key: cord-287742-y1j9x5ne
authors: Lee, Kai Wei; Yusof Khan, Abdul Hanif Khan; Ching, Siew Mooi; Chia, Peck Kee; Loh, Wei Chao; Abdul Rashid, Anna Misya'il; Baharin, Janudin; Inche Mat, Liyana Najwa; Wan Sulaiman, Wan Aliaa; Devaraj, Navin Kumar; Sivaratnam, Dhashani; Basri, Hamidon; Hoo, Fan Kee
title: Stroke and Novel Coronavirus Infection in Humans: A Systematic Review and Meta-Analysis
date: 2020-10-06
journal: Front Neurol
DOI: 10.3389/fneur.2020.579070
sha: 
doc_id: 287742
cord_uid: y1j9x5ne

Background: As the world witnessed the devastation caused by the coronavirus disease 2019 (COVID-19) outbreak, a growing body of literature on COVID-19 is also becoming increasingly available. Stroke has increasingly been reported as a complication of COVID-19 infection. However, a systematic synthesis of the available data has not been conducted. Therefore, we performed a systematic review and meta-analysis of currently available epidemiological, clinical, and laboratory data related to both stroke and COVID-19 infection. Methods: We systematically searched Medline, Cinahl, and PubMed for studies related to stroke and COVID-19 from inception up to June 4, 2020. We selected cohort studies, case series, and case reports that reported the occurrence of stroke in COVID-19 patients. A fixed-effects model was used to estimate the pooled frequency of stroke in COVID-19 patients with a 95% confidence interval (CI). Results: Twenty-eight studies were included in the systematic review and seven studies for the meta-analysis. The pooled frequency of stroke in COVID-19 patients was 1.1% (95% CI: 0.8, 1.3). The heterogeneity was low (I(2) = 0.0%). Even though the frequency of stroke among patients having COVID-19 infection was low, those with concomitant COVID-19 infection and stroke suffered from a more severe infection and eventually had a poorer prognosis with a higher mortality rate (46.7%) than COVID-19 alone. Many COVID-19 patients shared the common traditional risk factors for stroke. We noted that ischemic stroke involving the anterior circulation with large vessels occlusion is the most common type of stroke with more strokes seen in multi-territorial regions, suggesting systemic thromboembolism. An elevated level of D-dimers, C-reactive protein, ferritin, lactic acid dehydrogenase, troponin, ESR, fibrinogen, and a positive antiphospholipid antibody were also noted in this review. Conclusions: The occurrence of stroke in patients with COVID-19 infection is uncommon, but it may pose as an important prognostic marker and indicator of severity of infection, by causing large vessels occlusion and exhibiting a thrombo-inflammatory vascular picture. Physicians should be made aware and remain vigilant on the possible two-way relationship between stroke and COVID-19 infection. The rate of stroke among patients with COVID-19 infection may increase in the future as they share the common risk factors.

In December 2019, an outbreak of a novel respiratory infection was first detected in Wuhan, China, linked to three cases of patients presenting with pneumonia (1, 2) . The cause of the pneumonia was found to be a viral infection known as novel coronavirus disease , and by March 2020, the World Health Organization (WHO) declared this disease as a pandemic caused by a virus known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (3, 4) . The WHO stated in its report on the state of the world's health that humans are now facing a serious threat from COVID-19 (4, 5) , and it was now necessary to declare COVID-19 as a public health emergency (6) .

COVID-19's main presentation relates to the infection of the upper respiratory system, with clinical features such as fever, dry cough, myalgia, and malaise, and in more severe cases, patients may develop pneumonia that may proceed to the lifethreatening acute respiratory distress syndrome (ARDS) (7) . Patients infected with COVID-19 will also experience several mild neurological symptoms such as headache, dizziness and anosmia, to severe symptoms like altered level of consciousness, acute cerebrovascular events, seizures, and ataxia (8, 9) . In addition, COVID-19 could also cause viral encephalitis and hemorrhagic necrosis in the mesial temporal lobes and thalamus (10) (11) (12) . Stroke is one of the more disabling neurological complications being reported, where the first retrospective cohort of COVID-19 showed stroke occurrence in around 2% of the patients (13) . The American Stroke Association indicated that the risk of stroke doubled every 10 years after the age of 55, and therefore, stroke affects more older adults than younger ones (14, 15) . However, due to COVID-19, literature has reported an increasing number of premature strokes in the younger generation (16) .

