Opinions | How long covid reshapes the brain — and how we might treat it

Authors: Wes Ely August 25, 2022 The Washington Post

The young man pulled something from behind both ears. “I can’t hear anything without my new hearing aids,” said the 32-year-old husband and father. “My body is broken, Doc.” Once a fireman and emergency medical technician, he’d had covid more than 18 months before and was nearly deaf. He was also newly suffering from incapacitating anxiety, cognitive impairment and depression. Likewise, a 51-year-old woman told me through tears: “It’s almost two years. My old self is gone. I can’t even think clearly enough to keep my finances straight.” These are real people immersed in the global public health catastrophe of long covid, which the medical world is struggling to grasp and society is failing to confront.

As such stories clearly indicate, covid is biologically dangerous long after the initial viral infection. One of the leading hypotheses behind long covid is that the coronavirus is somehow able to establish a reservoir in tissues such as the gastrointestinal tract. I believe the explanation for long covid is more sinister.

The science makes it increasingly clear that covid-19 turns on inflammation and alters the nervous system even when the virus itself seems to be long gone. The virus starts by infecting nasal and respiratory lining cells, and the resulting inflammation sends molecules through the blood that trigger the release of cytokines in the brain. This can happen even in mild covid cases. Through these cell-to-cell conversations, cells in the nervous system called microglia and astrocytes are revved up in ways that continue for months — maybe years. It’s like a rock weighing down on the accelerator of a car, spinning its engine out of control. All of this causes injury to many cells, including neurons. It is past time we recognized this fact and began incorporating it into the ways we care for those who have survived covid.

For too long, the mysteries of long covid led many health-care professionals to dismiss it as an untreatable malady or a psychosomatic illness without a scientific basis. Some of this confusion comes down to the stuttering cadence of scientific progress. Early in the pandemic, autopsy findings from patients who died of covid “did not show encephalitis or other specific brain changes referable to the virus” as one report noted. Patients with profound neurological illnesses resulting from covid-19 had no trace of the virus in the cerebrospinal fluid encasing their brains.

These studies left most medical professionals mistakenly convinced that the virus was not damaging the brain. Accordingly, we narrowed our focus to the lungs and heart and then scratched our heads in wonder at the coma and delirium found in more than 80 percent of covid ICU patients. A robust study from the Netherlands showed that at least 12.5 percent of covid patients end up with long covid three months afterward, yet because “brain fog” wasn’t identified until later in the pandemic, these investigators didn’t include cognitive problems or mental health disorders in the data they collected. Thus, this otherwise beautifully executed study almost certainly underestimated the rate of long covid.

Since the early days of the pandemic, we’ve learned a great deal about the neurological effects of SARS-CoV-2. Earlier this year, the UK Biobank neuroimaging study showed that even mild covid can lead to an overall reduction in the size of the brain, with notable effects in the frontal cortex and limbic system. These findings help explain the profound anxiety, depression, memory loss and cognitive impairment experienced by so many long-covid patients.

new study published in the Lancet of more than 2.5 million people matched covid-19 patients with non-covid patients to determine the rate of recovery from mental health complaints and neurological deficits like the depression and brain fog in my own patients. What it revealed is partly encouraging and partly devastating: The anxiety and mood disorders in long covid tend to resolve over months, while serious dementia-like problems, psychosis and seizures persist at two years.

How COVID Could Screw You Worse With Each Reinfection

Authors: David Axe Tue, July 5, 2022

The more times you catch COVID, the sicker you’re likely to get with each reinfection. That’s the worrying conclusion of a new study drawing on data from the U.S. Veterans Administration.

Scientists stressed they need more data before they can say for sure whether, and why, COVID might get worse the second, third, or fourth time around. But with more and more people getting reinfected as the pandemic lurches toward its fourth year, the study hints at some of the possible long-term risks.

To get a handle on the health impact of reinfection, re-reinfection and even re-re-reinfection, three researchers—Ziyad Al-Aly from the Washington University School of Medicine plus Benjamin Bowe and Yan Xie, both from the V.A. St. Louis Health Care System—scrutinized the health records of 5.7 million American veterans.

Some 260,000 had caught COVID just once, and 40,000 had been reinfected at least one more time. The control group included 5.4 million people who never got COVID at all. Al-Aly, Bowe and Xie tracked health outcomes over a six-month period and came to a startling conclusion. “We show that, compared to people with first infection, reinfection contributes additional risks,” they wrote in their study, which hasn’t been peer-reviewed yet but is under consideration for publication in Nature.

Every time you catch COVID, your chance of getting really sick with somethinglikely COVID-related—seems to go up, Al-Aly, Bowe and Xie found. The risk of cardiovascular disorders, problems with blood-clotting, diabetes, fatigue, gastrointestinal and kidney disorders, mental health problems, musculoskeletal disorders and neurologic damage all increase with reinfection—this despite the antibodies that should result from repeat infections.

All of the conditions are directly associated with COVID or have been shown to get worse with COVID. “The constellation of findings show that reinfection adds non-trivial risks,” the researchers warned.

This risk could become a bigger deal as more people get reinfected. Globally, the death rate from COVID is going down, thanks in large part to growing population-wide immunity from past infection and vaccines.

But at the same time, non-fatal reinfections are piling up. Around half a billion people all over the world have caught COVID more than once, according to Al-Aly, Bowe and Xie’s study, citing data from the Johns Hopkins Coronavirus Resource Center. Many more reinfections, including “breakthrough” infections in the fully vaccinated, are likely as new variants and subvariants of COVID evolve to partially evade our antibodies.

The exact increase in risk from reinfection depends on the particular disorder in question—and whether you’ve been vaccinated and boosted. Broadly speaking, however, the likelihood of heart and clotting problems, fatigue and lung damage roughly doubles each time you catch COVID, Al-Aly, Bowe and Xie found.

Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, offered one important caveat: time. “In general, one would expect that COVID will do more damage with a longer infection,” he told The Daily Beast. A short-lasting COVID infection followed by another short case of COVID should be less damaging than, say, back-to-back long illnesses.

The longer your infections drag on, the greater the stress on your organs. “These are two blows instead of one,” Mokdad said.

But it’s possible the worsening outcomes resulting from reinfection have little or nothing to do with the cumulative stress of successive long illnesses. According to Peter Hotez, an expert in vaccine development at Baylor College, the escalating risk could result from a poorly-understood phenomenon called “immune enhancement.”

A virus undergoes immune enhancement when a person’s immune system, after initial exposure to the pathogen, backfires during reinfection. Someone suffering immune enhancement with regards to a particular disease is likely to get sicker and sicker each time they’re exposed.

Immune enhancement could explain Al-Aly, Bow and Xie’s observation of escalating risk from COVID reinfection. “If the observation is true,” Hotez stressed. But it’s possible the observation is inaccurate. Hotez said he’s “not convinced that reinfection is actually more severe.”

Anthony Alberg, a University of South Carolina epidemiologist, told The Daily Beast he, too, is somewhat skeptical. Just how much more risk you might accumulate with each case of COVID is really hard to predict. And Al-Aly, Bow and Xie’s study is too cursory to totally settle the uncertainty all on its own.

The main problem, Alberg explained, is tied to a classic logical dilemma: causation versus correlation. Just because veterans got sicker with each COVID infection doesn’t necessarily mean COVID is definitely to blame, he pointed out. The vets in the study who came down with COVID more than once maybe tended to belong to groups with overall worse health outcomes whether or not they caught COVID twice, thrice or never.

The Massive Screwup That Could Let COVID Bypass Our Vaccines

“Compared with veterans who were infected once with SARS-CoV-2, those who were infected two times or more were more likely to be older [or] Black people, reside in long-term care, be immunocompromised, have anxiety, depression and dementia and to have had cerebrovascular disease, cardiovascular disease diabetes and lung disease,” Alberg said.

COVID, in other words, might be beside the point. It’s possible the worsening outcomes in Al-Aly, Bow and Xie’s study are due to the fact that the reinfected patients “were on average older and with much poorer health status than those with one infection,” Alberg said, “not because of having been infected more than once.”

Untangling causation and correlation in a study of this scale could be tricky. “More evidence [is] needed on this topic before definitive conclusions can be reached,” Alberg said.

In the meantime, it should be easy for us to mitigate the potential risk. Anyone who comes down with COVID a second time shouldn’t hesitate to take a course of paxlovid or some other antiviral drug that’s approved for the disease. “We should continue to focus on making sure people are aware of the benefits of early treatment,” Jeffrey Klausner, an infectious diseases expert at the University of Southern California Keck School of Medicine, told The Daily Beast.

Better yet, we could focus on developing “strategies for reinfection prevention,” Al-Aly, Bow and Xie wrote.

The top priority, of course, should be vaccinating the unvaccinated. Even the best COVID vaccines aren’t 100-percent effective at preventing infection or reinfection—and they’re getting somewhat worse as SARS-CoV-2 evolves for greater immune-escape.

But even with cleverer viral mutations, the jabs are still pretty effective. You can’t get sicker and sicker with reinfection… if you never get infected in the first place.

Alzheimer’s-like signaling in brains of COVID-19 patients

Authors: Steve Reiken,Leah Sittenfeld,Haikel Dridi,Yang Liu,Xiaoping Liu,Andrew R. Marks First published: 03 February 2022  https://doi.org/10.1002/alz.12558



The mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood.


Brain lysates from control and COVID-19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer’s disease (AD)-linked signaling biochemistry. Post-translational modifications of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co-immunoprecipitation/immunoblotting of the brain lysates.


We provide evidence linking SARS-CoV-2 infection to activation of TGF-β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID-19 patients. RyR2 in COVID-19 brains demonstrated a “leaky” phenotype, which can promote cognitive and behavioral defects.


COVID-19 neuropathology includes AD-like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive defects associated with SARS-CoV-2 infection and long COVID.


1.1 Contextual background

Patients suffering from COVID-19 exhibit multi-system organ failure involving not only pulmonary1 but also cardiovascular,2 neural,3 and other systems. The pleiotropy and complexity of the organ system failures both complicate the care of COVID-19 patients and contribute, to a great extent, to the morbidity and mortality of the pandemic.4 Severe COVID-19 most commonly manifests as viral pneumonia-induced acute respiratory distress syndrome (ARDS).5 Respiratory failure results from severe inflammation in the lungs, which arises when SARS-CoV-2 infects lung cells. Cardiac manifestations are multifactorial and include hypoxia, hypotension, enhanced inflammatory status, angiotensin-converting enzyme 2 (ACE2) receptor downregulation, endogenous catecholamine adrenergic activation, and direct viral-induced myocardial damage.67 Moreover, patients with underlying cardiovascular disease or comorbidities, including congestive heart failure, hypertension, diabetes, and pulmonary diseases, are more susceptible to infection by SARS-CoV-2, with higher mortality.67

In addition to respiratory and cardiac manifestations, it has been reported that approximately one-third of patients with COVID-19 develop neurological symptoms, including headache, disturbed consciousness, and paresthesias.8 Brain tissue edema, stroke, neuronal degeneration, and neuronal encephalitis have also been reported.2810 In a recent study, diffuse neural inflammatory markers were found in >80% of COVID-19 patient brains, processes which could contribute to the observed neurological symptoms.11 Furthermore, another pair of frequent symptoms of infection by SARS-CoV-2 are hyposmia and hypogeusia, the loss of the ability to smell and taste, respectively.3 Interestingly, hyposmia has been reported in early-stage Alzheimer’s disease (AD),3 and AD type II astrocytosis has been observed in neuropathology studies of COVID-19 patients.10

Systemic failure in COVID-19 patients is likely due to SARS-CoV-2 invasion via the ACE2 receptor,9 which is highly expressed in pericytes of human heart8 and epithelial cells of the respiratory tract,12 kidney, intestine, and blood vessels. ACE2 is also expressed in the brain, especially in the respiratory center and hypothalamus in the brain stem, the thermal center, and cortex,13 which renders these tissues more vulnerable to viral invasion, although it remains uncertain whether SARS-CoV-2 virus directly infects neurons in the brain.14 The primary consequences of SARS-CoV-2 infection are inflammatory responses and oxidative stress in multiple organs and tissues.1517 Recently it has been shown that the high neutrophil-to-lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS) and ROS-induced tissue damage, contributing to COVID-19 disease severity.15

Recent studies have reported an inverse relationship between ACE2 and transforming growth factor-β (TGF-β). In cancer models, decreased levels of ACE2 correlated with increased levels of TGF-β.18 In the context of SARS-CoV-2 infection, downregulation of ACE2 has been observed, leading to increased fibrosis formation, as well as upregulation of TGF-β and other inflammatory pathways.19 Moreover, patients with severe COVID-19 symptoms had higher blood serum TGF-β concentrations than those with mild symptoms,20 thus further implicating the role of TGF-β and warranting further investigation.

Interestingly, reduced angiotensin/ACE2 activity has been associated with tau hyperphosphorylation and increased amyloid beta (Aβ) pathology in animal models of AD.2122 The link between reduced ACE2 activity and increased TGF-β and tau signaling in the context of SARS-CoV-2 infection needs further exploration.

