Keywords
COVID-19 - Intracranial Hemorrhages - Cerebral Hemorrhage - Hemorrhagic Stroke
Palavras-chave
COVID-19 - Hemorragias Intracranianas - Hemorragia Cerebral - Acidente Vascular Cerebral
Hemorrágico
INTRODUCTION
A few months after the outbreak of the novel coronavirus disease 2019 (COVID-19),
in March 2020, the World Health Organization (WHO) declared a pandemic. Within just
2 years, cumulative COVID-19 cases had reached 455 million, with a death toll of around
6 million worldwide.[1] The β-coronavirus, whose full name is severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2), causes an infection predominantly of the lower and upper respiratory
tract, but there is evidence of involvement of extrapulmonary sites: cardiovascular,
central nervous system, gastrointestinal, renal, hepatic, hematologic, and cutaneous.[2]
[3]
Neurological manifestations of COVID-19 include headache, dizziness, altered level
of consciousness, hyposmia, hypogeusia, cerebrovascular diseases (CVDs), polyneuropathies,
ataxia, and epileptic seizures. Although CVD events are among the least common manifestations,
they are one of the most serious and fatal.[4]
[5]
Imaging findings in the patients with neurological symptoms include numerous disorders,
with stroke being the most prevalent and dangerous. Hemorrhagic stroke has even higher
mortality and symptom severity than ischemic stroke.[6]
[7]
[8] Intracranial hemorrhages (ICHs) can be classified into five broad categories: intraparenchymal
hemorrhage (IPH); intraventricular hemorrhage (IVH); epidural hematoma (EDH); subdural
hematoma (SDH); and subarachnoid hemorrhage (SAH).[9]
[10]
The mechanisms behind neurological involvement, although not yet fully clear, include
direct and indirect damage caused by the virus upon invasion of the central nervous
system (CNS), involving both hematogenous and retrograde neuronal pathways in the
invasion of olfactory neurons.[11] The angiotensin II-converting enzyme (ACE2) receptor plays a key role in the mechanism
of cell invasion and breakdown of the blood-brain barrier (BBB). Respiratory epithelial
cells, neurons and glial cells express ACE2 receptors in abundance.[12] Nevertheless, there are also mechanisms of indirect injury mediated by the systemic
inflammatory syndrome promoted by the storm of proinflammatory cytokines and chemokines,
also implicated in the breakdown of the BBB.[13]
In general, endothelial dysfunction leads to a systemic prothrombotic state related
to high levels of proinflammatory cytokines and also angiotensin II.[14] Findings of abnormalities on coagulation tests and high serum levels of D-dimer,
ferritin, and LDH corroborate this hypothesis.[15]
[16] Thus, there is a greater tendency for ischemic than hemorrhagic events, and the
somewhat paradoxical occurrence of these intracranial hemorrhages might be attributed
to blood pressure dysregulation and BBB breakdown.[14]
Thus, the aim of this study was to report six original cases of COVID19-related cerebral
hemorrhages in patients who presented at a health care facility. Furthermore, the
current study, as part of a systematic review, aimed to assess the existing evidence
within the literature concerning cases of COVID-19 (confirmed through the real-time
polymerase chain reaction [RT-PCR] method) and their potential correlation with intracranial
hemorrhage. Additionally, the study aimed to delineate the demographic, clinical,
and radiologic characteristics associated with these cases.
METHODS
Case series
Six patients with cerebral hemorrhages related to COVID-19 infection were selected.
These cases were observed between 1st May 2020 and December 28th, 2020 at the Air
Force Hospital of Belém. The patients had a confirmed diagnosis of COVID-19 through
RT-PCR testing, and a diagnosis of ICH was established based on clinical-radiological
aspects. Neuroimaging was done in all patients. After reviewing the neuroimaging reports
for these patients, they were found to have documented radiographic evidence of hemorrhage.
Neuroimaging for these patients was reviewed by a fellowship-trained neuroradiologist
to verify the presence and type of hemorrhage. This diagnosis was further corroborated
by neuroimaging tests, which included computed tomography (CT) or magnetic resonance
imaging (MRI).
The six patients in this case series were not encompassed within the scope of the
systematic review conducted in this study.
Literature search strategy
A comprehensive, systematic search of the literature published between December 19,
2021, and May 7, 2022, held on the MEDLINE, PubMed, and NCBI electronic databases
was conducted using the following search terms: (hemorrhagic encephalopathy) OR (intracranial bleeding) OR (subarachnoid hemorrhage) OR (subdural hemorrhage) OR (intracranial hemorrhage) OR (hemorrhagic stroke) OR (cerebral hemorrhagic complication) OR (cerebral hemorrhage) AND (SARS-CoV-2 virus) OR (SARS CoV 2 virus) OR (2019-nCoV) OR (COVID-19) OR (2019 novel coronavirus).
