key: cord-1037200-kqicjw48
authors: Pouga, Lydia
title: Encephalitic syndrome and anosmia in COVID‐19: Do these clinical presentations really reflect SARS‐CoV‐2 neurotropism? A theory based on the review of 25 COVID‐19 cases
date: 2020-07-27
journal: J Med Virol
DOI: 10.1002/jmv.26309
sha: 251051c63abdcd3fa8feee69a45f257afa432f5c
doc_id: 1037200
cord_uid: kqicjw48

Since the discovery of coronavirus disease 2019 (COVID‐19), a disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the pathology showed different faces. There is an increasing number of cases described as (meningo)encephalitis although evidence often lacks. Anosmia, another atypical form of COVID‐19, has been considered as testimony of the potential of neuroinvasiveness of SARS‐CoV‐2, though this hypothesis remains highly speculative. We did a review of the cases reported as brain injury caused by SARS‐CoV‐2. Over 98 papers found, 21 were analyzed. Only four publications provided evidence of the presence of SARS‐CoV‐2 within the central nervous system (CNS). When facing acute neurological abnormalities during an infectious episode it is often difficult to disentangle neurological symptoms induced by the brain infection and those due to the impact of host immune response on the CNS. Cytokines release can disturb neural cells functioning and can have in the most severe cases vascular and cytotoxic effects. An inappropriate immune response can lead to the production of auto‐antibodies directed toward CNS components. In the case of proven SARS‐CoV‐2 brain invasion, the main hypothesis found in the literature focus on a neural pathway, especially the direct route via the nasal cavity, although the virus is likely to reach the CNS using other routes. Our ability to come up with hypotheses about the mechanisms by which the virus might interact with the CNS may help to keep in mind that all neurological symptoms observed during COVID‐19 do not always rely on CNS viral invasion.

They are often considered as both resulting from nervous system damage, the first one being linked to a direct central nervous system (CNS) involvement and the second one to a peripherical nervous system damage. 1 There is an increasing number of cases reporting as SARS-CoV-2 (meningo) encephalitis. Nevertheless, evidence is often lacking. Encephalitis can lead to diverse neurological symptoms (confusion, seizure, focal signs, and coma) that reflect brain injury. Meningitis is characterized by a neck stiffness and the presence of a cerebrospinal fluid (CSF) pleocytosis, without any parenchymal involvement. A sustained inflammatory response originating outside the brain can also lead to vascular and cells damage without any viral proliferation within the CNS (acute encephalopathy). 2 Many pathogens including coronaviruses can induce an auto-immune response directed toward the CNS after the resolution of an infection (acute disseminated encephalomyelitis [ADEM] ). 3 It is often difficult to distinguish encephalitis, meningitis, and neurological symptoms induced by metabolic, vascular, or auto-immune disorders occurring during or after a severe infection.

We reviewed all COVID-19 cases reporting a brain damage (except the ones related to ischemic stroke in the context of a severe infection) and we proposed the mechanisms by which SARS-CoV-2 could impair the CNS. It is urgent to clarify the different ways SARS-CoV-2 may interact with the CNS to distinguish the severe cases (ie, SARS-COV-2 encephalitis) from the ones related to a transient impact of SARS-CoV-2 infection on the CNS.

Among 98 records identified from Pubmed database (the search terms "central nervous system," "CNS," "neurological," "encephalitis," "meningitis," "meningoencephalitis," "meningo-encephalitis," "seizure," "seizures," "confusion," "encephalopathy," "COVID," "SARS,"

and "coronavirus" were used between 1st of December 2019 and 26th of May 2020), 85 titles and abstracts were screened (13 duplicates) with no language restrictions. SIxty-four were excluded because they were not relevant to the topic covered in this paper.

Twenty-one articles reported as SARS-CoV-2 brain injury were fully read, 4-24 corresponding to 25 cases.

