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
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.
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