key: cord-0806615-83q38zpq
authors: Reis, Jacques; Buguet, Alain; Román, Gustavo C.; Spencer, Peter S.
title: The Covid-19 pandemic, an Environmental Neurology perspective
date: 2022-03-22
journal: Rev Neurol (Paris)
DOI: 10.1016/j.neurol.2022.02.455
sha: 615ba2c77d83a1999c35f7a14085d9b7dcd284dc
doc_id: 806615
cord_uid: 83q38zpq

Neurologists have a particular interest in SARS-CoV-2 because the nervous system is a major participant in Covid-19, both in its acute phase and in its persistent post-Covid phase. The global spread of SARS-CoV-2 infection has revealed most of the challenges and risk factors that humanity will face in the future. We review from an Environmental Neurology perspective some characteristics that have underpinned the pandemic. We consider the agent, SARS-CoV-2, the spread of SARS-CoV-2 influenced by environmental factors, its impact on the brain and some containment measures on brain health. Several questions remain, including the differential clinical impact of variants, the impact of SARS-CoV-2 on sleep and wakefulness, and the neurological components of Long-Covid syndrome. We touch on the role of national leaders and public health policies that have underpinned management of the Covid-19 pandemic. Increased awareness, anticipation and preparedness are needed to address comparable future challenges.

The neurologistes interest in SARS-CoV-2 lies in the characteristics of virus-cell interaction that allow the virus entry into CNS tissue. The most used binding targets of the virus are the angiotensin-converting enzyme-2 cell membrane receptor (ACE2) and the transmembrane serine protease 2 (TMPRSS2), both of which are less expressed by brain cells compared to t'ose of the heart, lung and nose [15, 16] . Therefore SARS-CoV-2 must interact with other receptors e.g., Neuropilin 1 (NRP1), Cathepsin L (CTSL) and furin which are expressed at much higher levels in the brain [16, 17] . Qiao and colleagues [15] have shown, with cell lines and mouse tissue, that the CD147 receptor (which belongs to the Ig superfamily) is more expressed than ACE-2 in brain cells compared to lung and intestine cells. Although debated, the role of the CD147 receptor in the entry of SARS-CoV-2 is recognized [17] .

A second concern is related to the ongoing evolution of the virus responsible for Covid-19, evolving from the Wuhan wild-type SARS-CoV-2, since the first infections, to numerous lineages or variants due to mutations that routinely occur during replication of its genome [18] [19] [20] . For example, 5,775 distinct genome variants, including 2,969 missense mutations, 1,965 synonymous mutations, 484 mutations in the non-coding regions, 142 non-coding deletions, 100 in-frame deletions, 66 non-coding insertions, 36 stop-gained variants, 11 frameshift deletions and two in-frame insertions were identified through May 1, 2020 [20] . Most mutations have little to no impact on the virus's properties, e.g., transmissibility, interaction with host immunity, and infection severity [18] . Newly detected variants are clinically documented allowing a classification based on these and additional information as country first detected; virus spike mutations of interest; year and month of virus first detection; performance of vaccines and medicines, and diagnostic tools [18, 19, 21] . In May 2021, the World Health J o u r n a l P r e -p r o o f Organization (WHO) defined three main categories of SARS-CoV-2, namely variants of concern (VOC), variants of interest (VIC), and variants under monitoring (VUM) . A VOC has one or more mutations that may impact its epidemiologic, immunologic and pathogenic properties [20] . WHO recommended using the Greek Alphabet to name several variants, e.g., Alpha, Beta, Gamma, Delta, Omicron. The emergence of these variants, especially the latter, poses a major health threat and challenge for the control of the pandemic [22] , at least in the short term. The pathogen's diversity and dynamics also illustrate the adaptation-driven evolution of the virus [23] . The various clades (lineages), have different geographical distributions and may perhaps trigger different clinical presentations, e.g., clades G and GV showed a significantly higher prevalence among asymptomatic patients or those with mild symptoms [23] . Comparison among recent lineages shows that some variants are more transmissible and fatal than their ancestor [24] . For example, Delta is more transmissible and increases the hospitalization and mortality rate when compared to Alpha [25] , whereas Omicron is highly transmissible but, at this writing, is thought primarily to infect the upper respiratory tract, and less the lungs, thus resulting in a milder disease in most patients [26] .

A third question concerns the capacity of the new variants to impact the nervous system. The 2020 Wuhan wild-type virus triggered the quasi-pathognomonic symptoms of anosmia and dysgeusia in most countries; however, in China, these symptoms were uncommonly reported (around 5%). One hypothesis is that the Chinese people were infected by another clade [27] .

Symptoms have changed with the new variants. For example, anosmia is uncommon when infected by Omicron; in the ZOE COVID study, anosmia affected around 19% of study participants compared to 60% related to infection by wild type or Alpha variants [28] . The cellentry of Omicron differs from that of the other SARS-CoV-2 variants; its binding capacities to ACE2 is lower and Omicron also uses an endocytic pathway [29] . Whether and how these characteristics affect the ability of this variant to infect brain cells are unknown.

