Prevalence of Cerebral Venous Thrombosis in COVID-19 Patients: A Systematic Review ()
1. Introduction
Stroke is one of the major causes of mortality and long-term disability which is usually caused by hemorrhage or arterial occlusion [1]. Cerebral venous thrombosis (CVT) is a rare form of stroke and accounts for 0.5% of all stroke cases; CVT is associated with an increased mortality rate [2] [3]. The incidence of CVT is ranging from 0.22 to 1.32 per 100,000 annually [4]. CVT is more frequent in young adults and children [4] [5] and more common among females compared to males [4]. CVT can present with a multitude of symptoms and signs, and this makes it hard to distinguish it from other neurological conditions [2]. The early identification of symptoms and management improves the overall outcomes of CVT patients [2]. The risk factors of CVT are divided into genetic risks such as inherited thrombophilia and acquired risks such as trauma, surgery, cancer, exogenous hormones, pregnancy, and puerperium [6].
The SARS-CoV-2 virus that belongs to the corona family viruses caused COVID-19 disease. It was first isolated in December 2019 [7]. The patients with COVID-19 were suffering symptoms such as fever, lack of air, dry cough, headache, diarrhea, fatigue, and throat pain [8] ; however, there have been reports of multisystemic manifestations, including neurologic and thrombotic complications [9].
In this context, thrombosis following COVID-19 infection can be related to inflammation, plaque activation, endothelial dysfunction, and blood stasis [10]. There were many risk factors that have been hypothesized to contribute to thrombosis among COVID-19 patients; these factors include prothrombic events caused by cytokines storm, immobility, and reduced activity of thromboprophylaxis [11]. A study from Italy showed thrombotic events occurred in 7.7% of closed cases [12] , whereas another study reported that the incidence of thrombotic complications among COVID-19 patients in intensive care unit was 31% even with prophylaxis [13].
Although attention has been given to cerebrovascular thrombotic events, few reports have addressed the risk of CVT among COVID-19 patients. The large majority of these reports are case reports, so we performed this systematic review to assess the prevalence of CVT among COVID-19 patients by reviewing previous studies that reported such subject.
2. Method and Search Strategy
This systematic review follows the PRISMA checklist guidance for systematic review and meta-analysis [14]. We revised two databases for research, including PubMed and Google scholar databases.
We used several keywords for the searching process, including “CVT, COVID-19, Prevalence, Complications, and Effect.” We used these keywords in different combinations to get all articles related to our subject. All obtained titles from this primary exploration were revised, and all the studies which didn’t include CVT and COVID-19 were excluded. The findings were then explored to choose only full-text articles written in English and reporting CVT among COVID-19 patients.
3. Eligibility Criteria
We reviewed the remaining full-text articles written in English language and reported CVT among COVID-19 patients. Each of the case reports, review articles, and duplicate articles were all excluded. The inclusion criteria were original articles conducted on COVID-19 patients and experienced CVT, written in the English language, and not case reports. We showed the full description of the search strategy in Figure 1.
4. Data Review and Collection
We reviewed the abstracts of eligible articles, as well as the full article text. A pre-designed excel sheet was used to extract data of interest from the eligible
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Figure 1. Planning of eligible criteria.
studies. We then revised the extracted data. We transferred the selected data to a pre-designed table to summarize the main findings.
5. Results
This systematic review included six articles that met the eligible criteria [15] - [20] (Table 1). There were three studies published in 2021 [15] [16] [17] and three studies published in 2020 [18] [19]. One study was case series [20] , one study was an observational study [16] , whereas the remaining four studies were retrospective [15] [17] [18] [19] ; two studies were retrospective cohort [15] [17] , one study was retrospective observational [18] , and one was a retrospective study [19]. There were two multinational studies from different counties [16] [19] ; one study included patients from ten centers in four countries (Egypt, Pakistan, Singapore, UAE) [16] , whereas the other multinational study included patients from nine centers from three countries (Iran, USA, Singapore) [19]. Regarding the settings and strategy of the other four studies, the first study was from the USA and included two cohorts of influenza patients and individuals who received the mRNA vaccine [15]. The second study was conducted in the USA at six different tertiary care centers [17] , third study was from Wuhan, China [18] , and the fourth one was case series from the USA.
The total number of participants was 551,727. Male gender was predominant in three studies [16] [18] [20] , whereas it did not state the gender of participants in one study [17] , and in the other two studies, there was female dominance [15] [19]. The mean age of patients ranged between 34 years [20] and 53.3 years [18]. the first study reported 23 patients with CVT out of 537,913 patients with COVID-19 [15]. Another study reported 20 patients had CVT and recent COVID-19 [16]. One study reported 13 patients with CVT and COVID-19 and 57 patients with CVT and without COVID-19 [19]. The case series included three patients who developed CVT with COVID-19 [20].