Our laboratory has shown that stress-induced ryanodine receptor (RyR)/intracellular calcium release channel post-translational modifications, including oxidation and protein kinase A (PKA) hyperphosphorylation related to activation of the sympathetic nervous system and the resulting hyper-adrenergic state, deplete the channel stabilizing protein (calstabin) from the channel complex, destabilizing the closed state of the channel and causing RyR channels to leak Ca2+ out of the endoplasmic/sarcoplasmic reticulum (ER/SR) in multiple diseases.2329 Increased TGF-β activity can lead to RyR modification and leaky channels,30 and SR Ca2+ leak can cause mitochondrial Ca2+ overload and dysfunction.29 Increased TGF-β activity31 and mitochondrial dysfunction32 are also associated with SARS-CoV-2 infection.

Here we show that SARS-CoV-2 infection is associated with adrenergic and oxidative stress and activation of the TGF-β signaling pathway in the brains of patients who have succumbed to COVID-19. One consequence of this hyper-adrenergic and oxidative state is the development of tau pathology normally associated with AD. In this article, we investigate potential biochemical pathways linked to tau hyperphosphorylation. Based on recent evidence that has linked tau pathology to Ca2+ dysregulation associated with leaky RyR channels in the brain,333 we investigated RyR2 biochemistry and function in COVID-19 patient brains.


  1. Systematic review: The authors reviewed the literature using PubMed. While the mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood, there have been recent reports studying SARS-CoV-2 infection and brain biochemistry and neuropathology. These relevant citations are appropriately cited.
  2. Interpretation: Our findings link the inflammatory response to SARS-CoV-2 infection with the neuropathological pathways causing tau hyperphosphorylation typically associated with Alzheimer’s disease (AD). Furthermore, our data indicate a role for leaky ryanodine receptor 2 (RyR2) in the pathophysiology of SARS-CoV-2 infection.
  3. Future directions: The article proposes that the alteration of cellular calcium dynamics due to leaky RyR2 in COVID-19 brains is associated with the activation of neuropathological pathways that are also found in the brains of AD patients. Both the cortex and cerebellum of SARS-CoV-2–infected patients exhibited a reduced expression of the Ca2+ buffering protein calbindin. Decreased calbindin could render these tissues more vulnerable to cytosolic Ca2+ overload. Ex vivo treatment of the COVID-19 brain using a Rycal drug (ARM210) that targets RyR2 channels prevented intracellular Ca2+ leak in patient samples. Future experiments will explore calcium channels as a potential therapeutic target for the neurological complications associated with COVID-19.

1.2 Study conclusions and disease implications

Our results indicate that SARS-CoV-2 infection activates inflammatory signaling and oxidative stress pathways resulting in hyperphosphorylation of tau, but normal amyloid precursor protein (APP) processing in COVID-19 patient cortex and cerebellum. There was reduced calbindin expression in both cortex and cerebellum rendering both tissues vulnerable to Ca2+-mediated pathology. Moreover, COVID-19 cortex and cerebellum exhibited RyR Ca2+ release channels with the biochemical signature of ‘‘leaky’’ channels and increased activity consistent with pathological intracellular Ca2+ leak. RyR2 were oxidized, associated with increased NADPH oxidase 2 (NOX2), and were PKA hyperphosphorylated on serine 2808, both of which cause loss of the stabilizing subunit calstabin2 from the channel complex promoting leaky RyR2 channels in COVID-19 patient brains. Furthermore, ex vivo treatment of COVID-19 patient brain samples with the Rycal drug ARM210, which is currently undergoing clinical testing at the National Institutes of Health for RyR1-myopathy (ClinicalTrials.gov Identifier: NCT04141670), fixed the channel leak. Thus, our experiments demonstrate that SARS-CoV-2 infection activates biochemical pathways linked to the tau pathology associated with AD and that leaky RyR Ca2+ channels may be a potential therapeutic target for the neurological complications associated with COVID-19.

The molecular basis of how SARS-CoV-2 infection results in ‘‘long COVID’’ is not well understood, and questions regarding the role of defective Ca2+ signaling in the brain in COVID-19 remain unanswered. A recent comprehensive molecular investigation revealed extensive inflammation and degeneration in the brains of patients that died from COVID-19,34 including in patients with no reported neurological symptoms. These authors also reported overlap between marker genes of AD and genes that are upregulated in COVID-19 infection, consistent with the findings of increased tau pathophysiology reported in the present study. We propose a potential mechanism that may contribute to the neurological complications caused by SARS-CoV-2: defective intracellular Ca2+ regulation and activation of AD-like neuropathology.

TGF-β belongs to a family of cytokines involved in the formation of cellular fibrosis by promoting epithelial-to-mesenchymal transition, fibroblast proliferation, and differentiation.35 TGF-β activation has been shown to induce fibrosis in the lungs and other organs by activation of the SMAD-dependent pathway. We have previously reported that TGF-β/SMAD3 activation leads to NOX2/4 translocation to the cytosol and its association with RyR channels, promoting oxidization of the channels and depletion of the stabilizing subunit calstabin in skeletal muscle and in heart.2830 Alteration of Ca2+ signaling may be particularly crucial in COVID-19-infected patients with cardiovascular/neurological diseases due, in part, to the multifactorial RyR2 remodeling after the cytokine storm, increased TGF-β activation, and increased oxidative stress. Moreover, SARS-CoV-2–infected patients exhibited a hyperadrenergic state. The elevated expression of glutamate carboxypeptidase 2 (GCPII) in COVID-19 brains reported in the present study could also contribute directly to increased PKA signaling of RyR2 by reducing PKA inhibition via metabotropic glutamate receptor 3 (mGluR3).36 Hyperphosphorylation of RyR2 channels can promote pathological remodeling of the channel and exacerbate defective Ca2+ regulation in these tissues. The increased Ca2+/cAMP/PKA signaling could also open nearby K+ channels which could potentially weaken synaptic connectivity, reduce neuronal firing,36 and could activate Ca2+ dependent enzymes.

Interestingly, both the cortex and cerebellum of SARS-CoV–2-infected patients exhibited a reduced expression of the Ca2+ buffering protein calbindin. Decreased calbindin could render these tissues more vulnerable to the cytosolic Ca2+ overload. This finding is in accordance with previous studies showing reduced calbindin expression levels in Purkinje cells and the CA2 hippocampal region of AD patients3739 and in cortical pyramidal cells of aged individuals with tau pathology.3340 In contrast to the findings in the brains of COVID-19 patients in the present study, calbindin was not reduced in the cerebellum of AD patients, possibly protecting these cells from AD pathology.3941

Leaky RyR channels, leading to increased mitochondrial Ca2+ overload and ROS production and oxidative stress, have been shown to contribute to the development of tau pathology associated with AD.3232933 Recent studies of the effects of COVID-19 on the central nervous system have found memory deficits and biological markers similar to those seen in AD patients.4243 Our data demonstrate increased activity of enzymes responsible for phosphorylating tau (pAMPK, pGSK3β), as well as increased phosphorylation at multiple sites on tau in COVID-19 patient brains. The tau phosphorylation observed in these samples exhibited some differences from what is typically observed in AD, occurring in younger patients and in areas of the brain, specifically the cerebellum, that usually do not demonstrate tau pathology in AD patients. Taken together, these data suggest a potential contributing mechanism to the development of tau pathology in COVID-19 patients involving oxidative overload-driven RyR2 channel dysfunction. Furthermore, we propose that these pathological changes could be a significant contributing factor to the neurological manifestations of COVID-19 and in particular the “brain fog” associated with long COVID, and represent a potential therapeutic target for ameliorating these symptoms. For example, tau pathology in the cerebellum could explain the recent finding that 74% of hospitalized COVID-19 patients experienced coordination deficits.44 The data presented also raise the possibility that prior COVID-19 infection could be a potential risk factor for developing AD in the future.

The present study was limited to the use of existing autopsy brain tissues at the Columbia University Biobank from SARS-CoV-2–infected patients. The number of subjects is small and information on their cognitive function as well as their brain histopathology and levels of Aβ in cerebrospinal fluid and plasma are lacking. Furthermore, we did not have access to a suitable animal model of SARS-CoV-2 infection in which to test whether the observed biochemical changes in COVID-19 brains and potential cognitive and behavioral deficits associated with the brain fog of long COVID could be reversed or attenuated by therapeutic interventions. The design of future studies should include larger numbers of subjects that are age- and sex-matched. The cognitive function of SARS-CoV-2–infected patients who presented cognitive symptoms should be assessed and regularly monitored. Moreover, it is important to know whether the observed neuropathological signaling is unique to SARS-CoV-2 infection or are common to all other viral infections. Previous studies have reported cognitive impairment in Middle East respiratory syndrome45 as well as Ebola4647 patients. Retrospective studies comparing the incidence and the magnitude of cognitive impairments caused by these different viral infections would improve our understanding of these neurological complications of viral infections.


There were increased markers of oxidative stress (glutathione disulfide [GSSG]/ glutathione [GSH]) in the cortex (mesial temporal lobe) and cerebellum (cerebellar cortex, lateral hemisphere) of COVID-19 tissue. Kynurenic acid, a marker of inflammation, was increased in COVID-19 cortex and cerebellum brain lysates compared to controls, is in accordance with recent studies showing a positive correlation between kynurenic acid and cytokines and chemokine levels in COVID-19 patients.4850

To determine whether SARS-CoV-2 infection also increases tissue TGF-β activity, we measured SMAD3 phosphorylation, a downstream signal of TGF-β, in control and COVID-19 tissue lysates. Phosphorylated SMAD3 (pSMAD3) levels were increased in COVID-19 cortex and cerebellum brain lysates compared to controls, indicating that SARS-CoV-2 infection increased TGF-β signaling in these tissues. Interestingly, brain tissues from COVID-19 patients exhibited activation of the TGF-β pathway, despite the absence of the detectable (by immunohistochemistry and polymerase chain reaction, data not shown) virus in these tissues. These results suggest that the TGF-β pathway is activated systemically by SARS-CoV-2, resulting in its upregulation in the brain, as well as other organs. In addition to oxidative stress, COVID-19 brain tissues also demonstrated increased PKA and calmodulin-dependent protein kinase II association domain (CaMKII) activity, most likely associated with increased adrenergic stimulation. Both PKA and CaMKII phosphorylation of tau have been reported in tauopathies.5152

The hallmarks of AD brain neuropathology are the formation of Aβ plaques from abnormal APP processing by BACE1, as well as tau ‘‘tangles’’ caused by tau hyperphosphorylation.53 Brain lysates from COVID-19 patients’ autopsies demonstrated normal BACE1 and APP levels compared to controls. The patients analyzed in the present study were grouped by age (young ≤ 58 years old, old ≥ 66 years old) to account for normal, age-dependent changes in APP and tau pathology. Abnormal APP processing was only observed in brain lysates from patients diagnosed with AD. However, AMPK and GSK3β phosphorylation were increased in both the cortex and cerebellum in COVID-19 brains. Activation of these kinases in SARS-CoV-2–infected brains leads to a hyperphosphorylation of tau consistent with AD tau pathology in the cortex. COVID-19 brain lysates from older patients showed increased tau phosphorylation at S199, S202, S214, S262, and S356. Lysates from younger COVID-19 patients showed increased tau phosphorylation at S214, S262, and S356, but not at S199 and S202, demonstrating increased tau phosphorylation in both young and old individuals and suggesting a tau pathology similar to AD in COVID-19–affected patients. Interestingly, both young and old patient brains demonstrated increased tau phosphorylation in the cerebellum, which is not typical of AD.

RyR channels may be oxidized due to the activation of the TGF-β signaling pathway.30 NOX2 binding to RyR2 causes oxidation of the channel, which activates the channel, manifested as an increased open probability that can be assayed using 3[H]ryanodine binding.54 When the oxidization of the channel is at pathological levels, there is destabilization of the closed state of the channel, resulting in spontaneous Ca2+ release or leak.2730 To determine the effect of the increased TGF-β signaling associated with SARS-CoV-2 infection on NOX2/RyR2 interaction, RyR2 and NOX2 were co-immunoprecipitated from brain lysates of COVID-19 patients and controls. NOX2 associated with RyR2 in brain tissues from SARS-CoV-2–infected individuals were increased compared to controls.