Eligibility criteria
The search was limited to articles written in English. Articles identified by the
initial search strategy were independently evaluated by two authors (WL and MP) according
to the inclusion criteria: involving patients with COVID diagnosed by RT-PCR, a confirmed
diagnosis of ICH, description of the cases with individual demographic characteristics,
clinical-radiological aspects, interventions, and outcomes. Articles which were duplicates,
those that had only the abstract available or were editorial letter articles, as well
as those whose full-text was not in English, and those that involved pediatric patients
(age < 18) and patients with predominantly non-spontaneous hemorrhages were excluded.
Study selection and quality control
The Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia)
was used to import all titles and abstracts of the articles identified and remove
duplicate records. Potentially eligible articles were identified by screening the
titles and abstracts. The full texts of the studies selected were then thoroughly
reviewed for quality control by two authors (WL and MP) using the Newcastle-Ottawa
scale, and the eligibility of each study was determined. Any disagreements between
the investigators were resolved by consulting with the corresponding author (FP) ([Supplementary Material 1]
https://www.arquivosdeneuropsiquiatria.org/wp-content/uploads/2023/10/ANP-2022.0230-Supplementary-Material-1.docx).
Data extraction
The following information was collected from each study reviewed: surname of the first
author and year of publication, study design, sample size, demographic characteristics,
comorbidities, number of patients with hemorrhagic events in COVID-19 hospital admissions,
time interval from admission/initial symptoms to radiological diagnosis, initial laboratory
findings, antithrombotic therapy prior to onset of hemorrhagic event, type of ICH,
clinicoradiological scales applied on admission and/or discharge, mortality rates,
and discharge outcomes. Neuroimaging findings were divided into three major types:
intraparenchymal hemorrhage (IPH), subdural hematoma (SDH), and subarachnoid hemorrhage
(SAH). Additionally, regarding the hemorrhage distribution, we also classified three
subtypes: focal intracerebral hemorrhage (FICH), multifocal intracerebral hemorrhage
(MFIH), and multicompartmental hemorrhage (MCH).[9]
[10]
[17]
Synthesis of results
The synthesis of the data was performed with the aid of the Covidence and Excel (Microsoft
Corp., Redmond, WA, USA) programs, where data extracted were compiled into tables
with their respective categories. Primarily, the relevant findings on eligible cohort
and case series studies reporting ICH in COVID-19 hospitalizations were presented
in the form of a summary table ([Supplementary Material 2], Table 1) accompanied by a narrative description. A concise overview of the attributes of
the six patients featured in this case series has been incorporated into [Supplementary Material 2], Table 1. The remaining case reports identified by the search were subsequently compared against
our original case reports and stratified into additional tables by similar hemorrhagic
events ([Supplementary Material 2], Tables 2–4).
RESULTS
Case series
The cerebral hemorrhage causes identified in the six selected patients were as follows:
IPV/IVH in two cases, both accompanied by indications of intracranial hypertension
and uncus herniation; one case with SDH featuring mass effect on the right frontal,
temporal, and parietal lobes, alongside indications of intracranial hypertension;
two cases with CVT/IPH; and one case with IS/IPH. Detailed clinical and demographic
attributes of the patients within this case series can be found in [Supplementary Material 2].
Study identification and eligibility
Of a total of 1,624 articles retrieved in the literature search up to March 2022,
6 duplicate studies were removed, and 1,618 articles retained for screening of title
and abstract. After exclusion of 1,421 non-relevant studies, 197 studies were retrieved,
of which an additional 144 were subsequently excluded for the reasons presented in
[Figure 1]. The selection process resulted in a final total of 53 articles for inclusion in
the review.
Figure 1 PRISMA flow diagram of included articles. Source: PRISMA 2020 statement: an updated
guideline for reporting systematic reviews. Page MJ, McKenzie JE, Bossuyt PM, Boutron
I, Hoffmann TC, Mulrow CD, et al. BMJ. 2021;372:n71. DOI: 10.1136/bmj.n71. Available
from: http://www.prisma-statement.org/.