The pathophysiology for the development of stroke in patients with COVID-19 is multifactorial. Infection, in general, may increase the odds of stroke 1.4-fold, particularly in the early convalescence phase, and this association may also be similarly expected among COVID-19 patients (17) . Secondly, SARS-CoV-2 may potentially predispose to thrombogenesis and increase the risk of stroke by infecting the myocardium cells via ACE2 (angiotensin-converting enzyme II) receptor and causing vascular injury and inflammation (18) . COVID-19 has been shown to create a prothrombotic state as evidenced by high D-dimer titres that further propagate the risk of thrombosis (19) . Moreover, COVID-19 patients appear to be in a hyper inflammation state or cytokine storm like condition, which resulted in secretion of high interleukin-6 (IL-6) levels, which in turn translates to hyperviscosity and increases the risk for stroke propensity (20) . Apart from the increased thrombotic potential in large vessels in patients with COVID-19, the patient may also be susceptible to spontaneous intracerebral hemorrhage and micro thrombosis of small penetrating vessels owing to the potential risk of vascular endothelial damage (21) . There is growing evidence of the development of thromboembolic complications among patients with COVID-19, the occurrence of stroke. Several case studies have also shown that patients with pre-existing cerebrovascular disease may be at a higher risk for a poor outcome if they become infected with COVID-19 (22) (23) (24) . Given the worldwide COVID-19 cases are now over nine million as updated on June 26, 2020, and still rising in an exponential manner (25) , the understanding of the association between stroke and COVID-19 is essential in order to prevent debilitating sequelae associated with stroke and to aid in the prevention and management in these groups of patients.

Due to the novelty of the virus and the relatively short duration of the current COVID-19 outbreak, only a limited and scattered body of scientific evidence on the neurological complications of COVID-19 is currently available. Furthermore, the possible twoway association between COVID-19 and stroke has not yet been elucidated, and currently there are only limited data available on stroke co-occurrence and characterization in patients with COVID-19, which urgently needs further investigation and analysis to ensure a better outcome for this group of patients. Therefore, it is vital to perform this review in order to determine the frequency of stroke among COVID-19 patients and stroke characterization, as this may impact future management.

We, therefore, performed a systematic review and metaanalysis involving the epidemiological, clinical presentation, imaging characteristics, and laboratory finding related to both stroke and COVID-19 infection.

This systematic review study was registered with the Medical Research and Ethics Committee, Ministry of Health Malaysia (registration number: NMRR-20-1200-55395) and was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (26) (Appendix 1).

Two investigators (AHKYK and JB) independently searched the Medline, Cinahl, and PubMed databases for potential studies that were published in peer-reviewed journals from inception to June 4, 2020. We used the following search terms: (Cerebrovascular Accident OR CVA OR Stroke) AND (COVID-19 OR CORONAVIRUS OR 2019-NCOV) with limiters of ENGLISH and HUMAN. The search strategies with the Boolean or phrase operators are shown in Appendix 2. Subsequently, we removed duplications using Endnote R before the next process of screening the title and abstracts for suitability. Finally, the selected articles with their full text were assessed for their eligibility to be recruited into this systematic review and meta-analysis.

All relevant articles identified through the above comprehensive databases were imported into the Endnote R programme version X5. Initially, we performed de-duplication. Title and abstracts were then reviewed for their relevance and articles highlighting cases of COVID-19 and its relevance to stroke were reviewed in full text by four investigators (AHKYK, JB, PKC, and WCL) who are clinical neurologists with not <5 years of experience in the field of clinical neurology. Studies were selected based on inclusion criteria that these studies have data on the frequency of stroke in cases of COVID-19 or possess any data relevant to the relative risk of COVID-19 and stroke. Studies were excluded if they are a review paper, or there is no required data for both these conditions. We also excluded any study with patients who developed stroke prior to COVID-19 infection. Any disagreements between the investigators were resolved through discussions and consultations with another two senior investigators (SMC and FKH) before the final consensus for quantitative analysis was reached.

