COVID-19 and ischemic stroke - how to tame a dozing monster

Coronavirus disease 2019 (COVID-19) pneumonia is complicated by a high risk of
thrombotic complications, occurring with an incidence of 41% in intensive care
unit (ICU) patients and up to 9.2% at the general ward. These thrombotic
complications are strongly associated with poor clinical outcome and death. In
addition to pulmonary embolism, the most common complication, an increase in
the number of ischemic strokes is reported. The magnitude, cause(s) and impact
of this problem are currently unknown. We hypothesize that these ischemic
strokes are either caused by intensive coagulation-induced (local) thrombosis
and intracranial vessel wall inflammation, and/or are the result of a
paradoxical embolism through a patent foramen ovale (PFO). Furthermore, in view
of the intense procoagulant and proinflammatory COVID-19 response, we
hypothesize that, in addition to symptomatic ischemic stroke, associated with a
clear neurological deficit, COVID-19 patients are at risk of *clinically
silent* ischemic brain lesions, which may reduce the chance of good recovery
and return to functional independence.

(1) Determine the prevalence of (asymptomatic) silent brain infarcts among
patients with COVID-19 admitted to after discharge (at least <3 months after
positive PCR test) from the hospital, compared with healthy controls.
(2) Investigate risk factors of brain infarcts (symptomatic or asymptomatic)
(3) Establish functional outcomes after 3 and 12 months in COVID-19 patients
with and without brain infarcts (symptomatic or asymptomatic)
(4) Establish incidence of (new) silent brain infarcts after 3 months in
COVID-19 patients with and without brain infarcts (symptomatic or asymptomatic)
at baseline examination

CORONIS is an observational multicentre study.

(1) In a cross-sectional analysis, we will determine the prevalence of
(asymptomatic) silent brain infarcts via brain MRI among COVID-19 patients
admitted to or after discharge (at least <3 months after positive PCR) from the
hospital and in healthy (matched) controls without (previous) COVID-19
infection from the general population.
(2) In a case-control analysis we will investigate risk factors of brain
ischemia. Cases represent COVID-19 patients with (symptomatic or asymptomatic)
brain infarcts. Controls represent COVID-19 patients without any brain infarcts
on MRI.
(3) In a follow-up cohort study, we will determine the functional outcome at 3
and 12 months in COVID-19 patients with and without brain infarcts (symptomatic
or asymptomatic).
(4) In a follow-up cohort study, we will determine the incidence of new
(asymptomatic) silent brain infarcts 3 months after baseline MRI in COVID-19
patients with and without brain infarcts (symptomatic or asymptomatic).

The healthy participants (controls) undergo a standardised MRI protocol.

The COVID-19 patients undergo a standardised MRI protocol, plus a contrast MRI
to assess extra- and intracranial arterial wall enhancement, transthoracic
bubble contrast echocardiography to identify PFO, venapunction for blood
sampling, a short cognitive screening and a questionnaire to examine lifestyle.
In addition, patients will receive a Holter to monitor heart rhythm for a
period of 72 hours. At month 3 and 12-24, through a telephone interview
functional outcome will be measured.

All measurements are routinely applied in clinical practice. MRI is considered
to be safe and without risks, as long all safety measures are adequately
followed. For contrast-MRI a gadolinium-based contrast agent will be used. Side
effects of injection of this contrast agent occur very incidentally and include
mild effects such as nausea, headache and injection site reactions (sense of
warm feeling). In case of adverse effects, patients will be treated reasonably
and professionally. Similarly, transthoracic bubble contrast echocardiography
is considered to be safe and harmless to subjects and is associated with only
minor side effects, which occur very rarely. Collectively, we expect the
physical or psychological burden to be low and classify the risk of study
participation as negligible.