Characteristics of studies reviewed
Considering 22 cohort selected articles, the prevalence of hemorrhagic cerebrovascular
events among patients with COVID-19 was described in [Supplementary Material 2], along with epidemiological data. A total of 31 case reports and case series articles
were included to report the sex, age, comorbidities, initial symptoms, diagnostic
methods, radiological findings, treatment, and outcome. ([Supplementary Material 2])
Data synthesis
Incidence of ICH in COVID-19 patients with positive RT-PCR
For the cohort studies, the overall incidence of ICH was ∼ 0.26% among 168,703 patients
from the 22 studies evaluated. Regarding range, the studies with the lowest and highest
incidence reported 0.06% in 1,661 cases[5] and 23.7% in 80 patients[18] assessed, respectively.
Demographic aspects of patients with COVID-19 and ICH
Age and sex
For the overall 41 articles involving a total 414 cases, patients had a mean age of
60 years and were predominantly male (67%). Among the cohort studies only, patients
were 73% male and had a mean age of 62 years, while the cohorts of only 4 articles[19]
[20]
[21]
[22] had a mean age of < 60 years ([Supplementary Material 2], Table 1). However, for the reports and case series, patients had a mean age of 54 years and
60% were male.
Comorbidities
Only half of the cohort studies reported information on comorbidities[17]
[18]
[19]
[20]
[22]
[23]
[24]
[25]
[26]
[27]
[28] ([Supplementary Material 2], Table 1). Hypertension and type 2 diabetes mellitus (DM2) were cited in all such articles,
with prevalence ranges of hypertension of 37 to 100%, DM2 11 to 49.4%, and dyslipidemia
8.3 to 67%. The rates of atrial fibrillation[23]
[25]
[27]
[28] were 5.2 to 31.8%, tobacco use[18]
[20]
[24]
[25]
[26] 5.3 to 66.6%, coronary disease[19]
[28] 12.1 to 38%, and congestive heart failure[23]
[25] 17.1 to 24.7%.
Previous bleeding events[18]
[19]
[23]
[25] ranged from 12.5% to 18%. Cancer was cited in only 2 articles,[17]
[22] affecting 14 to 33% of the samples investigated. Other comorbidities, such as chronic
kidney disease,[23] obesity,[19] alcoholism,[25] and previous myocardial infarction,[17] were present in only one cohort each.
Anticoagulation prior to ICH onset
Twenty-five articles, including cohort studies, case series, and case reports, reported
administration of some form of anticoagulation in 43% of the 385 patients before the
diagnosis of cerebral hemorrhage. Of these, 167 patients (47.3%) used therapeutic
doses of anticoagulants, and antiplatelet agents were used in 4% of the 385 cases.
Initial clinical presentations
Out of the 125 COVID-19 cases, 73% initially had respiratory symptoms before the cerebrovascular
event, while the remainder had early neurological symptoms. Reported symptoms included
sudden severe headache, aphasia, hemiparesis, seizures, altered level of consciousness,
and coma.
The time elapsed between the initial symptoms and diagnosis of the event was reported
for 131 cases, revealing an average period of 10 days. However, some studies,[26]
[28]
[29]
[30] involving a total of 61 cases, described the time between patient admission and
diagnosis of the event, revealing a mean interval of 13 days. The National Institutes
of Health Stroke Scale (NIHSS) was used in 74 of the cases reviewed, with a mean score
of 19.7 while the Glasgow Coma Scale (GCS) was used in 90 patients, with scores averaging
7.7.
In-hospital events during hospitalization
Six articles reported other events during the hospital stay in 211 patients.[18]
[19]
[25]
[29]
[31]
[32] The complications presented were acute kidney injury (44%), sepsis (30%), myocardial
injury (14%), urinary tract infection (12%), deep vein thrombosis (7%), hepatic failure
(5%), and venous thromboembolism (3%).[18]
[19]
[25]
[29]
[31]
[32]
Characteristics of ICH
Of the 561 cases included in the review, descriptions of ICH neuroradiological features
were provided for 342 (61%). The most frequent presentations were IPH (50%) and SAH
(34%), followed by FICH (17%), MFH (15%), microhemorrhages (12%), IVH (11%), MCH (10%),
hemorrhagic conversion (9%), and SDH (7%). Analyzing the cohort studies only, the
distribution of hemorrhage types differed: IPH (45%), SAH (27%), microhemorrhages
(16%), MFH (15%), hemorrhagic conversion (10%), FICH (9%), SDH (9%), MCH (8%), and
IVH (7%) ([Supplementary Material 2]).
Intraparenchymal hemorrhage
IPH was reported in 36 articles, representing 170 patients. The location of the IPH
was supratentorial in 66% of cases and infratentorial in 14%, while the remainder
had a non-specified location. Additionally, lobar locations accounted for 32% and
non-lobar for 24% of cases. Supratentorial hemorrhages were described in 99 cases
with the following site distribution: lobar (51%), cortical (28%), basal ganglia (12%),
and thalamic (5%) ([Supplementary Material 2]) ([Figure 2]).