The participants should be those (age >18 years) with or without a confirmed diagnosis of stroke. Exposure was referred to as exposure to COVID-19 disease, whereby there were no limitations in severity criteria. Comparator was referred to as non-COVID-19 disease and COVID-19 patients without stroke. The main outcomes we examined in this review were percentage or frequency of stroke that occurs after COVID-19 infection, whereby the stroke incidence could be an ischemic and hemorrhagic stroke, venous stroke due to venous sinus thrombosis, or transient ischemic attack. The secondary outcomes were clinical presentation, the subtype of stroke, imaging characteristics, and laboratory finding related to both stroke and COVID-19 infection.

Four investigators were paired into two groups (group 1: AHKYK and JB; group 2: PKC and WCL) to perform the data extraction independently. The following data were extracted from every study: the last name of the first author, year of publication, country, severity status, study design, patient characteristics (ethnicity composition, gender, and mean age), comorbidities (diabetes, hyperlipidemia, hypertension, ischemic heart disease, heart failure, previous stroke, chronic kidney disease/end-stage renal disease, number of stroke patients per overall participants, any information relevant to strokes such as the location of stroke [arterial or venous]), types of stroke (ischemic or haemorrhagic), classification of stroke, mortality rate, and blood parameters. Another two investigators (AMAR and LNIM) performed proofreading to ensure no errors and bias in the data extraction.

Pooled frequency of stroke among COVID-19 patients was estimated using meta-analysis, and the data required for this was the number of patients with stroke and COVID-19 infection (nominator) divided by the total number of patients with COVID-19 infection (denominator). A synthesis of the findings in the aspect of clinical presentation, imaging characteristics, and laboratory finding extracted from included studies were summarized in tables. Pertaining to clinical presentation, we classified stroke based on vessels occlusion and TOAST, whereby data were presented either in N value or ultimate decisionmaker (Yes/No). The ultimate decision, either Yes or No, was used because the particular study had only one patient with stroke. Classification of stroke was based on imaging finding such as arterial vs. venous; ischemic vs. hemorrhagic; location of stroke (anterior circulation, posterior circulation, or multiple territories), whereby data were presented either in N value or ultimate decision-maker (Yes/No). Laboratory findings with clinical importance to inflammation due to stroke or viral infection were also examined, which include erythrocyte sedimentation rate, C-reactive protein, ferritin, D-dimer, lactic acid dehydrogenase, fibrinogen, antiphospholipid, procalcitonin, interleukin6, troponin, platelet, and prothrombin time. Blood parameters were presented in mean ± standard deviation or range.

The quality of the individual studies pertaining to cohort studies was determined using the checklist Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), which has 22 items that assess components in observational studies (27) . A "0" was given if that item was not reported; "1" was awarded if that item was sufficiently shown in the article. Each article's quality was graded as "good" if STROBE scores ≥14/22 or graded as "poor" if strobe score <14/22 (27) . Nevertheless, studies would have been included in this review regardless of the STROBE grading.

We used a quality appraisal checklist for case series studies developed by the Institute of Health Economics, which appraises over 20 items. This is a three-options checklist with Yes/Partial/Unclear/No depending on the clarity of items presented in case series (28) (Appendix 3).

A fixed-effect (DerSimonian and Laird method) meta-analysis method was employed to calculate the pooled frequency from these related studies, and it was reported with a 95% confidence interval (CI). I 2 index was used to assess the study's heterogeneity (i.e., low is <25%, moderate 25-50%, and high >50%) that indicated the total percent of discrepancy due to variation in the included studies (29) . We also examined publication bias by Begg's test and Egger's test for studies which entered metaanalysis (30) . A sensitivity analysis was conducted using leaveone-out meta-analysis to examine how individual studies affect the overall estimation of the rest of the studies. For statistical analysis, Open Meta(Analyst) R software was used, and this software can be accessed and downloaded from http://www. cebm.brown.edu/openmeta/index.html (31) .

We identified 571 manuscripts in the initial screening, as shown in Figure 1 . After removal of duplicate articles (n = 3), a total of 568 studies were retrieved for further assessment. After screening for its suitability through the individual title and abstract, 58 studies fulfilled both our inclusion and exclusion criteria. After careful evaluation, 28 articles were finally included for the systematic review and seven studies for the meta-analysis.

