A subsequent detailed analysis of the clinical characteristics and outcomes of these patients was performed, aimed at bridging the knowledge gap in the literature regarding the definitive impact of COVID-19 on individuals with acute cerebrovascular syndrome. Within this context, it is imperative for healthcare establishments to disseminate their clinical findings pertaining to patients undergoing treatment for COVID-19 who have concurrently manifested acute neurovascular syndromes. The availability of such data is crucial to enhance our comprehension of a multitude of clinical scenarios, including:
1) Identifying which patients would benefit from screening for SARS-CoV-2 infection, for instance, in the assessment of an acute stroke with an undetermined cause (what would be the optimal timing to request the infection detection test? Could the test result alter the treatment approach or necessitate a specific care protocol?);
2) Would it be possible, by considering the symptoms and signs upon admission in conjunction with clinical characteristics and personal history, to identify which patients might be at a heightened risk of developing an acute neurovascular syndrome even after COVID-19 vaccination and exhibiting signs of acute infection? Could this knowledge impact, for example, the administration of novel oral, intravenous, and immunomodulatory treatments for COVID-19?
3) Assessing the need to systematically screen patients with COVID-19, irrespective of respiratory symptoms, who present with stroke and lesion patterns consistent with microangiopathic disorders or coagulopathies, is crucial. This screening is aimed at identifying which patients are at an elevated risk of subsequent vascular incidents owing to the presence of either inherited or acquired coagulopathies. It is essential to consider that the virus could potentially act as a definitive risk factor, essentially an infectious catalyst provoking the onset or exacerbation of autoimmune diseases, autoinflammatory states, or thrombophilia. Alternatively, it could represent a transient influence, exacerbating complications from infectious agents.
Hence, it becomes evident that there exists a complexity and critical necessity to categorize these cases not solely relying on the conventional TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment), but to pursue a more comprehensive—yet simultaneously practical—classification. Such an approach can more accurately aid in assessing the risks of recurrent events, thus enabling the formulation of the most effective strategy regarding secondary prophylaxis.
The study included a cohort of 17 patients experiencing strokes (10 ischemic strokes and seven hemorrhagic strokes). The mean age was 59.8 years with a standard deviation of 14.6 years, and there was a slight female predominance with 9 female patients (52.9%). A substantial majority, 88.2%, were residents of São Paulo city, with the entirety hailing from the state of São Paulo. Notably, only two patients originated from the immediate outlying regions of Greater São Paulo, indicating that the patient demographic typically reflects the population served by our institution, with no inter-state referrals or transfers from distant municipalities.
It is noteworthy that the patients with cerebrovascular syndrome included in the study primarily presented with symptoms characteristic of an influenza-like syndrome, with fever and cough in 64% of the cases, and dyspnea in 53% of the cases. None reported anosmia or hyposmia as a primary complaint initially. Most case admissions were due to respiratory or systemic symptoms, with a lesser incidence of gastrointestinal symptoms, and none displayed changes in olfaction or taste. Data from the literature suggests that patients exhibiting more severe systemic manifestations may be indicative of advanced disease. However, it is not yet possible to determine from the available literature whether the presence or absence of olfactory and gustatory disturbances at clinical onset correlates with specific disease progressions or neurological outcomes.
The cardiovascular risk factors identified included hypertension in 64.7% of cases, diabetes mellitus in 52.9%, active smoking in 23.5%, chronic kidney disease in 11.8%, and obesity in 11.8%. It is critical to highlight that none of the cases involved patients with prior arrhythmias such as atrial fibrillation, a major risk factor commonly observed in stroke patients across numerous epidemiological studies. The absence of atrial fibrillation in our cases is noteworthy as it would constitute a significant confounding factor in the analysis of the targeted profile.
Another notable observation from the evaluation of the selected patients, consistent with findings in epidemiological studies on strokes and COVID-19, is the high rate of patients requiring hospitalization (88.2%). Among these hospitalized individuals, 80% required intensive care unit (ICU) support. In our case series, all these patients (100%) presented with severe COVID-19 infection, secondary bacterial infection, and required mechanical ventilation. Moreover, among those admitted to the ICU, 73.3% developed acute kidney injury necessitating hemodialysis, with a similar proportion succumbing to the illness (73.3%). These findings underscore the progression of these patients' conditions, despite receiving comprehensive clinical, neurological, hemodynamic, infectious, and 24-hour neurofunctional rehabilitation support in the face of severe COVID-19 and cerebrovascular events.
In this study, we delineate the clinical features of patients with neurological disorders diagnosed with cerebrovascular diseases, documenting the clinical ramifications in those infected with COVID-19 admitted to a major tertiary hospital in São Paulo, Brazil, during the first and second waves of the COVID-19 pandemic. Our case cohort revealed a diverse array of neurological disturbances associated with COVID-19, including inflammatory and non-inflammatory encephalopathy syndromes, reactivation of demyelinating diseases, neuromuscular junction diseases, movement disorders, epileptic crises, and acute polyneuropathy and myopathy, among others. Notably, from the pandemic's onset, the severity of cerebrovascular disease cases stood out prominently in neurological evaluations.
Research aimed at assessing the correlation between cerebrovascular diseases, stroke, and COVID-19 often faced obstacles due to intra-hospital investigative logistics during the pandemic, compounded by restrictions inherent to each service's internal protocols. The absence of detailed clinical, radiological, and laboratory outcomes for the neurological disturbances in hospitalized COVID-19 patients underscores the challenges encountered in understanding the natural history of COVID-19's complications within this patient cohort.