When performed (n = 10), the SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) in the CNS was positive only in four patients (40%). Among those four cases, comorbidities have been reported in two of them (50% vs 33% of the patients with a negative RT-PCR in the CNS), the virus was systematically found in the upper respiratory tract (the test was performed simultaneously in the CNS and in the nasopharynx only for two patients, and no other body compartment has been tested), and they all displayed a severe form except one (75% vs 33% of the patients with a negative RT-PCR), with one death and no recovery at the day of the publication for the other three severe cases.

Most of patients were males (n = 17, 68%) and reported comorbidities (n = 13, 52%). Alteration in mental status/confusion were the most reported neurological symptoms (n = 22, 88%). The neurological symptoms were concomitant with respiratory symptoms (n = 7, 28%) or appeared in the context of a worsening of initial respiratory symptoms (n = 7, 28%). Cerebral magnetic resonance imagery (MRI) performed in twelve patients revealed abnormalities in 50% of cases and showed inflammatory lesions that brain computed tomography (CT) failed to reveal (cases 2 5 and 9 14 ). Among the fourteen lumbar punctures performed, 50% were normal (no pleocytosis and no elevation of proteins level). A lymphocytic pleocytosis was found in five cases (36%). An elevation of proteins level in the CSF was reported only in two cases (14%). When performed (n = 8) SARS-CoV-2 RT-PCR on CSF samples were positive only in two cases (25%). Finally, almost half of the patients (n = 11, 44%) had a severe infection (intensive care unit, mechanical ventilation, death) with recovery in the majority of cases (n = 15/24, 62.5%) ( Table 1 ).

Although many authors presented their cases as SARS-CoV-2 (meningo) encephalitis, this diagnosis remains speculative without any evidence of the virus within the CNS. The neurological symptoms observed in the infant (case 5 9 ) and the child (case 7 12 ) reported in Table 1 with fast and total recovery are in favor of a moderated effect of cytokines on the brain. This mechanism has been recently proposed to explain aseptic CSF pleocytosis commonly observed in infants during urinary tract infections. 25 The apparition of neurological impairments after the resolution of respiratory symptoms observed in three patients in this paper (cases 10, 15 16, 19 and 24 23 ) are highly suggestive of ADEM.

Based on post-mortem data available about the brain of healthy people and patients with neurological diseases, we now know that CNS brain invasion by coronaviruses might probably occur more frequently than expected. 26 Animal studies have showed that coronaviruses are able to reach the CNS via peripheral nerves. 27 Based on these data and the neurological symptoms found in COVID-19 some have postulated that SARS-CoV-2 might have neurotropic properties. As a matter of fact, the presence of a virus within the CNS involves two concepts: the virus capacity to reach the CNS (neuroinvasiveness) and the virus capacity to proliferate efficiently within the CNS (neurovirulence). Neuroinvasiveness can be achieve by viruses able at using the machinery of neurons be transported within a neuron as seen in the case of herpes viruses. Viruses can also be present in the CNS using other pathways such as the bloodstream. In this case the virus does not need any particular affinity for neurons (neurotropism) (Figure 1 ).