Figure 2 Intraparenchymal hemorrhages. (A-B) Patient 1: 66 years-old male presenting with
decreased level of consciousness. Axial non-contrast CT images (A) showing an intraparenchymal hemorrhage in temporal lobe region with left to right
midline shift and (B) extension to fourth ventricle in association with left cerebellar hemorrhage. Patient
2: 59-year-old female presenting with seizures and decreased level of consciousness.
Axial and sagittal non-contrast CT images (C-D) demonstrating an extensive intraparenchymal hemorrhage involving left basal ganglia
and temporoparietal areas with a left to right midline shift and extension to posterior
horn of left lateral ventricle, associated with ventricular dilatation of posterior
horns of lateral ventricles.
Some cohorts specified IPH case characteristics in which, in this patient group, up
to 75% used anticoagulants, the majority were male (81%), initial symptoms were respiratory
(81%), and mean age was 61 years.[18]
[19]
[22]
[24]
[26]
[27] The volume of the IPH was measured in 54 patients, with a mean value of 37.1 cm3 (0.4–125 cm3). Moreover, the mean ICH score for 106 patients was 2.46. (0–5).[23]
[26]
[27]
[29]
Multicompartmental hemorrhages
A total of 16 studies including a total of 35 patients with MCH were identified. The
combinations of hemorrhage locations included IPH/SAH/IVH (n = 11), IPH/SAH (n = 10), IPH/SAH/SDH (n = 10), SDH/SAH (n = 2), and IPH/SDH (n = 1). Some cohorts specified MCH case characteristics, revealing that patients had
the same profile of IPH group, and more than half (53%) of these patients were on
anticoagulation agents ([Supplementary Material 2]).
Subarachnoid and subdural hemorrhages
Of a total of 118 cases reported in 34 articles, secondary or undetermined SAH was
the most prevalent cause, representing ∼ 75% of cases, while aneurysm and arterial
dissection represented 18% and 7% of patients, respectively. Six cohort studies described
SAH features, according to which up to 86% of patients were on anticoagulation agents,
most had initial respiratory symptoms (62%), and the mean age was 62 years.[17]
[18]
[19]
[21]
[26]
[27] When including case series and reports, the mean age was 54 years, 81% had respiratory
onset, and 68% used anticoagulants.
Only 25 patients in 8 studies reported SDH; these cases were either isolated (n = 20) or associated with multicompartmental hemorrhage (n = 5). Up to 70% of these patients were male and the mean age was 74 years, while
30% used anticoagulants (n = 20). ([Supplementary Material 2])
The aneurysmal arteries reported were the posterior inferior cerebellar artery (10%),
posterior cerebral artery (10%), anterior choroidal artery (10%), anterior communicating
artery (10%), middle cerebral artery (5%), and ophthalmic artery (5%). Moreover, the
dissecting arteries were vertebral artery (33%), posterior inferior cerebellar artery
(22%), anterior communicating artery (11%), middle cerebral artery (11%), posterior
cerebral artery (11%), and internal carotid artery (11%).
Hemorrhagic conversion
Thirty-two patients were identified, in 10 separate articles, who suffered a hemorrhagic
conversion of some kind during a COVID-19 infection. Ischemic stroke (IS) was the
main cause of these hemorrhages (n = 29) ([Figure 3]), followed by cerebral venous thrombosis (CVT) (n = 3).
Figure 3 Hemorrhagic transformation of cerebral venous thrombosis (CVT). (A-D) Patient 4: 39-year-old female presenting with severe progressive headache. Axial
non-contrast CT images (A) demonstrating the “cord sign” (black arrow) indicating thrombosis of cerebral cortical
veins; and (B): intraparenchymal hemorrhage in left parietal lobe with left-to-right midline shift.
Transcranial doppler (C-D) shows spectral image with spikes on middle cerebral artery monitoring, indicating
cerebral circulatory collapse.
Furthermore, among the case reports, 6 out of the 8 patients had respiratory symptoms,
with time from onset to diagnosis of 0 to 21 days, while the remaining 2 cases had
a typical acute stroke presentation. Only one patient was managed surgically, and
three patients had a poor prognosis with death or multiple organ failure, but none
had CVT ([Supplementary Material 2], Tables 1 and 4).