Given the increased oxidative stress and increased NOX2 binding to RyR2 seen in COVID-19 brains, RyR2 post-translational modifications were investigated. Immunoprecipitated RyR2 from brain lysates demonstrated increased oxidation, PKA phosphorylation on serine 2808, and depletion of the stabilizing protein subunit calstabin2 in SARS-CoV-2–infected tissues compared to controls. This biochemical remodeling of the channel is known as the ‘‘biochemical signature’’ of leaky RyR2235556 that is associated with destabilization of the closed state of the channel. This leads to SR/ER Ca2+ leak, which contributes to the pathophysiology of a number of diseases including AD.232426305557 RyR channel activity was determined by binding of 3[H]ryanodine, which binds only to the open state of the channel. RyR2 was immunoprecipitated from tissue lysates and ryanodine binding was measured at both 150 nM and 20 μM free Ca2+. RyR2 channels from SARS-CoV-2–infected brain tissue demonstrated abnormally high activity (increased ryanodine binding) compared to channels from control tissues at physiologically resting conditions (150 nM free Ca2+), when channels should be closed. Interestingly, cortex and cerebellum of SARS-CoV-2–infected patients also exhibited a reduced expression of the Ca2+ binding protein calbindin. Calbindin is typically not reduced in the cerebellum of AD patients, possibly providing some protection against AD pathology. The low calbindin levels in the cerebellum of COVID-19 brains could contribute to the observed tau pathology in this brain region. An additional atypical finding in the COVID-19 brains studied in this investigation is an increased level of GCPII. This could contribute to the observed RyR PKA phosphorylation by increasing cAMP and inhibiting the metabotropic glutamate receptor type 3.36


3.1 Methods

3.1.1 Human samples

De-identified human heart, lung, and brain tissue were obtained from the COVID BioBank at Columbia University. The cortex samples were from the mesial temporal lobe and the cerebellum samples were from the cerebellar cortex, lateral hemisphere. The Columbia University BioBank functions under standard operating procedures, quality assurance, and quality control for sample collection and maintenance. Age- and sex-matched controls exhibited absence of neurological disorders and cardiovascular or pulmonary diseases. Sex, age, and pathology of patients are listed in Table 1.TABLE 1. Sex, age, and pathology of COVID-19 patients

Patient NumberSexAgePathology
1Male57Acute hypoxic-ischemic injury in the hippocampus, pons, and cerebellum.
2Female38Hypoxic ischemic encephalopathy, severe, global.
3Male58Hypoxic/ischemic injury, global, widespread astrogliosis/microgliosis.
4Male84Dementia. Beta-amyloid plaques are noted in cortex and cerebellum.
5Female80Severe hypoxic ischemic encephalopathy, severe. Global astrogliosis and microgliosis. Mild Alzheimer-type pathology.
6Female74Acute hypoxic-ischemic encephalopathy, global, moderate to severe. Arteriolosclerosis, mild. Metabolic gliosis, moderate
7Male66Left frontal subacute hemorrhagic infarct. Multifocal subacute infarcts in pons and left cerebral peduncle. Global astrogliosis and microgliosis (see microscopic description). Alzheimer’s pathology.
8Female76Hypoxic ischemic encephalopathy, moderate. Alzheimer’s pathology. Atherosclerosis, moderate. Arteriolosclerosis, moderate
9Male72Hypoxic/ischemic injury, acute to subacute, involving hippocampus, medulla and cerebellum. Mild atherosclerosis. Mild arteriolosclerosis
10Male71Hypoxic-ischemic encephalopathy, acute, global, mild to moderate. Diffuse Lewy body disease, neocortical type, consistent with Parkinson disease dementia. Atherosclerosis, severe. Arteriolosclerosis, mild.

Lysate preparation and Western blots

Tissues (50 mg) were isotonically lysed using a Dounce homogenizer in 0.25 ml of 10 mM Tris maleate (pH 7.0) buffer with protease inhibitors (Complete inhibitors from Roche). Samples were centrifuged at 8000 × g for 20 minutes and the protein concentrations of the supernatants were determined by Bradford assay. To determine protein levels in tissue lysates, tissue proteins (20 μg) were separated by 4% to 20% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblots were developed using the following antibodies: pSMAD3 (Abcam, 1:1000), SMAD3 (Abcam, 1:1000), AMPK (Abcam, 1:1000), tau (Thermo Fisher, 1:1000), pTauS199 (Thermo Fisher, 1:1000), pTauS202/T205 (Abcam, 1:1000), pTauS262 (Abcam, 1:1000), GSK3β (Abcam, 1:1000), pGSK3βS9 (Abcam, 1:1000), pGSK3βT216 (Abcam, 1:1000), APP (Abcam, 1:1000), BACE1 (Abcam, 1:1000), GAPDH (Santa Cruz Biotech, 1:1000), CTF-β (Santa Cruz Biotechnology, Inc., 1:1000), Calbindin (Abcam, 1:1000), and GCPII (Thermo Fisher, 1:4000).

Analyses of ryanodine receptor complex

Tissue lysates (0.1 mg) were treated with buffer or 10 μM Rycal (ARM210) at 4°C. RyR2 was immunoprecipitated from 0.1 mg lung, heart, and brain using an anti-RyR2 specific antibody (2 μg) in 0.5 ml of a modified radioimmune precipitation assay buffer (50 mm Tris-HCl, pH 7.2, 0.9% NaCl, 5.0 mm NaF, 1.0 mm Na3VO4, 1% Triton X-100, and protease inhibitors; RIPA) overnight at 4°C. RyR2-specific antibody was an affinity-purified polyclonal rabbit antibody using the peptide CKPEFNNHKDYAQEK corresponding to amino acids 1367–1380 of mouse RyR2 with a cysteine residue added to the amino terminus. The immune complexes were incubated with protein A-Sepharose beads (Sigma) at 4°C for 1 hour, and the beads were washed three times with RIPA. The immunoprecipitates were size-fractionated on SDS-PAGE gels (4%–20% for RyR2, calstabin2, and NOX2) and transferred onto nitrocellulose membranes for 1 hour at 200 mA. Immunoblots were developed using the following primary antibodies: anti-RyR2 (Affinity BioReagents, 1:2500), anti-phospho-RyR-Ser(pS)-2808 (Affinity BioReagents 1:1000), anti- calstabin2 (FKBP12 C-19, Santa Cruz Biotechnology, Inc., 1:2500), and anti-NOX2 (Abcam, 1:1000). To determine channel oxidation, the carbonyl groups in the protein side chains were derivatized to DNP by reaction with 2,4-dinitrophenylhydrazine. The DNP signal associated with RyR2 was determined using a specific anti-DNP antibody according to the manufacturer using an Odyssey system (LI-COR Biosciences) with infrared-labeled anti-mouse and anti-rabbit immunoglobulin G (IgG; 1:5000) secondary antibodies.

Ryanodine binding

RyR2 was immunoprecipitated from 1.5 mg of tissue lysate using an anti-RyR2 specific antibody (25 μg) in 1.0 ml of a modified RIPA buffer overnight at 4°C. The immune complexes were incubated with protein A-Sepharose beads (Sigma) at 4°C for 1 hour, and the beads were washed three times with RIPA buffer, followed by two washes with ryanodine binding buffer (10 mM Tris-HCl, pH 6.8, 1 M NaCl, 1% CHAPS, 5 mg/ml phosphatidylcholine, and protease inhibitors). Immunoprecipitates were incubated in 0.2 ml of binding buffer containing 20 nM [3H] ryanodine and either of 150 nM and 20 μm free Ca2+ for 1 hour at 37°C. Samples were diluted with 1 ml of ice-cold washing buffer (25 mm Hepes, pH 7.1, 0.25 m KCl) and filtered through Whatman GF/B membrane filters pre-soaked with 1% polyethyleneimine in washing buffer. Filters were washed three times with 5 ml of washing buffer. The radioactivity remaining on the filters is determined by liquid scintillation counting to obtain bound [3H] ryanodine. Nonspecific binding was determined in the presence of 1000-fold excess of non-labeled ryanodine.

GSSG/GSH ratio measurement and SMAD3 phosphorylation

Approximately 20 mg of tissue suspended in 200 μL of ice-cold phosphate-buffered saline/0.5% NP-40, pH6.0 was used for lysis. Tissue was homogenized with a Dounce homogenizer with 10 to 15 passes. Samples were centrifuged at 8000 × g for 15 minutes at 4°C to remove any insoluble material. Supernatant was transferred to a clean tube. Deproteinizing of the samples was accomplished by adding 1 volume ice-cold 100% (w/v) trichloroacetic acid (TCA) into five volumes of sample and vortexing briefly to mix well. After incubating for 5 minutes on ice, samples were centrifuged at 12,000 × g for 5 minutes at 4°C and the supernatant was transferred to a fresh tube. The samples were neutralized by adding NaHCO3 to the supernatant and vortexing briefly. Samples were centrifuged at 13,000 × g for 15 minutes at 4°C and supernatant was collected. Samples were then deproteinized, neutralized, TCA was removed, and they were ready to use in the assay. The GSSG/GSH was determined using a ratio detection assay kit (Abcam, ab138881). Briefly, in two separate assay reactions, GSH (reduced) was measured directly with a GSH standard and Total GSH (GSH + GSSG) was measured by using a GSSG standard. A 96-well plate was set up with 50 μL duplicate samples and standards with known concentrations of GSH and GSSG. A Thiol green indicator was added, and the plate was incubated for 60 minutes at room temperature (RT). Fluorescence at Ex/Em = 490/520 nm was measured with a fluorescence microplate reader and the GSSG/GSH for samples were determined comparing fluorescence signal of samples with known standards.

Kynurenic acid assay

Kynurenic acid (KYNA) concentration in brain lysates was determined using an enzyme-linked immunosorbent assay (ELISA) kit for KYNA (ImmuSmol). Briefly, samples (50 μl) were added to a microtiter plate designed to extract the KCNA from the samples. An acylation reagent was added for 90 minutes at 37°C to derivatize the samples. After derivatization, 50 μl of the prepared standards and 100 μl samples were pipetted into the appropriate wells of the KYNA microtiter plate. KYNA Antiserum was added to all wells and the plate was incubated overnight at 4°C. After washing the plate four times, the enzyme conjugate was added to each well. The plate was incubated for 30 minutes at RT on a shaker at 500 rpm. The enzyme substrate was added to all wells and the plate was incubated for 20 minutes at RT. Stop solution was added to each well. A plate reader was used to determine the absorbance at 450 nm. The sample signals were compared to a standard curve.

PKA activity assay

PKA activity in brain lysates was determined using a PKA activity kit (Thermo Fisher, EIAPKA). Briefly, samples were added to a microtiter plate containing an immobilized PKA substrate that is phosphorylated by PKA in the presence of ATP. After incubating the samples with ATP at RT for 2 hours, the plate was incubated with the phospho-PKA substrate antibody for 60 minutes. After washing the plate with wash buffer, goat anti-rabbit IgG horseradish peroxidase (HRP) conjugate was added to each well. The plate was aspirated, washed, and TMB substrate was added to each well, which was then incubated for 30 minutes at RT. A plate reader was used to determine the absorbance at 450 nm. The sample signals were compared to a standard curve.

CaMKII activity assay

CaMKII activity in brain lysates was determined using the CycLex CaM kinase II Assay Kit (MBL International). Briefly, samples were added to a microtiter plate containing an immobilized CaMKII substrate that is phosphorylated by CaMKII in the presence of Mg2+ and ATP. After incubating the samples in kinase buffer containing Mg2+ and ATP at RT for 1 hour, the plate was washed and incubated with the HRP conjugated anti-phospho-CaMKII substrate antibody for 60 minutes. The plate was aspirated, washed, and TMB substrate was added to each well, which was then incubated for 30 minutes at RT. A plate reader was used to determine the absorbance at 450 nm. The sample signals were compared to a standard curve.


Group data are presented as mean ± standard deviation. Statistical comparisons between the two groups were determined using an unpaired t-test. Values of P < .05 were considered statistically significant. All statistical analyses were performed with GraphPad Prism 8.0.

3.2 Results

3.2.1 Oxidative stress and TGF-β, PKA, and CaMKII activation

Oxidative stress levels were determined in brain tissues (cortex, cerebellum) from COVID-19 patient autopsy tissues and controls by measuring the ratio of GSSG to GSH by an ELISA kit. COVID-19 patients exhibited significant oxidative stress with a 3.8- and 3.2-fold increase in GSSG/GSH ratios in cortex (Ctx) and cerebellum (CB) compared to controls, respectively (Figure 1A). High circulating levels of kynurenine have been reported in COVID-19.4850 However, the expression of KYNA in COVID-19 brain tissue has not been examined. Levels in the Ctx and CB were measured using an ELISA kit. COVID-19 brains had a significant increase in the Ctx and CB compared to controls (Figure 1A). An additional marker of tissue inflammation is increased cytokine expression. SMAD3 phosphorylation, a downstream signal of TGF-β, was increased in COVID-19 Ctx and CB tissue lysates compared to controls (Figure 1B and 1C). Increased adrenergic activation in the brain of patients infected with SARS-CoV-2 was also demonstrated by measuring PKA activity in the Ctx and CB and CaMKII activity was increased as well (Figure 1D).

Details are in the caption following the image
FIGURE 1Open in figure viewerIncreased oxidative stress, inflammatory and adrenergic signaling in brains of COVID-19 patients. A, Bar graph depicting the glutathione disulfide (GSSG)/ glutathione (GSH) ratio and kynurenic acid (KYNA) enzyme-linked immunsorbent assay signal from control (n = 6) and COVID-19 (n = 6) tissue lysates. CB, cerebellum; Ctx, cortex. Data are mean ± standard deviation (SD). *P < .05 control versus COVID-19. B, Western blots showing phospho-SMAD3 and total SMAD3 from control (n = 4) and COVID-19 (n = 7) brain lysates. C, Bar graphs depicting quantification of pSMAD3/SMAD3 from Western blot signals in B. D, Calmodulin-dependent protein kinase II association domain (CaMKII) and protein kinase A (PKA) activity of brain tissue lysates. Data are mean ± SD. *P < .05 control versus COVID-19

Activation of AD-linked signaling

Both PKA and CaMKII have been directly implicated in the increased phosphorylation of tau associated with AD.5152 Because COVID-19 brain lysates had increased PKA and CaMKII activity, AD-linked biochemistry was evaluated in the COVID-19 brain lysates. Normal APP processing was observed in COVID-19 brain lysates as demonstrated by normal BACE1 and APP levels compared to controls (Figure 2A and B). Abnormal APP processing was only observed in brain lysates from patients diagnosed with AD (see Table 1 for patient details). However, phosphorylation/activation of AMPK and GSK3β was observed in SARS-CoV-2–infected patient brain lysates. Activation of these kinases along with the activation of PKA and CaMKII (Figure 1) leads to a hyperphosphorylation of tau at multiple residues (Figure 2C and D). Tau hyperphosphorylation in the cerebellum is not typical of AD pathology. The CB tau pathology demonstrated in COVID-19 warrants further investigation.

