coauthors from other countries except the pioneer renal tubule, sweat gland, parathyroid, pituitary, pancreas, study by Mao et al., which has scored more than 1,000 adrenal, liver, and cerebrum. CoVs have also been detected citations as on August 1, 2020. Also, preprint platforms and in tissues such as endothelial cells of small and large arteries their publications were not considered in this study. and veins, type I and type II alveolar epithelial cells in normal This review analyzed 247 research and reviewed articles lungs, in the basal layer of the nonkeratinizing squamous using the keywords neurological manifestations, epithelium of nasal and oral mucosa and the nasopharynx, neuroinvasion, neuroimaging, coronavirus, COVID-19, basal cell layer of the epidermis extending to the basal cell SARS-CoV-2, cohort, population, analysis in all possible layer of hair follicles, endothelial and smooth muscle cells of combinations. The final list of included articles was generated the brain, etc. on the basis of relevance to the topics covered in this review. Clinical features of COVID-19 ranging from an After removal of duplicate, non-original articles and preprints, asymptomatic state to acute respiratory distress syndrome a total of 102 articles were used for an initial screening based and multi-organ dysfunction. SARS-CoV-2 leads to chronic on titles and abstracts. Out of 102 studies, 48 studies were inflammation of the lungs, severe dyspnea, fever, dry cough, selected for the full-text review. Finally, 5 reviews and 9 cyanosis, and complete lung failure in more vulnerable clinical studies were taken in the present study as they met the patients. The typical clinical features include fever, cough, 14–27 inclusion criteria (Figure 1). sore throat, headache, fatigue, myalgia, and breathlessness. In some patients, the disease can progress to pneumonia, respiratory failure, and ultimately death. The disease Results progression is associated with an increase in inflammatory cytokines including IL2, IL6, IL7, IL10, GCSF, IP10, The study find out that COVID-19 patients do have concurrent MCP1, MIP1A, and TNFα. The disease in neonates, infants, neurological manifestations that are subjected to further study. and children has been reported to be significantly milder We collected 97 reviews through the search strategy described than adults. in this review and finally included 5 studies that could fit in Singh and Agarwal 3 Figure 1. Flow Chart for Literature Search Results our inclusion criteria ( Table 1 ). Together these studies reported (also known as acute inflammatory demyelinating 14–18 many neurological features either in the cohort analysis or polyneuropathy), coma, seizures, ataxia, and psychosis. case studies. Headache and dizziness were the most common Similarly, to study individual neurological symptoms, we symptoms in COVID-19-positive patients, followed by further analyze the penetration of neurological symptoms in anosmia and ageusia. The other reported clinical features COVID-19 patients as per the inclusion criteria for were confusion, hyposmia, encephalopathy, corticospinal neurological and neuropsychiatric presentations ( Table 2 ). tract signs, acute cerebrovascular problems, acute ischemic Out of 150 research papers, we isolated 9 studies that reported stroke, olfactory disorders, gustatory dysfunction, cerebral neurological symptoms in a cohort of more than 50 COVID- venous sinus thrombosis, hypoxia, Guillain–Barré syndrome 19 patients. Table 1. Selected Review Reports of Neurological Manifestations Associated With COVID-19 S. No. Title Date of Publication No. of Studies/ Patients Conclusion From the Review 1 Neurological manifestations of May 10, 2020 31 studies Anosmia, headache seizures, stroke, and COVID-19: A systematic review Guillain–Barré syndrome and current update 2 A review of neurological compli- May 18, 2020 15 studies Headache, dizziness anosmia, ageusia, cations of COVID-19 Miller Fisher syndrome, olfactory dys- function, and encephalopathy 3 Neuropathogenesis and neuro- May 29, 2020 Not specifi ed Anosmia, ageusia, headache, stroke, logic manifestations of the coro- impairment of consciousness, seizures, naviruses in the age of coronavi- and encephalopathy rus disease 2019: A review 4 Neurological and musculoskeletal June 26, 2020 60 studies Anosmia, ageusia, myalgia, headache, back features of COVID-19: A system- pain, and dizziness atic review and meta-analysis 5 Neurological associations of July 02, 2020 901 patients Encephalopathy, encephalitis, Guillain– COVID-19 Barré syndrome, anosmia, ageusia, acute cerebrovascular disease, and stroke 4 Annals of Neurosciences Table 2. Selected Clinical Studies of Cohort Showing Neurological Manifestations Associated With COVID-19 