1. Impact on the human brain, the neurological manifestations of COVID-19

It is the second time in less than 20 years that an atypical coronavirus pneumonia with humanto-human transmission had appeared in China. Neurological manifestations of SARS-CoV-2 were rapidly reported and reviewed [1] . While involvement of the CNS in coronavirusassociated Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) were well-known [30] , the pathophysiologic mechanisms are still unclear [31] . SARS-CoV-2 appears to be a neurotropic virus able to infect neurons and glia [32] , J o u r n a l P r e -p r o o f although viral particles have been rarely found in human brain and its presence in the cerebrospinal fluid is inconstant [16, 32] . Additionally, evidence is largely lacking for direct CNS invasion of SARS-CoV-2 as a primary cause of neurologic sequelae [31] . Nevertheless, whether infection occurs directly or indirectly via the hematogenous route, or whether the resulting immunological response (cytokine storm) [16] plays the major role, there is a large spectrum of neural targets, including the brain, medulla oblongata, spinal cord, peripheral nerves and muscles. Thirty percent of symptomatic Covid-19 patients present with CNS involvement during the acute phase of the disease. Anosmia and dysgeusia are considered quasi pathognomonic symptoms of Covid-19, with smell and taste disorders occurring in up to 80% of patients [33] . Neurological symptoms affect 73% of hospitalized patients [30] .

2. Impact on the human brain and mind: neuro-psychological manifestations of Covid-19

After the acute phase of the illness, 10 to 30% of Covid-19 patients continue to experience pulmonary, cardiovascular and/or neurological symptoms, sometimes for several months. The so-called "long-haulers" with this post-acute syndrome ("Long Covid") often have multiple symptoms referable to the nervous system, including chronic fatigue (30-78%), headache (18-50%) cognitive symptoms (e.g., attention disorder, memory loss, anxiety), sleep disorder (11- [37] . Other studies have used this type of brain imaging to document such biological markers of Long-Covid [38, 39] .

Sleep disorders may occur during the disease course and/or after recovery [1, 40, 41] . Most studies of this phenomenon have relied on questionnaires administered to the general population and/or specific human groups (e.g., students, medical staff, etc.). A number of studies conducted around the world found that sleep quality deteriorated during lockdown episodes, especially among women. This was the case in France [42] , where people over 18 years of age were asked whether they encountered sleep problem at the beginning (1,005 persons), the end (2,003 participants) and following (1,736 people) the Spring 2020 lockdown.

Sleep problems diminished towards the end of the quarantine period and vanished progressively afterwards. In addition to insomnia, alterations in circadian sleep schedules were revealed through a bedtime phase delay of two hours (from 22:00 h to midnight) and a similar trend for rise time [43] . In 368 Saudi Arabia university students in quarantine, nightmares (a REM sleep parasomnia) were experienced in 31.8% of the participants, of whom 44.4% suffered new-onset nightmares [44] . These figures were increased when academic exams were conducted during quarantine, indicating that nightmares were dependent on stressor intensity. Using natural language processing tools, dream reports were analyzed [45] , and revealed higher proportions of words related to anger and sadness, in support of mental suffering. We may thus conclude that the measures adopted by authorities in every country have led to changes in sleep behavior and/or quality. Nevertheless, the sleep of Covid-19 patients has been widely overlooked. An early meta-analysis [46] included 31 publications on 5,153 patients with confirmed Covid-19.

The authors found that 47% of patients experienced anxiety, 45% depression and 34% sleep disturbances (defined as poor sleep quality, sleep initiation or maintenance, excessive somnolence, sleep-schedule disorders or insomnia). However objective findings on sleep illness are rare. One patient with PCR-confirmed Covid-19 presenting fever, asthenia and insomnia declared restless leg syndrome that was in favor of iron dysmetabolism [47] . In turn, sleeprelated disorders may also influence COVID-19 morbidity and mortality. Obstructive sleep apnea (OSA) syndrome was identified early as a risk factor [48] , although obesity is commonly observed in OSA patients and represents in itself a major risk factor of morbidity and mortality in Covid-19 patients. Circadian rhythm alterations, associated with the psychological problems imposed by the Covid-19 pandemic, compromise the quality of sleep and the immune system, as sleep influences immunity maintenance and immune responses [49] .

Our group and others also alerted the scientific community on disorders potentially appearing after recovery. The possible occurrence of narcolepsies was argued [50] , as such a syndrome had occurred in Chinese children after the 2009 H1N1 influenza outbreak, as well as in children in Europe and Brazil after pediatric vaccination. Such disorders of sleep and circadian clock are also observed in other infectious diseases, such as African sleeping sickness [51] .

