MENINGOENCEPHALITIS ASSOCIATED WITH SARS-COV-2

The aim of this work is to clarify the incidence of meningitis/encephalitis in SARS-CoV-2 patients. We conducted an initial search in PubMed using the Medical Subject Headings (MeSH) terms "meningitis," and "encephalitis,", and "COVID-19" to affirm the need for a review on the topic of the relationship between meningitis/encephalitis and SARS-CoV-2 infection. We included case series, case reports and review articles of COVID-19 patients with these neurological symptoms. Through PubMed database we identified 110 records. After removal of duplicates, we screened 70 record, and 43 were excluded because they focused on different SARS-CoV-2 neurological complications. For eligibility, we assessed 27 full-text articles which met inclusion criteria. Seven articles were excluded, and twenty studies were included in the narrative review, in which encephalitis and/or meningitis case reports/case series were reported. Neurological manifestations of COVID-19 are not rare, especially meningoencephalitis; the hypoxic/metabolic changes produced by the inflammatory response against the virus cytokine storm can lead to encephalopathy, and the presence of comorbidities and other neurological diseases, such as Alzheimer's disease, predispose to these metabolic changes. Further study are needed to investigate the biological mechanisms of neurological complications of COVID-19.


I. INTRODUCTION
The Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) was firstly and officially identified on January 2020 in Wuhan, China, from a patient with atypical pneumonia 1 ; the COVID-19 global pandemic was declared two months later, affecting millions of people and engaged clinicians around the world in an unprecedented effort to limit the viral spread and treat affected patients 2 . As of August 18, 2020, the COVID-19 pandemic has resulted in more than 22 million confirmed cases worldwide and more than 780.000 deaths. SARS-CoV-2 primarily affects the respiratory tract; the most common clinical symptoms are fatigue, cough, shortness of breath, and mainly respiratory tract symptoms 3 . Coronaviruses are respiratory viruses with neurotropic capacities, which allow them to avoid the immune response; viral RNA has been found in the cerebrospinal fluid, after SARS-CoV exposure, in patients with encephalitis, ischemic stroke and polyneuropathy [4][5][6] . Neurological SARS-CoV-2 virus-associated symptoms are not uncommon, and an increasing number of cases have presented with neurologic manifestations (such as headache, anosmia, taste disorders, Guillan-Barrè syndrome, and meningoencephalitis) and can be devastating complications 7,8 ; the common neurological symptoms included olfactory (60.6%) and gustatory (61%) disorders, especially in mild cases 9 . In one of most representative case series from Wuhan, China, 36.4% of patients had neurological complications 10 . The pathophysiological mechanisms have not been completely established, but the hypoxic/metabolic changes, produced by the inflammatory response against the virus cytokine storm, can lead to encephalopathy [11][12] . The SARS-CoV-2 infection involves the central nervous system due to the direct neuroinvasion and, mainly, the neurological sequelae due to the systemic innate-mediated hyper-inflammation.
The possible routes of neuroinvasiveness of SARS-CoV-2 are well summarized by Khan and Gomes 13 ; the hematogenous route, through which the virus infects endothelial cells of the blood-brain barrier and invades neuronal tissue, and the neuronal retrograde spread, via olfactory nerves from the nasal cavity through cribriform plate, the virus reaching the central nervous systems, are the most accepted theories 14 . Besides, a recent theory suggested that neuroinvasion via the enteric pathway can be possible, due to the enteric nervous system invasion or reaching the central nervous system via intestinal vagal afferents 15. Low levels of Angiotensin-converting enzyme 2 (ACE2), a functional receptor for the SARS-CoV-2, has been detected in the human brain 16 ; moreover, a recent study demonstrated that the brain is the principal target organ

MENINGOENCEPHALITIS ASSOCIATED WITH SARS-CORONAVIRUS-2 Università degli Studi di Salerno
for SARS-CoV in transgenic mice for human ACE2 receptor 17 . Moreover, a potential role of the spike glycoprotein (S1)-S1 IgG antibody complex was hypotized to facilitate the entry of the virus into the host immune cells 18 . The purpose of this brief review is to clarify the incidence of meningitis/encephalitis SARS-CoV-2 associated.
II. METHODOLOGY

Search Strategy and Study Selection
We conducted an initial search in PubMed using the Medical Subject Headings (MeSH) terms "meningitis," and "encephalitis,", and "COVID-19" to affirm the need for a review on the topic of the relationship between meningitis/encephalitis and SARS-CoV-2 infection. The research protocol was designed to define the objective and the methodology of the study; the protocol was neither registered nor published. The search strategy was chosen in consultation with a senior librarian at the University of Salerno (Salerno, Italy). A comprehensive review of the English-language literature was performed by using the following databases: the National Library of Medicine's version of PubMed (1988 to June 2020). The last search was performed on August 16, 2020. We included case series, case reports and review articles of COVID-19 patients affected by neurological symptoms. After exclusion of duplicates, all articles were evaluated through title and abstract screening by two independent reviewers (Pietro De Luca and Giorgio Iaconetta). The same two reviewers performed an accurate reading of all full-text articles assessed for eligibility, and performed a collection of data to minimize the risk of bias. Inconsistencies regarding inclusion of a given study were adjudicated by a third reviewer (Ettore Cassandro).

III. RESULTS
Through PubMed database we identified 110 records. After removal of duplicates , we screened 70 record, and 43 were excluded because they focused on different SARS-CoV-2 neurological complications. For eligibility, we assessed 27 full-text articles which met inclusion criteria. Seven articles were excluded for the following reasons: a) Articles in Polish (n= 1), b) Article in Chinese (n= 6). Twenty studies were included in the narrative review, in which encephalitis and/or meningitis case reports/case series were reported.

IV. DISCUSSION
The SARS-CoV-2 infection is not only a respiratory disease; neurological involvement is not rare.  36 , who suggested that the presence of neurological disease predisposes to hypoxic/metabolic changes and to encephalopathy; in addition they found that encephalitis is common in older patients (>50-year-old), in patients critically ill, and most of these patients presented lung abnormalities and many of them were already on mechanical ventilation, or in the intensive care unit when encephalopathy developed. Besides, cortical and subcortical T2/FLAIR signal changes are common neuroimaging abnormalities. Moreover, several Authors confirmed that, in some cases, the neurological symptoms can even precede the respiratory ones or can be the only symptoms in COVID-19 patients 37 .
An earlier recognition of a neurological impairment in patients with a mild or asymptomatic respiratory infection can be challenging, also to prevent the long-term neurological sequelae and to contain social and economic costs 38

V. CONCLUSION
Neurological manifestations of COVID-19 are not rare, especially meningoencephalitis, which could be a devastating SARS-CoV-2 associated Central Nervous System complications, especially in older and critical patients, in which can cause lifelong disability and death. The hypoxic/metabolic changes produced by the inflammatory response against the virus cytokine storm can lead to encephalopathy, and the presence of comorbidities and other neurological diseases (as Alzheimer's disease) predispose to these metabolic changes. Also the autoimmune response can play a role in the pathogenesis of brain damage related to SARS-CoV-2. Further studies are needed to investigate the biological mechanisms of neurological complications of COVID-19.