Details are in the caption following the image
FIGURE 2Open in figure viewerHyperphosphorylation of tau but normal amyloid precursor protein (APP) processing in COVID-19 brains. A, Brain (CB, cerebellum; Ctx, cortex) lysates were separated by 4% to 20% polyacrylamide gel electrophoresis. Immunoblots were developed for pAMPK, AMPK, GSK3β, pGSK3β (T216), APP, BACE1, and GAPDH loading control. The numbers (1–10) above immunoblots refer to patient numbers listed in Table 1. B, Bar graphs showing quantification of pAMPK, pGSK3β, APP/GAPDH, and BACE1/GAPDH from Western blots in (A). Data are mean ± standard deviation (SD). *P < .05 control versus COVID-19; **P < .05 CB versus Ctx; #P < .05 COVID (Young) versus COVID (Old). C, Immunoblots of brain lysates showing total tau and tau phosphorylation on residues S199, S202/T205, S214, S262, and S356. D, Bar graphs showing quantification phosphorylated tau at the residues shown on Western blots in (C). Data are mean ± SD. *P < .05 control versus COVID-19; **P < .05 CB versus Ctx; #P < .05 COVID (Young) versus COVID (Old)

RyR2 channel oxidation and leak

RyR2 biochemistry was investigated to determine whether RyR2 in COVID-19 brain tissues demonstrated a “leaky” phenotype. Increased NOX2/RyR2 binding was shown in Ctx and CB lysates from SARS-CoV-2–infected individuals compared to controls using co-immunoprecipitation (Figure 3A and B). In addition, RyR2 from SARS-CoV-2–infected brains had increased oxidation, increased serine 2808 PKA phosphorylation, and depletion of the stabilizing protein subunit calstabin2 compared to controls (Figure 3A and B). RyR channels exhibiting these characteristics can be inappropriately activated at low cytosolic Ca2+ concentrations resulting in a pathological ER/SR Ca2+ leak. 3[H]Ryanodine binding to immunoprecipitated RyR2 was measured at both 150 nM and 20 μM free Ca2+. Because ryanodine binds only to the open state of the channel under these conditions, 3[H]Ryanodine binding may be used as a surrogate measure of channel open probability. The total amount of RyR immunoprecipitated was the same for control and COVID-19 samples (data not shown). Increased RyR2 channel activity at resting conditions (150 nM free Ca2+) was observed in COVID-19 channels compared to controls (Figure 3C). Under these conditions, RyR channels should be closed. Rebinding of calstabin2 to RyR2, using a Rycal, has been shown to reduce SR/ER Ca2+ leak, despite the persistence of the channel remodeling. Indeed, calstabin2 binding to RyR2 was increased when COVID-19 patient brain tissue lysates were treated ex vivo with the Rycal drug ARM210 (Figure 3A and B). Abnormal RyR2 activity observed at resting Ca2+ concentration was also decreased by Rycal treatment (Figure 3C).

Details are in the caption following the image
FIGURE 3Open in figure viewerDysregulation of calcium-handling proteins in COVID-19 brains. A, Western blots depicting ryanodine receptor 2 (RyR2) oxidation, protein kinase A (PKA) phosphorylation, and calstabin2 or NADPH oxidase 2 (NOX2) bound to the channel from brain (CB, cerebellum; Ctx, cortex) lysates. B, Bar graphs quantifying DNP/RyR2, pS2808/RyR2, and calstabin2 and NOX2 bound to the channel from the Western blots. Data are mean ± standard deviation (SD). *P < .05 control versus COVID-19; # P < .05 COVID-19 versus COVID-19+ARM210. C, 3[H]ryanodine binding from immunoprecipitated RyR2. Bar graphs show ryanodine binding at 150 nM Ca2+ as a percent of maximum binding (Ca2+ = 20 μM). Data are mean ± SD. *P < .05 control versus COVID-19; #P < .05 COVID-19 versus COVID-19+ARM210. D, Western blots showing the levels of glutamate carboxypeptidase 2 (GCPII), calbindin, and GAPDH loading control in brain (Ctx, CB). E, Bar graphs quantifying GCPII/GAPDH and calbindin/GAPDH from the western blots. Data are mean ± SD. *P < .05 control versus COVID-19

An interesting finding concerning the tau phosphorylation in brain lysates from SARS-CoV-2 patients was the increase of phosphorylation at multiple sites in the cerebellum. This is atypical of AD. One potential mechanism to explain this finding is the significantly decreased levels of calbindin expressed in COVID-19 cerebellum (Figure 3D3E). The decreased cerebellar calbindin levels could make this area of the brain more susceptible to Ca2+-induced activation of enzymes upstream of tau phosphorylation. Moreover, increased GCPII expression was observed in COVID-19 cortex and cerebellar lysates (Figure 3D3E), which would reduce mGluR3 inhibition of PKA signaling and could contribute to the PKA hyperphosphorylation of RyR2.

Model for the role for leaky RyR2 in the pathophysiology of SARS-CoV-2 infection

Our data indicate a role for leaky RyR2 in the pathophysiology of SARS-CoV-2 infection (Figure 4). In addition to the brain of COVID-19 patients, we observed increased systemic oxidative stress and activation of the TGF-β signaling pathway in lung, and heart, which correlates with oxidation-driven biochemical remodeling of RyR2 (Figure 3 and S1 in supporting inormation). This RyR2 remodeling results in intracellular Ca2+ leak, which can play a role in heart failure progression, pulmonary insufficiency, as well as cognitive dysfunction.232628 The alteration of cellular Ca2+ dynamics has also been implicated in COVID-19 pathology.5859 Taken together, the present data suggest that leaky RyR2 may play a role in the long-term sequelae of COVID-19, including the “brain fog” associated with SARS-CoV-2 infection which could be a forme fruste of AD,60 and could predispose long COVID patients to developing AD later in life. Leaky RyR2 channels may be a therapeutic target for amelioration of some of the persistent cognitive deficits associated with long COVID.

Details are in the caption following the image
FIGURE 4Open in figure viewerSARS-CoV-2 infection results in leaky ryanodine receptor 2 (RyR2) that may contribute to cardiac, pulmonary, and cognitive dysfunction. SARS-CoV-2 infection targets cells via the angiotensin-converting enzyme 2 (ACE2) receptor, inducing inflammasome stress response/activation of stress signaling pathways. This results in increased transforming growth factor-β (TGF-β) signaling, which activates SMAD3 (pSMAD) and increases NADPH oxidase 2 (NOX2) expression and the amount of NOX2 associated with RyR2. Increased NOX2 activity at RyR2 oxidizes the channel, causing calstabin2 depletion from the channel macromolecular complex, destabilization of the closed state, and ER/SR calcium leak that is known to contribute to cardiac dysfunction,55 arrhythmias,61 pulmonary insufficiency,2325 and cognitive and behavioral abnormalities associated with neurodegenreation.2426 Decreased calbindin in COVID-19 may render brain more susceptible to tau pathology. Rycal drugs fix the RyR2 channel leak by restoring calstabin2 binding and stabilizing the channel closed state. Fixing leaky RyR2 may improve cardiac, pulmonary, and cognitive function in COVID-19.

Uptake of SARS-CoV-2 spike protein in human cerebrovascular cells

Authors:  Bhavana Kunkalikar Mar 24 2022 Reviewed by Danielle Ellis, B.Sc. BioRxiv

A recent study posted to the bioRxiv* preprint server assessed the uptake of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein in human cerebrovascular cells via the lipid raft ganglioside.  

Study: SARS-CoV-2 spike proteins uptake mediated by lipid raft ganglioside GM1 in human cerebrovascular cells. Image Credit: Dotted Yeti
Study: SARS-CoV-2 spike proteins uptake mediated by lipid raft ganglioside GM1 in human cerebrovascular cells. Image Credit: Dotted Yeti

Various studies have reported the effects of coronavirus disease 2019 (COVID-19) on the respiratory organs and non-respiratory ones, including the brain. However, there is still a lack of knowledge about the SARS-CoV-2 uptake mechanism involved in the viral entry into the human cerebrovasculature cells. 

About the study

The present study investigated the mechanism of SARS-CoV-2 S protein uptake by three types of cerebrovascular cells: endothelial cells, smooth muscle cells, and pericytes.

The team obtained human cerebral microvascular endothelial cells (hCMEC/D3), human
brain vascular smooth muscle cells (HBVSMCs), and human brain vascular pericytes (HBVPs). The cells were expanded separately and then pre-incubated with the inhibitor before being exposed to SARS-CoV-2 S protein in an incubator. S protein uptake without the inhibitor was then estimated as a percentage of control wells. 

The in vitro cell viability of the unlabeled wild type (WT) S protein was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The team also used immobilized recombinant human angiotensin-converting enzyme 2 (ACE2) to assess its binding ability to the S protein.  

Images of the whole well were taken, followed by all fluorescence quantification. The custom pixel classifiers measured the fluorescence intensity while the cell count was calculated using Qupath’s cell counter. Furthermore, primary antibodies were used in the immunocytochemistry (ICC) and imaged.


The study results showed that the uptake mechanism associated with the SARS-CoV-2 WT S proteins (SP-555) was mostly observed on the hCMEC/D3 cell surface while the HBVP and HBVSMC cells showed more internalization. Also, each cell type reached equilibrium after six hours since the 100 nanometers (nm) SP-555 signal started. Furthermore, the endothelial cells showed the lowest ability to uptake S protein compared to the smooth muscle cells and the pericytes, possibly because of the different cell sizes.

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Similar binding affinities were observed for the HBVMC and the hCMEC/D3 cells, while ACE2 and SP-555 binding showed lower values than the other two. Notably, SARS-CoV-2 S was not toxic towards the type of cells tested in this study. Also, in the MTT assay, increased levels of formazan were found at higher S concentrations in the hCMEC/D3 cells, indicating elevated metabolic activity in these cells because of the higher mitochondria content present in the cerebral endothelium. 

The team also noted receptor binding in the S uptake patterns in the cell types, highlighting ACE2 as the major binding site for the viral protein. Notably, interactions between ACE2 and SP-555 were also confirmed, while these interactions were localized twice more in the hCMEC/D3 cells than in the other two cell types studied. 

A 40% reduction of SP-555 uptake in the presence of excess unlabeled αACE2 indicated the co-localization of SP-555 with αACE2. On the other hand, excess unlabeled S protein reduced the bound labeled S protein uptake by 50% to 60% for the three cell types. The assessment of S uptake at different temperatures showed that the uptake was 2.2 to 5.5 times higher at 37oC than at 4oC, suggesting greater protein interaction with the cell types at 37oC.

The study showed that a sialic acid-binding lectin, called wheat germ agglutinin (WGA), increased the uptake of SP-555 by 2.4 times in the hCMEC/D3, 3.2 times in the HBVP, and 1.4 times in the HBVMC cell types. In contrast, a polysaccharide glycosaminoglycans (GAGs) called heparin reduced the S uptake by 30% to 60% in the HBVMC and the HBVP cells, while no such change was observed in the hCMEC/D3 cells. Anti-ganglioside 1 (GM1) antibody (αGMI) also reduced the S protein uptake by 60% to 80% in the three cell types. Moreover, the decrease in uptake observed in the presence of both αACE2 and αGM1 antibodies was similar to that observed with αGM1 alone.

Furthermore, in the hCMEC/D3 cells, an increased S uptake of 1.5, 1.9, and 2.8 times was noted for mutations found in SARS-CoV-2 variants of concern, including D614G, N501Y, and E484K, respectively, as compared to the WT S protein. In the HBVP cells, while D614G showed no difference in uptake, an increase of 1.7 times was found for both N501Y and E484K mutants. Lastly, in the HBVSMC cells, an increase of 3.2, 5.0, and 3.8 times was observed in the uptake of the D614G, N501Y, and E484K mutants.  


To summarize, the study findings showed that the mechanism of SARS-CoV-2 S protein uptake via the GM1/lipid raft is crucial as the inhibition of this entry point can serve as a potential target against SARS-CoV-2 infections.

COVID-19 and cerebrovascular diseases: a comprehensive overview

Authors: Georgios TsivgoulisLina PalaiodimouRamin Zand

First Published December 8, 2020 Review Article Find in PubMed https://doi.org /10.1177/1756286420978004


Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as ‘red flags’ to alarm clinicians in recognizing COVID-19-related stroke.


Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been declared as a Public Health Emergency of International Concern by the World Health Organization.1 Since its outbreak in December 2019, SARS-CoV-2 has spread in more than 235 countries, and as of 25 September 2020, it has infected 32,029,704 patients.2 Characteristically, COVID-19 affects the respiratory system, producing symptoms ranging from mild upper-airway manifestations to pneumonia and severe acute respiratory distress syndrome.3 COVID-19 is increasingly recognized as a multi-system disease with apparent involvement of other organ systems and clinical gastrointestinal, cardiological, dermatological and other extrapulmonary manifestations.48

COVID-19 affection of the nervous system has also been reported, including both the central nervous system (CNS) and peripheral nervous system (PNS).9 A growing number of case series and cohort studies have been published identifying neurological symptoms associated with COVID-19. CNS manifestations may include headache, dizziness, seizures, confusion, delirium, and coma. PNS involvement may be presented as hypogeusia, hyposmia, other cranial neuropathies or generalized weakness due to Guillain–Barré and intensive-care-unit-acquired polyneuropathy or myopathy.

