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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 17  |  Issue : 3  |  Page : 157-160

Neurological manifestations of COVID-19 (severe acute respiratory syndrome coronavirus 2)


1 Department of Neurology, Indraprastha Apollo Hospitals, New Delhi, India
2 Department of Internal Medicine, Geetanjali Medical College, Udaipur, Rajasthan, India
3 Department of Internal Medicine, Indraprastha Apollo Hospitals, New Delhi, India

Date of Submission25-Jun-2020
Date of Acceptance27-Jun-2020
Date of Web Publication07-Aug-2020

Correspondence Address:
Vinit Suri
D-343, Defence Colony, New Delhi - 110 024
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_63_20

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  Abstract 


Coronaviruses including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known to affect primarily the respiratory system with additional manifestations on the enteric, hepatic, and cardiac systems as well. Neurological manifestations are increasingly being reported from all over the world though only as case reports and short case series. Neurological manifestations are not uncommon and may be seen in up to a third of patients with COVID-19 infection and may range from minor symptoms of headache, dizziness, anosmia, and ageusia to severe neurological illnesses including encephalitis, acute necrotizing hemorrhagic encephalitis, stroke, myelitis, and Guillain–Barre syndrome. Neurological symptoms may occasionally be the presenting or sole manifestation of COVID-19 infection, and a high index of suspicion is required while dealing with such cases during the COVID-19 pandemic. A Medline search was made till June 20, 2020 using the keywords SARS-CoV-2, COVID-19, and Neurological Manifestations for the review.

Keywords: COVID-19, neurological manifestations, severe acute respiratory syndrome coronavirus 2


How to cite this article:
Suri V, Suri K, Jain S, Suri K. Neurological manifestations of COVID-19 (severe acute respiratory syndrome coronavirus 2). Apollo Med 2020;17:157-60

How to cite this URL:
Suri V, Suri K, Jain S, Suri K. Neurological manifestations of COVID-19 (severe acute respiratory syndrome coronavirus 2). Apollo Med [serial online] 2020 [cited 2020 Oct 26];17:157-60. Available from: https://www.apollomedicine.org/text.asp?2020/17/3/157/291734


  Introduction Top


The coronavirus is an enveloped positive-sense, single-stranded RNA virus. The coronaviruses belong to the family Coronaviridae in the order Nidovirales, and members of this family include the pathogenic human coronavirus (HCoV) (including the HCoV-229E, HCoV-OC43, HCoV-HKV1, and HCoV-NL63) and the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). The SARS-CoV-2 or COVID-19 is the seventh virus in the coronavirus family and genetically is 79.5% identical to the SARS-CoV and 50% to the MERS-CoV.[1]

The coronaviruses are predominantly respiratory viruses, although they may also cause enteric, hepatic, cardiac, and neurological diseases. SARS-CoV and MERS-CoV have been known to cause many neurological manifestations in the past pandemics,[2],[3] and their viral nucleic acid has been documented in the cerebrospinal fluid (CSF) and in the brain or autopsy findings,[4],[5] suggesting a neurotropic and neuroinvasive potential. Experimental data for SARS-CoV-2 (COVID-19) are currently limited since the infection started in December 2019 from Wuhan, Hubei Province, China, and are limited to case reports and small series. However, it is expected to behave in a similar manner to the SARS-CoV and MERS-CoV viruses which have been shown to be both neuroinvasive and neurotropic and causing a wide range of neurological manifestations.


  Mechanisms of Neurological Manifestations Top


Hypoxic injury

Severe respiratory involvement may result in systemic hypoxia, hypercarbia, and anaerobic metabolism resulting in neuronal swelling and brain edema. This mechanism can lead to manifestations such as encephalopathy, delirium, acute confusional state, agitation, and dysexecutive syndrome.

Immune-mediated injury

Immune mediated injury results predominantly from the cytokine storm wherein elevated levels of inflammatory cytokines (especially IL-6) as well as activation of macrophages, T- lymphocytes and endothelial cells, result in vascular leakage, activation of complement and coagulation pathways and disseminated intravascular coagulation, resulting in neuronal injury. This immune injury may affect the central nervous system (CNS) and result in cerebrovascular stroke, immune-mediated necrotizing encephalitis, or myelitis. Production of certain antibodies against specific gangliosides may also be responsible for producing syndromes such as Guillain–Barre syndrome (GBS) and other immune-related neuropathies and plexitis syndromes.