No. of Neuro- Author, Type of logically Affected SARS-CoV-2 Diag- Major Neurological Clinical S. No. Study, and Country Patients nostic Test Presentation Brain Abnormalities Findings 1. Mao et al., ret- 214 RT-PCR positive Dizziness, headache, hy- Not available rospective study, pogeusia, hyposmia, acute China cerebrovascular diseases, impaired consciousness, and skeletal muscle injury 2. Helms et al., ob- 58 RT-PCR positive Agitation, confusion, dys- MRI showed leptomeningeal servational study, executive syndrome, and enhancement, perfusion abnor- France encephalopathy malities, and cerebral ischemic stroke 3. Varatharaj et al., 125 RT-PCR positive, or Ischemic stroke, intracere- Not available UK-wide surveil- anti-SARS-CoV-2 bral hemorrhage, cerebral lance study, UK IgM, or IgG positive vasculitis, encephalopathy, encephalitis, Guillain–Barré syndrome and variants, neu- rocognitive (dementia-like) syndrome, psychiatric disor- der, psychosis, dementia-like syndrome, and affective disorder 4. Romero-Sánchez 841 RT-PCR positive, or Myalgia, headache, dizziness, Electroencephalogram  et al., ALBACOVID anti-SARS-CoV-2 anosmia, dysgeusia, impaired showed moderate encepha- registry, retrospec- IgM, or IgG positive consciousness, myopathy, lopathy in two patients, one tive, observational dysautonomia, cerebrovascu- patient showed MRI pattern study, Spain lar diseases, seizures, move- resembling posterior revers- ment disorders, encephalitis, ible encephalopathy syndrome, Guillain–Barré syndrome, one patient showed bilateral and optic neuritis temporal hyperintensity in FLAIR sequences of brain MRI 5. Benussi et al., retro- 56 RT-PCR positive, Ischemic attack, ischemic Not available spective study, Italy bronchoalveolar stroke, hemorrhagic stroke, lavage and epilepsy 6. Lu et al., prospec- 60 RT-PCR positive Mood change, fatigue, head- Diffusion tensor imaging and tive study, China ache, vision change, myalgia, 3D high-resolution T1 weight- impaired mobility, memory ed image showed significantly loss, taste loss, limb numb- higher bilateral gray matter ness, tremor, smell loss, and volumes (GMVs) in olfactory hearing loss cortices, hippocampi, insu- las, left Rolandic operculum, left Heschl’s gyrus, and right cingulated gyrus and a general decline of MD, AD, RD accom- panied with an increase of FA in white matter, especially AD in the right CR, EC and SFF and MD in SFF 7. Yan et al., cross- 59 RT-PCR positive Anosmia and ageusia Not available sectional study, USA 8. Lechien et al., Euro- 417 RT-PCR positive Olfactory dysfunction, anos- Not available pean study mia, hyposmia, and gustatory disorders 9. Kandemirli et al., 749 Not specified Not available Cortical, subcortical, and deep observational study, white matter FLAIR signal Turkey abnormality Singh and Agarwal 5 Mao and coworkers reported that 36.4% of the 214 patients positivity in order of descending frequency included fatigue had neurological symptoms. 24.8% of these patients exhibited (81%), ageusia (71%), fever (70%), anosmia (68%), myalgia or arthralgia (63%), diarrhea (48%), and nausea (27%). central nervous system (CNS) symptoms, the most common A multicenter European study by Lechien et al. showed of which were dizziness (16.8%) and headache (13.1%) and that 85.6% and 88.8% of a total of 357 patients reported less common were the alteration of mental status, acute olfactory and gustatory dysfunctions, respectively, with the cerebrovascular accident (CVA), ataxia, and seizures. olfactory dysfunction emerging before other symptoms in Helms et al. reported neurological complications in an 11.8% cases. 284 (79.6%) patients were anosmic and 73 observational case series of 58 patients admitted to the (20.4%) were hyposmic. Phantosmia and parosmia were intensive care unit (ICU) for acute respiratory distress reported in 12.6% and 32.4% of patients, respectively. syndrome, in Strasbourg, France. Neurological findings were Structural changes in the brain can provide excellent seen in 14% of patients at admission and 69% of cases were inputs to understand the effect of COVID-19 on the brain and seen when they were weaned off sedation and paralytics. The nervous system. Lu et al. reported cerebral microstructural most frequently observed symptoms were confusion (65%), changes in COVID-19 patients. Neurological symptoms were agitation (69%), upper motor neuron syndrome signs like present in 55% of COVID-19 patients. They further found hyperreflexia with clonus and positive Babinski’s sign (69%) that the recovered COVID-19 patients were more likely to during the ICU stay, and a dysexecutive syndrome (33%) have enlarged olfactory cortices, hippocampi, insulas, after discharge. Magnetic resonance imaging (MRI) of the Heschl’s gyrus, Rolandic operculum