Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Sunday, September 6, 2020

Effects of COVID-19 on the Nervous System

Lots to unpack here and you don't want any of these sequelae.  The only thing I will be making sure gets done is heparin to treat the hypercoagulable state, but I'm not medically trained so ask your doctor how all these effects can be prevented. 

I'm going to be asking for heparin as a blood thinner because of this:

Common FDA-approved drug may effectively neutralize virus that causes COVID-19

But your doctor needs to resolve this conundrum:

Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients

But Hypoxemia suggests something different.  The transit of the bubbles suggested vasodilation of the lung capillaries, Poor said. That could mean that blood may be flowing too fast through those capillaries to absorb enough oxygen.

COVID Hypoxemia: Finally, an Explanation

The latest here:

Effects of COVID-19 on the Nervous System

Published:August 19, 2020DOI:https://doi.org/10.1016/j.cell.2020.08.028
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Summary

Neurological complications have emerged as a significant cause of morbidity and mortality in the ongoing COVID-19 pandemic. Beside respiratory insufficiency, many hospitalized patients exhibit neurological manifestations ranging from headache and loss of smell, to confusion and disabling strokes. COVID-19 is also anticipated to take a toll on the nervous system in the long term. Here, we will provide a critical appraisal of the potential for neurotropism and mechanisms of neuropathogenesis of SARS-CoV-2 as they relate to the acute and chronic neurological consequences of the infection. Finally, we will examine potential avenues for future research and therapeutic development.

Introduction

There is increasing evidence that the nervous system is frequently involved in patients hospitalized with coronavirus disease 2019 (COVID-19). This is not surprising, because neurological manifestations have also long been described in infections from other respiratory viruses, including coronaviruses (
). However, the neurological manifestations of COVID-19 are common and disabling enough to have attracted widespread attention in the scientific and lay press for their short- and long-term impact on population health (
;
). A large body of clinical data from tertiary referral centers is rapidly accumulating on this topic worldwide, often with conflicting observations, partly reflecting the preliminary and incomplete nature of the available data. Here, we provide a succinct summary of the nervous system involvement in COVID-19. In particular, we will focus on the mechanisms of pathogenicity, on the acute and delayed neurological manifestations reported to date, and on how the nervous system involvement compares to that of other respiratory viruses. Finally, we will attempt to flesh out caveats and unanswered questions that may help gain a better appreciation of this critical aspect of COVID-19 and chart a path forward to minimize its harmful nervous system involvement.

 COVID-19 and Mechanisms of SARS-CoV-2 Pathogenesis

Beta-coronaviruses are a common cause of self-limited respiratory tract infections, but the strains responsible for the Middle Eastern respiratory syndrome (MERS-CoV), the severe acute respiratory syndrome (SARS-CoV-1), and COVID-19 (SARS-CoV-2) cause more severe disease (
). Although COVID-19 seems to have a lower case-fatality rate (≈0.7%) than SARS (≈10%) and MERS (≈30%) (
), the large number of patients affected has caused over 0.8 million deaths worldwide thus far, with many more expected based on current trends. The male sex is more susceptible to the infection, and disease severity and mortality are higher in older individuals (
;
;
). Besides the pulmonary disease, extra-pulmonary manifestations are being increasingly appreciated, including neurological involvement.