Direct invasion of the central nervous system

Angiotensin-converting enzyme-2 (ACE-2) is the target receptor for the coronaviruses including the SARS-CoV-2 (COVID-19) and is used by the virus for attachment to the cell and subsequent internalization, following which the viral RNA is released into the cytoplasm, replicated, and after the formation of envelope protein and incorporation of the viral RNA into it, the virus is then released into the systemic circulation resulting in further spread. The concentration of ACE-2 receptors in various organs determines the severity of manifestations in that organ. ACE-2 receptors are found in the glial cells in the brain and spinal cord, neurons, and brain vessels, which permit SARS-CoV-2 to target them.[6]

Direct invasion of the CNS may occur by certain mechanisms which include:

  1. Retrograde transmission through the olfactory nerves, from the olfactory epithelium traversing through the cribriform plate. There has been a postulation that viral spread through the nasal route, resulting in anosmia/ageusia without respiratory symptoms, may result in a milder form of disease compared to when the spread occurs to the pulmonary region and lower respiratory tract
  2. Hematogenous spread – after reaching the respiratory airways, SARS-CoV-2 can cross the basolateral surfaces of the epithelial cells into the blood circulation and enter the brain after infecting endothelial cells of the blood–brain barrier or epithelial cells of the blood–CSF barrier in the choroid plexus of the ventricles
  3. Transneuronal retrograde spread – the SARS-CoV-2 may infect the peripheral neurons and then invade the CNS through the axonal retrograde transport which has been well documented for other coronaviruses.[7] Some patients have been observed to have a vagal spread from the respiratory system presenting as ageusia, dysphagia, dysarthria with diaphragmatic paresis, and unexplained tachycardia, and patients with gastrointestinal tract infection have also been known to spread to the CNS through enteric nerves or the sympathetic nerves.



  Neurological Manifestations of Covid-19 Top


The neurological manifestations of COVID-19 have been subdivided into three categories – those involving the CNS, peripheral nervous system (PNS), and those involving the musculoskeletal system [Table 1].
Table 1: Neurological manifestations of severe acute respiratory syndrome coronavirus 2

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While most patients with SARS-CoV-2 infection will suffer only from a mild or severe respiratory illness, neurological manifestations have been well described in these patients. A study from Wuhan, China,[8] showed that 36.4% (78 of 214) of patients showed neurological manifestations. The study revealed CNS involvement in 24.8% (53 of 214), PNS in 8.9% (19 of 214), and skeletal muscle injury in 10.7% (23 of 214) of patients. The most common CNS symptoms were headache (13.1%) and dizziness (16.8%). Serious CNS manifestations included acute cerebrovascular disease (5.7%) and impaired consciousness (14.8%). The most common manifestations in the PNS included taste impairment (5.6%) and impairment of sensation of smell (5.1%). Most importantly, neurological symptoms occurred early in the illness and two of the six stroke patients presented primarily with neurological manifestations without any symptoms of fever, cough, or respiratory symptoms. Another prospective case series from France[9] of 58 patients reported a higher percentage of neurological manifestations of 84% (49 of 58). Agitation (69%) was the most common CNS manifestation, followed by acute confusional state (65%), and a dysexecutive syndrome at discharge was observed in 36% of patients. Ischemic stroke was identified on magnetic resonance imaging (MRI) in 3 of 13 patients (23%) who had undergone an MRI evaluation and 2 of these patients were asymptomatic from the stroke. Leptomeningeal enhancement was seen in 8 of the 13 patients (62%) who were evaluated with an MRI.


  Central Nervous System Manifestations Top


Minor manifestations

Headache and dizziness were the most common among the mild CNS manifestations reported.[8] Alterations in mood including depression and nonspecific anxiety phenomenon have also been described, especially in patients who survived severe acute respiratory distress syndrome (ARDS). Disorders of attention, memory, impaired visuospatial abilities, and executive function have been described. A high incidence (67%) of dysexecutive function was reported at the time of discharge in the series from France.[9]

Toxic encephalopathy

An infectious toxic encephalopathy, referring to a reversible brain dysfunction syndrome and resulting from multiple factors including systemic toxemia, metabolic abnormalities, and hypoxia during the process of acute infection has been described. It manifests as an acute delirium resulting from cerebral edema without any evidence of inflammation in the CSF analysis and has been observed in patients suffering from SARS-CoV-2 infection.[8],[9]

Encephalitis

Evidence of SARS-CoV-2 causing an infective encephalitis was confirmed by identifying the SARS-COV-2 in the CSF of patients by genome sequencing by the treating team of Beijing Ditan Hospital.[10] Moriguchi et al.[11] reported the first case of COVID-19 viral encephalitis in Japan in a 24-year-old presenting with seizures and altered sensorium. MRI was suggestive of right lateral ventriculitis and encephalitis with CSF sample positive for SARS-CoV-2 but negative in nasopharyngeal swab. This case provides important information that encephalitis may be the presenting feature of COVID-19 infection even when the nasopharyngeal swab may be negative and provides evidence of the neuroinvasive and neurotropic potential of SARS-CoV-2 virus. Another case of CSF negative acute hemorrhagic necrotizing encephalopathy was reported from the USA[12] in a lady in late 50s who presented with cough, fever, and altered sensorium of 3-day duration with MRI revealing hemorrhagic rim-enhancing lesions within the bilateral thalami, medial temporal lobe, and subinsular region. CSF was negative for SARS-CoV-2 and other pathogens, though nasopharyngeal swab was positive, suggesting cytokine storm to be the proposed mechanism for the syndrome rather than direct viral invasion.