In the first case series reporting on the neurological manifestations of COVID-19, cerebrovascular disease was reported with a higher prevalence in COVID-19 patients who were more seriously infected.10 Since then, multiple studies have been published, arguing whether there is a causal or coincidental relationship between COVID-19 and cerebrovascular disease.

In this narrative review, we present the possible pathophysiological mechanisms linking cerebrovascular disease and COVID-19, describe the clinical syndromes and their prognosis and provide a ‘red flag’ system to alert clinicians for prompt recognition of cerebrovascular disease during COVID-19.


We systematically searched the literature through MEDLINE and EMBASE, using the following keywords and their combination: SARS-CoV-2, COVID-19, cerebrovascular disease, stroke, ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, cerebral venous thrombosis, cerebral sinus, and vein thrombosis. We evaluated only peer-reviewed articles that had been published or had been officially accepted for publication. References of retrieved articles were also screened. Case reports, case series, editorials, reviews, case-control, and cohort studies were evaluated, and relevant information was abstracted. The literature search protocol was conducted by three independent authors (GT, LP, and AHK). The last literature search was conducted on 1 September 2020. Characteristic images of cerebrovascular disease manifestations in COVID-19 patients have been provided by co-authors using previously unpublished data from COVID-19 tertiary care referral centers from Europe, North America, and Asia.


Possible pathophysiological mechanisms linking cerebrovascular disease and COVID-19

Several common cerebrovascular risk factors have been associated with severe COVID-19 as well, including cardiovascular disease, diabetes mellitus, hypertension, smoking, advanced age, and previous history of stroke.11 This raises the question whether their relationship is causal or if they just coincide. Several possible pathophysiological mechanisms have been recently described (Figure 1).

Figure 1. Potential pathophysiological mechanisms underlying cerebrovascular involvement in COVID-19.

SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, leading to the receptors’ inactivation. ACE2 dysregulation contributes to the post-ischemic inflammation cascade, resulting in decreased perfusion in the ischemic zone and the development of larger infarct volume in the case of ischemic stroke (IS). In addition, ACE2 dysfunction may subsequently cause hypertensive peaks and impairment of cerebrovascular endothelium, contributing to the pathogenesis of intracerebral hemorrhage (ICH). Virus-related cardiac injury, including myocardial ischemia and cardiac arrhythmias such as atrial fibrillation, may cause cardio-embolism and subsequently, IS. COVID-19-related hypercoagulability may determine in situ arterial thrombosis and IS. Another potential IS mechanism related to hypercoagulability is paradoxical emboli of generated venous thrombi through right-to-left shunts. Cerebral venous thrombosis may also be caused by hypercoagulability and in situ thrombosis. Furthermore, COVID-19-related coagulopathy may present as dysfunctional hemostasis and predispose to ICH, especially when therapeutic anticoagulation is administered. Cytokine storm-mediated endotheliitis and vasculitis of the CNS due to SARS-CoV-2 infection causes vessel remodeling, leading to vessel occlusion or injury and IS or ICH, respectively. Finally, a primarily immune-mediated critical illness during COVID-19, hypoxemia, and systemic hypotension may induce hypoxic/ischemic encephalopathy or cerebral microbleeds with or without leukoencephalopathy.

CNS, central nervous system; COVID-19, coronavirus disease 2019; DVT, deep venous thrombosis; PE, pulmonary embolism; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Targeting angiotensin-converting enzyme 2 (ACE2) receptor

SARS-CoV-2 is known to bind to the ACE2 receptor, causing the inactivation of the receptor and leading to dysfunction in blood pressure regulation.12,13 In turn, this could lead to hypertensive peaks that could be particularly important in the pathogenesis of intracerebral hemorrhage (ICH). However, data to date have suggested that patients with ICH and COVID-19 present with lower systolic blood pressure, relative to spontaneous ICH.14 Furthermore, ACE2 dysregulation may also contribute to the post-ischemic inflammation cascade through the accumulation of angiotensin 2, resulting in decreased perfusion in the ischemic zone and the development of larger infarct volumes.15,16 The impaired endothelial function in cerebral arteries caused by ACE2 inactivation has also been implicated in the pathogenesis of cerebrovascular events, including both ischemic and hemorrhagic stroke.17,18

Cardiovascular complications associated with COVID-19

Virus-related cardiac injury in patients with COVID-19 has been associated with ACE2 dysregulation, imbalanced immune response leading to cytokine storm, hypoxia related to respiratory dysfunction and treatment-adverse events.6 Specifically, SARS-CoV-2 infection can be complicated with decompensated heart failure, myocarditis, acute myocardial infarction and cardiac arrhythmias, including incident atrial fibrillation.6,19,20 The aforementioned cardiac manifestations of COVID-19 may lead to subsequent cardio-embolism and cerebral infarction.

Coagulopathy associated with COVID-19

Various reports have been published regarding hypercoagulability associated with severe COVID-19 illness, due to immobilization, dehydration, inflammation, elevated fibrinogen, endothelial cell injury, and platelet activation.2124 The hypercoagulability may further add to the risk of developing cerebral venous thrombosis (CVT) or ischemic stroke (IS).2325 The COVID-19-associated prothrombotic state is accompanied by high D-dimer levels, elevated ferritin, and in some cases, detectable lupus anticoagulant, anticardiolipin immunoglobulin A (IgA), and antiphospholipid IgA and immunoglobulin M (IgM) autoantibodies directed against β2-glycoprotein-1.22,26 On the other hand, it is well established that such autoantibodies appear in many conditions characterized by profound immune activation with no apparent pathogenic role.

Hypercoagulability due to SARS-CoV-2 infection has also been associated with a higher incidence of deep vein thrombosis.27,28 Right-to-left shunt and paradoxical embolism of generated venous thrombi through a patent foramen ovale might act as an etiopathogenic mechanism in younger patients with cryptogenic cerebral ischemia without any vascular risk factors for stroke. In addition to intracardiac shunts, the right-to-left shunt may be associated with intrapulmonary causes, such as pulmonary vascular dilatations or pulmonary arteriovenous malformations. In a recently published study, contrast-enhanced transcranial Doppler was performed in mechanically ventilated patients with COVID-19 pneumonia and detected microbubbles in 83% of the patients.29 The detection of microbubbles was attributable to pulmonary vasodilatations which may also explain the disproportionate hypoxemia seen in COVID-19 patients.29

On the other hand, coagulopathy associated with COVID-19 may present as dysfunctional hemostasis, prolonged prothrombin time and bleeding disorder, especially in severely infected patients. The characteristics of COVID-19 coagulopathy are similar but not perfectly matched to those of disseminated intravascular coagulopathy.30 Characteristically, COVID-19 coagulopathy manifests with significantly elevated D-dimers, but only mild thrombocytopenia and slightly prolonged prothrombin time, and rarely meets the diagnostic criteria of disseminated intravascular coagulopathy according to the International Society on Thrombosis and Haemostasis.31,32 Nevertheless, the disruption of hemostasis in COVID-19 may contribute to an increased risk of secondary intracranial hemorrhage, especially when therapeutic anticoagulation is also administered.

Triggering CNS vasculitis and endotheliitis

SARS-CoV-2 viral-like particles may be detected in brain capillary endothelium, as was recently noted in an autopsy study.33 This finding supports the viral neurotropism and potentially implicates SARS-CoV-2 in a direct effect on cerebral vessels with subsequent endothelium dysfunction and degeneration.34 SARS-CoV-2 has also been implicated in triggering CNS vasculitis, possibly through an inflammatory response mediated by the cytokine storm and specifically interleukin-6.3538 This is not new for viral infections, since other viruses (e.g. varicella zoster, human immunodeficiency virus, hepatitis C virus, hepatitis B, cytomegalovirus, parvovirus b19) may trigger such a response.39 Inflammation of cerebral vasculature may lead to arterial remodeling with either stenosed or dilated, fragile vessels with subsequent ischemic or hemorrhagic stroke, respectively. Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome may mimic primary angiitis of the CNS and have been recently described in COVID-19 patients.4042 IS, ICH, and convexal subarachnoid hemorrhage are common manifestations of reversible cerebral vasoconstriction syndrome.43

Critical illness due to COVID-19

A significant percentage of patients with SARS-CoV-2 infection present with serious manifestations and may need intubation, mechanical ventilation, and prolonged hospitalization in intensive care units, mostly due to pulmonary complications. Hypoxemia and systemic hypotension due to primarily immune-mediated critical illness may further induce hypoxic/ischemic encephalopathy and contributes to IS, mostly in watershed territories or presenting as cortical laminar necrosis.44 Additionally, prolonged hypoxemia and respiratory failure have been associated with cerebral microbleeds and/or leukoencephalopathy.45

Cerebrovascular manifestations associated with COVID-19

Reports of cerebrovascular complications associated with COVID-19 are continuously increasing.

Ischemic stroke

A recently published, prospective, multinational study reported 123 patients who presented with acute IS out of a total of 17,799 SARS-CoV-2-infected patients.46 This result corresponds to a non-weighted risk of 0.7% for IS among patients hospitalized for COVID-19. Other cohort studies reporting IS risk among hospital admissions for COVID-19 also presented similar results (Table 1). These data underscore that COVID-19 may be associated with a small but non-negligible risk for IS. Another important fact is that IS is reported as the initial manifestation and reason for hospitalization in 26% of COVID-19-confirmed patients.47

Table 1. Cohort studies reporting cerebrovascular events in COVID-19 patients during general hospital admission.

Table 1. Cohort studies reporting cerebrovascular events in COVID-19 patients during general hospital admission.View larger version

Regarding the IS subtype according to Trial of ORG 10172 in Acute Stroke Treatment classification, COVID-19 was reported to be associated with a higher incidence of cryptogenic stroke.47,48,56,60 According to a retrospective cohort study performed in a major health system in New York, cryptogenic stroke was twice more prevalent in COVID-19 positive patients compared with both a contemporary control group consisting of COVID-19 negative patients and a historical control group derived from patients treated in the same period in 2019.48 The presented high rates of cryptogenic stroke could further alarm clinicians regarding hypercoagulability state, in situ arterial thrombosis from endothelitis and occult cardioembolism or paradoxical embolism, both of which require deeper investigation and consideration of therapeutic anticoagulation.6163 Other studies, which also included hospitalized COVID-19 patients, reported an incidence of up to 35% for cryptogenic stroke among IS patients.51,52,64 Finally, it should be noted that different case series of stroke complicating COVID-19 patients have reported a decreased prevalence of lacunar infarction (⩽10%) among IS patients.46,48 This observation indicates the potential lack of association between COVID-19 and intrinsic small-vessel disease. However, since lacunar strokes are generally associated with less severe symptoms compared with large-vessel occlusion (LVO) strokes, the patients may have not undergone neuroimaging evaluation with brain MRI and ascertainment of acute cerebral ischemia mechanism leading to the under-representation of lacunar strokes in patient cohorts.

Another important observation regarding IS incidence in patients with COVID-19 is the report of younger patients without known risk factors presenting with stroke due to LVO.65 Also, COVID-19 patients with LVO were younger compared with both contemporary controls of COVID-19-negative patients and historical controls, as investigated in different studies.66,67 In another case series, it was shown that among patients hospitalized for stroke due to LVO, more than half tested positive for SARS-CoV-2.67 Almost a quarter of COVID-19 patients admitted for acute IS is reported to be due to LVO.52,68 An illustrative case of a patient with LVO stroke and concurrent COVID-19 is presented in Figure 2. Multifocal LVOs is another matter of concern in those patients, since multivessel obstruction is presented significantly more frequently in SARS-CoV-2 positive patients.66,68

Figure 2. Imaging evaluation of a patient with acute proximal occlusion of the right middle cerebral artery during hospitalization for COVID-19.

A 65-year-old man with a history of hypertension and diabetes mellitus presented with acute left-sided hemiplegia, dysarthria, neglect, and right-gaze deviation. He had minimal respiratory symptoms. Emergency brain CT and CTA scanning were performed. Acute proximal right middle cerebral artery (MCA) occlusion was demonstrated on CTA (panel A, arrow) with evolving right MCA infarction. Right MCA occlusion was also confirmed on CTA 3D reconstruction (panel B, dotted circle). At that time, D-dimer levels were 2.8 ng/ml (normal values <500 ng/ml). The patient was not eligible for either intravenous thrombolysis due to delayed presentation or mechanical thrombectomy due to an unfavorable perfusion profile. Brain MRI was subsequently performed, showing restricted diffusion in right MCA territory, confirmative of large right MCA infarct (panel C). SARS-CoV-2 infection was confirmed at day 9 of hospitalization. On the 3-month follow up, the patient had modified Rankin Scale score of 4 with persistent severe left hemiparesis.

