Initially, neurological manifestations were not the focus of attention in the scientific discourse of SARS-CoV-2. In the meantime, an increasing number of articles on the neurological manifestations of SARS-CoV-2 have been published, even first reviews that summarize these data [34–36]. While previously published reviews covered a wide range of neurological symptoms and included case reports for all outcomes, we focused on CNS disorders and prespecified a best-evidence approach. Although ours is a rapid review, it has methodological advantages such as a discriminated literature search, a risk of bias and GRADE assessment, and the inclusion of a quantitative analysis (regarding acute ischemic stroke). We consider these steps necessary to assess the available evidence.
Our meta-analysis of four cohort studies including a total of 851 patients with COVID-19 infections showed that 3.3% (95% CI: 2.2–4.9; follow-up range one to five weeks) suffered from an ischemic stroke. The Wuhan study was the only one of the included publications that provided the data of the total population and of the stroke patients separately[6]. A comparison of these results with an epidemiological study of patients with ischemic stroke in China (n = 19,604, median age 65 years) is limited due to the low number of cases in the Wuhan COVID-19 study. However, in the Wuhan COVID-19 study, previous cardio-cerebrovascular diseases were known in fewer patients with an acute cerebrovascular event (23.1% vs. 42.7% [atrial fibrillation and previous stroke or TIA]), and diabetes was two times more frequent than in the epidemiological study (46.2% vs. 20.7) [6, 37]. The percentage of patients with previous arterial hypertension was similar in both studies. In regard to age, a case series of five COVID-19 ischemic stroke patients with a lower age (ranged between 33 and 49 years) remains outstanding [38].
In comparison to our meta-analysis, Yaghi et al. described a lower rate of ischemic strokes in patients with COVID-19 infections in New York City with a follow-up of up to four weeks [39]. Referring to 3,556 hospitalized COVID-19 patients, the researchers reported 32 patients with COVID-19 that suffered from an ischemic stroke. That indicates an incidence of ischemic stroke in COVID-19 patients of 0.9%. However, they did not specify where they derived the number of 3,556 COVID-19 patients and did not state the characteristics of the total population. Furthermore, not all of the 3,556 COVID-19 patients were tested for SARS-CoV-2 with a PCR test. The fact that stroke patients without respiratory symptoms of COVID-19 may have been wrongly excluded should not be underestimated. Particularly, as we know, patients with severe cases of COVID-19 have fewer typical symptoms, such as dry cough and fever, than patients with mild cases of COVID-19. [22] In regard to the data provided, it is not possible to draw conclusions about the stroke incidence and, therefore, we decided against a post-hoc inclusion of this study. In contrast, in the two larger studies included in our meta-analysis, COVID-19 was laboratory proven in all patients, and the baseline characteristics of the population were described in detail [6, 21].
In the past, respiratory infections in general were repeatedly associated with an increased incidence of ischemic stroke [40–43]. In 2018, Blackburn et al. presented their results of a time-series analysis of English hospital admissions for stroke and myocardial infarction [40]. They reported that respiratory viruses except parainfluenza were significantly associated with ischemic stroke admission in the elderly (≥ 75 years). In particular, influenza was widely discussed in the scientific discourse because an influenza vaccination is available and may possibly lead to a risk reduction [44]. However, the evidence is limited due to the lack of randomized controlled studies. A high concentration of C-reactive protein (CRP) was also discussed as a marker of elevated risk of ischemic stroke [45]. In the Wuhan study, the mean CRP concentration in patients with cerebrovascular events was significantly higher than in those without (51.1 mg/dl vs. 12.1 mg/dl) [6]. Nevertheless, the relevance of CRP to ischemic cerebrovascular disease remains unclear. Associations with ischemic stroke depend significantly on conventional risk factors and other laboratory signs of inflammation [45]. Of course, treatment teams must also consider laboratory signs and the general risks of hypercoagulability. Further, confounding atrial fibrillation must be taken into account because previous studies showed that new-onset atrial fibrillation occurs more frequently in the context of sepsis [46, 47]. The presence of atrial fibrillation was not explicitly stated in any of the included studies of our meta-analysis.