The Covid-19 pandemic has revealed and highlighted specific vulnerabilities of several human populations to virus infection. Biological vulnerability in humans is linked with age, gender, genetic and ethnic background, and pre-existing co-morbid illness.

Genetic factors may modulate susceptibility/resistance to SARS-CoV-2 infection and the severity of the resulting illness [52, 53] . They include gene polymorphisms and comorbidities, such as the association of ACE1 with cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and of alpha-1 anti-trypsin deficiency with lack of control over inflammatory mediators [52] . The polymorphism of genes encoding ACE2 and the transmembrane protease serine 2 (TMPPSS2) influence individual susceptibility to Covid-19 [54] . With regard to blood group phenotype, there is weak evidence that subjects with group-O are less susceptible than non-O individuals to SARS-CoV-2 infection, while the O type has no detectable effect on Covid-19 severity [55]. A recent review examined the susceptibility to SARS-CoV-2 and the polymorphism of a large number of genes involved in the different stages of virus-cell interactions [56] . "Classical twin studies indicated 31% heritability for predicted COVID-19" [53] . Substantially higher death rates from Covid-19 among Africans and African-Americans may be related to several gene polymorphism, e.g., androgen receptor gene (AR), ACE gene, ACE2 expression, apolipoprotein E gene (APOE), in African-American males. A lower frequency of a gene variant encoding for the IFIH1 protein, which is involved in innate immunity, has also been shown [53] .

The evolutionary history of Homo sapiens provides some interesting clues as to the differential susceptibility among people with disparate ethnic backgrounds and geographical origins [57].

Some Neanderthal ancestry genes located on chromosome 12 (OAS locus) may be protective (20% reduction of relative risk) [58] while other Neanderthal-inherited genes located on chromosome 3 may increase the risk of severe Covid-19 [59] . An ACE2 haplotype present among 20% and 60% of European and South Asian populations respectively, has been linked to a lower fatality rate among South Asians [57] . Evolutionary genetics has shown that genomes of East Asian populations bear the signature of a circa 25,000-year-old coronavirus epidemic; this interaction between ancient coronaviruses and human hosts, shown by the presence of selected gene variants encoding virus-interacting proteins, suggests adaptive mechanisms in East Asian populations [60] .

In addition to genetic abnormalities involving the innate immune system, neutralizing immunoglobulin G (IgG) autoantibodies (ABs) against various interferons (omega, alpha, both and I INF) have been observed. These ABs account for life-threatening Covid-19 in at least 2.6% of women and 12.5% of men [61] . In addition to the biased sex ratio, the ABs against I IFN offer an explanation for the higher risk of critical Covid-19 in patients over 65. Rare before age 65, the ABs are more often detected from 4% (range 70 to 79 years) to 7% thereafter [62] .

Therefore, 25% of severe cases of Covid-19 might be explained by genetic and immunologic abnormalities of the host 2 .

Epidemiological studies have pointed to gender-associated risks for severe and fatal forms of Covid-19, such that the risk is double for adult males vs. females. Biological factors include sex hormones that differentially regulate the innate and adaptative immunological system, its interaction with adiposity, the entry of SARS-CoV-2 into cells (ACE2, TMPPSS), and probably the susceptibility to tissue injury [63] . Several studies point to an inherited X-linked recessive TLR7 gene deficiency in a small percentage of younger-adult Covid-19 cases with severe forms of Covid-19 [62, 64] . The TLR7 gene is involved in the innate immunity response; its loss-offunction impairs the types I and II interferon pathway [64] . Other important components of innate immunity are the mucin proteins that offer first-line protection to all epithelial cells, in combination with mucosal antibodies, the secretory IgA. In the case of SARS, epidemiological suggested sex-differences, as human females may be more resistant than human males.

However, until now, no data on this topic are available for SARS-CoV-2 [65] .

Early victims of Covid-19 were senior patients (death occurred mostly in >80-year-old persons) and those with multiple risk factors, such as hypertension, obesity, diabetes and cardiovascular disease. Surprisingly, children appeared less prone to illness, such that the death rate in this and TMPPSS2 [67] .

The seven-fold increased risk of stroke in Covid-19 appears to be associated with a specific vulnerability of the brain's endothelial cells [68] resulting in dysfunction of the endothelium [67] The direct infection, which may trigger localized phenomena including thrombosis and cellular permeability, occurs through a flow-dependent expression of ACE2, as ACE2 is physiologically poorly expressed in these cells. "Viral S protein binding triggers a unique gene expression profile in brain endothelia that may explain the association of SARS-CoV-2 infection with cerebrovascular events" [68] . ACE2 expression is also increased in case of arterial hypertension [68] .