COVID-19, coronavirus disease 2019; CT, computed tomography; CTA, computed tomography angiography; MRI, magnetic resonance imaging; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

In patients admitted with acute IS during the period of COVID-19 restrictions, significant concern has been raised regarding the delivery of acute reperfusion treatments. This gains even more importance, especially in the aforementioned patients with LVO, who may need mechanical thrombectomy. Initially, patients were thought to be reluctant to seek medical help for stroke symptoms due to their fear of contracting COVID-19, and subsequently presented with substantial delay to the emergency department, outside the time window for available acute reperfusion therapies.69,70 Different cohort studies evaluated the management in the acute phase of stroke patients during COVID-19 restrictions compared with historical controls treated in the same periods before the pandemic. Several of them have underscored the negative effect of lockdown on the management of IS, depicting reductions of stroke admissions, the total number of thrombolysis and/or thrombectomy and significant increases in treatment times.7175

However, the American Heart Association/American Stroke Association Stroke Council Leadership responded promptly with emergency guidance to the need of addressing those issues and securing the delivery of acute stroke treatments.70 A ‘protected code stroke’ was recommended and a focused framework was provided with the aim of COVID-19-specific screening, personal protective equipment, and crisis resource management during acute stroke treatment.76 In addition, the European Society of Neurosonology and Cerebral Hemodynamics issued practice recommendations for neurovascular investigations of acute stroke patients during the COVID-19 pandemic aiming to highlight the utility of ultrasound as a non-invasive, easily repeatable bedside real-time examination of cerebral vessels.77 Finally, the European Stroke Organization and other organizations addressed to the public and underscored that patients with stroke symptoms should seek medical help as soon as possible, despite COVID-19 restrictions.78 Hopefully, such measures will contribute to the stabilization of stroke treatment delivery despite those unprecedented times.

Cerebral hemorrhage

Several case reports and cohort studies have recently been published presenting COVID-19 patients with parenchymal hemorrhage,58,59,7985 subarachnoid hemorrhage,14,58,59,86 and subdural hematoma.59 A retrospective case series of five patients showed that COVID-19 patients with ICH were younger than expected and mostly suffered from lobar ICH.85 One of the patients described in this report had multifocal ICH without any underlying vascular abnormality.85 Similar results were presented in a retrospective cohort study, that showed 0.5% of hospitalized COVID-19 patients to be diagnosed with hemorrhagic stroke, with coagulopathy being the most common etiology.58 A large, deep intracerebral hematoma with an irregular, multi-lobular shape identified in a COVID-19 patient is presented in Figure 3.

Figure 3. Imaging evaluation of a COVID-19 patient with large, multi-lobular intracerebral hemorrhage.

A 55-year-old woman with a history of diabetes mellitus and hypertension was quarantined at home due to SARS-CoV-2 infection with mild respiratory symptoms. At 12 days later, she deteriorated, presenting dyspnea and respiratory failure. She was admitted to the ICU for mechanical ventilation. On day 11 of hospitalization, she became apneic on the ventilator, with fixed, dilated pupils. An emergent brain CT scan was performed showing a large, left-sided intracerebral hemorrhage causing compression of the ipsilateral lateral ventricle and midline shift to the right (panel A). The hematoma had an irregular, multi-lobular shape (panel A and B). No hypertensive spike was confirmed. The patient expired 1 day after neurological worsening.

COVID-19, coronavirus disease 2019; CT, computed tomography; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

However, among general hospital admissions of COVID-19 patients, only a minor proportion exhibited ICH (Table 1). Similarly, COVID-19 patients who were hospitalized in neurological wards did not have significantly more cerebral hemorrhagic events compared with non-COVID-19 patients.87 Based on these observations, it remains unknown whether COVID-19 has a causal association with ICH through ACE2 inactivation, endothelial dysfunction/degeneration, coagulopathy or hypocoagulability, or rather, whether secondary effects of COVID-19 such as renal failure/cirrhosis with concomitant therapeutic anticoagulation in a critically ill older population is the culprit. The atypical multifocal nature of many of the reported ICH cases to date would suggest some form of underlying vasculopathy which likely acts synergistically with the aforementioned factors in causing ICH. One pathological report to date has confirmed underlying endothelial reactivity, as well as endothelial and neuropil degeneration in a COVID-19 patient with ICH.34

Cerebral microbleeds have also been demonstrated in critically ill COVID-19 patients and can present with or without leukoencephalopathy.45,88 The atypical location of cerebral microbleeds in the corpus callosum and juxtacortical region may raise the suspicion of SARS-CoV-2 infection in critically ill patients.42 However, a very similar pattern has previously been presented in critically ill non-COVID-19 patients with respiratory failure.89,90 These neuroimaging findings are associated with worse neurological status and longer hospitalization in COVID-19, and likely reflect a more advanced stage of critical illness.45

Cerebral venous thrombosis

Venous thromboembolic events, such as pulmonary embolism and deep venous thrombosis, are detected with high frequency in COVID-19 patients hospitalized in intensive care units, even despite anticoagulation treatment.91 The risk of thrombosis associated with COVID-19 may also be responsible for CVT. Numerous case reports have been published about COVID-19 patients presenting with CVT.9299 In addition, cases with more atypical presentations, such as cortical or deep cerebral venous thrombosis, have been described.100,101 Six patients were diagnosed with CVT among 17,799 hospitalized SARS-CoV-2 patients.46 Headache and impaired consciousness may complicate or even be the presenting symptoms of both COVID-19 and CVT (Figure 4). For that reason, clinicians should be quite vigilant in order to timely diagnose CVT-complicating COVID-19.102 Clinicians should also be able to differentiate COVID-19 patients with primary ICH and hemorrhagic infarction due to CVT, since the latter requires anticoagulant treatment in therapeutic dosage.103 Finally, CVT involving the internal cerebral veins may be challenging to differentiate from acute hemorrhagic necrotizing encephalitis (Weston–Hurst syndrome), which is another COVID-19 CNS complication that may symmetrically affect basal ganglia and thalami with hemorrhagic lesions.104

Figure 4. Imaging evaluation of a COVID-19 patient with cerebral venous thrombosis.

A 59-year-old woman presented with a thunderclap headache followed by a severe progressive headache. Her neurological examination revealed bilateral papilledema. In the brain CT scan, she had an ischemic occipital lesion (panel A). Brain MRV demonstrated lack of flow in the left transverse and sigmoid sinuses, confirming the diagnosis of cerebral venous sinus thrombosis (panel B). In addition, the patient reported she had a fever, cough, and sore throat 10 days before her neurological symptoms. Chest CT showed diffuse ground-glass opacification (panel C). A positive SARS-CoV2 PCR confirmed the diagnosis of COVID-19.

COVID-19, coronavirus disease 2019; CT, computed tomography; MRV, magnetic resonance venography; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Red flags for COVID-19-associated stroke diagnosis

Prompt diagnosis and treatment of acute cerebrovascular disease complicating COVID-19 are essential since co-existing stroke appears to negatively influence the outcome in patients with SARS-CoV-2 infection.50,105 Several clinical and neuroimaging characteristics are present and can raise suspicion in COVID-19 associated stroke diagnosis. The adjunctive use of artificial intelligence may expedite an accurate diagnosis and is already developing in the field of COVID-19-related brain injury.106

Ischemic strokes in COVID-19 patients often present with multi-territorial arterial distribution, embolic pattern, and hemorrhagic transformation.64,107114 A COVID-19 patient diagnosed with multi-territorial arterial infarctions of an embolic pattern in the absence of vascular risk factors is shown in Figure 5. Large cerebral vessel occlusions with significant thrombus burden and a propensity for clot fragmentation is well documented in the literature.46,65,67,68,108,110,115 Characteristically, LVO may affect younger patients without known risk factors for stroke, it is associated with higher in-hospital mortality and may represent the initial manifestation leading to hospitalization during SARS-CoV-2 infection.65,67,115,116 Hypercoagulable state, cardioembolism, or paradoxical embolism due to COVID-19 may be potential reasons for such a stroke presentation. Furthermore, unexpected IS locations, such as in the corpus callosum or a frequent involvement of posterior circulation, have been associated with COVID-19.117119 Increased incidence of hemorrhagic transformation of ischemic infarcts has also been observed in COVID-19 stroke patients.56,111 Whether the dysfunctional hemostasis or the increased use of anticoagulants could be associated with the likelihood of hemorrhagic transformation remains currently unknown. Finally, level of consciousness was recently reported as an important component in a risk stratification score related to severe COVID-19.120 Confusion may not only be an important parameter relating to the severity of a multisystem disease like COVID-19, but in addition, it may underlie the presence of cerebrovascular disease. Unsuccessful recovery after ventilation weaning should alarm clinicians about the possibility of cerebrovascular disease development, and mandates appropriate neuroimaging studies.111

Figure 5. Imaging evaluation of a COVID-19 patient with multi-territorial ischemic infarcts.

An 83-year-old man with a history of hypertension, diabetes, hyperlipidemia, and prior ischemic stroke with no residual symptoms, presented to the emergency department with seizure-like activity and acute respiratory failure, likely due to aspiration. Brain MRI was performed showing restricted diffusion in the territories of both the right middle cerebral artery (MCA; panel A) and the right posterior cerebral artery (PCA; panel B), indicating right MCA and PCA acute ischemic stroke. He was intubated in the emergency department for decreased level of consciousness, hypoxia, and airway protection and initially admitted to the medical ICU. On presentation and the day after presentation, nasopharyngeal swab tests were performed and were both negative for SARS-CoV-2. At 10 days after initial presentation, a third nasopharyngeal swab was performed and found positive, confirming SARS-CoV-2 infection. Despite initial hypoxia and multiorgan failure, the patient improved systematically and was eventually weaned off the ventilator after 1 month of ICU hospitalization. However, the neurological examination did not improve accordingly, and the patient did not fully regain his level of consciousness. For that reason, a brain MRI was repeated and disclosed acute left MCA (panel C and D) and additional right MCA (panel D) territory recurrent ischemic infarcts. The patient was finally discharged to a long-term nursing facility and expired approximately 2.5 months after his initial presentation.

COVID-19, coronavirus disease 2019; ICU, intensive care unit; MRI, magnetic resonance imaging; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

ICH may complicate in COVID-19 patients that are younger than expected for conventional ICH.85 Coagulopathy was reported as the most common etiology of ICH, whereas COVID-19-negative patients most often suffered from hypertension-related ICH.58 Coagulopathy is reflected by the significantly higher levels of D-dimers, which may be considered as a ‘red flag’ for COVID-19-associated ICH.58 Furthermore, although spontaneous ICH most typically presents as deep hemorrhage in patients with negative COVID-19 history, lobar and multi-focal hematomas without underlying macrovascular abnormalities are commonly reported in COVID-19 patients.58,85 Cerebral microbleeds represent a recently described neuroimaging finding in COVID-19 patients, which is associated with critical illness.45,88 In addition, anticoagulation treatment prior to the manifestation of hemorrhagic stroke in COVID-19 patients has been consistently reported in a recent case series from New York City.75

Development of CVT in patients without other risk factors of hypercoagulability should alert clinicians to the possibility of SARS-CoV-2 infection, especially in the presence of excessively high (>2.0 ng/ml) D-dimer levels. Persisting headache and altered consciousness with confusion and/or agitation, coupled with high levels of D-dimers, may be a hint for CVT complication that should be promptly diagnosed and anticoagulated.103

Prognosis of cerebrovascular events associated with COVID-19

Data regarding the long-term prognosis of COVID-19 patients with cerebrovascular events are scarce. Most studies report clinical outcomes at discharge. In a single-center study, it was shown that positive patients had higher National Institutes of Health Stroke Scale score and were less likely to achieve functional independency at discharge.87 Moreover, the mortality rate in COVID-19 stroke patients was higher compared with contemporary SARS-CoV-2-negative stroke patients.87 Similar results are confirmed in other cohort studies investigating cerebrovascular disease in COVID-19 patients compared with COVID-19-negative patients (Table 2). A high mortality rate was also reported in a multinational cohort study, for both ischemic and hemorrhagic COVID-19 stroke patients.56 Additionally, in the same study it was shown that 17.4% of COVID-19 IS patients suffered from a hemorrhagic transformation of the infarction.56

Table 2. Cohort studies reporting clinical outcomes at discharge of COVID-19 patients with cerebrovascular disease compared with COVID-19-negative patients.

Table 2. Cohort studies reporting clinical outcomes at discharge of COVID-19 patients with cerebrovascular disease compared with COVID-19-negative patients.View larger version

Irrespective of SARS-CoV-2 positivity, the COVID-19 pandemic and the subsequently imposed restrictions had a negative influence on mortality and functional outcomes in stroke patients in general. Higher incidence of mortality and worse functional outcomes at discharge were reported in different cohort studies evaluating stroke patients who were admitted during the COVID-19 pandemic, compared with historical controls of the pre-COVID-19 period.60,64,71,72,122125 These alarming results may be attributable to delays in the presentation of stroke patients and subsequent lower rates of recanalization therapies. Furthermore, longer hospitalization stay was needed for the acute management of stroke patients during COVID-19 pandemic.60,64,71,72,122 Severe neurological impairment of the stroke patients, limited medical and laboratory resources, assignment, and transfer of medical personnel from stroke wards to COVID-19 designated wards might explain the need for the extension of hospitalization.

