How the Coronavirus Attacks the Brain

 I'm going to be asking for heparin immediately hoping that swift application will neutralize the virus before it can get to the brain.

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

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

You can't listen to me, I'm not medically trained.

How the Coronavirus Attacks the Brain

It’s not just the lungs — the pathogen may enter brain cells, causing symptoms like delirium and confusion, scientists reported.

Brain scans of coronavirus patients from a study published in July. Some develop serious neurological complications, including nerve damage, scientists have found.Credit...Ross W. Paterson, Rachel L. Brown, et al./Brain, Oxford University Press

By Apoorva Mandavilli

• Sept. 9, 2020

The coronavirus targets the lungs foremost, but also the kidneys, liver and blood vessels. Still, about half of patients report neurological symptoms, including headaches, confusion and delirium, suggesting the virus may also attack the brain.

A new study offers the first clear evidence that, in some people, the coronavirus invades brain cells, hijacking them to make copies of itself. The virus also seems to suck up all of the oxygen nearby, starving neighboring cells to death.

It’s unclear how the virus gets to the brain or how often it sets off this trail of destruction. Infection of the brain is likely to be rare, but some people may be susceptible because of their genetic backgrounds, a high viral load or other reasons.

“If the brain does become infected, it could have a lethal consequence,” said Akiko Iwasaki, an immunologist at Yale University who led the work.

Continue reading the main story

The study was posted online on Wednesday and has not yet been vetted by experts for publication. But several researchers said it was careful and elegant, showing in multiple ways that the virus can infect brain cells.

Scientists have had to rely on brain imaging and patient symptoms to infer effects on the brain, but “we hadn’t really seen much evidence that the virus can infect the brain, even though we knew it was a potential possibility,” said Dr. Michael Zandi, consultant neurologist at the National Hospital for Neurology and Neurosurgery in Britain. “This data just provides a little bit more evidence that it certainly can.”

Dr. Zandi and his colleagues published research in July showing that some patients with Covid-19, the illness caused by the coronavirus, develop serious neurological complications, including nerve damage.

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In the new study, Dr. Iwasaki and her colleagues documented brain infection in three ways: in brain tissue from a person who died of Covid-19, in a mouse model and in organoids — clusters of brain cells in a lab dish meant to mimic the brain’s three-dimensional structure.

Other pathogens — including the Zika virus — are known to infect brain cells. Immune cells then flood the damaged sites, trying to cleanse the brain by destroying infected cells.

Continue reading the main story

The coronavirus is much stealthier: It exploits the brain cells’ machinery to multiply, but doesn’t destroy them. Instead, it chokes off oxygen to adjacent cells, causing them to wither and die.(This probably explains why autopsies of brains didn't show clotting, it kills brain cells a different way.)

The researchers didn’t find any evidence of an immune response to remedy this problem. “It’s kind of a silent infection,” Dr. Iwasaki said. “This virus has a lot of evasion mechanisms.”

Coronavirus Schools Briefing: It’s back to school — or is it?

These findings are consistent with other observations in organoids infected with the coronavirus, said Alysson Muotri, a neuroscientist at the University of California, San Diego, who has also studied the Zika virus.

The coronavirus seems to rapidly decrease the number of synapses, the connections between neurons. “Days after infection, and we already see a dramatic reduction in the amount of synapses,” Dr. Muotri said. “We don’t know yet if that is reversible or not.”

The virus infects a cell via a protein on its surface called ACE2. That protein appears throughout the body and especially in the lungs, explaining why they are favored targets of the virus.

Previous studies have suggested, based on a proxy for protein levels, that the brain has very little ACE2 and is likely to be spared. But Dr. Iwasaki and her colleagues looked more closely and found that the virus could indeed enter brain cells using this doorway.

“It’s pretty clear that it is expressed in the neurons and it’s required for entry,” Dr. Iwasaki said.

 

Autopsies indicate blood clots are lethal in COVID-19

I don't know how you are supposed to self treat this if you get it but not bad enough to go to a hospital. I'm hoping my 325 aspirin is enough. Or may be I just  demand a Lovenox shot. Not sure if walk in clinics would have anticoagulation therapies immediately available.

Autopsies indicate blood clots are lethal in COVID-19

In mid-March, pathologist Sigurd Lax pulled on a water-repellant surgery coat, a surgical cap, special booties to cover his shoes, a respiratory mask, and two pairs of gloves, then walked into an operating room at Hospital Graz II in Austria. There before him lay a patient who died of COVID-19 only 48 hours earlier.

“COVID-19 is a new disease, and we really want to know what’s underlying it,” Lax says. There’s only one method to determine what causes illness and death. “It’s doing an autopsy.”

Methodically, Lax sliced into the patient, taking care not to spray any bodily fluids into the air. He’d waited two days to perform the autopsy to reduce the risk of transmitting SARS-CoV-2, the coronavirus that causes COVID-19. With little known about the illness at the time, he and his colleagues wanted to take extra precautions to avoid getting sick. Waiting 48 hours after death to perform the autopsy, however, didn’t rid the body of SARS-CoV-2 RNA.