and cingulate gyrus, and brain in patients who developed unexplained encephalopathic a general decline of mean diffusivity (MD), axial diffusivity features revealed leptomeningeal enhancement (62%), 20 (AD), radial diffusivity (RD) accompanied by an increase of perfusion abnormalities (100%), and ischemic CVA (23%). fractional anisotropy (FA) in white matter (WM), especially In one UK-wide national surveillance study of 125 patients AD in the right coronal radiata (CR), external capsule (EC) with COVID-19 and neurological or psychiatric disease and superior frontal-occipital fasciculus (SFF), and MD in reported over three weeks showed that 39 (31%) patients had SFF as compared to non-COVID-19 volunteers. Global gray altered mental status, which included 16 (13%) with matter volume (GMV), GMVs in the left Rolandic operculum, encephalopathy [of whom seven (6%) had encephalitis], and right cingulate, bilateral hippocampi, left Heschl’s gyrus, and 23 (18%) with a neuropsychiatric diagnosis, including 10 global MD of WM were found to correlate with memory loss. (8%) with psychosis, 6 (5%) with neurocognitive (dementia- GMVs in the right cingulate gyrus and left hippocampus were like) syndrome, and 4 (3%) with an affective disorder. related to smell loss. Notably, 77 (62%) patients had a cerebrovascular event: 57 Kandemirli et al. showed that COVID-19 patients had (46%) ischemic strokes, 9 (7%) intracerebral hemorrhages, 1 acute findings in brain MRI, which include a cortical, (<1%) had CNS vasculitis, and 10 (8%) presented other subcortical, and deep white matter fluid-attenuated inversion cerebrovascular events. recovery (WM FLAIR) signal abnormality. Abnormalities Romero-Sánchez et al. reported that in 841 patients were also present in the frontal lobe, parietal lobe, occipital hospitalized with COVID-19 in Spain, myalgia (17.2%), lobe, temporal lobe, insular cortex, and cingulated gyrus. headache (14.1%), and dizziness (6.1%) were present mostly We have also analyzed neuropsychiatric conditions in in the early stages of infection. Anosmia (4.9%) and the COVID-19 pandemic and found that many conditions dysgeusia (6.2%) were the next most common symptoms. like anxiety, amnesia, hallucinations, depression, sleep The other symptoms reported were disorders of consciousness disorder, delirium, mood swings, and suicidal thoughts (19.6%), myopathy (3.1%), dysautonomia (2.5%), were also present in the general population because of cerebrovascular diseases (1.7%), seizures (0.7%), movement increased psychosocial stress, psychotropic drugs usage, disorders (0.7%), encephalitis (n = 1), Guillain–Barré etc., during the pandemic. Thus, neurological and syndrome (n = 1), and optic neuritis (n = 1). Neurological neuropsychiatric manifestations can become a more complications were the main cause of death in 4.1% of all pressing concern as the pandemic spreads and has longer- deceased study subjects. term effects on the general population. Benussi et al. from Italy observed a significant increase in cerebrovascular disease rates in the COVID-19 group (n = 43, 76.8% vs. n = 68, 58.1%, P = .02), with a similar Discussion distribution between transient ischemic attack (n = 5, 11.6% vs. n = 8, 11.9%), ischemic stroke (n = 35, 81.4% vs. n = 50, There are only a few studies that have shown the relation 74.6%), and hemorrhagic stroke (n = 3, 7.0% vs. n = 9, between the SARS-CoV-2 infection and neurological 13.4%) within groups. complications in COVID-19 patient cohorts. The human Smell and taste loss showed the largest magnitudes of brain has been reported to express ACE2 receptors that have association with COVID‐19 positivity reported in 68% been detected in glial cells and neurons in mice, which makes (40/59) and 71% (42/59) of COVID-19-positive subjects by them a potential target of SARS-CoV-2. Neurologists Yan et al. Self‐reported symptoms associated with COVID‐19 categorized neurological manifestations into nonspecific 6 Annals of Neurosciences symptoms (headache, dizziness, or myalgia), neuropsychiatric changes in the brain after the SARS-CoV-2 infection. disorders (insomnia, depression, anxiety, or psychosis), CNS Restrictions imposed during pandemic like lockdown have shown number of psychosocial effects in the community. disorders (direct viral infection, encephalitis, disorders of Symptoms such as anxiety, amnesia, hallucinations, consciousness, seizures, and stroke), peripheral nervous depression, sleep disorder, delirium, mood swings, and system disorders (cranial neuropathies, anosmia/dysgeusia, suicidal thoughts were observed in COVID-19 patients as and peripheral neuropathy), myopathy, demyelinating events, well as in the general population. and cerebrovascular manifestations. This study is based on the findings