The main characteristics of the included studies are shown in Table 1 . A total sample of 8,771 participants was included in the systematic review. These studies were conducted in many countries worldwide including in China (13, 40, 43) , France (37, 39, 48, 50) , India (42) , Iran (51), Italy (32, 33, 46) , the Netherlands (34), Philippines (52), Spain (44, 53) , Turkey (58), UK (41, 55) , and the USA (21, 35, 36, 45, 47, 49, 54, 56, 57) . Out of 27 studies, eight studies were of retrospective cohort study design, 11 were case series, and nine were case reports. The mean age of the participants ranged from 36 to 81 years old, giving a grand mean age of participants from the included studies of 62.9 ± 12.2 years, with more than half of them being males (64.1%). The overall mortality rate among stroke patients ranged from 22.2 to 43.0%; the average mortality rate for stroke patients with COVID-19 and non-COVID-19 infection were 46.7 and 8.7%, respectively. A majority of the respondents were diagnosed with COVID-19 using the reverse transcriptasepolymerase chain reaction (RT-PCR) tests conducted on samples collected either from the nasopharyngeal or oropharyngeal swab, and some also had concurrent confirmation by the antibody serology test.

Eight studies had reported data eligible for the estimation of the pooled frequency of stroke among patients with COVID-19, and therefore the pooled frequency using the fixed-effect model is presented below in Figure 2 . However, we decided to exclude the article by Benussi et al. in the final analysis due to its high heterogeneity. The pooled frequency of stroke among patients with COVID-19 as derived from the final seven studies was 1.1% (95% CI: 0.8, 1.3) and had a low degree of heterogeneity (I 2 = 0.0%, p = 0.359) if the article by Benussi et al. (33) was excluded from the meta-analysis. The pooled frequency increased to 2.7% and heterogeneity was also extremely high (I 2 = 96.3, p < 0.001) if the article by Benussi et al. (33) was included in the metaanalysis. Egger's test and Begg's test (p < 0.05) suggested that there was publication bias; sensitivity analysis also identified all seven studies in the meta-analysis had substantial influences on the pooled frequency of stroke among COVID-19 patients, which cause variation in a pooled frequency ranging from 1.0 to 1.2.

The data on stroke patients in different groups of severe vs. Table 2 . Among the seven retrospective studies, two studies provided the number of patients having a stroke in the different groups of severe and non-severe COVID-19 infection (13, 32) . One study reported the number of patients having a stroke in the different groups of with or without COVID-19 infection (33) . Among patients who suffered from a stroke and classified according to the severity of the infection, the majority were placed in the severe COVID-19 infection group, whereby 60 patients were classified as severe compared to 29 in the non-severe group. Among patients who suffered from a stroke, 150 patients had COVID-19 infection, whereas 141 patients had no COVID-19 infection. The average days to develop stroke among patients after the onset of COVID-19 infection was 6.9 ± 4.5 days.

Regarding the severity stratification for COVID-19 infection, we observed that multiple stratification approaches were used across studies such as severe and non-severe infections that were based on admission to intensive care unit vs. general ward, the presentation of respiratory failure warranting intubation and ventilation, ARDS criteria, and according to guidelines from American Thoracic Society for community-acquired pneumonia as per Table 2 .

The imaging findings in COVID-19 patients are summarized in Table 3 . Majority of strokes seen among COVID-19 patients were arterial stroke (98.5%) while venous stroke was seen only in three patients (1.5%). Ischemic stroke was the predominant stroke, and it was observed in 90.3% of stroke cases as compared to 9.7% patients presenting with hemorrhagic stroke. More than half of stroke happened in anterior circulation (60.0%), followed by the multiple territories (28.0%) and posterior circulation (12.0%). Among the 29 cases of stroke involving the anterior circulation, 28 cases occurred in middle cerebral artery (MCA) region, and only two cases involved the anterior cerebral artery (ACA) region. Table 4 summarized the stroke classification based on large vessels occlusion (LVO) and the TOAST (Trial of ORG 10172 in acute stroke treatment) classification (59) in patients with COVID-19. The numbers of stroke were almost equal for LVO (47 stroke cases in 10 studies) and non-LVO (42 cases in 10 studies). Location of LVOs involved were M1 vessels (21, 37, 41, 42, 44, 45, 47, 53, 54) , M2 vessel (41, 42, 44, 45, 47, 53) , internal carotid (21, 37, 42, 45, 47, 53) , multiteritorial (37, 47) , posterior cerebral (41, 45) , basilar (37), ACA (21, 53) , and the vertebral artery (41) .