“We don’t know if the virus is still infectious,” Lax says, but finding its genetic material lingering in the patient’s tissues prompted him to be even more cautious. This autopsy was the first of 11 he and his colleagues have performed on patients who died from COVID-19. In May, the pathologists’ published a paper in the Annals of Internal Medicine reporting what they’d found.

Lax, a professor of pathology at the Johannes Kepler University Linz, spoke with The Scientist about the results and what they reveal about possible therapeutics for COVID-19.

The Scientist: As you started performing these autopsies, what was most striking in terms of damage done to the body?

Sigurd Lax:Both lungs were symmetrically damaged, with damage to the alveoli, the tiny air sacs of the lungs. The pleurae, the double-lined membranes, surrounding the lungs showed very little inflammatory changes, a little fluid. Most cases had a strongly dilated heart, but the abdomen was not really involved. That was what we saw at first view.

TS: In your paper, you write that patients had blood clots in their small to mid-sized pulmonary arteries. What’s the significance of this finding?

SL: We saw an occlusion of multiple pulmonary arteries, usually in the periphery. There were some clots in the larger branches, but we think seeing more of them in the periphery means the clots are thrombotic rather than embolic. [Editor’s note: thrombotic clots develop in a blood vessel where there is damage, in this case in the lungs, while embolic clots form elsewhere, in a blood vessel in the leg, for example, and travel through body and become lodged in blood vessels of the lung.] And this concurs also with findings in pediatric cases, where you have occlusion of arteries in the fingers, for example, or necrosis in back, so in the skin on their back. So it’s not the pulmonary embolism which is the major cause of severe illness but the inflammation of the blood vessels and a change in the clotting system of the blood. And this causes occlusion of the pulmonary arteries, which increases the pressure of pulmonary circulation and then leads to an insufficiency of the heart to pump blood through the body properly.

TS: Does the virus cause the blood clots to form or is it the immune response to the virus that causes them?

SL:So far that’s not clear. I think one can speculate that either one or the other or both may be the reason, but I think it might be more the immune response, that inflammatory mechanisms lead to the thrombosis.

TS: When doing the autopsies, did you focus mainly on the lungs or were there other body regions that you also examined, such as the brain?

SL:In the first cases we only looked at the brain in one case, but we’ve done more autopsies since the paper came out and from those, the central nervous system doesn’t seem to be really specifically affected, at least grossly. I don’t have so far any microscopic data, but the analysis is ongoing.

TS:There have been reports that infection with SARS-CoV-2 could cause diabetes by leading to damage of insulin-producing cells. Was there any indication of that in the autopsies?

SL:Not really. I think there’s a coincidence with diabetes. I think that has to do with the vascular changes caused by diabetes. . . . These patients due to their diabetes have atherosclerosis, then they have heart disease, and this aggravates the course of these COVID-19–associated pulmonary changes because, you know, when you have a strong heart, you will be able to overcome the infection, but if you have some associated disease, particularly heart diseases, you will undergo cardiac failure.

TS: What do your results say, right now, about treating COVID-19 patients with a severe form of the disease?

SL:Right after being admitted to the hospital, ten out of our eleven patients received an anticoagulant at a prophylactic level to prevent clotting in the blood.(You talked about doing 11 autopsies, so even with immediate anticoagulation those 10 still died? What is the solution then?) We did not find thrombosis in the deep arteries of the pelvis and the deep blood vessels of the pelvis and upper legs, but the treatment was not enough to prevent thrombosis in the pulmonary arteries.

TS:Given the autopsy data and all of the information researchers are gathering on COVID-19, what are the biggest questions that have yet to be answered?

SL:What we really don’t know at the moment is how the virus goes through the body, what are the sequence of changes caused by the virus. That’s not completely solved.

Editor’s note: This interview has been edited for brevity.

To read more, click here

Intact Brain Network Function in an Unresponsive Patient with COVID ‐19

You don't want this to occur. So YOU WILL NEED TO ENSURE YOUR DOCTOR DOES THE FOLLOWING:

The autopsy findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage. 

I don't know what you should be doing if you get it but not badly enough to go to a hospital. That to me if the most important thing our medical professionals should be giving us.  Of course that is self treatment which goes against everything doctors stand for.

 

Intact Brain Network Function in an Unresponsive Patient with COVID ‐19

David Fischer M.D.

Zachary D. Threlkeld M.D.

Yelena G. Bodien Ph.D.

John E. Kirsch Ph.D.

Susie Y. Huang M.D., Ph.D.

Pamela W. Schaefer M.D.

Otto Rapalino M.D.

… See all authors

First published: 01 July 2020

https://doi.org/10.1002/ana.25838

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25838.

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Abstract

Many patients with severe coronavirus disease 2019 (COVID‐19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID‐19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID‐19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness.

COVID-19 Is an Independent Stroke Risk Factor

This is absolutely appalling. Suggesting monitoring rather than action. Just maybe you want what other ER docs are already doing.

The autopsy findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage.

The latest here:

COVID-19 Is an Independent Stroke Risk Factor

After adjusting for traditional vascular risk factors, radiologists encourage aggressive monitoring of COVID-19 patients for blood flow changes to the brain.