 Brain Expression of SARS-CoV-2 Receptors and Related Proteins

Similar to SARS-CoV-1, SARS-CoV-2 utilizes angiotensin converting enzyme-2 (ACE2) as the main docking receptor and needs proteolytic processing of the spike protein by transmembrane protease serine 2 (TMPRSS2) for efficient cell entry (
). ACE2 protein has been observed in human brain vessels (
), a finding recently attributed to expression in pericytes and smooth muscle cells in the vascular wall, but not in the endothelium lining cerebral vessels (
). However, data mining of human brain single-nuclear RNA sequencing (RNA-seq) data also found expression in the choroid plexus and neocortical neurons, although the number of positive neurons was small (∼2% or less) (
). No expression in microglia, endothelial cells, and pericytes was observed (
). Besides ACE2, SARS-CoV-2 may utilize basigin (BSG; CD147) (
) and neuropilin-1 (NRP1) (
) as docking receptors, while a range of proteases including TMPRSS11A/B, cathepsin B and L, and furin (FURIN) have been shown to facilitate viral cell entry and replication (
). Results from human single nuclei RNA-seq databases we mined (
;
) are presented in Figures 1 and S1. Collectively, the data suggest that vascular wall cells may express ACE2 in the human brain at low levels, but non-canonical SARS-CoV-2 receptors are present in several brain cell types making them vulnerable to the virus. However, there is also evidence for a strong antiviral defense system in the brain vasculature (Figures 1 and S1), which, in concert with the endothelium’s ability to sense circulating interferon (IFN) type I signals, would limit SARS-CoV-2 entry into the brain.
Figure thumbnail gr1
Figure 1Expression Profiles of Selected Genes Relevant to SARS-CoV-2 Brain Entry
Figure thumbnail figs1
Figure S1Expression Profiles of Selected Genes Relevant to SARS-CoV-2 Brain Entry in Single Nuclear RNA-Seq Profiles of Human Brain Tissue, Related to “”

 Nervous System Invasion

The possibility of CNS invasion for SARS-CoV-2 has been suggested by analogy with the neurotropism of other coronaviruses, mainly SARS-CoV-1, MERS-CoV, and OC43 (
). Organoids and in vivo studies in human ACE2 transgenic mice have shown that SARS-CoV-2 can infect neurons and cause neuronal death in an ACE2-dependent manner (
). In brain cells derived from human pluripotent stem cells, dopaminergic neurons, but not cortical neurons or microglia, were particularly susceptible to SARS-CoV-2 infection (
). Clinical-pathological studies that have tested for the presence of the virus in the brain or the cerebrospinal fluid (CSF) have had mixed results. Some studies have shown SARS-CoV-2 RNA in brain post-mortem or in the CSF in patients with encephalopathy or encephalitis, but at very low levels (
;
). Other studies could not detect viral invasion, even though there was evidence of CSF inflammation (
;
). Considering the inconsistent data and the low levels of viral RNA, when detected, the possibility of artifact or contamination has been raised (
).

 Potential Routes of Brain Entry

Examination of how the virus could enter the nervous system may help assess the likelihood for direct invasion and pathogenicity. Based on other coronaviruses, several potential routes of entry for SARS-CoV-2 have been proposed (
).

 Olfactory Route

Infection of olfactory system is consistent with the observation that loss of smell is a frequent neurological manifestation in COVID-19 (see Neurological Manifestations of COVID-19) and with evidence of increased MRI signal in the olfactory cortex suggestive of infection (
). The virus could be internalized in nerve terminals by endocytosis, transported retrogradely, and spread trans-synaptically to other brain regions, as described for other coronaviruses (
). ACE2 and TMPRSS2 have been detected in the nasal mucosa at the RNA and protein levels, but they seem to be localized to epithelial cells (sustentacular cells), not olfactory neurons (
), although another report suggests neuronal involvement (
). Therefore, it is unclear if the virus is restricted to the olfactory epithelium or reaches olfactory neurons.