The findings of the included studies were various, so we could summarize the main findings into main points. Regarding the occurrence of CVT among COVID-19 patients, there were four studies reported that point [15] [17] [18] [19] ; one study reported the incidence of CVT to be 42.8/million individuals after COVID-19 diagnosis, and the incidence of CVT was higher among COVID-19 patients compared to those with influenza or received mRNA COVID-19 vaccine
The same study also reported the incidence of portal vein thrombosis (PVT), which was higher compared to CVT. The incidence of PVT after COVID-19 diagnosis was 392.3/million individuals, which was also higher compared to a matched cohort of individuals with influenza or received mRNA vaccine [15].
Another study reported that only 12 patients out of 13,500 COVID-19 patients had imaging-proved CVT. The incidence of CVT was 8.8/10,000 during three months, and the incidence of CVT was found to be higher compared to the incidence of CVT among the general population, which is 5 per million annually [17]. In the third study, the prevalence of CVT, cerebral hemorrhage, and acute
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Table 1. Systematic review studies of prevalence of cerebral venous thrombosis in COVID19 patients.
ischemic stroke among 221 patients with COVID-19 was 0.5%, 5%, and 0.5%, respectively [18]. The last study reported the inclusion of 13 patients with CVT and COVID-19 and compared this group with another group with CVT and without COVID-19. However, the number of patients with CVT and COVID-19 was 13 patients, and it was lower than the other group with CVT and without COVID-19, which included 57 patients [19].
The risk factors associated with developing CVT among COVID-19 patients were reported in three studies [16] [18] [19]. These risk factors include elder patients [16] [18] [19] , male gender [16] and severe COVID-19 [18].
The symptoms associated with the presentation of CVT among COVID-19 patients were reported in three studies [16] [17] [20]. They included headache (85%), seizure (65%), and 45% had respiratory symptoms without neurological manifestations. The major imaging findings were infarction (65%) and hemorrhage (20%). Superior sagittal sinus was the most common site of thrombosis [16]. Another study reported 58% of patients had neurological symptoms in first 24 hours of the onset of respiratory symptoms. The main radiological findings were venous infarction, hemorrhage, or both [17]. In the case series, two patients out of three had hemorrhagic venous infarction [20].
The findings regarding diagnostic markers of CVT among COVID-19 patients were reported in first study [16]. Elevation of acute inflammatory markers was found, including D-dimer (87.5%), erythrocyte sedimentation rate (69%), C-reactive protein (47%), and homocysteine (50%) [16]. Third study reported markers regarding cardiovascular disease in general; also, there was an increase in the inflammatory response and an increase in D-dimer and C-reactive protein [18].
The management of patients was reported in two studies [17] [18]. One study reported that the management was done through anticoagulation, endovascular thrombectomy, and surgical hematoma evacuation [17]. Another study reported that six patients received antiplatelet treatment with aspirin or clopidogrel, but three patients died, whereas the remaining five patients received anticoagulation treatment, and only one died [18]. The mortality rate was reported in five studies [16] [17] [18] [19] [20] , and it was 20% [16] , 25% [17] , and 38% [18].
6. Discussion
In our review, we found there is an association between COVID-19 disease and CVT. For instance, the incidence of CVT among COVID-19 patients was 8.8 per 10,000 compared to the general population, patients with influenza, and individuals who received mRNA vaccine [17]. In the general population, the risk factors of CVT were females, young age and malignancy in elderly patients [5] [6] [21] [22]. In our review, older age and male gender were the major risk factors for CVT among COVID-19 patients. This can be attributed to the impact of COVID-19, which may change the susceptibility of patients to develop CVT.
The most common presentation of CVT in COVID-19 patients was headache, followed by seizure [16]. Thus, COVID-19 patients can have CVT without neurological manifestations. Laboratory wise, COVID-19 with CVT showed elevation in D-dimer and markers of inflammation, such as C-reactive protein [16] [18]. We found that the elevation in D-dimer levels was associated with an increase in the rate of vascular complications [23].
Also, we found that the antiplatelet therapy such as aspirin and clopidogrel wasn't effective in the treatment of CVT patients. Three patients out of six patients who received that regimen died, whereas, among five patients who received anticoagulation treatment, only one patient died [18]. However, this may be attributed to the severity of CVT, and anti-platelets may be not appropriate for the conditions of patients and lead to death, which was not mentioned in the study. Another study reported using anticoagulation, surgical hematoma evacuation, and endovascular thrombectomy for CVT patients; the mortality rate reported was 25% among 12 patients [17].
7. Conclusion
The accurate incidence and prevalence of CVT among COVID-19 patients is hard to report due to the lack of the number of studies and variations between the studies and included populations. However, we could conclude that the incidence of CVT is high among COVID-19 patients compared to the general population, patients with influenza, and those who received the mRNA vaccine. This warns us and encourages us to make attention to the development of CVT among COVID-19 patients, so CVT should be suspected and expected in COVID-19 patients. Older age was the major risk factor reported. A management strategy or treatment regimen should be established based on the severity of CVT patients as the mortality rate among those patients was high.