According to the classification of stroke based on the TOAST criteria, we found that large vessels and cryptogenic were the most common type of stroke (28.9%), followed by cardioembolic (15.7%), small vessels (14.0%), and others (12.4%). A majority of the studies did not classify their stroke type with the TOAST classification. Table 5 shows the data on comorbidities among participants in the included studies. Hypertension (50.9%) was found to be the highest in percentage among the comorbidities, followed by diabetes (40.0%), atrial fibrillation (23.9%), hyperlipidaemia (17.0%), history of ischemic heart disease (14.8%), smoking (10.5%), previous stroke (6.7%), malignancy (4.5%), chronic kidney disease or end-stage renal disease (2.9%), and finally heart failure (0.4%).

Daa on the blood parameters are shown in Table 6 . Functions of each of the blood tests and its normal range are summarized in A majority of the studies included had an elevated mean for the D-dimer test, which ranged from 0.71 to 28.5 mg/L except for the study done by Lodigiani et al. (32) , in which the mean of Ddimer was 0.389 on day 4-6 among the survivors, and an elevated D-dimer of 0.943 was reported among the non-survivors.

For the fibrinogen test, a majority of studies reported that the mean for fibrinogen was out of the normal range (200-400 mg/dL), in which they ranged from 462.8 to 6,050 mg/dL, except for the study done by Valderrama et al., which had a normal level (235 mg/dL) (21) .

Similarly, a majority of the studies did not capture information on the presence of antiphospholipid, except the studies by 56) reported the absence of antiphospholipid antibodies. For the procalcitonin titres, three studies had a blood test result of below 1.0 mg/mL, which ranged from 0.23 to 0.8 ng/mL (43, 44, 52) , with the highest mean for procalcitonin concentration reported in the study by Avula et al. (4.9 ng/mL) (42) . We observed that only three studies captured information on interleukin-6 (IL-6) levels among patients with COVID-19 and stroke, which ranged from 3 to 10.5 pg/mL, which are the studies by Avula et al. (42) , Barios Lopez et al. (44) , and Yaghi et al. (36) . Data of all these studies reported a normal reading for IL-6 levels. For the troponin test, seven studies reported data on the troponin concentration (33, 41-44, 48, 52) . Three out of the seven studies reported an (45) . For the platelet level, the mean ranged from 112 to 303 ×10 9 , and the levels were all within the normal range in the included studies, except for the study done by Christian Oliver et al. (52) , which had a slightly elevated level (409 × 10 9 ). The normal range for clotting time (prothrombin test) is 11-13.5 s (60). Among the included studies, six studies reported a normal mean for the prothrombin time, and these studies included the studies by Benussi et al. 

The aim of this current study is to perform a systematic review and meta-analysis concerning the epidemiological, clinical presentation, imaging characteristics, and laboratory findings related to both stroke and COVID-19 infection.

Coronaviruses are divided into four genera, in which the new coronavirus (SARS-CoV-2) is classified into the beta genus, which includes viruses causing SARS and MERS (Middle East Respiratory Syndrome) as well (61) . There are now at least seven human coronaviruses, including SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL-63, and HCoV-HKU1 (38) . Studies on previous human coronaviruses infections indicated that the virus does not remain confined to the respiratory system and may also disseminate to other organs, including the central nervous system via the angiotensinconverting enzyme type 2 receptor (ACE-2) (62, 63) . The possibility of neurological complications may stem from the neurotropic and neurovirulent property of SARS-CoV-2, which are also seen in other human coronaviruses (64) .