There is no evidence at this time that preexisting neurologic diseases increase the risk of the occurrence of neurologic complications in Covid-19 [31] . However, underlying neurological diseases constitute a risk factor for developing a severe form of Covid-19, particularly those with significant bulbar and respiratory weakness (e.g., neuromuscular disorders) or other neurologic disability [31] . Obviously, such factors increase Covid-19 severity, worsening the underlying disease and provoking a higher mortality rate [31] . Disabilities related to cognitive impairment [31] , Alzheimer's disease [70] , Multiple Sclerosis (MS), assessed by the EDSS score [69] , are independent risk factors for severe Covid-19. However, no association has been J o u r n a l P r e -p r o o f found between MS Disease Modifying Treatments exposure and Covid-19 severity [71] . A preexisting mental illness worsens clinical outcomes in Covid-19, with a doubled rate of more severe course and mortality rate compared to patients with no mental disorder [72] . Another hypothetical concern is related to the risk of neurodegenerative disease, triggered or induced by the SARS-CoV-2 infection, leading to a delayed disorder, such as Parkinson's disease or dementia [1, 70, 73] .

Vulnerability also takes into account the probability of exposure/infection by SARS-CoV-2 as a function of personal occupation, housing conditions, education, and other factors. Thus, this pandemic has shown that Covid-19 has a very unequal occurrence in populations across the world; risk factors are linked to socio-economic status, including those in poverty and low-class jobs, and to minorities, migrants and refugees [74] . The built environment and high urban population density in megacities also favor infectious disease transmission [75] . Health policy has had to address cultural behaviors as well as religious beliefs and practices. Several communities have ignored or rejected common health-protection advice and mandates issued by medical and state authorities [76] . To the contrary, most religious leaders have encouraged those in their charge to accept public health rules issued by authorities [77] .

As pointed out before, pandemics reveal societal vulnerabilities linked with lifestyle and values.

Most societies and communities have adopted a lifestyle based on individualism, "liberty" and freedom of movement. Today life is characterized by an extraordinary increase of rapid and widespread transportation means, temporary or permanent national and international migration, and progressive urbanization resulting in crowded megacities; all of these behaviors can promote the spread of infectious agents and associated human and animal diseases.

Socioeconomic and demographic drivers relevant to viral transmission from wildlife to humans and among humans include ecosystem conversion, meat consumption that requires deep changes in land-use and agricultural practices, urbanization, and connectivity among cities [78] .

Mass gathering, which is known to favor the spread of epidemic diseases, is another societal trend [79] . There is little doubt that Superspreading social or cultural Events (SSE) have been a major cause for the rapid spread of SARS-CoV-2 in the human population [80] . Several SSEassociated cases have been scrutinized, for example those in Boston USA [81] and in Austria [82] ; these share common characteristics [80] : "Closed environments, environments with poor ventilation, crowded places, and long durations of potential exposure". Recognized since the SARS epidemic, the rapid worldwide spread of SARS-CoV-2 was related to international air Page 13 of 32 J o u r n a l P r e -p r o o f traffic patterns and the intermingling of people in airport hubs. As in the case of SARS, the diffusion of SARS-CoV-2 may be modelled as "a function of airline network accessibility" [83] . On the other hand, while in-flight transmission of SARS-CoV-2 among airline passengers has occurred, this has not become a major problem apparently because face masking is enforced and the flow of air and its filtration reduce ambient contamination (vide infra).

Although SARS-CoV-2 is an airborne transmissible virus. Since its emergence, the routes of human contamination have been debated, especially by the World Health Organization.

Acceptance that Covid-19 results from human contact with an aerosol-transmissible virus, rather than from contact with surfaces contaminated by droplets and fomites, took a surprisingly long time, despite several publications [84, 85] 2. The human-to-human contamination A remarkable aspect of the Covid-19 pandemic is the variation in human-to-human virus transmission, favored at the individual level by virus superspreaders and at the community level, by SSEs, phenomena that were well-known before the Covid-19 pandemic [86, 87] . These facts have major public health consequences as SARS-CoV-2 transmission is stochastic [80] . Secondary viral transmission is described by the mathematical overdispersion k parameter.

Thus, with k=0.1, around 10% of contaminated people are responsible for 70-80% of all secondary transmissions [88] ; in other words, a single superspreader can infect a disproportionate number of contacts [87] . If correct, this means that most individuals (40-70%) did not infect anybody else [89] . These data have been obtained from study of subjects infected with the Wuhan SARS-CoV-2 wild type.

Early in the pandemic, attention was drawn to the k parameter [90] , unfortunately, identification of superspreaders has been retrospective [87] . Their biological capacities remain unknown [87] even though several hypotheses have been proposed, including an ability to propagate the virus better because of higher viral particle emission [80] , i.e., loud speaking resulting in the exhalation of more virus-loaded air [89] and, of course, the number, proximity and duration of interpersonal contacts [80] in indoor vs. outdoor settings with/without masking. When tracing is possible, identification of critical factors promoting viral transmission may lead to public health protective measures [80] .