There is a significant link between the virus that causes COVID-19 and strokes, newly published research reveals, indicating providers should adjust their treatment of these patients accordingly.
In the American Journal of Neuroradiology, investigators from Ichan School of Medicine at Mount Sinai published the results of an evaluation of more than 120 patients admitted for possible stroke during the pandemic to six New York City hospitals. Their findings indicate that clinicians should more actively monitor these patients to identify any problems as soon as possible.
“This is the first major peer-reviewed study to show that COVID-19 infection is a risk factor for acute strokes,” said lead study author Puneet Belani, M.D., assistant professor of radiology and neurosurgery. “Patients with COVID-19 should be evaluated early for acute neurological changes and timely workup should be performed in patients suspected to have stroke to reduce morbidity and mortality.”
Belani’s team conducted a retrospective, case-control study with 41 patients. Each patient had a stroke confirmed with non-contrast head CT followed by vascular imaging, and the researchers compared that analysis to 82 control participants who, with the same image confirmation, had no evidence of stroke.
Based on their evaluation, they determined that more than 46 percent of patients with acute ischemic stroke also had COVID-19 infection. The same was true for only 18 percent of the control group. After they adjusted for sex, age, and other risk factors, the association between the virus and stroke was clear.
“We found that COVID-19 is an independent risk factor for imaging-confirmed acute ischemic stroke during stroke alert evaluation, after controlling for traditional vascular risk factors,” the team said. “This finding suggests that COVID-19 infection is associated with increased morbidity and mortality that transcends the primary cardiopulmonary sequelae from the infection.”

Coronavirus autopsies: A story of 38 brains, 87 lungs and 42 hearts

I got two takeaways from this; 

1. Blood thinners/anti-coagulation immediately.

2. Oxygen uptake, maybe these?

Sesquiterpenes, a natural compound found in essential oils of Vetiver, Patchouli, Cedarwood, Sandalwood and Frankincense, can increase levels of oxygen in the brain by up to 28 percent 

Or this?

University of Glasgow Study Demonstrates the Ability of Oxycyte® to Supply Oxygen to Critical Penumbral Tissue in Acute Ischemic Stroke  

Or this? having red blood cells release more oxygen.

Methylene blue shows promise for improving short-term memory

 

Coronavirus autopsies: A story of 38 brains, 87 lungs and 42 hearts

The findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage.

Cerebral ischemic and hemorrhagic complications of coronavirus disease 2019

You did not do timely intervention, I'm sure you didn't start anti-coagulation therapies IMMEDIATELY upon diagnosis of COVID-19, you waited until the LVO had already occurred. And you falsely think reperfusion is the correct endpoint. I'm going to demand anti-coagulation IMMEDIATELY UPON DIAGNOSIS, I don't care what the fuck my doctor thinks. I'm not going to die just because clinical results haven't been published.  You obviously can't listen to me, I'm not medically trained. 

This statement from research is why I'm so adamant about this:

The autopsies of lungs showed lots of alveolar(lungs) capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza.

Cerebral ischemic and hemorrhagic complications of coronavirus disease 2019

Ahmad Sweid1, Batoul Hammoud2, Kimon Bekelis3, Symeon Missios3, Stavropoula I Tjoumakaris1, Michael R Gooch1, Nabeel A Herial1, Hekmat Zarzour1, Victor Romo4, Maureen DePrince1, Robert H Rosenwasser1 and Pascal Jabbour1

Abstract 

Background: 
The coronavirus disease 2019 is associated with neurological manifestations including stroke.
Objectives: 
We present a case series of coronavirus disease 2019 patients from two institutions with acute cerebrovascular pathologies. In addition, we present a pooled analysis of published data on large vessel occlusion in the setting of coronavirus disease 2019 and a concise summary of the pathophysiology of acute cerebrovascular disease in the setting of coronavirus disease 2019.
Methods: A retrospective study across two institutions was conducted between 20 March 2020 and 20 May 2020, for patients developing acute cerebrovascular disease and diagnosed with coronavirus disease 2019. We performed a literature review using the PubMed search engine.
Results: 
The total sample size was 22 patients. The mean age was 59.5 years, and 12 patients were female. The cerebrovascular pathologies were 17 cases of acute ischemic stroke, 3 cases of aneurysm rupture, and 2 cases of sinus thrombosis. Of the stroke and sinus thrombosis patients, the mean National Institute of Health Stroke Scale was 13.8 8.0, and 16 (84.2%) patients underwent a mechanical thrombectomy procedure. A favorable thrombolysis in cerebral infarction score was achieved in all patients. Of the 16 patients that underwent a mechanical thrombectomy, the mortality incidence was five (31.3%). Of all patients (22), three (13.6%) patients developed hemorrhagic conversion requiring decompressive surgery. Eleven (50%) patients had a poor functional status (modified Rankin Score 3–6) at discharge, and the total mortality incidence was eight (36.4%).
Conclusions: 
Despite timely intervention and favorable reperfusion, the mortality rate in coronavirus disease 2019 patients with large vessel occlusion was high in our series and in the pooled analysis. Notable features were younger age group, involvement of both the arterial and venous vasculature, multivessel involvement, and complicated procedures due to the clot consistency and burden.