 Blood-Brain Barrier

The blood-brain barrier (BBB) is a common route of entry of blood-borne viruses into the brain (
). In COVID-19, dissemination of the virus into the blood has been described, albeit with widely ranging frequencies (1% to 41%) (
;
), and the virus could access the brain by crossing the BBB. Crossing the intact BBB would require internalization and transport of the virus across the cerebral endothelium, in which the expression of SARS-CoV-2 docking proteins remains unclear (Figure 1). ACE2 immunoreactivity was observed in brain vessels of a patient who died with multiple ischemic infarcts but the cellular localization was not determined (
). The possibility of entry through other putative SARS-CoV-2 receptors expressed more widely in the cerebral vasculature, such as NRP1 and BSG, cannot be ruled out (
). On the other hand, SARS-CoV-2-associated cytokines, including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF), and IL-17 disrupt the BBB (
) and could facilitate the entry of the virus (Figure 2). SARS-CoV-2 has been postulated to induce endothelial infection and inflammation in peripheral vessels (
), but direct evidence in cerebral endothelial cells has not been thus far provided. Rather, a lack of florid cerebrovascular inflammation has been noted in several autopsy studies (
;
;
;
). Comorbidities often seen in COVID-19, including cardiovascular risk factor or pre-existing neurological diseases, could, alone or in combination with cytokines, increase BBB permeability (
). For example, in a COVID-19 patient with Parkinson’s disease, electron microscopy revealed viral particles in frontal lobe microvessels and neurons, suggesting trans-endothelial entry (
). Another Parkinson’s disease patient with obesity, hypertension, and diabetes, exhibited at autopsy, in addition to hypoxic-ischemic neuronal damage, microhemorrhages, white matter lesions, and enlarged perivascular spaces, but no evidence of SARS-CoV-2 in the brain (
). SARS-CoV-2 could also enter the brain through the median eminence of the hypothalamus and other circumventricular organs, brain regions with a leaky BBB due to openings (fenestrae) in the capillary wall (
). Although the size of the viral particle (80–120 nm) is larger than endothelial fenestrae (
), preliminary data suggest that median eminence capillaries and tanycytes express ACE2 and TMPRSS, which could allow virus entry into the hypothalamus (
). Owing to its widespread connection, the hypothalamus could serve as a gateway to the entire brain.
Figure thumbnail gr2
Figure 2Potential Mechanisms of Vascular Damage and Brain Entry of SARS-CoV-2

 Infiltration of Infected Immune Cells

Viruses can enter the brain carried by infected immune cells, which can also serve as reservoir (
). Monocytes, neutrophils, and T cells traffic into the brain through the vasculature, the meninges, and the choroid plexus (
), and these sites could be entry points for infected immune cells. Conclusive evidence of infection of immune cells by SARS-CoV-2 has not been provided thus far (
). SARS-CoV-2 nucleocapsid protein (NP) immunoreactivity was observed in CD68+ cells in lymphoid organs (
), while single-cell RNA seq data showed viral RNA in macrophages in bronchoalveolar lavage of COVID-19 patients (
). However, it remains unclear if this is due to actual virus propagation in macrophages or to phagocytic uptake of virus infected cells or extracellular virions (
;
). Furthermore, several autopsy series have revealed a notable lack of immune cell infiltration (
;
;
).
In summary, SARS-CoV-2 can infect neurons in vitro and cause neuronal death, but data from CSF and autopsy studies do not provide consistent evidence of direct CNS invasion. However, effects on the median eminence and other circumventricular organs cannot be ruled out and may play a role in the systemic manifestations of the disease.

 Indirect Brain Effects of Systemic Factors

Several major organs are targeted by COVID-19 resulting in life threatening systemic complications.

 Lung Damage and Respiratory Failure

The lung is the organ most affected in COVID-19, with massive alveolar damage, edema, inflammatory cell infiltration, microvascular thrombosis, microvascular damage, and hemorrhage (
). SARS-CoV-2 has been detected mainly in pneumocytes and epithelial progenitors (
;
). The respiratory failure resulting from lung damage leads to severe hypoxia (adult respiratory distress syndrome [ARDS]) requiring assisted ventilation (
). Consistent with hypoxic brain injury, autopsy studies in COVID-19 have shown neuronal damage in brain regions most vulnerable to hypoxia, including neocortex, hippocampus, and cerebellum (
;
;
).