The transmissibility of the different variants (Alpha, Delta and Omicron) versus wild-type SARS-CoV-2 must be taken into account, as these variants have a higher transmissibility and higher secondary infection rate. A Thai retrospective study found that the secondary infection rate in households increased from 16.6% (known rate for the wild-type) to 48% (for certain contemporaneous variants) [91] . At a Finnish hospital, an index case triggered an outbreak due to the Delta variant, infecting 58 patients and 45 health care workers (HCW). "Transmission occurred despite the use of personal protective equipment by the HCW, and a high two-dose COVID-19 vaccination coverage" [92] . So-called breakthrough cases, in which SARS-CoV-2 provoked Covid-19 in fully vaccinated people, seem to be increasingly common with the At the beginning of the pandemic in 2020, Italian and Chinese scientists, joined by other Western countries teams, concluded that air pollution seemed to favor the aerosolized spread of SARS-CoV-2 [93] [94] [95] . High rates of air pollution, notably due to particulate matters (PM), may also lower the host's immune system and thereby favor viral infection. Air pollution is a major risk factor for several non-communicable diseases, creating a pre-existing poorer health condition that is linked with an increased susceptibility to SARS-CoV-2, Covid-19 severity, hospitalization and risk of death [93] [94] [95] . Among air pollutants, PM10 (10 µm in diameter) may serve as carriers attaching viruses that spread in ambient air. As inhaled PM carries microorganisms inside the body, PM act as a cofactor and may contribute to the accentuated cardiovascular effects of Covid-19. PM reportedly may promote clinical severity and increase the risk of death. In the USA, an ecological regression analysis showed that an increase of 1 µg/m 3 of PM2.5 was associated with an 11% increase in the Covid-19 death rate [96] . Another gaseous pollutant, NO2, a marker for traffic-related air pollution, is also involved in the pandemic. In Los Angeles County neighborhoods, the annual NO2 level is associated with Covid-19 incidence and mortality [97] . These findings were discussed by the European Union's Joint Research Centre (JRC) team [98] .

In October 2020, the JRC issued a 36-page report that analyzed the literature published between March and July 2020. The report found that "a significant impact of outdoor air pollution on the spreading or severity of the disease has not been demonstrated yet" because of methodological shortcomings in many articles. However, the report attributed 7% of Covid-19 deaths to air pollution. Reviewing several articles issued in the first semester of 2020, Bourdrel and colleagues [99] concluded that the relationship (association and/or causality) between air pollution and the pandemic remained unclear, although the health effects of air pollution are supported by experimental and epidemiological data [100] .

Presently, interest in the contribution of environmental factors to Covid-19 is extended to all meteorological and air pollution conditions [101] [102] [103] . Thus, it is established that the virus favors cold, dry and polluted air. Another aspect is the inequity in human exposure to polluted air, which is higher in industrial regions (e.g., the Po Valley in Italy) versus rural areas [93] and also in some American counties inhabited by ethnic communities (Blacks and Latinos) and lower socioeconomic groups [95] [96] . This factor also contributes to the differential Covid-19 mortality rate among different populations worldwide.

Along with air pollution, meteorological characteristics (temperature, humidity, wind speed, UV radiations) have often been investigated "based on unreliable data and questionable modelling techniques that did not account for numerous factors that were co-occurring at the beginning of the pandemic" [104] leading to incomplete and even false policy conclusions [105] . Therefore, the World Meteorological Organization (WMO) established a Covid-19 Task Team [103] to review available data. Elaborated since September 2020 and published in January 2021, its report stated notably: "Epidemiological studies of COVID- 19 [103] . The role of meteorological factors is now accepted;

for example, their role in the USA is higher in northern than southern counties. They act on SARS-CoV-2 transmissibility, which is moderately associated with cold and dry weather and low levels of ultraviolet radiation, with humidity playing the largest role [106] .

Mathematical modelling using a logarithmic regression to analyze the worldwide distribution of Covid-19 cases (less prevalent in countries closer to equator, where heat and humidity are higher) predicted in January 2021 that the "threat of epidemic resurgence may increase during winter" and conversely decrease in summer, although not vanishing [107] . The resurgence of Delta and the exponential spread of Omicron are consistent with this prediction. "An increase J o u r n a l P r e -p r o o f in absolute latitude by 1°C is associated with a 4.3% increase in COVID-19 per 10 6 inhabitants" [107] , confirming that SARS-CoV-2 is sensitive to temperature and longer sunlight exposure.

During the first pandemic wave, the high rate of Covid-19 deaths in some parts of Europe (Northern Italy, France, Spain, and UK) compared to other regions (Germany, Switzerland, Austria, and Denmark) was reported to correlate with relative levels of environmental contamination (air pollution, pesticides, dioxins, chlorinated water), which may affect immune function [108] . The efficacy and persistence of post-vaccination immunity to SARS-CoV-2 should consider the impact of exposure to environmental pollutants that may modify immune responses [100] .