Interventions for ICH
Interventions targeting ICH were reported in 10 cohort studies involving a total of
269 cases[17]
[18]
[19]
[20]
[22]
[24]
[25]
[26]
[27]
[33] ([Supplementary Material 1], Table 1). Surgical management was performed in 29 patients (10.7%), 16 of whom had external
ventricular shunt (EVD), 5 hematoma drainage with decompressive craniectomy, 2 aneurysm
embolization by coiling or flow deviation, 2 had invasive monitoring of intracranial
pressure (ICP), and the remaining reports were unclear on the type of surgical approach
employed. Management solely by intensive care measures occurred in 45 patients (16.7%).
However, the use of specific measures to control ICP or hemorrhage was not specified.
Mortality in COVID-19 patients with ICH
Among the cohort studies, 11 articles described the mortality rate, which ranged from
0 to 84.6%[17]
[18]
[19]
[20]
[22]
[23]
[24]
[25]
[26]
[27]
[28] ([Supplementary Material 2]). The overall mortality rate in these studies was 44%, for a total of 313 patients
out of 114,706 cases hospitalized with COVID-19. The mortality rate from cerebrovascular
hemorrhagic events in hospitalized patients with a confirmed diagnosis of COVID-19
by the RT-PCR method was 0.12%. When case series studies and case reports were included,
a total of 427 patients were obtained with an overall mortality rate of 46.3%.
Outcomes reported
Other outcomes were reported in 7 cohort studies,[17]
[18]
[20]
[22]
[24]
[25]
[27] with descriptions of hospital discharge (non-routine, to home or to rehabilitation)
in 57.5% of a total of 245 patients. In addition, modified Rankin Scale (mRS) scores
at discharge were variably reported and incomplete for the majority of the studies
reviewed. Only 4 articles[20]
[22]
[24]
[26] mentioned a poor prognosis at discharge (mRS > 3), in 69.5% of a total of 23 patients
who were evaluated at discharge with this scale ([Supplementary Material 2]). Including case series and case report studies, hospital discharge was reported
in 53.5% out of a total of 327 patients, while there was a poor prognosis (mRS > 3)
in 73% of a total of 110 patients ([Supplementary Material 2]).
DISCUSSION
Several epidemiological studies have reported a significant reduction in hospital
admissions involving stroke cases of all types during the first wave period. The decrease
in admissions reported by these studies ranged from 12 to 45.6%.[34]
[35]
[36]
[37]
There was a more significant reduction for transient ischemic attack (TIA) and IS
admissions, although no significant decrease for hemorrhagic stroke cases, possibly
explained by the low incidence of this type of event.[35]
[37]
[38]
[39] Other authors found similar results, but reported a significant decrease in hemorrhagic
stroke cases.[36]
[37]
[40]
To investigate this impact, a large observational study involving 187 major stroke
centers in 40 countries assessed the impact of the COVID-19 pandemic on hospital admissions
for ischemic and hemorrhagic stroke, as well as for the volume of mechanical thrombectomy.
A significant global decline was reported in all stroke care indicators during the
early COVID-19 pandemic, including a drop in the volume of mechanical thrombectomy
procedures (12.7%), overall stroke admissions (19.2%), IS/TIA admissions (15.1%),
and of ICH hospitalization cases (11.5%).[41]
Possible explanations for this phenomenon include the cancellation of elective surgeries
due to the pandemic, leading to a decrease in perioperative stroke. The lockdown situation
may have been a factor improving medication adherence, which can lead to a decrease
in cerebrovascular diseases.[41]
These findings are consistent with the reported increase of in-hospital mortality
for stroke in some studies,[35]
[37]
[42]
[43]
[44] while other studies also found a more marked increase for ICH.[17]
[23]
[27]
[28]
[33] In addition, there is a contradiction if the pandemics caused a change in the proportion
of moderate/severe stroke (NIHSS scale > 5), with some studies reporting an increase,[36]
[42] while others found no significant change.[34]
[37]
[39]
However, in an observational study of patients aged > 80 years, it was noted that
the onset of stroke did not increase the risk of death, and those who survived COVID-19
and an acute stroke had similar outcomes to those without this complication. Active
smoking, previous history of stroke, along with a low BMI were identified as significant
risk factors for cerebrovascular complications in this age group.[45] Among our original cases reported, the 2 patients aged > 70 years had a good prognosis,
including complete functional recovery after the stroke event.