The occasional delay in disease identification and hesitancy to seek hospital admission during the pandemic's initial peak—stemming from fear, isolation, or patient protection—may have worsened the severity of both the disease and neurological disorders at the time of medical diagnosis, thereby contributing to an adverse prognosis for these patients in our geographical area.6,7
Based on the systematic review by Purja et al.9, the neurological complications of COVID-19 are diverse, and direct viral neuroinvasion is rare. The authors identified 2,387 studies on this relationship and included 167 in which the PCR test (polymerase chain reaction) for SARS-CoV-2 virus detection was performed in cerebrospinal fluid (CSF) from 101 patients. The PCR test was positive in only four CSF samples out of the 101 cases, and olfactory dysfunction was present in just two of these four cases. Therefore, we may infer that the direct cytopathic effect of the virus on host cells is not the most likely mechanism behind neurological complications.
The observed central and peripheral neurological manifestations were heterogeneous. The most common neurological diagnoses were Guillain-Barré syndrome (GBS) and its variants (24%), followed by encephalopathy (21%), which may be more associated with autoimmune conditions and/or complications in hemostasis and perfusion of target organs rather than the direct effect of the virus. Thus, we note that the findings of the systematic review, as well as in our studied patient group, have a common point.
It is evident that complications can be significantly more severe in a subset of patients who are more susceptible to the inflammatory and/or immune effects mediated by systemic inflammation, hence the importance of closely monitoring cases in patients with higher cardiovascular risk factors (which are also risk factors for metabolic syndrome, a systemic inflammatory disease). In our group, we present these factors using the mnemonic of SHOCK (Fig. 02).8,9
There are three primary mechanisms by which a virus may breach the blood-brain barrier (BBB): transcellular migration, paracellular migration, and the 'Trojan horse' approach, wherein viral particles are phagocytized by neutrophils and macrophages that transport the virus to the central nervous system. Recently, specialized viral molecules called fusogens have been identified as agents capable of fusing the viral envelope with neuronal or glioneuronal cell membranes, facilitating entry into the cells and leading to the formation of syncytial units between neurons and glial cells. This process remains poorly characterized and elusive in detection but could potentially shed light on some of the neurological sequelae of viral infections of the nervous system. Additionally, it may provide insight into the severity of neurological complications following stroke, whether ischemic or hemorrhagic.8,9,10,11,12
The viral crossing of the blood-brain barrier (BBB) precipitates three principal events: endotheliopathy, an inflammatory response, and the activation of immunity. These events instigate the activation of astrocytes and microglia, the release of pro-inflammatory cytokines, and a specific immunological response of the central nervous system (CNS) that may subsequently be responsible for neural tissue damage and the neurological symptoms of neuro-COVID. Understanding the pathophysiology of neurological manifestations is increasingly critical, even now, amid widespread vaccination against SARS-CoV-2, as the interaction between host and virus remains extensive. The response to viral exposure is markedly heterogeneous and individualized, with the progression to either a mild or severe clinical picture remaining enigmatic, particularly concerning acute phase risk factors and the development of chronic COVID. Various hypotheses regarding its pathogenesis have been considered, including the potential for a persistent SARS-CoV-2 reservoir in tissues and immunological dysregulation with viral transactivation (for instance, in relation to herpesvirus family agents such as Epstein-Barr virus and human herpesvirus 6). Moreover, studies have revealed SARS-CoV-2's impact on the microbiota, particularly the virome, as well as instances of autoimmune activation, immune system dysregulations, coagulopathy with endothelial dysfunction, brainstem alterations, neural signaling disturbances, and genetic changes.8,10,13,14
The precise underlying mechanism that triggers stroke in patients with COVID-19 remains elusive, but pre-pandemic studies suggest that cerebrovascular pathology following viral infection may result from endothelial dysfunction driven by inflammation and hypercoagulability15. It is observed that inflammation-induced damage to the endothelium, whether systemic or local, can trigger a cascade of coagulation events, leading to thrombosis, destabilization of atherosclerotic plaques, and occlusion of major blood vessels, ultimately resulting in ischemic stroke16. Furthermore, the SARS-CoV-2 virus reduces the levels of the ACE2 enzyme, leading to an increase in Angiotensin II, which, in turn, activates the Angiotensin II type 1 receptor (Ang2). This activation results in the production of inflammatory cytokines such as IL-6, TNF-α, MCP-1, and IL-8 through the NF-κB signaling pathway. This cascade of events causes immune-mediated dysfunction and injury 17. Additionally, patients diagnosed with COVID-19 are observed to be at a higher risk of developing a state of hypercoagulability within their vasculature. Research indicates that these individuals exhibit elevated levels of factor VIII, fibrinogen, and D-dimer, all of which are directly involved in the coagulation process.19,20
It is important to remember that the ACE2 enzyme is known as a critical enzyme in the renin-angiotensin system (RAS), which regulates blood pressure, fluid and electrolyte balance, and vascular resistance. Additionally, ACE2 plays a role in inactivating angiotensin II.21, 22 Therefore, the downregulation of ACE2 expression during SARS-CoV-2 infection can lead to an increase in Ang2 levels in the serum. This, in turn, can impair endothelial function and contribute to the dysregulation of blood pressure, thereby increasing the risk of hemorrhagic stroke.23 When considering that in previously hypertensive patients, ACE2 expression is already low, it can be presumed that when SARS-CoV-2 binds to ACE2 receptors, the ability of ACE2 to reduce blood pressure will be concurrently reduced. Therefore, COVID-19 infection is more likely to induce cerebral hemorrhage in such cases.24, 25 Therefore, it is reasonable to assume that in patients with COVID-19, the cytokine storm and elevated blood pressure may increase the risk of hemorrhagic stroke. However, despite all this evidence, molecular medicine studies, and previous studies on the relationship between viral infection and strokes, whether hemorrhagic or not, it is difficult to establish certainty of a cause-and-effect relationship and claim that stroke is directly related to COVID-19 infection.26