 Systemic Inflammation and Immune Dysregulation

A key feature of COVID-19 is a maladaptive immune response characterized by hyperactivity of innate immunity followed by immunosuppression (
;
;
;
). Improvement of T cell function coincides with remission of symptoms and declining viral loads (
), attesting to the link between immuno-suppression and disease severity. In patients with severe disease, the cytokine release syndrome can develop (
;
). Most COVID-19 patients exhibit increased circulating levels of IL-6, IL-1β, and TNF, as well as IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, and MIP1α2, and serum levels of IL-6 and TNF reflect disease severity (
). Even in the absence of SARS-CoV-2 brain invasion, viral proteins shed in the circulation and molecular complexes from damaged cells, such as the nuclear protein high mobility group box 1 (HMGB1) (
), could enter the brain through a compromised BBB (Figure 2). After brain entry, these molecules could act as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patters (DAMPs), and induce an innate immune response in pericytes, brain-resident macrophages, and microglia, which express toll-like receptors (TLR) (Figure 2). TLR2 mediates the pro-inflammatory effects of SARS-CoV spike protein on human macrophages through nuclear factor κB (NF-κB) (
). Such innate immune response increases cytokine production and impair brain function (
). In mice, viral infections increase circulating levels of IFNα/β leading to activation IFNR1 on cerebral endothelial cells and CXCL10-CXCR3-mediated cognitive impairment (cytokine sickness behavior) (
). An IFN type I response does occur in COVID-19 and is thought to be protective (
), but could contribute to the alterations in consciousness (see Neurological Manifestation of COVID-19).

 The Hypothalamus: Target and Culprit of Immune Dysregulation

The brain, the hypothalamus in particular, could also contribute to the immune dysregulation (Figure 3). Several cytokines upregulated in COVID-19 (IL-6, IL-1β, and TNF) are powerful activators of the hypothalamic-pituitary-adrenocortical (HPA) axis (
). The HPA axis is central to the regulation of systemic immune activity and is activated by BBB dysfunction and neurovascular inflammation (
). As mentioned above, COVID-19 is associated with immunosuppression and lymphopenia. In stroke and brain trauma, adrenergic stress involving β-adrenergic receptors results in massive systemic immunosuppression (
). The mechanisms of these effects involve activation of the HPA, leading to the release of norepinephrine and glucocorticoids. These mediators act synergistically to induce splenic atrophy, T cell apoptosis, and natural killer (NK) cell deficiency. In the bone marrow, tyrosine hydroxylase and norepinephrine trigger a response in mesenchymal stromal cells, most likely through β3-adrenergic receptors, resulting in a reduction of cell retention (
). Downregulation of these factors, in concert with calprotectin release from damaged lungs, may increase hematopoietic stem cell proliferation skewed toward the myeloid lineage (emergency myelopoiesis) (
;
), which results in lymphopenia and neutrophilia, two key hematological features of COVID-19 (
;
;
) (Figure 3). Importantly, in SARS, HPA activation and glucocorticoid levels are correlated with neutrophilia and lymphopenia (
).
Figure thumbnail gr3
Figure 3Potential Role of the HPA Axis in the Immune Dysregulation of COVID-19

 Hypercoagulable State

Another key feature of COVID-19 is a profound coagulopathy responsible for some of the most frequent and harmful complications of the disease. In a multicenter study, 88% of patients exhibited evidence of a hypercoagulable state (
). COVID-19 coagulopathy is characterized by a distinctive pro-coagulant state with increased cloth strength, increased D-dimers (fibrin breakdown products indicative of intravascular thrombosis), and increased fibrinogen, without significant changes in the number of platelets or prolongation of clotting time parameters (
). Coagulopathy and thrombosis may start in the lungs and other infected organs with endothelial damage, complement activation, the procoagulant action of IL-6, and neutrophil recruitment (
;
). In turn, neutrophils release extracellular traps (NETs) in COVID-19 (
), a lattice of chromatin and histones that activates clotting, which contributes to intravascular thrombosis by trapping cells and platelets in many organs including the brain.