Acute myelitis

Acute myelitis was reported in a 66-year-old male from Wuhan, China,[13] who had presented with acute flaccid paraplegia with sensory level at D10 with polymerase chain reaction (PCR) for nasopharyngeal secretion positive for COVID-19. Authors awttributed the presentation to a cytokine storm, but could not conduct the PCR for COVID-19 in the CSF and nor obtain an MRI image of the spinal cord.

Cerebrovascular accident or stroke

Multiple mechanisms including hypercoagulability leading to macro- and microthrombi formation in vessels, hypoxic injury, direct injury to blood vessels and blood–brain barrier, and the cytokine storm, have been proposed in the pathogenesis of stroke in patients with COVID-19 infection. A coincidental occurrence of stroke in patients with underlying hypertension, coronary artery disease, diabetes and other risk factors, and COVID-19 infection cannot however be excluded in some patients. The series from Wuhan, China,[8] revealed an incidence of 5.7% of strokes in their series with five of the strokes being ischemic and one hemorrhagic. The French cohort[9] revealed three cases of ischemic stroke seen on radiological imaging, and importantly, two of them were asymptomatic for the stroke manifestations. A case of intracranial bleed in a 79-year-old COVID-19 positive male with no history of hypertension was reported from Iran.[14]


  Peripheral Nervous System Manifestations Top


Anosmia and ageusia

The most common manifestation in the PNS includes anosmia/hyposmia and hypogeusia/ageusia. A single-center study from the USA analyzed chemosensory dysfunction in 59 COVID-19 patients and 203 COVID-19 negative patients with influenza-like presentation using an Internet-based cross-sectional survey and demonstrated loss of smell in 68% COVID positive versus 16% COVID negative patients and loss of taste in 71% COVID positive versus 12% COVID negative patients.[15] Another report from a large cohort of 10,069 patients from Iran, employing a online questionnaire-based survey, observed an incidence of anosmia/hyposmia in 48.2% of respondents, whereas 83.38% had loss or reduced sense of taste.[16] In fact, it has been recommended that any patient presenting with isolated anosmia or ageusia during the pandemic should be screened for SARS-CoV-2.

Guillain–Barre syndrome

SARS-CoV-2 patients may manifest with GBS. GBS is an immune-mediated disorder with molecular mimicry playing a major role in its genesis and other coronaviruses including SARS and MERS, have also been known to cause GBS.[17] Zhao et al.[18] reported the first case of GBS in a 61-year-old female with a travel history to Wuhan, China. A report from Northern Italy, reported a series of five patients of GBS in patients with COVID-19 positivity.[19] Miller Fisher variant has also been reported in a 50-year-old male with a 5-day history of cough, malaise, fever with right ophthalmoplegia, and positivity for GD1b-IgG antibody and PCR positivity for COVID-19 from the nasopharyngeal swab.[20]

Infranuclear seventh cranial nerve palsy (Bell's palsy)

A few cases of Bell's palsy have been reported in COVID-19 patients in the absence of herpes zoster or the presence of other viral antigens. Facial nerve damage has been attributed to an immune injury caused by the SARS-CoV-2 infection though whether this is a coincidental occurrence or a direct effect of the SARS-CoV-2 infection has to be confirmed by future research.[21]

Critical illness and entrapment neuropathy

Critical illness, entrapment neuropathy, and pressure palsies may occur in patients with SARS-COV-2 related to sepsis and usage of neuromuscular blockage and steroids in critically ill patients with no definite specific relation to the SARS-CoV-2 infection itself.


  Skeletomuscular Symptoms Top


Myalgic pains and elevated Creatine phosphokinase indicating skeletal muscle injury have been reported in 19.3% by Mao et al.[8] Critical illness myopathy, acute quadriplegic myopathy, thick filament myopathy, and necrotizing myopathy have also been observed in coronavirus-infected patients.[22]


  Conclusion Top


SARS-CoV-2 is primarily a respiratory illness with a large number of patients presenting with mild symptoms of cough, fever, malaise and the severely ill patients presenting with pneumonia, and respiratory failure and ARDS. Neurological manifestations are not uncommon and may occur in up to a third of patients ranging from mild manifestations of anosmia and ageusia to severe neurological syndromes including encephalitis, stroke, GBS, and myelitis. Neurological complications are usually observed in severely ill COVID-19 patients, but, importantly, may precede the respiratory symptoms or may be the only manifestation of COVID-19 infection. This is of extreme importance for patients presenting with these neurological manifestations during the pandemic even in the absence of classical symptoms of fever, cough, and respiratory illness. There is accumulating evidence suggesting that SARS-CoV-2 virus which is primarily a respiratory tract pathogen may also be neurotropic, neuroinvasive, and neurovirulent.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
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