The association of stroke with viral infection is wellestablished, albeit uncommon. In general, viral infection, particularly those in the early convalescence phase, increases the odds of stroke by 1.4-folds (17) . A previous study amongst SARS-COV-1 patients showed that LVO occurred in a small percentage of patients (2.4%) that were infected in which the two patients had cardiac dysfunction, disseminated intravascular coagulation, and significant hypotension before the onset of stroke (65) . A similar trend among MERS patients also showed that only a small number of patients developed stroke associated with preceding disseminated intravascular coagulation in one of the patients (66) . In this current review, the pooled frequency of stroke was 1.1%. We decided to remove Benussi et al. (33) in the final result as the study was conducted in a stroke hub for COVID-19 in Italy, which explained the high frequency of stroke (76.8%) among patients with COVID-19. We found that overall, patients with COVID-19 exhibited a lower percentage of stroke, which was 1.1% of patients with COVID-19. This is similar to the worldwide prevalence of stroke (1.12%) (67) but much lower as compared to the prevalence of stroke in the United States (2.5%) and in China (3.1%) (68, 69) . The association of stroke seen in patients with COVID-19 may be attributed to the shared traditional risk factors for stroke also seen in COVID-19 patients. Literature reported that the traditional risk factors for stroke are diabetes, hypertension, hyperlipidemia, smoking, atrial fibrillation, previous stroke, ischemic heart disease, and family history of stroke, in which the estimated relative risk for total stroke associated with hypertension was 5.43 (70), 2.28 for diabetes (71), 1.64 for obesity (72), 1.46 for atrial fibrillation (73), and 1.10 for chronic kidney disease (74) . Our finding is consistent with the literature that reported that more than half of COVID-19 patients with stroke had comorbidities of hypertension, followed by diabetes, atrial fibrillation, hyperlipidaemia, and/or history of ischemic heart disease.

Ischemic stroke is the most common type of stroke seen in this review as compared to less frequently occurring haemorrhagic and transient ischemic stroke. Hypertension, diabetes, and cardiovascular disease are known risk factors for ischemic stroke (75) . In addition, the risk factors of hemorrhagic and ischemic strokes were also relatively similar (INTERSTROKE study). A recent review showed that all infections increase the risk of acute ischemic stroke, although its pathophysiology is not adequately explained (76) .

Anterior circulation is the most common site for stroke, with more than half of the strokes occurring in the middle cerebral artery, followed by the multiple territories. Interestingly in our review, a quarter of the stroke was multi-territorial. This may be due to the propensity of systemic embolisation and microvascular thrombosis that typically occurs in COVID-19 infection due to the excessive production of prothrombotic factors and dysregulation of the anti-thrombotic properties (77) , whereas strokes are less commonly seen in the posterior and anterior cerebral arteries (78) . This observation is similar to the non-COVID-19 related stroke.

A recent report pointed out the propensity of LVO to occur in patients with COVID-19 and its tendency to occur in the younger age group (45) . In our review of the currently available literature, half of the reported stroke cases were due to an LVO as compared to non-large vessel occlusion. This rate is much higher as compared to the general population where LVO usually occurs in around one-third of the patients (79) . Furthermore, among studies that used the TOAST classification, one-third reported stroke types as cryptogenic and others that indicate that there are other underlying pathologies apart from the traditional risk factors that contribute to the occurrence of stroke in patients with COVID-19.

Apart from the possible neuropathic property of SARS-CoV-2 that causes direct endothelial injury via the ACE-type 2 receptor (80) and sharing of the common traditional risk factors for stroke, the pathophysiology of stroke in COVID-19 patients could also be attributed to the pro-inflammatory and hypercoagulable state predisposing to thrombosis. The thrombo-inflammatory nature of SARS-CoV-2 was noted as to be associated with elevated levels of D-dimer, fibrinogen, platelet, and IL-6 (77). Furthermore, the excessive systemic immune response that may be seen in this novel infection may be due to immunopathogenicity in which the over-stimulation of the immune system by this virus leads to attacks to one's own immune system (81) . Cytokine storm may also occur as our immune system goes into an overdrive, leading to a massive influx of SARS-related inflammatory cytokine such as interleukin-1β, IL6, IL12, interferon-γ, inducible protein−10, and monocyte chemoattractant protein-1 (81, 82) . These excessive inflammatory cascades may lead to two main sequelae [i.e., production of prothrombotic factors and endothelium damage due to dysregulation of antithrombotic properties, subsequently leading to microvascular thrombosis with potential for systemic embolization (77, 83) ]. Moreover, inflammatory markers [e.g., C-reactive protein and fibrinogen, are independent risk factors for ischemic stroke and may also predispose to atherosclerosis and endothelial dysfunction that can be further exacerbated by infection (81, 84) ].

Hypercoagulable state, on the other hand, as demonstrated by elevated D-dimer levels, abnormality in clotting variables, and hyperferritinemia, not only increases the risk of a thromboembolic event but is also an independent predictor for poor prognosis and mortality (4, 40) . The role of other thrombotic markers such as the antiphospholipid antibodies, albeit their role in COVID-19, are also uncertain but may also contribute to the hypercoagulable state (43) .

