Introduction

Coronavirus disease 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belonging to the coronavirus family. Coronaviruses are known to cause various self-limiting viral diseases, but recent years have seen few diseases that are known to cause severe respiratory syndrome and the latest addition to this is COVID-19.1 2

The primary target of SARS-CoV-2 is peripheral mucosal cells of respiratory tract.3 It is mostly invasive in nature with wide spectrum of diseases ranging from asymptomatic cases to severe acute respiratory distress syndrome.

However, recent days have seen few cases where virus has affected extrapulmonary organ such as nervous system.3 4 5 6 7 8 9 One case of viral encephalitis with positive cerebrospinal fluid (CSF) for viral protein has been reported in China.10 It is also reported in few studies that patients also present with symptoms of anosmia and dysgeusia.11 12 Previous coronavirus pandemics such as SARS-CoV and Middle East respiratory syndrome (MERS) have clearly shown involvement of central and peripheral nervous system infections. These finding can also be clearly be applied on the present pandemic.

In the present study, we will discuss about the various mode/mechanism of coronavirus infection of central and peripheral system and the possible symptoms due to this infection. It also aims to determine the neurological involvement and its manifestations in COVID-19 patients.

Materials and Methods

The present study was a narrative review done to review the existing literature on SARS-CoV-2 and its involvement in central and peripheral nervous system. The articles were searched and retrieved using techniques of systemic review, that is, Preferred Reporting Items for Systemic Review and Meta-Analysis (PRISMA) guidelines. Electronic database such as PubMed (Medline) and Google Scholar were searched systematically for articles published from December 1, 2019 to June 5, 2020. Articles were searched using following keywords: “COVID-19” OR “CORONAVIRUS” OR “SARS-CoV-2” AND “NEUROLOGICAL MANIFESTATION.”

Authors first searched abstract of the article using the above-mentioned keywords. Articles that were written in English and whose complete text was available were included in the final list.

A total of 189 articles were initially selected by the authors.

Out of 189 articles, 104 articles were removed on initial screening by the authors because their title does not match with the study objectives. In the second step, 32 articles were removed because they were review articles or opinion of different experts. Twelve articles were further removed because their main text was available in languages other than English. Furthermore, 11 more articles were removed from the main list because they were duplicate article. Thus, after second stage of screening, a total of 30 articles remained.

The authors looked for the complete text of the selected articles. Of the 30 articles selected in the second stage, 11 articles were further removed because their complete text could not be retrieved or unavailable for review.

Thus, a final list of 17 articles was prepared and following information were extracted from selected studies: study design, main result, and limitation of the study. Methodology section was also assessed by the authors.

Results

After an extensive literature search using a web-based search engines, a total of 189 article were suggested. Out of this, we prepared a list of 17 articles based on inclusion and exclusion criteria for review. Majority of these article were descriptive studies describing spectrum of signs and symptoms among admitted patients.3 4 5 6 7 8 9 10 11 12 Majority of these studies showed that patients may develop signs and symptoms suggestive of neurological involvement. Most common central nervous system (CNS) symptoms reported were headache, followed by dizziness and confusion. Similarly, the most common sign of peripheral nervous system involvement was loss of taste and smell.12 13 14 15

One case of viral encephalitis with positive CSF for viral protein10 was also reported; however, one case series did not find out positive CSF in their patients.16 17 On case report presented two patients present with Miller-Fisher syndrome and polyneuritis cranialis. Similarly, one case report of myoclonic seizure was also reported in COVID-19-positive patient who had no respiratory symptom.18 However, none of the study is specifically designed to study the neurological symptoms in COVID-19 patients.

Discussion

It is noted in the present study that there is a scarcity of literature showing clear evidences of neurological manifestations in current COVID-19 pandemic. However, findings of previous coronavirus pandemics can also be safely applied on the current SARS-CoV-2 pandemic. In 2003, SARS-CoV epidemic, patients with neurological manifestation had their CSF positive for the virus.2 19 In study of patients suffering for MERS, neurological manifestation was also reported in few patients.20 21 So, it is quite imperative to presume that the current pandemic will also have patients presenting with different neurological manifestations. Some of these manifestations will be specifics such as cerebrovascular accidents, seizures, meningitis, and encephalitis, whereas majority will have nonspecific symptoms such as confusion, dizziness, headache, and myalgia.12 13 14

Most of the studies related to COVID-19 had few symptoms of CNS involvement such as headache, confusion, dizziness,12 13 14 15 and cerebrovascular accidents.6 Similarly, symptoms such as loss of taste and smell are suggestive of peripheral nervous system involvement.

Mechanism for CNS Involvement

Various mechanism has been proposed for the neuronal involvements such as direct infection injuries, hypoxic injuries, and immune mediated.

Direct injuries are mostly taking place through direct seeding of the virus into the neuronal tissue through blood circulation22 or via olfactory nerve pathways.19 Direct seeding of the virus leads to viral encephalitis. Entry of virus through olfactory nerve is the most suggested pathway by different researchers. Mouse hepatitis virus model23 also supports this hypothesis. Virus migrates through sensory or motor neurons in both anterograde or retrograde directions through neuronal proteins, dynein, and kinesin.24 Entry of the virus through olfactory nerve pathway takes place in early phase of the infection. There are studies which indicate that patients present first with neurological symptoms are later found to be COVID-19 positive.25

CNS involvement mostly takes place in the second week of the infection due to hypoxic injuries caused by the decrease oxygenation of blood. Due to decreased oxygen saturation in the blood, there is anerobic metabolism in the mitochondria of the brain cells leading to accumulation of the acid in the neuronal tissues, resulting in cerebral vasodilation, swelling of brain cells, interstitial edema, obstruction to blood flow leading to ischemia that result in headache and dizziness.26 In severe cases, there is a raised intracranial tension that results in drowsiness, bulbar conjunctival edema, and even coma. In patients who are prone to cerebrovascular accidents, hypoxia results in cerebral stroke via a release of cytokine storms that mostly happen in second week. This is mostly through immune mediation.27

Another mechanism is related to the CNS manifestation. Persistence of the virus in the neuronal tissue and their ability to infect macrophages, microglia, and astrocytes result in release of large quantities of proinflammatory cytokines such as interleukin-2 (IL-2), IL-5, IL-6, and tumor necrosis factor-alpha. These cytokines are important for the cytokine storms and are directly corelated with the severity of the infection.28

Clinical Manifestations in COVID-19 Infection

Conclusion

The present study concludes that there is a scarcity of good quality research that specifically focuses on neurological involvements in COVID-19 patients. Also, the present study concludes that there is enough evidence to prove that SARS-CoV-2 infection affects neurological tissues both in central and peripheral nervous system. Various mechanisms are proposed to explain the pathophysiology of neurological manifestations in COVID-19-positive patients that need to be established and verified. This should be supplemented with biochemical and electrophysiological studies.

However, the present study also concludes that some patients, especially those with severe infection, may have clinical and subclinical neurological manifestation that can be assigned to impaired electrolyte and metabolic derangement. This should also be considered while evaluating patients with neurological manifestations.