1 Lockdown, air pollution and stroke

The first prolonged lockdown of populations designed to slow and stop the spread of Covid-19 drastically decreased air pollution worldwide [109] . However, the decrease was differential, with a drop of nitrite oxides (NOx) related to car traffic, but the persistence of the pollution by PM produced by building heating as well as agricultural practice. In France, an unexpected and marked reduction in mortality rate, mostly in low Covid-19-incidence departments, occurred during the first quarantine period [110, 111] , being associated with a drop in the strokehospitalization rate [110, 112] . However, the interaction between reduced air pollution in March 2020 and the increase in the risk of stroke induced by SARS-CoV-2 infection, has not been properly addressed [112] .

Substantial human health benefits related to cardiovascular disease morbidity and mortality were linked with the Covid-19-related lock-down in China, where levels of vehicular air pollution (NOx, PM 2.5) were also substantially reduced [113] . Additionally, China's strict lock-down and quarantine policies, border and travel controls, prompt virus tracing and widespread immunization of its population, greatly reduced the number of Covid-19 cases, hospitalizations and deaths relative to the experience of Europe and the USA. By the end of 2021, the U.S. population had experienced >150-fold the number of Covid-19-related deaths than the official number in China, a country with a population >4 times that of the U.S. [114] .

Neurologists cannot ignore the major impact of the Covid-19 pandemic on mental health and sleep quality (vide supra). Already recognized (in 2019) as leading causes of the global healthrelated burden, depressive and anxiety disorders increased worldwide in 2020 in prevalence and burden [115] . In their review, Brooks and colleagues anticipated the psychological impact of Covid-1, based on previous knowledge (specifically the societal disruption that lockdown, infection, and quarantine would cause). "Most of the adverse effects come from the imposition of a restriction of liberty" [116] . They pointed also to populations at-risk, namely health workers and people with pre-existing psychiatric illness. They recommended several measures to reduce the expected psychological consequences of lockdowns. Clearly, crisis management can be a direct cause of psychosocial distress.

Decision-making during the Covid-19 pandemic was influenced by gender, determining differences in public health measures taken by female versus male leaders [117, 118] . In the Spring 2020, lower death rates were observed in countries with governments led by women as in Denmark, Finland, Germany, Norway, Iceland, New Zealand and Taiwan, as well as in several U.S. and Brazil states. On the opposite, several male leaders lacked (and still lack) anticipation or denied the magnitude of the health crisis. Women politicians showed greater empathy [117] and use of less aggressive words and war metaphors [119] than their male counterparts.

Widely broadcasted, communication from political leaders led to the false belief that the pandemic was caused by an unknown virus. For Frankel [120] at the Harvard Kennedy School and knowledgeable analysts, however, the viral pandemic represented a "known-unknown" phenomenon not an "unknown-unknown" entity, and was likely to occur. Some governments and so-called experts released false opinions to the media to hide ignorance and lack of preparation [121] , not considering the fake news peddled by some social networks. The critical importance of aerosol transmission of respiratory viruses was originally overlooked [84] , although Flügge droplets were described in the 1890s, and SARS-CoV-1 was known to diffuse indoor via airborne aerosols [122] , reaching distances >60 m [123] .

The medico-scientific community also failed to anticipate the debilitating post-infectious syndrome, Long-Covid, although the comparable Myalgic Encephalomyelitis/ Chronic-Fatigue Syndrome (ME/CFS) had been described six decades ago [124] and also acknowledged in SARS [125] . A long and indefensible debate about treatments, notably for outpatients with benign/mild Covid-19, took place in the early phase of the pandemic [126] . Unethical practices, J o u r n a l P r e -p r o o f such as therapeutic abstention, were not exempt of health consequences regarding lack of treatment, postponed hospitalization and increased morbidity and mortality [127] .

Public health policies were blurred by Inertia, ideology and ignorance (the devastating three Is, recognized in the fight against global poverty [128] ). On January 15, 2020, six days after WHO announced a coronavirus-related outbreak in Wuhan (China), the World Economic Forum published their 2020 Global Risk Report [129] and deplored the unpreparedness against outbreaks of new emerging infectious diseases. The unpreparedness was such that the health threat was minimized by "experts", journalists and prominent politicians [130, 131] , except for some countries [132] . As a consequence, successes and failures should be scrutinized carefully by experts [133] .

Teaching environmental health, risk-management and decision-making under uncertainty [134] should be considered as an absolute necessity for political leaders and decision-makers, and a large panel of disciplines (neuroscience, anthropology, virology, immunology, veterinary medicine, biology, but also political sciences). This represents a unique opportunity to reach a better level of awareness, anticipation and preparedness for future environmental health shocks.

Anticipation, mitigation, and avoidance of foreseeable disasters will require increased surveillance, detection and identification of a new disease surfacing in humans and/or animals. Therefore, as proposed by the Lancet Covid-19 Commission [135], the teaching procedure should promote, via an independent international council, the evaluation of public health policies and that of the benefit/risk ratio of the different treatments and vaccines.