Neuropathological Features of Covid-19

Interesting that the acute hypoxic injury is not large enough to be called stroke, probably because it is diffused throughout the brain and would never show up in a CT or MRI scan.  Also that the autopsies of lungs showed lots of alveolar(lungs) capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza. So lots of thrombi in the lungs but not in the brain, something doesn't sound right here. This means that my massive anti-coagulation strategy needs to be immediately applied after diagnosis

 

Neuropathological Features of Covid-19

To the Editor:

Neurologic symptoms, including headache, altered mental status, and anosmia, occur in many patients with Covid-19.^1-3 We report the neuropathological findings from autopsies of 18 consecutive patients with SARS-CoV-2 infection who died in a single teaching hospital between April 14 and April 29, 2020.

All the patients had nasopharyngeal swab samples that were positive for SARS-CoV-2 on qualitative reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays. The median age was 62 years (interquartile range, 53 to 75), and 14 patients (78%) were men. The presenting neurologic symptoms were myalgia (in 3 patients), headache (in 2), and decreased taste (in 1). Coexisting conditions included diabetes mellitus (in 12 patients), hypertension (in 11), cardiovascular disease (in 5), hyperlipidemia (in 5), chronic kidney disease (in 4), prior stroke (in 4), dementia (in 4), and treated anaplastic astrocytoma (in 1) (see Tables S1 and S2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

The patients had presented a median of 2 days (interquartile range, 0 to 5) after the onset of the first symptoms of SARS-CoV-2 infection and were hospitalized for a median of 6 days (interquartile range, 2 to 9) before death (Fig. S1A); 11 received mechanical ventilation. According to a retrospective chart review by neurologists, all the patients had a confusional state or decreased arousal from sedation for ventilation. Brain magnetic resonance imaging, electroencephalographic imaging, and cerebrospinal fluid examinations were not performed. Cranial computed tomography without contrast was performed in 3 patients and showed no acute abnormalities; the tumor resection cavity in the patient with a known anaplastic astrocytoma was seen.

Table 1. Gross Findings and Results of Histologic Analysis to Detect SARS-CoV-2.

Death occurred 0 to 32 days after the onset of symptoms (median, 8 days; mean, 10 days). Autopsies were performed in a uniform manner with sampling of 10 standard brain areas. Specimens were fixed in formalin and stained with hematoxylin and eosin, as described in the Materials and Methods section in the Supplementary Appendix. Gross inspection showed atherosclerosis in 14 brain specimens but no acute stroke, herniation, or olfactory bulb damage. Residual anaplastic astrocytoma was seen in the patient who had received a diagnosis of anaplastic astrocytoma previously (Table 1). Microscopic examination (Fig. S1B) showed acute hypoxic injury in the cerebrum and cerebellum in all the patients, with loss of neurons in the cerebral cortex, hippocampus, and cerebellar Purkinje cell layer, but no thrombi or vasculitis. Rare foci of perivascular lymphocytes were detected in 2 brain specimens, and focal leptomeningeal inflammation was detected in 1 brain specimen. No microscopic abnormalities were observed in the olfactory bulbs or tracts (Fig. S2).

Testing of brain tissue was performed with quantitative RT-PCR (qRT-PCR) for the SARS-CoV-2 nucleocapsid protein (techniques are described in the Materials and Methods section in the Supplementary Appendix). As shown in Table S3, for 2 patients, all 10 sections were tested, and for the remaining 16 patients, 2 sections were tested (1 from the frontal lobe and olfactory nerve and 1 from the medulla). The results were equivocal (defined as a viral load of <5.0 copies per cubic millimeter) in 5 of 10 brain sections from 1 patient and in 4 of 10 sections from another patient (Table S3); the remaining 11 sections obtained from these 2 patients were negative. In 32 sections obtained from the remaining 16 patients, 3 sections from the medulla and 3 sections from the frontal lobes and olfactory nerves were positive (5.0 to 59.4 copies per cubic millimeter); the results were equivocal in 20 sections and negative in 6 sections. The test results in relation to the interval between the onset of symptoms and death were inconsistent (Fig. S1).

Immunohistochemical analysis (as described in the Supplementary Appendix) was performed to detect SARS-CoV-2 in the same tissue blocks analyzed by qRT-PCR (in 52 blocks from 18 patients). There was no staining in the neurons, glia, endothelium, or immune cells. Nonspecific staining in the choroid plexus was observed in 8 sections obtained from 7 patients; however, this signal was present in negative control brains and did not correlate with the qRT-PCR results (Figs. S1 and S3). The tumor blocks obtained from the patient with anaplastic astrocytoma were not tested by qRT-PCR or immunohistochemical analysis to detect SARS-CoV-2.