Some large meta-analyses involving more than 60,000 patients reported the incidence
of CVDs among the group of SARS Cov2-positive admissions, where rates ranged from
1.2 to 1.4% for general CVDs[46]
[47]
[48] and from 0.2 to 0.3% for ICH.[46]
[47] Additionally, CVD in these patients was associated with more severe infectious disease
and an ∼ 5-fold increased mortality,[46]
[48] while a severe infection increased the risk of CVD and ICH by ∼ 3-fold and 7-fold,
respectively. The reported mortality rates for ICH and IS were 44.7% and 36.2 to 38%,
respectively.[47]
[49]
Although these meta-analyses did not include solely RT-PCR confirmed cases, slightly
different results were found in two other meta-analyses which selected only patients
confirmed by this method. Slightly higher incidence rates were found for CVD (1.5%)
and ICH (0.15–0.7%),[50]
[51] with higher mortality rates for ICH (48.6%).[50] However, a lower mortality rate was reported for IS (22.8%).[51] In the present review, based on data from 22 cohorts and a total of 168,703 cases,
the ICH incidence was 0.26%, a rate consistent with the studies cited. The mortality
rate was 44%, calculated using data from 11 cohorts including a total of 114,706 cases.
When compared these with our six cases of positive RT-PCR, an even higher mortality
rate of 50% was found.
Clinical-radiological aspects
In general, the most common neurological symptoms described in COVID-19 patients are
headache, altered level of consciousness (ALC), dizziness, ageusia and anosmia, while
other less common symptoms reported include visual impairment, CVD, seizures, occipital
neuralgia, ataxia, tremor, and tics.[4]
[5]
[27] Severe infections were more likely in the presence of CVD and ALC[27] and to be reported in hypertensive patients, who were older, had fewer typical symptoms,
and were more likely to develop neurological manifestations, especially acute CVD.[4]
Several of the articles reported the time between admission and neuroimaging, with
mean values ranging from 11 to 29 days.[22]
[26]
[28]
[52] The interval between the onset of symptoms and diagnosis was similar, lying within
the range 2 to 29 days.[19]
[24]
[27]
[29]
[52]
[53]
[54]
[55] Acute stroke signs were the initial manifestation of COVID-19 in only 11 to 44%
of admissions.[26]
[29]
[32]
[44]
[50]
[52]
[54]
[56] Our 6 cases are in agreement with the literature as presenting a 10 days median
time and 33% of neurologic symptoms onset. At admission, the main neurologic sign
was the depressed level of conscience, and the NIHSS ranged from 4 to 12 points.
Despite a wide variety of radiological findings in hospitalized cases (19), it is
uncommon for patients to be diagnosed with COVID-19 using brain magnetic resonance
imaging (MRI). Microhemorrhages, IS and ICHs are the most prevalent presentations.
Other less common findings include hypoxic anoxic brain injury, encephalitis, acute
disseminated encephalomyelitis (ADEM), leukoencephalopathy, transient perivascular
inflammation of the carotid artery syndrome (TIPIC), and posterior reversible encephalopathy
syndrome (PRES).[6]
[7]
[8]
[44]
[53]
[57]
[58]
The ICH group had the highest mortality rate,[7]
[44] followed by patients with leukoencephalopathy and IS, whereas patients with microhemorrhages
or encephalitis as sole neuroimaging findings had the lowest mortality rates.[7] Patients in intensive care unit (ICU) had significantly higher incidences of cerebral
microhemorrhages and encephalitis/encephalopathy.[58]
COVID-19 patients are also at a higher risk for hemorrhagic conversion of their stroke,
accompanied by an increased mortality rate.[23]
[33] Nonetheless, multicompartmental hemorrhage is the ICH subtype with the highest mortality
rate, followed by MFH presentations, while SDH had the lowest mortality rate.[17]
Considering patients without COVID-19, lobar hemorrhages are often associated with
structural changes such as cerebral amyloid angiopathy, arteriovenous malformations
or brain tumors.[59] Independent associated risk factors were anticoagulation, a prior history of IS
and APOE e2 or e4 genotype, which had a specific association with lobar ICH.[60]
Hypertension is the leading attributable risk of non-lobar ICH, followed by prior
history of IS and anticoagulation. Interestingly, hypercholesterolemia was less frequent
in non-lobar ICH cases.[60] The most common locations of hypertensive ICH are the basal ganglia (caudate nucleus
and putamen), thalamus, cerebellum, midbrain, and pons.[59]
[60]
The results of the present review revealed a predominance of hypertension over DM2,
dyslipidemia, and other comorbidities. Nevertheless, a distinct proportion of IPH
was found, whereas patients had predominantly lobar locations (32%) as opposed to
non-lobar (24%). In addition to the association with lobar ICH and ApoE e4e4 allele,
recent findings suggest an increased risk of severe COVID-19 infection in this population,
independent of preexisting dementia, hypertension, and DM2.[61]
[62] APOE ε4 carriers also present an increased susceptibility to SARS-CoV-2 infection
with higher serum indicators of inflammation.[63]
Our case series had an expected predominance of hypertension as comorbidity, considering
that all the intraparenchymal hemorrhages were in lobar locations and 40% in non-lobar.