 Systemic Organ Failure

COVID-19 also damages other organs. Metabolic and pathological evidence of damage to the kidney, heart, liver, gastrointestinal tract, and endocrine organs has been provided (
;
;
;
;
). The resulting systemic metabolic changes, including water and electrolyte imbalance, hormonal dysfunction, and accumulation of toxic metabolites, could also contribute to some of the more non-specific nervous system manifestations of the disease, like confusion, agitation, headache, etc. Cardiac involvement could impact the brain by reducing cerebral perfusion or, as discussed in the next section, could be an embolic source leading to ischemic strokes.

Neurological Manifestations of COVID-19

Numerous neurological abnormalities have been described in patients with COVID-19. These involve the central and peripheral nervous system, range from mild to fatal, and can occur in patients with severe or otherwise asymptomatic SARS-CoV-2 infection. Neurological abnormalities have been described in ∼30% of patients who required hospitalization for COVID-19, 45% of those with severe respiratory illness and 85% of those with ARDS (
;
). In patients with mild COVID-19, neurological symptoms are mostly confined to nonspecific abnormalities such as malaise, dizziness, headache, and loss of smell and taste (
), routinely observed in respiratory virus infections such as the influenza (
). While serious neurological complications have been reported in patients with otherwise mild COVID-19 (
), the most severe complications occur in critically ill patients and are associated with significantly higher mortality (
;
).

 Encephalopathy and Encephalitis

Alterations in mental status (confusion, disorientation, agitation, and somnolence), collectively defined as encephalopathy, have been consistently reported in various cohorts with COVID-19. Altered mental status occurs rarely (<5%), even in COVID-19 patients requiring hospitalization for respiratory illness (
), but affects the majority of critically ill COVID-19 patients with ARDS (
). A key question is whether this alteration in mental status represents an encephalopathy caused by systemic illness or encephalitis directly caused by the SARS-CoV-2 virus itself. Several cases have been reported of COVID-19 patients (
;
;
;
;
) who appear to meet established diagnostic criteria for infectious encephalitis, which include altered mental status, fever, seizures, white blood cells in the CSF, and focal brain abnormalities on neuroimaging (
). In at least two reported cases, SARS-CoV-2 was detected in the CSF (
;
), although, as discussed in the previous section (Nervous System Invasion), only modest amounts of viral RNA were detected. In at least one COVID-19 case, the diagnosis of temporal lobe encephalitis was confirmed by biopsy that showed perivascular lymphocytic infiltrates and hypoxic neuronal damage (
), but the presence of SARS-CoV2 or other viruses in brain or CSF was not documented. Indeed, most samples of CSF in patients with neurological abnormalities in the setting of COVID-19 have not revealed evidence of SARS-CoV-2 (
), and most samples of brain tissue from autopsies of COVID-19 patients have not revealed evidence of encephalitis (see Nervous System Invasion). Besides encephalitis, most COVID-19 patients have other reasons for their altered mental status. Delirium, confusional states, and coma appear most common in COVID-19-related critical illness (
;
;
), which is often marked by hypoxia, hypotension, renal failure, the need for heavy doses of sedatives, and prolonged immobility and isolation (
)—all factors well known to cause encephalopathy (
). The rarity of cases clinically consistent with encephalitis, the paucity of histopathological evidence of encephalitis, and the many alternative explanations for the altered mental status, suggest that SARS-CoV-2 brain invasion is a possible but rare cause of encephalopathy.