of neurological symptoms in the COVID-19 population, which further Conclusion discusses present and future implications in the COVID-19 management. By reviewing cohort-based studies, we have Neurological manifestations of COVID-19 have not been analyzed common as well as other neurological symptoms studied in detail yet. It is possible that patients having severe that need attention in health care settings. These findings also illness, developed CNS and neurological manifestations. have relevance for follow-up studies as many of the patients The most commonly reported neurological symptoms such showed up psychiatric problems that do not involve any as anosmia, gustatory impairment along with altered mental underlying pathology but were occurred because of a status should not be ignored and the patients in these cases psychosocial effect on the brain and behavior. It has been must be tested for COVID-19. Based on the available pieces established that CoVs have a potential to reach brain receptors of evidence, it is suggested that health care units taking care through the ACE2 receptor which is present in many tissues of infected patients must now include neurologists to gain of the brain and is proposed through two routes, i.e., olfactory more perspective into the nature of the infections, which can bulb and cribriform plate. be neurological. More autopsies on brains of the COVID-19 First, we analyzed the review papers that reported patients with neurological symptoms need to be performed neurological symptoms in COVID-19 patients. Based on the to establish the neuroinfection track of the disease. A through inclusion criteria, five studies came out to be most neurological assessment should be performed to note appropriate, which show that neurological symptoms such as neurological symptoms (e.g., headache, dizziness, etc.) and anosmia and ageusia were the most common and were noted signs (e.g., change in mental status, meningeal signs, etc.), in all five studies (5/5). It was followed by headache (4/5), detailed clinical, neurological, and electrophysiological stroke (3/5), encephalopathy (3/5), seizures (2/5), encephalitis investigations (e.g., electroencephalogram) of the patients (1/5), Guillain–Barré syndrome (1/5), and Miller Fisher particularly those with a change in mental status should be syndrome (1/5). Other less common neurological symptoms followed. Attempts to isolate SARS-CoV-2 from CSF may that were reported in review studies were impaired clarify the roles played by this virus in causing neurological consciousness, acute cerebrovascular disease, myalgia, back manifestations. Medical imaging and neuropathology will pain, and dizziness. undoubtedly play an essential role in detecting abnormalities To further study the prevalence of each neurological in the olfactory bulb, cranial nerves, and brains of COVID- symptom, we analyzed clinical research studies which have 19 patients. recruited a large number of COVID-19 patients. We analyzed studies from different countries across the globe to see if Author Contribution these symptoms are emerging from all over or have Dr Rachna Agarwal designed the study and approved the final geographical restrictions, because lockdown conditions in manuscript. Kamal Pratap Singh performed the literature analysis different countries can give rise to different neurological and wrote the manuscript. manifestations. A more detailed examination of symptoms revealed that apart from the findings from review studies Declaration of Conflicting Interests there are many more neurological symptoms that are emerging The authors declared no potential conflicts of interest with respect to out after the critical examination of patients. These symptoms the research, authorship, and/or publication of this article are hearing loss, skeletal muscle injury, agitation, confusion, dysexecutive syndrome, intracerebral hemorrhage, cerebral Ethical Statement vasculitis, psychosis, myopathy, dysautonomia, optic neuritis, No ethical consent was required from the Institutional Ethics epilepsy, mood change, fatigue, memory loss, limb numbness, Committee. tremor, etc. In some cases, these findings were very well substantiated by examining structural changes in the brain by Funding performing brain MRI, diffusion tensor imaging, and 3D high-resolution T1 weighted image, which shows that these The authors received no financial support for the research, kinds of studies should be performed in future to see the exact authorship, and/or publication of this article. Singh and Agarwal 7 ORCID iD 16. Zubair AS, McAlpine LS, et al. 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Annals of NeurosciencesSAGE

Published: Jan 1, 2021

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