The Covid-19 pandemic may be seen as a global human health catastrophe triggered by an environmental agent and amplified by human behavior. Analysis of the acute, chronic and potential long-term neurological impact of Covid-19 is susceptible to the methods employed in Environmental Neurology. This holistic approach is praised by Horton in his editorial "Covid-19 is not a pandemic" but "a syndemic characterized by biological and social interactions, as well as a broad array of human beliefs and behaviors that increase individual susceptibility to adverse health outcomes." [136] . The link between the COVID-19 pandemic, environmental factors, climate and health has also been highlighted by the HERA-COVID-19 working group [137] .

Changing humanity and its foolish behaviors is a utopian dream. However, two possible approaches exist: top-down regulation and bottom-up pressures. Societal awareness and activist protestation can both offer creative solutions and influence decision-makers' policies.

The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries

A call from the European Academy of Neurology on COVID-19

A call for a global COVID-19 Neuro Research Coalition

The European Academy of Neurology COVID-19 Registry (ENERGY): an international instrument for surveillance of neurological complications in patients with COVID-19

The neurological sequelae of pandemics and epidemics

Characteristics of microbes most likely to cause pandemics and global catastrophes

Exploring lessons learned from a century of outbreaks: Readiness for 2030

Bat coronaviruses in China

One world--one health

A review of studies on animal reservoirs of the SARS coronavirus

Zoonosis emergence linked to agricultural intensification and environmental change

Science, not speculation, is essential to determine how SARS-CoV-2 reached humans

The expression of SARS-CoV-2 receptor ACE2 and CD147, and protease TMPRSS2 in human and mouse brain cells and mouse brain tissues

Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier?

SARS-CoV-2 Entry: At the crossroads of CD147 and ACE2

World Health Organisation. Tracking SARS-CoV-2 variants

SARS-CoV-2 Variant Classifications and Definitions

Variant analysis of SARS-CoV-2 genomes

European Center for Disease Control and Prevention. SARS-CoV-2 variants of concern as of 22

Interplay between emerging SARS-CoV-2 variants and pandemic

Global dynamics of SARS-CoV-2 clades and their relation to COVID-19 epidemiology

Beyond Omicron: what's next for COVID's viral evolution

Importance of epidemiological factors in the evaluation of transmissibility and clinical severity of SARS-CoV-2 variants

Omicron's feeble attack on the lungs could make it less dangerous

COVID-19 and anosmia: A review based on up-todate knowledge

What are the symptoms of omicron? 11 janvier 2022

Omicron spike mediated immune escape, infectivity and cell-cell fusion

Neurological manifestations associated with SARS-CoV-2 and other coronaviruses: A narrative review for clinicians

19 and vaccination in the setting of neurologic disease: An emerging issue in Neurology

Neurological Involvement in COVID-19 and potential mechanisms: A review

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study

18 F-FDG-PET Imaging for

Brain and skeletal muscle alterations

Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex

Neurologic manifestations of hospitalized patients with Coronavirus Disease

SARS-CoV-2 infection and sleep disturbances: nitric oxide involvement and therapeutic opportunity

Would we recover better sleep at the end of Covid-19? A relative improvement observed at the population level with the end of the lockdown in France

The impact of SARS-CoV-2 on sleep

Nightmares' pattern and predictors among a Saudi university students during COVID-19 pandemic

Dreaming during the Covid-19 pandemic: Computational assessment of dream reports reveals mental suffering related to fear of contagion

The prevalence of depression, anxiety, and sleep disturbances in COVID-19 patients: A meta-analysis

COVID-19-associated sleep disorders: A case report

Sleep apnea and COVID-19 mortality and hospitalization

Sleep and immunity in times of COVID-19

Narcolepsy and COVID-19: sleeping on an opportunity?

Management of African trypanosomisasis of the CNS: Polysomnography as a noninvasive staging tool

Does genetic predisposition contribute to the exacerbation of COVID-19 symptoms in individuals with comorbidities and explain the huge mortality disparity between the East and the West?

Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity

Role of genetic variants and gene expression in the susceptibility and severity of COVID-19

COVID-19 is inherited from Neandertals

The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

An ancient viral epidemic involving host coronavirus interacting genes more than 20,000 years ago in East Asia

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Immuno-endocrinology of COVID-19: The key role of sex hormones. Front Endocrinol (Lausanne)

Presence of genetic variants among young men with severe COVID-19

Mucin signature as a potential tool to predict susceptibility to COVID-19

How kids' immune systems can evade COVID

The UGT2A1/UGT2A2 locus is associated with COVID-19-related loss of smell or taste

Flowmediated susceptibility and molecular response of cerebral endothelia to SARS

A review of ischemic stroke in COVID-19: currently known pathophysiological mechanisms