In conclusion, histopathological examination of brain specimens obtained from 18 patients who died 0 to 32 days after the onset of symptoms of Covid-19 showed only hypoxic changes and did not show encephalitis or other specific brain changes referable to the virus. There was no cytoplasmic viral staining on immunohistochemical analysis. The virus was detected at low levels in 6 brain sections obtained from 5 patients; these levels were not consistently related to the interval from the onset of symptoms to death. Positive tests may have been due to in situ virions or viral RNA from blood.

Isaac H. Solomon, M.D., Ph.D.
Brigham and Women’s Hospital, Boston, MA
ihsolomon@bwh.harvard.edu

Erica Normandin, B.A.
Broad Institute, Cambridge, MA

Shamik Bhattacharyya, M.D.
Brigham and Women’s Hospital, Boston, MA

Shibani S. Mukerji, M.D., Ph.D.
Kiana Keller, B.S.
Massachusetts General Hospital, Boston, MA

Ahya S. Ali, M.B., B.S.
Brigham and Women’s Hospital, Boston, MA

Gordon Adams, B.A.
Broad Institute, Cambridge, MA

Jason L. Hornick, M.D., Ph.D.
Robert F. Padera, Jr., M.D., Ph.D.
Brigham and Women’s Hospital, Boston, MA

Pardis Sabeti, M.D., D.Phil.
Broad Institute, Cambridge, MA

Supported by a grant (2U19AI110818, to Ms. Normandin and Dr. Sabeti) from the National Institutes of Health (NIH), a grant (to Ms. Normandin and Dr. Sabeti) from the Howard Hughes Medical Institute, and a grant (K23MH115812, to Dr. Mukerji) from the NIH.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on June 12, 2020, at NEJM.org.

Dr. Solomon and Ms. Normandin contributed equally to this letter.

Defining causality in COVID-19 and neurological disorders

While these people wait for more clinical evidence to come in, I am using the results from autopsies on lungs showing lots of micro-thrombi to conclude it is a clotting problem. The solution is clot busting tPA and blood thinners like Lovenox and warfarin. I'm not going to die just because my doctor is waiting for clear clinical studies, I will take charge and direct my doctor on what to do. Doing this fast enough should prevent the need for mechanical ventilation.  A friend was on blood thinner eliquis, got COVID-19 and survived, age 70+. But I'm not medically trained so don't listen to me. 

Defining causality in COVID-19 and neurological disorders

1. Mark Ellul1,2,3,
2. Aravinthan Varatharaj4,5,
3. Timothy R Nicholson6,
4. Thomas Arthur Pollak6,
5. Naomi Thomas7,8,
6. Ava Easton9,
7. Michael S Zandi10,
8. Hadi Manji10,
9. Tom Solomon1,2,3,
10. Alan Carson11,
11. http://orcid.org/0000-0003-0267-3180Martin R Turner12,
12. Rachel Kneen1,3,13,
13. http://orcid.org/0000-0002-1268-5102Ian Galea4,5,
14. Sarah Pett14,15,
15. Rhys Huw Thomas7,16,
16. http://orcid.org/0000-0002-8693-8926Benedict Daniel Michael1,2,3
17. CoroNerve Steering Committee

Author affiliations

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http://dx.doi.org/10.1136/jnnp-2020-323667

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When faced with acute neurological presentations in a patient with COVID-19, how confident can one be that SARS-CoV2 is causal?

Introduction

Clinicians are increasingly recognising neurological presentations occur in some patients.1 A case series from Wuhan described associated neurological syndromes (eg, ‘dizziness’ and ‘impaired consciousness’), but with little detail regarding symptomatology, and cerebrospinal fluid (CSF) and neuroimaging findings.2 The extent to which these disorders were caused by the virus per se, rather than being complications of critical illness, unmasking of degenerative disease, or iatrogenic effects of repurposed medications is not clear.

Numerous case reports have since emerged and, at the time of writing, published cases include encephalopathy,3 encephalitis,4 Guillain-Barré syndrome (GBS)5 and stroke.6 In most of these cases, the virus has been identified in respiratory samples, and in a small number in CSF. So far, the reporting of clinical features has been extremely variable, for example, several cases have claimed to report encephalitis without clear evidence of central nervous system (CNS) inflammation, which would not meet established definitions of the disease.7

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is associated with neurological manifestations is of critical importance as this may result in substantial morbidity and mortality.

Defining causality

It is crucial that neurologists and neuropsychiatrists apply a systematic strategy to determine whether there is evidence that SARS-CoV2 is causing these manifestations, whether they are a consequence of severe systemic disease alone, or simply coincidence. In 1965, Hill proposed criteria on which to build an argument for disease causation, which can be applied to COVID-19.8

What is the strength of the association? So far, it appears fairly weak. >2.5 million people have been infected with SARS-CoV2 and to date (to the authors’ knowledge) there have been only 93 published cases of neurological manifestations (about 5/100 000). However, reported cases are an underestimate of the real incidence, and this underscores the need for proper epidemiological study.

What is the consistency of the association? So far, there have been published reports of neurological manifestations across the globe, including from China, Japan, Italy, France, the USA and the UK. Although the numbers are low, these are not isolated incidences and have occurred throughout the evolution of the pandemic.