Apart from the observation that SARS-CoV-2 is a risk factor of mortality in stroke patients, it has also been shown that COVID-19 patients who experienced an acute IS during the infection had significantly lower rates of survival compared with those without a stroke.50,105 In addition, a previous history of stroke was an independent risk factor for severe pneumonia leading to critical illness, the need for ventilation, and mortality in COVID-19 patients.126,127

In ICH patients, COVID-19 was negatively associated with prognosis. A higher mortality rate was observed in COVID-19 patients compared to both contemporary and historical negative controls with ICH.58 In another cohort, all COVID-19 patients with hemorrhagic lesions on brain MRI suffered from acute respiratory distress syndrome and were hospitalized in intensive care units.88 A total of 20% patients with hemorrhagic lesions died during hospitalization, compared with 6% of COVID-19 patients with other non-hemorrhagic lesions.88

Impact of COVID-19 pandemic on stroke management

The COVID-19 pandemic and the imposed restrictions severely impacted stroke management.9,69 Since the first weeks of the outbreak, declining numbers of stroke admissions have been reported in the literature.128,129 Patients with transient or minor stroke symptoms are more likely to avoid seeking medical help due to their fear of contracting the virus.130 Moreover, the availability of acute reperfusion therapies, including both intravenous thrombolysis and mechanical thrombectomy has been limited, according to recent reports from North America and Europe.7175 When administered, treatment time metrics are prolonged, negatively impacting the effectiveness of the treatments.131 The performance of the more time-consuming, multiparametric stroke neuroimaging techniques is reported to have also declined, which, in turn, impedes the recognition of eligible patients for acute reperfusion therapies.132

In order to safely implement acute stroke management during the COVID-19-imposed restrictions, a ‘protected code stroke’ has been proposed.76 When a stroke patient presents to the emergency department, the clinicians should specifically ask for signs and symptoms compatible with COVID-19 infection, such as a history of fever, cough, dyspnea, diarrhea, hyposmia, or hypogeusia.133 History taking regarding COVID-19 should not be limited to the stroke patient, but should also include patients’ close contacts. Temperature checks can be used as an initial, feasible, and inexpensive screening tool upon patient presentation. In cases of positive COVID-19 history or confirmed fever, a nasopharyngeal swab should be tested for SARS-CoV-2 and repeated if negative and clinical suspicion is high, according to local COVID-19 protocols. Rapid antigen tests with high sensitivity and specificity can be used while in triage and may be a game changer in this regard. However, in cases of acute stroke, the management should not be delayed, and the patient should be treated as suspected COVID-19 by the minimum number of medical personnel and appropriate infection control measures, in order to minimize exposure.134

When indicated, intravenous thrombolysis with bolus tenecteplase might be considered as an alternative to alteplase bolus, and 1 h infusion to reduce the acute treatment duration and staff exposure.135 In addition, a minimum number of medical personnel, who should be experienced in donning and doffing personal protective equipment with safety, should perform mechanical thrombectomy procedures. If possible, mechanical thrombectomy under conscious sedation should be considered as the first line if the patient is stable.136 If general anesthesia and endotracheal intubation are needed, extreme caution is mandatory, since the latter is an aerosol and airborne-generating procedure. Ideally, intubation, mechanical ventilation, and extubation of the patient should be performed in negative-pressure rooms.136 Finally, acute stroke care should be provided by experienced stroke teams and the involved specialized personnel should not be redeployed to other hospital departments due to COVID-19-specific demands.137

During further hospitalization, transcranial ultrasound may be used to monitor intracranial vessel patency in IS patients who have received recanalization treatments, since it is a feasible, bedside test and can limit patient transportation.77 If further neuroimaging is needed, brain MRI may be performed for the differential diagnosis of COVID-19 patients with neurological manifestations.138 Moreover, regarding secondary prevention treatment in the subacute phase, prophylactic anticoagulant treatment is indicated in COVID-19 stroke patients.139,140 Finally, possible underlying mechanisms and deteriorating factors, such as hypoxia, coagulation disorder, and electrolyte imbalance should be managed, and cardiac function should be supported if needed during stroke hospitalization.

As for the long-term management and functional improvement, the COVID-19 stroke patients will not only require rehabilitation for their stroke, but also for the long-term consequences associated with a severe COVID-19 infection. The multidisciplinary stroke rehabilitation team needs to adapt to cater for both needs. It is of importance to initiate and maintain an inpatient rehabilitation program for the most severely affected patients.141 Tele-rehabilitation through electronic communication technologies may be a viable procedure for milder cases and their caregivers, limiting unnecessary transportation and close contacts, and providing protection against SARS-CoV-2 transmission.142,143 Finally, mental health should also be preserved. Stroke patients may often experience depression and anxiety, while anxiety itself may act as an additional trigger factor for acute stroke.144,145 Psychiatric support becomes even more important during the COVID-19 pandemic, since self-isolation, physical distancing, imposed restrictions and the fear of contracting the virus may pose additional emotional threats.146


The causative versus incidental relationship between SARS-CoV-2 and stroke may still be debatable. Our narrative review presents the potential underlying mechanisms of the association between COVID-19 and cerebrovascular disease. ACE2 receptor dysregulation, excessive immune response, coagulation disorders, cardiac complications, and critical illness can lead to the development of different cerebrovascular disease manifestations during SARS-CoV-2 infection. However, stroke incidence in COVID-19 patients appears to be lower (0.5–1.5%) than what was originally reported from the Wuhan outbreak (5–6%).10,4648 This discrepancy might partially be explained by the fact that during the first weeks of the pandemic, prophylactic anticoagulation treatment was not administered as a standard of care in every COVID-19 patient.

Several key aspects should be summarized based on the presented review. Cryptogenic ischemia due to LVO appears to be the most common manifestation of acute cerebral ischemia, while lacunar stroke is rarely reported to complicate SARS-CoV-2 infection. Coagulation disorders, in situ arterial thrombosis, paradoxical embolization through right-to-left shunts, and occult paroxysmal atrial fibrillation should be scrutinized as indicated. Lobar or subcortical ICH that may be temporally associated with the initiation of anticoagulation therapy appears to be the most prevalent hemorrhagic CNS manifestation of COVID-19. CVT may also present as a hemorrhagic transformation of the cerebral venous infarction and should be included in the differential diagnosis of hemorrhagic lesions in COVID-19 patients. Importantly, CVT may seldom (≈0.5%) represent the initial manifestation of COVID-19 in patients with underlying hypercoagulability.

The adverse outcomes of COVID-19 patients with co-existing cerebrovascular disease mandate physician alertness for timely diagnosis and swift delivery of available acute stroke therapies. Several clinical and neuroimaging characteristics may be utilized as red flags to promote diagnosis. Younger age of patients, the absence of known stroke risk factors, difficulties in weaning from mechanical ventilation, high D-dimer levels, spontaneously prolonged international normalized ratio (INR)/partial thromboplastin time (PTT), multi-territorial acute infarctions, unexpected stroke locations (e.g. splenium of the corpus callosum), and LVOs should alarm clinicians about the co-existence of stroke and SARS-CoV-2 infection. Despite COVID-19-imposed restrictions, acute treatment should be offered as indicated through a safe pathway for both the patients and the medical personnel. Tele-neurology and remote imaging access may minimize exposure of vascular neurologists during the management of SARS-CoV-2 infected patients and should be used when feasible.147,148

The limitations of the present review should be acknowledged. First, this is a narrative review of the literature with the aim of discussing the association between COVID-19 and stroke. Cohort studies and case series included in this review are highly heterogenous regarding stroke diagnostic work-up, acute management, study populations, and use of contemporary versus historical controls. Furthermore, we did not review studies that have been submitted but not accepted to international medical journals. Ideally, an up-to-date systematic review and meta-analysis of included cohort studies may be conducted, investigating the incidence, treatment, and outcomes of cerebrovascular disease in COVID-19 patients and providing future directions in stroke diagnosis and management in the COVID-19 era.


Neurological manifestations are not uncommon during SARS-CoV-2 infection. Among those, cerebrovascular disease was initially reported with an alarming incidence of 6% in a small Chinese cohort.10 However, recent studies in the international larger dataset report a smaller but non-negligible risk of stroke (0.5–1.5%) in infected patients.4648 Whether this smaller risk could be attributed to the standard prophylactic anticoagulation given in every hospitalized patient is not known. ACE2 receptor dysregulation, inflammation, coagulopathy, COVID-19-associated cardiac involvement with subsequent cardio-embolism, and critical illness may all act as pathogenetic mechanisms for developing IS, hemorrhagic stroke, and CVT. Longer duration of hospitalization, worse functional outcomes at discharge, and higher in-hospital mortality are reported in COVID-19 associated stroke. For that reason, prompt stroke diagnosis and preservation of high-quality acute stroke treatment should be emphasized. Several clinical characteristics, such as younger age of patients and lack of known stroke risk factors, as well as neuroimaging (multi-territorial cerebral ischemia of embolic pattern due to underlying LVO) and laboratory (excessive elevation of D-dimer levels and spontaneously prolonged INR/PTT at hospital admission) caveats could further assist clinicians in diagnosing cerebrovascular disease in patients with SARS-CoV-2 infection.

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement
The authors declare that there is no conflict of interest.


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Age- and Sex-Specific Incidence of Cerebral Venous Sinus Thrombosis Associated With Ad26.COV2.S COVID-19 Vaccination

Authors: Aneel A. Ashrani, MD, MS1Daniel J. Crusan, BS2Tanya Petterson, MS2et al

JAMA Intern Med. 2022;182(1):80-83. doi:10.1001/jamainternmed.2021.6352

Recent reports14 suggest a possible association between Ad26.COV2.S (Johnson & Johnson/Janssen) COVID-19 vaccination and cerebral venous sinus thrombosis (CVST). Estimates of postvaccination CVST risk require accurate age- and sex-specific prepandemic CVST incidence rates; however, reported rates vary widely.5 We compared the age- and sex-specific CVST rates after Ad26.COV2.S vaccination with the prepandemic CVST rate in the population.Methods

In this population-based cohort study, to estimate the risk of CVST after Ad26.COV2.S vaccination, we first identified all incident cases of CVST in Olmsted County, Minnesota from January 1, 2001, through December 31, 2015 (eMethods in the Supplement). Sex-and age-adjusted incidence rates were adjusted to the 2010 US census population. We used CDC Vaccine Adverse Event Reporting System (VAERS) data from February 28, 2021 (vaccine approval date) to May 7, 2021, to estimate the incidence of CVST after Ad26.COV2.S vaccination assuming 3 (15, 30, and 92 days) plausible postvaccination periods during which individuals were considered to be at risk of CVST. We then compared post-Ad26.COV2.S vaccination CVST rates with prepandemic rates to estimate postvaccination CVST risk. This study was approved by the Mayo Clinic institutional review board. Medical records of Olmsted County residents with CVST were reviewed only if the residents had signed an authorization for accessing their medical records for research purposes. SAS, version 9.4 (SAS Institute Inc) and R, version 4.0.3 (R Project for Statistical Computing) were used for statistical analyses. Significance was set at a 2-sided P < .05.Results

From 2001 through 2015, 39 Olmsted County residents developed acute incident CVST. A total of 29 patients (74.4%) had a predisposing venous thromboembolism risk factor (eg, infection, active cancer, or oral contraceptives [for women]) within 92 days before the event. The median age at diagnosis was 41 years (range, 22-84 years); 22 residents with CVST (56.4%) were female. The overall age- and sex-adjusted CVST incidence was 2.34 per 100 000 person-years (PY) (95% CI, 1.60-3.08 per 100 000 PY). Age-adjusted CVST rates for female and male individuals were 2.46 per 100 000 PY (95% CI, 1.43-3.49 per 100 000 PY) and 2.34 per 100 000 PY (95% CI, 1.22-3.46 per 100 000 PY), respectively. Men aged 65 years or older had the highest CVST rate (6.22 per 100 000 PY; 95% CI, 2.50-12.82 per 100 000 PY), followed by women aged 18 to 29 years (4.71 per 100 000 person-years; 95% CI, 2.26-8.66 per 100 000 PY) (Table 1).

As of May 7, 2021, 8 727 851 Ad26.COV2.S vaccine doses had been administered in the US; 46 potential CVST events occurring within 92 days after Ad26.COV2.S vaccination were reported to VAERS. Eight events were excluded because they were potentially duplicate reports (4) or were not objectively diagnosed (4). Twenty-seven of 38 objectively diagnosed cases of CVST after Ad26.COV2.S vaccination (71.1%) occurred in female individuals. The median patient age was 45 years (range, 19-75 years). The median time from vaccination to CVST was 9 days (IQR, 6-13 days; range, 1-51 days); 31 of 38 cases of CVST (81.6%) occurred within 15 days after vaccination, and 36 (94.7%) occurred within 30 days.