COVID-19 and Alzheimer's Disease

Clinical characteristics and outcomes in patients With Coronavirus Disease 2019 and Multiple Sclerosis

Biological and psychological factors determining neuropsychiatric outcomes in COVID-19

COVID-19 and selective vulnerability to Parkinson's disease

The devastating effects of the COVID-19 Pandemic among ethnic minorities, migrants and refugees

Neurology in Migrants and Refugees

COVID-19, the built environment, and health

The delay in confirming COVID-19 cases linked to a religious group in Korea

How religion affects global pandemics

The socioeconomic and environmental drivers of the COVID-19 pandemic: A review

WHO Novel Coronavirus-19 Mass Gatherings Expert Group. Mass gathering events and reducing further global spread of COVID-19: a political and public health dilemma

Superspreading events in the transmission dynamics of SARS-CoV-2: Opportunities for interventions and control

Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events

Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2

Airline networks and the international diffusion of severe acute respiratory syndrome (SARS)

It is time to address airborne transmission of coronavirus disease 2019 (COVID-19)

Ten scientific reasons in support of airborne transmission of SARS-CoV-2

Superspreading and the effect of individual variation on disease emergence

The role of super-spreaders in infectious disease

Centre for the Mathematical Modelling of Infectious Diseases

Estimating the overdispersion in COVID-19 transmission using outbreak sizes outside China

Superspreading drives the COVID pandemic-and could help to tame it

Secondary attack rate and superspreading events for SARS-CoV-2

Transmissibility of SARS-CoV-2 variants as a secondary attack in Thai households: A retrospective study

An outbreak caused by the SARS-CoV-2 Delta variant (B.1.617.2) in a secondary care hospital in Finland

Factors determining the diffusion of COVID-19 and suggested strategy to prevent future accelerated viral infectivity similar to COVID

Regional and global contributions of air pollution to risk of death from COVID-19

Potential role of particulate matter in the spreading of COVID-19 in Northern Italy: first observational study based on initial epidemic diffusion

Air pollution and COVID-19 mortality in the United States: Strengths and limitations of an ecological regression analysis

Spatial analysis of COVID-19 and traffic-related air pollution in Los Angeles

Do environmental factors such as weather conditions and air pollution influence COVID-19 outbreaks. Publications Office of the European Union

The impact of outdoor air pollution on COVID-19: a review of evidence from in vitro, animal, and human studies

On estimating the additional incidence of COVID-19 among populations exposed to polluted ambient air: methodical approaches and some practical results

Emerging role of air pollution and meteorological parameters in COVID-19

Impact of meteorological conditions and air pollution on COVID-19 pandemic transmission in Italy

Review on Meteorological and Air Quality Factors Affecting the COVID-19 Pandemic

The 2020 WMO Symposium on Climatological, Meteorological and Environmental factors in the COVID-19 pandemic: A special issue from symposium presentations. One Health

Role of meteorological factors in the transmission of SARS-CoV-2 in the United States

The association between COVID-19, air pollution, and climate change

Climate and the spread of COVID-19

Is there a role for environmental and metabolic factors predisposing to severe COVID-19?

Rapid response to: The positive effects of covid-19. Re:COVID-19 confinement (lockdown) and de-confinement: A unique opportunity to study prospectively the impact of air pollution on human health

Impact de la pollution de l'air ambiant sur la mortalité en France métropolitaine : réduction en lien avec le confinement du printemps 2020 et impact à long terme pour la période

Hospitalizations for stroke in France during the COVID-19 pandemic before, during, and after the national lockdown

Air pollution reduction and mortality benefit during the COVID-19 outbreak in China

COVID-19 Mental Disorders Collaborators. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic

The psychological impact of quarantine and how to reduce it: rapid review of the evidence

Women's leadership is associated with fewer deaths during the COVID-19 crisis: Quantitative and qualitative analyses of United States governors

Under pressure: Women's leadership during the COVID-19 crisis

Words matter: political and gender analysis of speeches made by heads of government during the COVID-19 pandemic

Black Swans like COVID-19 are predictable

COVID-19 Conspiracies and beyond: How physicians can deal with patients' misinformation

Evidence of airborne transmission of the severe acute respiratory syndrome virus

Multi-zone modeling of probable SARS virus transmission by airflow between flats in Block E

Benign myalgic encephalomyelitis

Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study

Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) Infection

Therapy for early COVID-19: A critical need

Poor economics: A radical rethinking of the way to fight global poverty. Public Affairs. 2011, 320 p. French issue

The World Economic Forum Publ

New Zealand eliminates COVID-19

A global panel database of pandemic policies (Oxford COVID-19 Government Response Tracker)

Decision-making under uncertainty in environmental health policy: new approaches

Offline: COVID-19 is not a pandemic

HERA-COVID-19 working group. The COVID-19 pandemic and global environmental change: Emerging research needs

Proceedings of a Forum. Preparing for Future Pandemics