 Ischemic Stroke

Stroke is not uncommon among patients hospitalized with COVID-19, with reported rates ranging from 1%–3% in hospitalized patients and up to 6% of critically ill patients (
;
;
), 7-fold higher than in patients hospitalized with influenza even after adjustment for illness severity (
). Early case reports described unusual embolic strokes in otherwise young healthy individuals with COVID-19 (
), but in subsequent case series, patients were generally older and had numerous vascular comorbidities (
). Therefore, it remains unclear whether these strokes were caused by SARS-CoV-2 or represented the background incidence of stroke in these high-risk populations that also happened to be infected at the time. It is plausible that SARS-CoV-2 infection does play some role in causing stroke, given that infections in general increases stroke risk (
). The COVID-19-related hypercoagulability would be expected to increase susceptibility to cerebrovascular events, as reported in an autopsy series in which widespread microthrombi and patches of infarction were observed some brains (
). Patients with COVID-19 may be at risk of cardioembolic stroke. Acute cardiac injury and clinically significant arrhythmias have been reported in approximately10% of hospitalized COVID-19 patients and 20%–40% of those requiring intensive care (
;
;
). SARS-CoV-2 infection may rarely cause myocarditis and heart failure even in the absence of significant pulmonary involvement (
). Myocardial injury and arrhythmias, such as atrial fibrillation, in the setting of severe infection may result in cardiac embolism and brain infarction (
). A substantial proportion of critically ill patients with COVID-19 may also develop secondary bacteremia in addition to the primary viral illness. In one case series, approximately10% of patients requiring mechanical ventilation had bacteremia (
), which increases the risk of stroke by over 20-fold (
). Septic emboli to the brain often result in bleeding, and in a postmortem magnetic resonance imaging study, 10% of brains had evidence of hemorrhage (
).Taken together, these clinical findings suggest that SARS-CoV-2 may adversely affect the brain via multiple pathophysiological pathways that culminate in vascular brain injury.

 Post-infectious Neurological Complications

SARS-CoV-2 unleashes a dysregulated systemic immune response (see Systemic Inflammation and Immune Dysregulation), which can have delayed effects on the nervous system. These immune-mediated manifestations involve both the central and peripheral nervous system and occur typically after the acute phase of the infection subsides. In the CNS, reported cases in COVID-19 resemble classic post-infectious inflammatory conditions such as acute disseminated encephalomyelitis (
) and acute necrotizing hemorrhagic encephalopathy (
). Peripherally, several cases of Guillain-Barre syndrome, a neuropathy caused by an immune attack on peripheral nerves, have been reported in patients with recent COVID-19 (
). Most reported cases describe classic features of this syndrome, such as generalized weakness, evidence of demyelination on nerve conduction studies, and elevated proteins without white blood cells in CSF (
). The Miller-Fisher variant of Guillain-Barre syndrome, characterized by cranial nerve involvement, has also been reported, including at least one case with detectable anti-ganglioside antibodies suggesting an immune attack on the peripheral nerves (
). SARS-CoV-2 was not detected in any of the CSF samples (
), supporting an immune mechanism rather than direct infection.

 Intensive Care-Related Neurological Manifestations

The relatively high frequency of altered mental status in hospitalized COVID-19 patients is congruent with the severity of their illness. Most critically ill COVID-19 patients require mechanical ventilation (
) and an agitated confusional state (delirium) occurs in more than 80% of mechanically ventilated patients in intensive care units (
). Patients with ARDS, which frequently complicates severe COVID-19, are at particularly high risk of delirium, likely because of hypoxemia heavy doses of sedatives, administration of paralytic agents, or other causes (
;
).

 Comparison with Other Viral Respiratory Infections

Many neurological abnormalities seen in COVID-19 mirror those of other viral respiratory illnesses. All of the reported COVID-19 related post-infectious inflammatory conditions of the nervous system, such as Guillain-Barre syndrome, acute necrotizing hemorrhagic encephalopathy, and acute disseminated encephalomyelitis, are classically seen after infections, including other coronaviruses (
). Influenza is occasionally associated with an encephalopathy or full blown encephalitis, with evidence of influenza virus in the cerebrospinal fluid (
). Comparing the large numbers of patients infected by SARS-CoV-2 worldwide and the relative paucity of reported encephalitis cases, SARS-CoV-2 seems more similar to other common respiratory viral pathogens like influenza than to neurotropic pathogens that target specifically the brain, such as the herpes simplex virus. In general, however, COVID-19 is more debilitating than other common viral respiratory illnesses. Physicians have been struck by the frequency of thrombotic complications observed in critically ill COVID-19 patients, to the point that some hospitals instituted protocols for empiric, high-dose anticoagulation in patients with elevated D-dimer levels (
). Emerging data seem to confirm this observation: in one multicenter study, patients with COVID-19 and acute respiratory distress syndrome had twice the incidence of thrombotic complications compared to a matched cohort with ARDS from other causes (
). This also applies to thrombotic complications affecting the brain, because the proportion of COVID-19-related hospitalizations complicated by stroke seems much higher than that seen in influenza (
). Based on neuroinflammation-associated abnormalities in the clotting cascade in brain (
), activated protein C or thrombin inhibitors could also be of therapeutic value.