The overall incidence rate of post–Ad26.COV2.S vaccination CVST was 8.65 per 100 000 PY (95% CI, 5.88-12.28 per 100 000 PY) at 15 days, 5.02 per 100 000 PY (95% CI, 3.52-6.95 per 100 000 PY) at 30 days, and 1.73 per 100 000 PY (95% CI, 1.22-2.37 per 100 000 PY) at 92 days (Table 2). The 15-day postvaccination CVST incidence rates for female and male individuals were 13.01 per 100 000 PY (95% CI, 8.24-19.52 per 100 000 PY) and 4.41 per 100 000 PY (95% CI, 1.90-8.68 per 100 000 PY), respectively. The postvaccination CVST rate among females was 5.1-fold higher compared with the pre-COVID-19 pandemic rate (13.01 vs 2.53 per 100 000 PY; P < .001) (Table 2). This risk was highest among women aged 40 to 49 years (29.50 per 100 000 PY; 95% CI, 13.50-55.95 per 100 000 PY), followed by women aged 30 to 39 years (26.50 per 100 000 PY; 10.65-54.63 per 100 000 PY).Discussion

In this population-based cohort study, we found that the CVST incidence rate 15 days after Ad26.COV2.S vaccination was significantly higher than the prepandemic rate. However, the higher rate of this rare adverse effect must be considered in the context of the effectiveness of the vaccine in preventing COVID-19 (absolute reduction of severe or critical COVID-19 of 940 per 100 000 PY).6

Most CVST events occurred within 15 days after vaccination, which is likely the highest at-risk period. The postvaccination CVST rate among females was higher than the prepandemic rate among females. The highest risk was among women aged 30 to 49 years, but the absolute CVST risk was still low in this group (up to 29.5 per 100 000 PY among women aged 40-49 years). The reason that women had a higher incidence of postvaccination CVST is unclear; concomitant CVST risk factors or autoantibody production might have been involved.2 The overall prepandemic CVST incidence rate was slightly higher in our study than in other studies (0.22-1.57 per 100 000 PY)5 likely because we captured all objectively diagnosed incident CVST cases in a well-defined population, including those discovered at autopsy.

The present study avoided referral bias and included only objectively diagnosed and confirmed cases. Only cases with adequate details or imaging findings reported on VAERS were used. Study limitations include possible ascertainment bias by including only objectively diagnosed CVST cases. VAERS reporting is voluntary and subject to reporting biases. VAERS monitors vaccine adverse events but does not prove causality.Back to topArticle Information

Accepted for Publication: September 12, 2021.

Published Online: November 1, 2021. doi:10.1001/jamainternmed.2021.6352

Corresponding Author: Aneel A. Ashrani, MD, MS, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (ashrani.aneel@mayo.edu).

Author Contributions: Dr Ashrani and Mr Crusan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ashrani, Petterson, Bailey, Heit.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ashrani, Crusan, Petterson.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Crusan, Petterson, Bailey.

Obtained funding: Ashrani, Heit.

Administrative, technical, or material support: Ashrani, Heit.

Supervision: Ashrani, Petterson, Bailey, Heit.

Conflict of Interest Disclosures: Dr Ashrani reported receiving grants from the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH) during the conduct of the study. Mr Crusan reported receiving grants from the NIH during the conduct of the study. Dr Heit reported receiving grants from the NHLBI, NIH during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported in part by grant R01HL66216 from the NHLBI, NIH (Drs Ashrani and Bailey), the Rochester Epidemiology Project (grant R01AG034676 from the National Institute on Aging, NIH), and the Mayo Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.


1.Centers for Disease Control and Prevention. Cases of cerebral venous sinus thrombosis with thrombocytopenia after receipt of the Johnson & Johnson COVID-19 vaccine New release. April 13, 2021. Accessed April 21, 2021.  https://emergency.cdc.gov/han/2021/han00442.asp

2.See  I, Su  JR, Lale  A,  et al.  US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021.   JAMA. 2021;325(24):2448-2456. doi:10.1001/jama.2021.7517
ArticlePubMedGoogle ScholarCrossref

3.Shay  DK, Gee  J, Su  JR,  et al.  Safety monitoring of the Janssen (Johnson & Johnson) COVID-19 vaccine—United States, March-April 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(18):680-684. doi:10.15585/mmwr.mm7018e2PubMedGoogle ScholarCrossref

4.Shimabukuro  T. Update: thrombosis with thrombocytopenia syndrome (TTS) following COVID-19 vaccination. Paper presented at: Advisory Committee on Immunization Practices; May 12, 2021.

5.Devasagayam  S, Wyatt  B, Leyden  J, Kleinig  T.  Cerebral venous sinus thrombosis incidence is higher than previously thought: a retrospective population-based study.   Stroke. 2016;47(9):2180-2182. doi:10.1161/STROKEAHA.116.013617PubMedGoogle ScholarCrossref

6.Sadoff  J, Gray  G, Vandebosch  A,  et al; ENSEMBLE Study Group.  Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-19.   N Engl J Med. 2021;384(23):2187-2201. doi:10.1056/NEJMoa2101544PubMedGoogle ScholarCrossref

Clinical determinants of the severity of COVID-19: A systematic review and meta-analysis




We aimed to systematically identify the possible risk factors responsible for severe cases.


We searched PubMed, Embase, Web of science and Cochrane Library for epidemiological studies of confirmed COVID-19, which include information about clinical characteristics and severity of patients’ disease. We analyzed the potential associations between clinical characteristics and severe cases.


We identified a total of 41 eligible studies including 21060 patients with COVID-19. Severe cases were potentially associated with advanced age (Standard Mean Difference (SMD) = 1.73, 95% CI: 1.34–2.12), male gender (Odds Ratio (OR) = 1.51, 95% CI:1.33–1.71), obesity (OR = 1.89, 95% CI: 1.44–2.46), history of smoking (OR = 1.40, 95% CI:1.06–1.85), hypertension (OR = 2.42, 95% CI: 2.03–2.88), diabetes (OR = 2.40, 95% CI: 1.98–2.91), coronary heart disease (OR: 2.87, 95% CI: 2.22–3.71), chronic kidney disease (CKD) (OR = 2.97, 95% CI: 1.63–5.41), cerebrovascular disease (OR = 2.47, 95% CI: 1.54–3.97), chronic obstructive pulmonary disease (COPD) (OR = 2.88, 95% CI: 1.89–4.38), malignancy (OR = 2.60, 95% CI: 2.00–3.40), and chronic liver disease (OR = 1.51, 95% CI: 1.06–2.17). Acute respiratory distress syndrome (ARDS) (OR = 39.59, 95% CI: 19.99–78.41), shock (OR = 21.50, 95% CI: 10.49–44.06) and acute kidney injury (AKI) (OR = 8.84, 95% CI: 4.34–18.00) were most likely to prevent recovery. In summary, patients with severe conditions had a higher rate of comorbidities and complications than patients with non-severe conditions.


Patients who were male, with advanced age, obesity, a history of smoking, hypertension, diabetes, malignancy, coronary heart disease, hypertension, chronic liver disease, COPD, or CKD are more likely to develop severe COVID-19 symptoms. ARDS, shock and AKI were thought to be the main hinderances to recovery.

For More Information: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250602

Neurologic Manifestations Associations of COVID-19

High-quality epidemiologic data is still urgently needed to better understand neurologic effects of COVID-19.

Authors: Shraddha Mainali, MD; and Marin Darsie, MD VIEW/PRINT PDF

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to prevail as a deadly pandemic and unparalleled global crisis. More than 74 million people have been infected globally, and over 1.6 million have died as of mid-December 2020. The virus transmits mainly through close contacts and respiratory droplets.1 Although the mean incubation period is 3 to 9 days (range, 0-24 days), transmission may occur prior to symptom onset, and about 18% of cases remain asymptomatic.2 The highest rates of coronavirus disease 2019 (COVID-19) in the US have been reported in adults age 18 to 29 and 50 to 64 years, representing 23.8% and 20.5% of cases, respectively.3 Although adults age 65 and older make up only 14.6% of total cases in the US, they account for the vast majority of deaths (79.9%).3 Similarly, men appear to be more vulnerable to the disease, accounting for 69% of intensive care unit (ICU) admissions and 58% of deaths despite nearly equal disease prevalence between men and women.4 In terms of ethnicity, Black Americans account for 15.6% of COVID-19 infections and 19.7% of related deaths, whereas Hispanic/Latinx Americans account for 26.3% of COVID-19 infections and 15.7% of COVID-19 deaths, despite these groups comprising 13.4% and 16.7% of the US population, respectively.3,5

The most commonly reported symptoms are fever, dry cough, fatigue, dyspnea, and anorexia.2 Numerous studies have also reported a spectrum of neurologic dysfunctions, including mild symptoms (eg, headache, anosmia, and dysgeusia) to severe complications (eg, stroke and encephalitis). Despite the prolific reports of neurologic associations and complications of COVID-19 in the face of a raging pandemic with limited resources, there is a significant lack of control for important confounders including the severity of systemic disease, exacerbation or recrudescence of preexisting neurologic disease, iatrogenic complications, and hospital-acquired conditions. Moreover, given the ubiquity of the virus, it is challenging to parse COVID-19–related complications from coexisting conditions. There is an urgent need for high-quality epidemiologic data reflecting COVID-19 prevalence by age, sex, race, and ethnicity on a local, state, national, and international level.

Neurologic and Neuropsychiatric Manifestations of COVID-19

Prevalence estimates of acute neurologic dysfunctions caused by COVID-19 are widely variable, with reports ranging from 3.5% to 36.4%.6 A recent study from Chicago showed that in those with COVID-19 who develop neurologic complications, 42% had neurologic complaints at disease onset, 63% had them during hospitalization, and 82% experienced them during the course of illness.7 Considering the widespread nature of the pandemic, with millions infected globally, neurologic complications of COVID-19 could lead to a significant increase in morbidity, mortality, and economic burden.

People over age 50 with comorbidities (eg, hypertension, diabetes, and cardiovascular disease) are prone to neurologic complications.2,8 Common nonspecific symptoms include headache, fatigue, malaise, myalgia, nausea, vomiting, confusion, anorexia, and dizziness. COVID-19 is known characteristically to affect taste (dysgeusia) and smell (anosmia) in the absence of coryza with variable prevalence estimates ranging from 5% to 85%.9 Since the first report on hospitalized individuals in Wuhan, China, numerous other reports have indicated a spectrum of mild-to-severe neurologic complications, including cerebrovascular events, seizures, demyelinating disease, and encephalitis.8,10-13 As a result of fragmented data from across the world with diverse neurologic manifestations and multiple potential mechanisms of injury, the classification of neurologic dysfunctions in COVID-19 is complex and varies across the literature. Here we present 2 pragmatic classification approaches based on 1) type and site of neurologic manifestations disease categories.

For More Information: https://practicalneurology.com/articles/2021-jan/neurologic-manifestations-associations-of-covid-19

Potential mechanisms of cerebrovascular diseases in COVID-19 patients

Authors: Manxue Lou 1Dezhi Yuan 2 3Shengtao Liao 4Linyan Tong 1Jinfang Li 5Affiliations expand


Since the outbreak of coronavirus disease 2019 (COVID-19) in 2019, it is gaining worldwide attention at the moment. Apart from respiratory manifestations, neurological dysfunction in COVID-19 patients, especially the occurrence of cerebrovascular diseases (CVD), has been intensively investigated. In this review, the effects of COVID-19 infection on CVD were summarized as follows: (I) angiotensin-converting enzyme 2 (ACE2) may be involved in the attack on vascular endothelial cells by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to endothelial damage and increased subintimal inflammation, which are followed by hemorrhage or thrombosis; (II) SARS-CoV-2 could alter the expression/activity of ACE2, consequently resulting in the disruption of renin-angiotensin system which is associated with the occurrence and progression of atherosclerosis; (III) upregulation of neutrophil extracellular traps has been detected in COVID-19 patients, which is closely associated with immunothrombosis; (IV) the inflammatory cascade induced by SARS-CoV-2 often leads to hypercoagulability and promotes the formation and progress of atherosclerosis; (V) antiphospholipid antibodies are also detected in plasma of some severe cases, which aggravate the thrombosis through the formation of immune complexes; (VI) hyperglycemia in COVID-19 patients may trigger CVD by increasing oxidative stress and blood viscosity; (VII) the COVID-19 outbreak is a global emergency and causes psychological stress, which could be a potential risk factor of CVD as coagulation, and fibrinolysis may be affected. In this review, we aimed to further our understanding of CVD-associated COVID-19 infection, which could improve the therapeutic outcomes of patients. Personalized treatments should be offered to COVID-19 patients at greater risk for stroke in future clinical practice.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33534131/

The Impact of the Covid 19 Pandemic on Cerebrovascular Disease: CORD-Papers-2021-06-28


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a systemic disease that affects nearly all organ systems through infection and subsequent dysregulation of the vascular endothelium. One of the most striking phenomena has been a coronavirus disease 2019 (COVID-19)associated coagulopathy. Given these findings, questions naturally emerged about the prothrombotic impact of COVID-19 on cerebrovascular disease and whether ischemic stroke is a clinical feature specific to COVID-19 pathophysiology. Early reports from China and several sites in the northeastern United States seemed to confirm these suspicions. Since these initial reports, many cohort studies worldwide observed decreased rates of stroke since the start of the pandemic, raising concerns for a broader impact of the pandemic on stroke treatment. In this review, we provide a comprehensive assessment of how the pandemic has affected stroke presentation, epidemiology, treatment, and outcomes to better understand the impact of COVID-19 on cerebrovascular disease. Much evidence suggests that this decline in stroke admissions stems from the global response to the virus, which has made it more difficult for patients to get to the hospital once symptoms start. However, there does not appear to be a demonstrable impact on quality metrics once patients arrive at the hospital. Despite initial concerns, there is insufficient evidence to ascribe a causal relationship specific to the pathogenicity of SARS-CoV-2 on the cerebral vasculature. Nevertheless, when patients infected with SARS-CoV-2 present with stroke, their presentation is likely to be more severe, and they have a markedly higher rate of in-hospital mortality than patients with either acute ischemic stroke or COVID-19 alone.

For More Information: https://covid19-data.nist.gov/pid/rest/local/paper/the_impact_of_the_covid_19_pandemic_on_cerebrovascular_disease