Therefore, these findings are consistent with the literature evidence found in this
review.
Severe acute respiratory syndrome coronavirus 2-infected stroke patients exhibited
particular clinical aspects compared with non-infected patients. The infection was
associated with a higher prevalence of younger patients, hemorrhagic conversion of
IS,[33] severe NIHSS scores, elevated D-dimer levels,[26]
[33]
[64] thrombocytopenia,[33]
[43]
[64] elevated PTT,[64] elevated INR, and in-hospital stroke.[43]
Considering only ICH, COVID-19 patients were younger with higher rates of malignancies,[25] elevated INR, PTT, and fibrinogen levels, yet decreased frequency of hypertension.[27] No significant changes were reported for other risk factors, such as DM2, dyslipidemia,
smoking, ischemic heart disease, or atrial fibrillation.[20]
[25]
[26]
[27] These patients also had more severe NIHSS and ICH scores at admission.[26]
[27]
Although these cases present with higher median neutrophil-to-lymphocyte ratios, there
was no significant difference when compared with control groups.[27]
The comparison between COVID-19 cases with and without ICH yielded more discrepant
results. Those with hemorrhagic events were older and had higher rates of prior stroke,
hypertension, DM2, dyslipidemia, congestive heart failure, ischemic heart disease,
and smoking,[25]
[54] but a lower rate of atrial fibrillation[28] and thrombocytopenia.[54] When considering microbleeds alone, the only significant increase was in the rate
of disturbance of consciousness prior to MRI, severity of lung computed tomography
(CT), days of intubation, and duration of hospital or ICU stay.[18]
Anticoagulant use
Cohort studies have shown conflicting data on the risk of ICH while in use of therapeutic
anticoagulation among patients with and without COVID-19. Some studies report no increased
risk of bleeding or mortality,[25]
[26]
[33] while others showed a 2 to 7-fold increase in risk of hemorrhagic events[27]
[28] and a 13-fold higher mortality risk.[27]
In the current review, the use of anticoagulation was reported in 43.3% of the 385
patients before diagnosis of ICH, of which 161 patients (47.3%) used therapeutic doses.
The prevalence of anticoagulation in cohorts was higher in patients with SAH (86%),
followed by MFH (82%), and lower in those with SDH (29%). Some cohort studies reported
the use of anticoagulants in 16 to 100% of patients.[17]
[18]
[19]
[20]
[22]
[24]
[25]
[26]
[27]
[28]
[33] The main indication was for the hypercoagulability of patients with COVID-19, expressed
by high levels of D-dimer.[17]
[27]
[65] Of all the cohort and case series studies reviewed, alterations in D-dimer were
observed in 13 studies, with values ranging from 231 ng/ml to 117,608 ng/mL. The mean
value of 10 studies was ∼ 2,912 ng/ml.
Pathophysiology of ICH in COVID-19 infection
The coronavirus, akin to other respiratory viruses, has neurotropism and the ability
to invade the CNS in two ways: hematogenous and retrograde neuronal pathways. This
ability to infect neurons from the olfactory bulb can also explain complaints of hyposmia
and anosmia. The hematogenous route is identified as the main form of CNS infection,
since the virus can infect endothelial capillary cells in the brain or infect leukocytes.
Additionally, similarly to SARS-CoV, SARS-CoV-2 exploits the ACE2 receptor for cell
entry.[14]
[66]
ACE2 (is a critical enzyme in the renin-angiotensin-aldosterone (RAAS) system that
regulates blood pressure, fluid and electrolyte balance, and vascular resistance.