Future Directions and Conclusions

The findings reviewed above indicate that neurological manifestations are common in COVID-19 and constitute a defining aspect of the symptomatology of the disease. A caveat is that most clinical data are derived from case series on patients ill enough to require hospitalization at tertiary care centers, providing a biased representation of the frequency and type of the neurological manifestations. Similarly, basic science investigations exploring the mechanism of disease have largely emphasized concepts and findings that emerged from other coronaviruses, and there is limited new data on the interaction of SARS-CoV-2 with the brain and its vasculature. Therefore, conclusions based of existing literature have to be considered preliminary and subject to further scrutiny, verification, and validation. Here are some of the outstanding questions:
  • Do the neurological manifestations of COVID-19 reflect brain invasion? The encephalopathy is most likely a consequence of systemic factors, such as cytokine sickness, hypoxia, and metabolic dysfunction due to peripheral organ failure, while the strokes seem to be related more to hypercoagulability and endothelial injury than to SARS-CoV-2 vasculitis affecting brain vessels. The loss of taste and smell has been attributed to invasion of the olfactory neural system, but consistent evidence is lacking. In some cases, the possibility of a SARS-CoV-2 encephalitis could not be ruled out based on the potential for the virus to infect neurons (
    ), but definitive clinical and pathological evidence of neurotropism is lacking. A major problem is that the molecular mechanisms of cellular entry for SARS-CoV-2 are not entirely clear. While ACE2 is thought to be the main receptors in some cell types, its expression levels do not seem to correlate with the infectivity potential. For example, the virus gains access to human pluripotent stem cell-derived dopaminergic neurons despite low levels of ACE2 (
    ). Systematic investigation of non-canonical docking and accessory proteins for SARS-CoV-2 (Figures 1 and S1), their cellular localization and function in human neurons, glia, and vascular cells would help address this question.
  • Does the brain contribute to the immune dysregulation? SARS-CoV-2 and inflammatory mediators may gain access to the median eminence and activate hypothalamic neurohumoral pathways that mediate immune dysregulation through the adrenergic system, as described in other brain diseases (Figure 3). Considering the importance of the immune dysregulation in COVID-19 severity and outcome, a better understanding of the contribution of the hypothalamus may suggest pharmacological approaches to dampen the immune dysregulation (
    ).
  • Does the brain contribute to respiratory failure and hypertension? Similarly, entry of the virus and/or proinflammatory molecules through the subfornical organ and the area postrema could also affect brainstem autonomic pathways controlling blood pressure and breathing (
    ). Alterations in blood pressure, both hypertension (
    ) and severe hypotension in critically patients (
    ), are highly prevalent in COVID-19. Furthermore, it has been suggested that involvement of brainstem respiratory nuclei may contribute to the respiratory failure (
    ), but no alterations in respiratory centers or chemoreceptors (carotid bodies) was observed at autopsy in a patient with respiratory dysregulation (
    ). To date, evidence of central autonomic involvement is lacking.
  • What are the long-term neurological and neuropsychiatric consequences of COVID-19? Respiratory virus infections are associated with neurological and psychiatric sequelae, including Parkinsonism, dementia, depression, post-traumatic stress disorder, and anxiety (
    ;
    ). Brain infection is not required for these long-term effects. Inflammation and cytokine elevation in sepsis survivors are linked to subsequent hippocampal atrophy and cognitive impairment (
    ). Experimental studies suggest a link between activation of the NLRP3 inflammasome, which may occur in COVID-19, and Alzheimer pathology (
    ). ARDS survivors also exhibit increased incidence of long-term depression, anxiety, and cognitive impairment (
    ). Whether these late manifestations are related to non-resolving inflammation or a low-grade immune process driven by molecular mimicry or dysregulated adaptive immunity remains to be established. Chronic damage to systemic organs can also harm the brain through chronic hypoxia, metabolic dysfunction, and hormonal dysregulation. Based on these considerations, significant long-term neurological and psychiatric sequelae have to be anticipated in COVID-19, especially in survivors of severe disease.