To what extent is the relationship specific? The range of neurological manifestations reported in association with SARS-CoV2 is wide, from the CNS through to peripheral nerves. However, in previous pandemics, similar central and peripheral associations have been well recognised.9

What can temporality tell us about the association? The delay between infection and the neurological presentation may give a clue to mechanisms. Direct CNS infection might be expected to be contemporaneous with, or shortly after, fever and respiratory symptoms. Parainfectious disease, owing to innate immune responses, such as acute necrotising encephalopathy, usually occurs in the days following infection. Post-infectious syndromes, due to adaptive immune responses, such as GBS, are typically in the few weeks following infection. In most reported cases, respiratory disease has occurred a few days prior to the onset of the neurological syndrome although significant delays between a neurological presentation and COVID-19 diagnosis in some raise the possibility of nosocomial infection.

Hill asks us to look for a biological gradient. In general, those with neurological manifestations have had severe COVID-19 respiratory disease suggesting the possibility that higher viral loads and/or more fulminant inflammatory responses may be accountable for both.

Is there biological plausibility? Many human viruses can enter the CNS and some coronaviruses exhibit neurotropism in animal models.10 The syndromes described so far could plausibly be related to primary infection with SARS-CoV2, although improved understanding of host responses is needed.

Hill asks us to consider the coherence of the evidence. Perhaps our best sources of coherent data are the SARS and Middle East respiratory syndrome (MERS) epidemics: coronaviruses with about 80% and 50% homology to SARS-CoV2, respectively. Neurological syndromes were reported in association with both, including acute disseminated encephalomyelitis-like presentations with MERS and encephalopathy/encephalitis with SARS.11

Is there any possibility of experimental evidence? The ideal investigational vehicle would be a case control study, but this presents design challenges as exposure is high and we do not yet have validated widespread antibody testing to ascertain seroprevalence.

Can we learn by analogy with other similar scenarios? Other respiratory viruses, most notably influenza, are well-established triggers of CNS damage. During the H1N1 pandemic, neurological syndromes were well described, including acute necrotising encephalopathy bearing striking resemblance to the case recently described with COVID-19.9 So, the emergence of neurological disorders associated with pandemic viral infections is less the exception, and more the norm.

Conclusions

As always, our evidence must be founded on clear and systematic assessment of the clinical syndromes, supported by well-designed laboratory studies. Cases must be reported in line with clear clinical case definitions, both systematically and transparently, and with honesty about negative or missing results.

These aims are best served by standardisation and centralisation of case reporting, which calls for a truly collaborative approach between neurologists, neuropsychiatrists and allied colleagues.

To address this, we have established the CoroNerve Studies Group as a collaboration between professional bodies in the UK (CoroNerve.com), and similar studies are underway in other countries. However, a joined-up international approach is necessary. To begin this process, a complimentary initiative, the COVID-Neuro Network, through Brain Infections Global, is supporting collaboration among several lower and middle-income countries.

We all must learn the lessons from previous pandemics, and the principles of Bradford Hill if we are to translate these rapidly growing datasets into meaningful advances in our understanding of the neurological complications of COVID-19.

Acknowledgments

CoroNerve Study Management Group: Mark Ellul, Ian Galea, Rachel Kneen, Benedict Michael, Sarah Pett, Naomi Thomas, Rhys Thomas, Ara Varantharaj. CoroNerve Steering Committee: Laura Benjamin, Jonathan Coles, Nicholas WS Davies, Ava Easton, Hadi Manji, David Menon, Craig Smith, Tom Solomon, Michael Zandi.

High plasma viscosity seen in critically ill COVID-19 patients

Until you find causation I'm going to be demanding my doctor give me tPA immediately. Would an autopsy be able to determine viscosity because the autopsy results from the lungs mentioned thrombi all over the place?

High plasma viscosity seen in critically ill COVID-19 patients

Abnormally high plasma viscosity could be contributing to the thrombotic complications seen in many COVID-19 patients, a new report suggests.

Dr. Cheryl L. Maier of Emory University School of Medicine in Atlanta describe 15 COVID-19 patients with thickened blood who were admitted to their intensive-care unit in a letter in The Lancet.

"We found that the sickest patients had the highest plasma viscosity levels, more than twice normal levels," Dr. Maier told Reuters Health by email. "These levels were similar to those seen in a type of blood disorder called Waldenstrom macroglobulinemia, where the high viscosity leads to dangerous sludging of the blood in the brain and other organs."

She added, "Plasma exchange is the key treatment of hyperviscosity in diseases like Waldenstrom macroglobulinemia, but we need further studies to understand its impact on patients with COVID-19 hyperviscosity."

Fourteen of the 15 patients in the report had acute respiratory distress syndrome and were on ventilators, 14 had encephalopathy, 12 required vasopressor treatment for shock and 11 needed continuous renal replacement therapy due to failing kidneys.

Five patients with D-dimer concentrations of 3 ug/mL or above and confirmed or suspected thrombosis were given therapeutic anticoagulation. Four patients with lower D-dimer concentrations received low-dose treatment with low-molecular-weight heparin (LMWH) or subcutaneous heparin. Six who had high D-dimer concentrations but no known clotting received subtherapeutic doses of LMWH or IV heparin.