This enzyme is extensively expressed in alveolar epithelial cells (type 2 pneumocytes),
oral and esophageal mucosa, as well as in vascular endothelial cells, smooth muscle,
glial cells, and in some neurons, including those in the cardiorespiratory center
of the brainstem.[11]
[14]
[67]
Severe acute respiratory syndrome coronavirus 2 infection in humans is mediated by
S (spike) glycoprotein binding, by the receptor-binding domain (RBD) to ACE2 receptors
in host cells, which leads to downregulation of ACE2 expression. This negative regulation
during SARS-CoV-2 infection can increase serum levels of angiotensin II, causing endothelial
function impairment and blood pressure dysregulation. Therefore, blood pressure fluctuations
with an increased risk of hemorrhagic cerebrovascular events can occur.[11]
[14]
The affinity of the SARS-CoV-2 spike protein to ACE2 receptors in brain capillary
endothelium can also cause direct vascular injury. The explanation for this involves
the process of binding of viral particles by the endothelial cells and, subsequently,
damage to the endothelial lining that can cause ruptures and bleeding. This same process
can occur within neurons from the viral invasion of the CNS.[11]
[67]
There is a release of cytokines and proteases that accompanies the immune response
to SARS-CoV-2 infection, involving massively increased levels of interleukin 6 (IL-6),
IL-7, IL-10, IL-1β, interferon-gamma (IFN) -γ), and tumor necrosis factor α (TNF-α),
while there is a reduction in CD4 + and CD8 + T cells, indicating that the cytokine
storm attenuates adaptive immunity against SARS-CoV infection.[13]
[68] In critically-ill patients with COVID-19, higher serum levels of inflammatory markers
(e.g., C-reactive protein and D-dimers) and an increase in neutrophil-lymphocyte ratio
can be seen, also present in the inflammatory process of ICH.[27]
[69]
[70]
The cytokine storm usually starts in the second week of infection, with the activation
of macrophages, dendritic cells, other immune cells, and subsequent massive release
of proinflammatory cytokines.[68] Consequently, via a mechanism that is still unclear, changes in the permeability
of the BBB can be impaired, facilitating the influx of inflammatory molecules to activate
C macrophages and microglia. Ultimately, these cells become hyper-activated and start
producing their own set of inflammatory molecules, which can lead to cerebral edema
and even hemorrhagic events.[56]
[68]
Thus, BBB breakdown is a possible additional mechanism for several cerebrovascular
events associated with this infection, such as hemorrhagic transformation of IS, ICHs,
and cases of PRES reported in some patients with COVID-19.[71]
[72]
[73]
The binding of spike protein may also promote a downregulation of ACE 2 expression
in the brain, thereby triggering an increase in local angiotensin II levels and reduction
in the vasodilator heptapeptide (angiotensin 1–7). Ang 1–7 acts as a neuroprotective
factor by stimulating the release of prostaglandin and nitric oxide, as well as inhibiting
the growth of smooth muscle cells and action of catecholamines.[67]
[74]
Patients with hypertension normally have low ACE2 expression, which is further reinforced
with SARS-CoV-2 infection, increasing the risk of stroke.[75] The intrinsic relationship between systolic BP variability and poor prognosis of
cerebral hemorrhage should be pointed out, as a high variation in BP during the first
24 hours of admission was associated with an unfavorable hospital prognosis in patients
with ICH. The lack of BP control might be explained by autonomic dysfunction, with
sympathetic predominance, associated with the production of proinflammatory cytokines,
hyperglycemia, and increased permeability of the BBB, which are present in SARS Cov2
infection.[75]
[76]
Diabetic patients with COVID-19 are at increased risk of serious complications. The
possible mechanisms that lead to an increased risk of stroke in these patients include
excessive proinflammatory responses and reduced ACE2 expression by advanced glycosylation,
leading to increases in angiotensin I and II.[77]
Coagulation disorders may be a plausible hypothesis to explain how SARS-CoV-2 infection
can induce brain hemorrhage, as patients with COVID-19 may suffer from consumption
coagulopathy with prolonged prothrombin time and reduced fibrinogen, both of which
also contribute to secondary cerebral hemorrhage.[75]
The older population has several aggravating factors for the development of intravascular
hemorrhages, such as cerebral microembolism, white matter lesions, vascular basement
membrane thickening, and increased BBB permeability, which promote endothelial damage,
changes in elasticity, and subsequent fluctuations in blood flow and pressure causing
loss of self-regulation and increase in ICH risk.[78]
Study limitations
The main limitation of this review was the lack of complete data from the majority
of articles in the literature. Especially in relation to data from laboratory tests,
in-hospital outcomes, and rehabilitation. Furthermore, some studies failed to report
details of the statistical method, which imposed difficulty to standardize a measure
of central tendency. In this way, as the COVID-19 pandemics is a recent object of
study, the overall quality and details of the studies could have been compromised
by the urge to provide enlightenment about clinical manifestations of COVID-19.
In conclusion, despite the unusual association, the combination of these two diseases
is associated with high rates of mortality and morbidity, as well as more severe clinical-radiological
presentations. Further studies are needed to provide robust evidence on the exact
pathophysiology behind the occurrence of intracranial hemorrhages after COVID-19 infection.