 Experimental Models

Models would help address these outstanding questions and facilitate therapeutic development. Unfortunately, mice, the most popular laboratory animals, are not susceptible to SARS-CoV-2 due to differences between mouse and human ACE2 (
). Mice expressing human ACE2 have been developed and show evidence of brain infection, but only minimal symptoms of disease (
). Hamsters, ferrets, cats, and non-human primates could be more viable models (
). Reproducing the systemic effects of the disease would be critical for studying the neurological aspects of COVID-19. In vitro approaches involving human pluripotent stem cells organoids and co-cultures are useful to examine infectious mechanisms in brain cells (
;
) but do not provide insight into the harmful systemic effects. Therefore, there is a pressing need to develop animal models that are amenable to investigate not only the effects of SARS-CoV-2 on brain cells, but also the systemic effects of the infection and the long-term neuropsychiatric consequences.

 Therapeutic Considerations

Until safe and effective vaccines are developed, therapeutic efforts have to focus on antiviral agents and on how to best manage respiratory insufficiency, organ failure, hypercoagulable state, and immune dysregulation. There is no specific treatment for the neurological manifestations, which are managed according to standard protocols. However, because the neurological complications emerge mainly in severe systemic disease, minimizing hypoxia and protecting the brain from cytokines, DAMPs, PAMPs, and thromboembolic complications are important therapeutic goals. Immunosuppression with steroids improves mortality in patients with severe disease, but not in those with milder forms (
). Furthermore, more nuanced approaches to counteract the immune dysregulation, such as targeting specific cytokines or inflammatory pathways are also being tested (
). Whether these interventions reduce the short- and long-term neurological and psychiatric complications remain to be established.
In conclusion, the neurological manifestations of COVID-19 constitute a major public health challenge not only for the acute effects on the brain, but also for the long-term harm to brain health that may ensue. These delayed manifestations are anticipated to be significant, because they are likely to also affect patients who did not show neurological symptoms in the acute phase. Therefore, clinical and laboratory efforts aiming to elucidate the mechanisms of the acute effects on the brain of SARS-CoV-2 need to be coupled with investigations on the deleterious delayed neuropsychiatric sequelae of the infection. These efforts should be driven by a close cooperation between clinical and basic scientists and take advantage of the wealth of clinical-epidemiological data and biological specimens that are accumulating worldwide. Considering that COVID-19 is still raging in many countries, including the United States, and there might be a seasonal resurgence of infection, it is imperative that a concerted effort is implemented swiftly and on a large scale.

Acknowledgments

The authors are supported by NIH ( R01-NS34179 , R01-NS100447 , R37-NS089323 , R01-NS095441 , R01-NS/HL37853 to C.I.; R01NS097443 to H.K.; and NS094507 and NS081179 to J.A.

Declaration of Interests

C.I. serves on the Scientific Advisory Board of Broadview Ventures. H.K. serves as co-PI for the NIH-funded ARCADIA trial (NINDS U01NS095869) that receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics, serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke AF trial (uncompensated), serves on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim, and has served on an advisory board for Roivant Sciences related to Factor XI inhibition. J.A. has no conflict of interests to declare.
 
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