Virus can take advantage of the increased local blood vessels per- F I G U R E 1 Possible mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brain invasion. 1A, The primary viremia: during a viral infection a small amount of virus can reach the bloodstream. As lymphatic vessels drain into the circulatory system, virus particles can freely reach the bloodstream via this way. Taking advantage from the disruption of the blood-brain-barrier (BBB) caused by the inflammation or using ACE-2 receptors present at the surface of BBB endothelial cells, SARS-COV-2 could then enter the CSF (2A), without any proliferation within the brain parenchyma (3A). In this case symptoms would be limited to a meningeal syndrome. 1B. The shortcut pathway from nasal cavity: When SARS-CoV-2 enters the nasal cavity it could reach the CNS via two routes. 2Bi: It could "passively" reach the CSF via the OECs that have an open connection with the CSF; the CNS immune response should prevent spread of SARS-CoV-2 into the brain parenchyma (3A). 2Bii: SARS-CoV-2 could also invade ORNs with the assumption that ACE-2 is present in those cells; in this case the virus would use a nerve pathway by being transported retrogradely from ORNs to the OB and could continue to spread through chains of connected neurons to reach the brain (3B), which might result in possible irreversible damage to the CNS. 1C, The secondary viremia: during a sustained viral replication due to the host inability to clear the viral proliferation a large amount of virus is produced and the respiratory epithelium can be disrupted, allowing the virus to reach the bloodstream. The virus could then cross the endothelial barrier by taking advantage from the disruption of the BBB caused by the inflammation or using ACE-2 receptors present at the surface of BBB endothelial cells (2C). The ineffective immune response leads to a viral proliferation within the brain parenchyma leading to neural cells damages and severe neurological symptoms (3C). ACE-2., angiotensin converting enzyme II; CNS, central nervous system; CoM, comorbidities; CSF, cerebrospinal fluid; NE, nasal epithelium; OB, olfactory bulb; OEC, olfactory ensheathing cell; ORN, olfactory receptor neuron replication due to the host inability to clear the viral infection. 28 After having reached the bloodstream the virus can use three ways to enter the brain: invading the endothelial cells of the blood-brainbarrier (BBB) (Figure 1 , 1C/2C/3C), crossing the epithelial cells of the blood-CSF barrier in the choroid plexus, or using the immune cells ("Trojan horse") which are naturally able to migrate across the BBB during inflammation. 29 To our knowledge the only human cases of proven coronavirus brain invasion associated with neurological It has been shown that SARS-CoV can infect and replicate within peripheral blood mononuclear cells (PBMCs), although the viral replication was limited. 33 The capacity of SARS-CoV-2 to infect and to replicate within PBMCs, which can cross the BBB ("Trojan horse"), remains unknown. The viral gene expression of SARS-CoV-2 in patients PBMCs has not been reported yet. 34 According to these preliminary data the "Trojan horse" mechanism does not appear to contribute to SARS-CoV-2 brain invasion.

enzyme II (ACE-2). 35 It has been shown that in the human brain ACE2

protein might be present only in the endothelial and the smooth muscle cells present in brain arteries and veins. 36 The autopsy per- suggest the major roles of host innate immune response and viral factors (strain, route of inoculation, amount of virus) in limiting or promoting HSV access to the CNS. 45 We can postulate that SARS-CoV-2 encephalitis would occur only in patients with a higher susceptibility to SARS-CoV-2 (higher density of ACE2 in the ORNs, relative deficit in CNS innate immune response) or in the case of a more virulent strain of SARS-CoV-2 able to reach the CNS directly from the olfactory route. Contrary to meningoencephalitis observed during a secondary viremia in patients with comorbidities and with a severe infection, an encephalitis that would occur via a nerve pathway could be observed in young people without comorbidities, as for the two proven cases of (meningo)encephalitis in this review (cases 2 5 and 23 22 ). According to this hypothesis neurological symptoms might be isolated or may precede low respiratory tract symptoms. More importantly, the diagnosis could be missed if the lumbar puncture is performed too early after the onset of neurological symptoms, such as observed in HSE. 46 

This paper highlights the fact that in most cases the neurological symptoms reported in the literature were more related to the indirect impact of SARS-CoV-2 on brain rather than to a parenchymal invasion. COVID-19 pandemic should not eclipse other neurological infections: Streptococcus pneumoniae and enteroviruses remain the principal cause of meningoencephalitis. 38 This review also highlighted the necessity to perform a brain MRI as this imagery is superior to CT in highlighting parenchymal lesions linked to meningoencephalitis or vasculitis complications. 47 In patients with severe neurological symptoms, multiple samples should be performed (in different body compartments but also repeatedly) and the viral genomic sequences compared when possible.

The author thank Emmanuel Ellenberg for his help with English language editing.

Lydia Pouga http://orcid.org/0000-0002-2574-0254

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How to cite this article: Pouga L. Encephalitic syndrome and anosmia in COVID-19: Do these clinical presentations really reflect SARS-CoV-2 neurotropism? A theory based on the review of 25 COVID-19 cases