Genetically related coronaviruses caused SARS and MERS pandemics. During these past pandemics, virus-related neurological symptoms and acute cerebrovascular disease were rather a marginal issue. [48] The latter had been associated with the intravenous administration of immunoglobulins. Umapathi et al. reported five patients with large artery cerebral infarctions among 206 SARS patients in Singapore. Three of the five patients received intravenous immunoglobulins. The proportion of critically ill cases was 23.3%; further information on the age and comorbidities of the study population was not reported [49]. In comparison, the proportion of severe cases in the two larger COVID-19 studies was 42.7% and 17.3%, respectively [6, 21].
In SARS and MERS, there have also been isolated case reports of associated infectious/inflammatory brain diseases, of which only two showed positive PCR results in CSF analyses [12, 15, 50]. In addition, in SARS, the virus was detected in the brain tissue of an affected patient [14] and of autopsied patients [11, 13]. The current pandemic involves several isolated cases of infectious/inflammatory brain diseases associated with SARS-CoV-2, however, only two cases in which the virus was detected in the patient’s CSF [26–28]. It is generally accepted that a positive PCR result in the CSF is an indication of direct viral infection of the brain. However, one must bear in mind that during COVID-19, a marked systemic inflammatory response syndrome (SIRS) has been described [51]. In this context, the proinflammatory cytokine storm is likely to lead to an increased permeability of the blood–brain barrier [52]. The receptor by which SARS-Cov-2 enters its host cell is the angiotensin-converting enzyme 2 (ACE2) receptor. Immunohistochemistry for the ACE2 receptor in CNS tissue, though with limited description, failed to show neuronal or glial positivity but did confirm it in the brain vasculature [8]. Hence, viral replication in the brain’s microvasculature in parallel with an open blood–brain barrier could explain the CSF detection of virus particles despite the absence of neuronal/glial cell invasion. An additional receptor binding the spike protein of SARS-Cov-2 has been possibly recognized in CD147 through an in vitro experiment, and CD147 is widely present in the CNS [53]. However, taken together with the paucity of reports on meningoencephalitis associated with COVID-19, direct CNS infection seems to be rare or confined to very special patient/virus constellations during SARS-Cov-2.
In both reported cases referenced in the current review, the CSF results were not presented sufficiently to allow a more precise interpretation regarding an impairment of the blood–brain barrier, and the results of important diagnostic tests were missing (e.g., brain imaging, exclusion of further neurotropic viruses, intrathecal synthesis of antibodies) [26–28]. At least, the following must be considered: CSF tests for SARS-CoV-2 were rarely reported, and the test accuracy of the various test kits was not specified. It is to be expected that a possible positive result can also be a false positive. That is why the data extraction of case reports included whether the CSF PCR tests were repeated. Overall, in only two case studies were the PCR tests on the CSF samples repeated [24, 28], and in one the results were SARS-CoV-2-positive twice [28].
Overall, our results support the assumptions of other reviews. Considering the results in context with those of previously published studies, the following implications can be outlined: The treatment team for patients with an infection of SARS-CoV-2, particularly with severe disease progression, should be aware of the development of neurological signs and symptoms. The integration of neurologists into the multiprofessional COVID-19 treatment team can help detect neurological complications early. Introducing a suitable risk assessment concerning hypercoagulability in severe COVID-19 cases may be particularly important, following a recent meta-analysis that revealed that acute cerebrovascular disease in COVID-19 patients was associated with an increased poor composite outcome and mortality [54].
Furthermore, in the pandemic situation, even if the symptoms are exclusively neurological, a SARS-CoV-2 infection should be considered, and patients should be tested accordingly.
Obviously, more clinical studies are needed to improve the current evidence of the neurological CNS manifestations of SARS-CoV-2. In our search we also identified ongoing studies, which can provide more detailed information, for example, on the prevalence of acute encephalopathy in severely ill COVID-19 patients or on the long-term cognitive deficits in COVID-19 patients with acute neurological symptoms [55, 56].