Plasma viscosity was above 95% of normal in all patients, and ranged from 1.9 to 4.2 centipoise (cP). The normal range is 1.4-1.8 cP.

Thrombotic complications occurred in all four patients who had plasma viscosity exceeding 3.5 cP, including one patient with pulmonary embolism (PE), one with limb ischemia and suspected PE, and two with clotting related to continuous renal replacement therapy.

Plasma viscosity was strongly associated with illness severity based on Plasma Viscosity and Sequential Organ Failure Assessment Scores (Pearson's r=0.84, R2=0.71, P<0.001).

"We found a strong correlation between plasma viscosity and illness severity," Dr. Maier said. "But correlation does not equal causation, and we need more studies to understand whether viscosity is simply a marker of disease or actually contributing to it. As part of this work, we're investigating what components of plasma cause the hyperviscosity."

She added, "We use plasma exchange to treat hyperviscosity in other diseases, and we're beginning to use it in some patients with COVID-19. We need larger studies to evaluate the impact of plasma exchange in COVID-19 and we're currently developing a clinical trial here at Emory."

"There's still a lot we don't know about COVID-19, and there's more going on with these atypical blood clots than we first realized," Dr. Maier said. "Hyperviscosity may be an important piece of the puzzle in linking severe inflammation to poor outcomes in COVID-19."

--Anne Harding

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Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

You better hope doctors figure this out by the time you get COVID-19.  I however will be demanding massive anti-coagulation therapies because of the clotting seen in autopsies. I'm not medically trained so don't listen to me.

 

Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

Letterio S. Politi, MD^1,2,3; Ettore Salsano, MD⁴; Marco Grimaldi, MD¹

Author Affiliations Article Information

JAMA Neurol. Published online May 29, 2020. doi:10.1001/jamaneurol.2020.2125

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The neurotropism of human coronaviruses has already been demonstrated in small animals, and in autoptic studies the severe acute respiratory syndrome coronavirus (SARS-CoV), which was responsible for the SARS outbreak during 2002 to 2003, was found in the brains of patients with infection.¹ It has been proposed that the neuroinvasive potential of the novel SARS-CoV-2, responsible for coronavirus disease 2019 (COVID-19), may be at least partially responsible for the respiratory failure of patients with COVID-19.² In this article, we share the magnetic resonance imaging (MRI) evidence of in vivo brain alteration presumably due to SARS-CoV-2 and demonstrate that anosmia can represent the predominant symptom in COVID-19.

A 25-year-old female radiographer with no significant medical history who had been working in a COVID-19 ward presented with a mild dry cough that lasted for 1 day, followed by persistent severe anosmia and dysgeusia. She did not have a fever. She had no trauma, seizure, or hypoglycemic event. Three days later, nasal fibroscopic evaluation results were unremarkable, and noncontrast chest and maxillofacial computed tomography results were negative. On the same day, a brain MRI was also performed. On 3-dimensional and 2-dimensional fluid-attenuated inversion recovery images, a cortical hyperintensity was evident in the right gyrus rectus (Figure 1) and a subtle hyperintensity was present in the olfactory bulbs (Figure 1). Because many patients in Italy are experiencing anosmia³ and the cortical signal alteration was suggestive of viral infection, a swab test was performed and reverse transcription–polymerase chain reaction analysis yielded positive results for SARS-CoV-2. During a follow-up MRI performed 28 days later, the signal alteration in the cortex completely disappeared and the olfactory bulbs were thinner and slightly less hyperintense (Figure 2⁴). The patient recovered from anosmia. No brain abnormalities were seen in 2 other patients with COVID-19 presenting anosmia who underwent brain MRI 12 and 25 days from symptom onset.

Figure 1.  Brain Magnetic Resonance Imaging Alterations in a Patient With Coronavirus Disease 2019 (COVID-19) Presenting With Anosmia 4 Days From Symptom Onset

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Coronal (A) and axial (B) reformatted 3-dimensional fluid-attenuated inversion recovery (FLAIR) images showing cortical hyperintensity in the right gyrus rectus (yellow arrowheads in A and B). In the inset in A, a coronal 2-dimensional FLAIR image shows subtle hyperintensity in the bilateral olfactory bulbs (white arrowheads). The cortical hyperintensity is present only in the posterior portion of the right gyrus rectus (B). Accordingly, the cortical hyperintensity of the right gyrus rectus is evident in the more posterior coronal image (A) and not in the anterior coronal one (inset).