In our review, several markers are commonly used to identify the thrombo-inflammatory nature of COVID-19 (e.g., D-dimers, CRP, ferritin, fibrinogen, antiphospholipid antibodies, LDH, and troponin). Based on our observation, CRP was the most commonly used biomarker, followed by D-dimer, LDH, troponin, and antiphospholipid tests. In this review, stroke patients with COVID-19 consistently presented with an elevated level of D dimers, CRP, ferritin, LDH, troponin, ESR, fibrinogen, and with positive antiphospholipid antibodies reported in some studies. IL-6 and pro-calcitonin were only reported in a few studies and were not found to be elevated.

Although the mean age of patients with COVID-19 and stroke in our review was 62.9 years, many case series and case reports have shown that those in the younger age group or those with no comorbidities more commonly presented with stroke (42, 43, 49, 50, 53, 56, 58) . Furthermore, stroke is shown to occur early in the illness with mean onset at 6.9 days, with reports even showing that patients may present with stroke and at the same time have asymptomatic COVID-19 infection (42, 49) . Unfortunately, patients with COVID-19 and stroke had a more severe COVID-19 infection and a poorer prognosis with a higher mortality rate as shown by this current review. The mean mortality rate among stroke patients with COVID-19 infection was 46.7% compared to only 8.7% among those without COVID-19 infection, and this could be attributed to the severity of infections in patients concurrently having neurological complications (13, 53, 54, 56) .

A subgroup analysis was done among the population cohorts of the Benussi 

Although COVID-19 may predominantly present with respiratory symptoms, this review may create awareness among clinicians on potential presentation of stroke in those having this infection, especially for those with severe infection. As many of the patients share similar traditional risk factors for stroke, the presentation of a patient with stroke to the emergency department in this current pandemic must be reviewed cautiously and treated with high suspicion of the potential presence of SARS-CoV-2 infection in order to prevent further dissemination and deterioration. The role of specific blood tests as a potential thrombo-inflammatory marker can be a guide to predict the possible thromboembolic occurrence and disease severity, hence providing muchneeded guidance for physicians in taking necessary preventative measures.

This is the first systematic review summarizing the findings in relation to both COVID-19 and stroke. We found a high incidence of stroke among patients with COVID-19. The majority are ischemic stroke, involve large vessels occlusion, and occurs predominantly in the middle cerebral artery. We also found hypertension as the most common comorbidity among this study participants. Most of the laboratory tests except for IL-6 and procalcitonin appeared to be useful for indicating the presence of inflammation and the prothrombotic state as a predictor for stroke, although results varied between the studies. This review has several limitations. First, the majority of studies did not provide data based on the severity of the infection, and therefore meta-synthesis for severe cases of COVID-19 and the risk of stroke cannot be performed with the existing studies. Similarly, it is impossible to meta-synthesize the risk of stroke associated with COVID-19 infection for all studies due to the lack of data on stroke characteristics among non-COVID-19 patients. Second, due to the lack of data of comorbidities for participants in the control group, analysis of the associated factors for stroke cannot be performed for this review.

Third, we also found that many varied types of blood tests were used for identifying inflammation and hypercoagulable state; thus, the usefulness of laboratory tests results in identifying patients with high risk for stroke could not be determined with the existing literature. Future research with bigger sample size is needed to rectify these important issues.

The occurrence of stroke in patients with COVID-19 infection is uncommon but poses as an important prognostic marker and severity indicator. This brief review suggests that ischemic stroke may occur early in the course of the illness, and may also affect patients in the younger age groups with no comorbidities, causing large vessel occlusion and exhibiting thrombo-inflammatory vascular picture. Given that many patients with COVID-19 share the common traditional risk factors for stroke, physicians must be vigilant in the future for an increase in the number of strokes in patients with COVID-19 as the pandemic continues and to take appropriate preventive measures. 

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This research received its funding from the Universiti Putra Malaysia under Putra Grant initiative (UPM/700-1/3/Geran Putra). The funder had no role in study design, data collection and analysis, preparation of the manuscript, or decision to publish.

We would like to thank the Director General of Health Malaysia for his permission to publish this article.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur. 2020.579070/full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2020 Lee, Yusof Khan, Ching, Chia, Loh, Abdul Rashid, Baharin, Inche Mat, Wan Sulaiman, Devaraj, Sivaratnam, Basri and Hoo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.