Figure 2.  Follow-up Magnetic Resonance Imaging Study in the Same Patient 28 Days From Symptom Onset

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Coronal (A) and axial (B) reformatted 3-dimensional fluid-attenuated inversion recover (FLAIR) images showing complete resolution of the previously seen signal alteration within the cortex of the right gyrus rectus. In the inset, a coronal 2-dimensional FLAIR image shows a slight reduction of the hyperintensity and the thickness of the olfactory bulbs, suggesting a postinfection olfactory loss.⁴

To our knowledge, this is the first report of in vivo human brain involvement in a patient with COVID-19 showing a signal alteration compatible with viral brain invasion in a cortical region (ie, posterior gyrus rectus) that is associated with olfaction. Alternative diagnoses (eg, status epilepticus, posterior reversible encephalopathy syndrome–like alterations, other viral infections, and anti–N-methyl-d-aspartate receptor encephalitis) are unlikely given the clinical context. Based on the MRI findings, including the slight olfactory bulb changes, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway and cause an olfactory dysfunction of sensorineural origin; cerebrospinal fluid and pathology studies are required to confirm this hypothesis. Ours and others’ observations of normal brain imaging in other patients with COVID-19–associated olfactory dysfunctions⁴ and the disappearance of the cortical MRI abnormalities in the follow-up study of this patient suggest that imaging changes are not always present in COVID-19 or might be limited to the very early phase of the infection. Further, anosmia can be the predominant COVID-19 manifestation, and this should be considered for the identification and isolation of patients with infection to avoid disease spread.

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Article Information

Corresponding Author: Letterio S. Politi, MD, IRCCS Istituto Clinico Humanitas, via Alessandro Manzoni 56, Rozzano 20089, Italy (letterio.politi@hunimed.eu).

Published Online: May 29, 2020. doi:10.1001/jamaneurol.2020.2125

Analysis of COVID-19 autopsies reveals many new details about this disease

You'll have to hope that your medical staff knows about these anticoagulation strategies. 

Analysis of COVID-19 autopsies reveals many new details about this disease

MedicalXpress Breaking News-and-Events|May 29, 2020

Pathologists at The Mount Sinai Hospital, at the epicenter of the COVID-19 global pandemic, have prepared one of the largest, most comprehensive analysis of autopsies of COVID-19 victims to date, revealing many complex new details about the disease. The analysis was released on the preprint server MedRxiv.

"An essential contribution of pathology is the understanding of the biology of the disease and the range of organ damage, and for this reason, we decided to uncompromisingly perform as many autopsies as possible," said Carlos Cordon-Cardo, MD, PhD, Irene Heinz Given and John LaPorte Given Professor and Chair of the Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Molecular and Cell-Based Medicine, and co-author of the study.

"Post-mortem examinations (autopsies) are the gold standard for the elucidation of the underlying pathophysiology of disease. Despite a rapidly growing body of literature focusing on the clinical impact and molecular microbiology of SARS-CoV-2, autopsy studies have comparatively been few and far between," said Mary Fowkes, MD, PhD, Director of the Autopsy Service, and senior author of the paper. SARS-CoV-2 is the virus that causes COVID-19.

To date, the team has performed more than 90 autopsies on deceased COVID-19 patients at The Mount Sinai Hospital. The published work analyzes the first 67. Gross anatomical findings were combined with the clinical history and laboratory data for all 67 patients. Microscopic examinations were carried out by the team, using special stains, immunochemistry, electron microscopy, and molecular pathology assays.

COVID-19 was initially conceptualized as a primarily respiratory illness, but the Mount Sinai analysis laid out in detail that it also causes damage to the thin layer of cells that line blood vessels (endothelium), which underlies the clotting abnormalities and hypoxia observed in severely ill patients who develop multi-organ failure that leads to death in some patients.

"The physical evidence we ascertained through our postmortem analyses helps elucidate the mechanisms behind some of the clinical symptoms observed by physicians treating COVID-19 patients, including thromboembolisms and neuropsychiatric disorders," says Clare Bryce, MBChB, Associate Professor of Pathology, Molecular and Cell Based Medicine, and, first author of the study.

The lungs in nearly all cases showed diffuse damage to the alveoli, the small sacs where oxygen and carbon dioxide are exchanged with the blood. This damage is the typical microscopic evidence of clinical acute respiratory distress syndrome (ARDS), with most cases showing fibrin (a fibrous, non-globular protein involved in the clotting of blood) and/or platelet thrombi, or clots, to varying extents. This same pathology is found in most cases of ARDS, including those related to other coronoaviruses. However, the totality of findings in the autopsy series as a whole, with blood clots in multiple other organ systems—most notably the brain, kidney, and liver—reflects endothelial damage as an underlying process, which would also correlate with the activation of the coagulation cascade and persistent elevation of blood markers of inflammation.

The examined brains showed a surprising scarcity of inflammation, with only a few cases showing small foci of chronic inflammation. However, a surprising number of cases showed microthrombi with small and patchy evidence of tissue death caused by blockage of blood vessels in both peripheral and deep parts of the brain. These small microinfarcts may explain some of the psychological changes seen in some COVID-19 positive patients.

This study brings new light into the pathophysiology of COVID-19, offering justification for novel treatment plans, including the anticoagulation strategies being put into effect by clinical leaders including Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief at The Mount Sinai Hospital.

Psychostimulant Use and Fatal Stroke in Young Adults

I bet the autopsies don't give enough detail to say exactly what brain cells died and that caused death.  Fearmongering in general.  Be careful out there.

Psychostimulant Use and Fatal Stroke inYoung Adults