Introduction
Severe acute respiratory syndrome 2 (SARS-CoV-2) is the causal agent of the COVID-19 outbreak (1). At the global level, according to the National Center for Surveillance and Control of Communicable Diseases, a total of 244,089,628 cases of infection and 4,958,793 COVID-19-associated deaths had been confirmed (as of October 2021) (2).
Being primarily a respiratory disease with major pulmonary complications, it is characterized by fever, a non-productive cough, respiratory difficulties, dyspnea, and hypoxia in most patients, and signs of interstitial pneumonia on X-rays or CT scans; however, COVID-19 may also affect other organs, including the brain (3). Thromboembolic events have been reported after infection with SARS-CoV-2, primarily in the pulmonary vasculature, as well as an increased rate of thromboembolic complications of the nervous system with subsequent cerebrovascular accidents (4). The most common complication after infection with SARS-CoV-2 remains ischemic stroke, but cases of cerebral venous sinus thrombosis have been confirmed (4).
This infectious disease, caused by the most recently discovered coronavirus, COVID-19, can induce hypercoagulability associated with an increased prevalence of venous thromboembolism grouped with thrombotic complications, primarily connected to pulmonary vascularization, but these thrombotic complications may also involve the vasculature of the brain (for 2% of the patients with confirmed SARS-CoV-2 infection). Currently, the mechanism of thrombophilia associated with COVID-19 infection is not completely understood. However, it is known that the severe inflammatory response after the infection with SARS-CoV-2 virus leads to an outburst of cytokines which induces a pro-coagulable state. The virus has a specific pro-coagulative effect, and infection with this virus produces large-scale endothelial dysfunction and inflammation. Both Von Willebrand factor (VWF) and factor VIII (FVIII) are known to be highly rated for patients with COVID-19. These factors are not only connected to the risk of inflammation and thrombosis but are strongly connected to endothelial lesions. A decrease in the FVIII/VWF ratio in patients infected with the SARS-CoV-2 virus is associated with a higher risk of aggravation of the respiratory state followed by an increased need for oxygen (4).
A well-known characteristic of infection with SARS-CoV-2 is coagulopathy and the fact that hypercoagulability may lead to other complications associated with COVID-19, in particular, venous thromboembolic events and stroke. Disseminated intravascular coagulation, increased D-dimer levels, modified fibrinogen levels, fibrin or fibrinogen degradation products, thrombocytopenia, and the presence of antiphospholipid antibodies are all linked to SARS-CoV-2 infection and severity. However, there are a few case reports that have described cerebral venous sinus thrombosis (CVST) associated with SARS-CoV-2 infection (5).
Cerebral venous thrombosis (CVT) is caused by complete or partial occlusion of the major cerebral venous sinuses (thrombosis of the major cerebral venous sinuses) or smaller cortical supply veins and represents a common cause of stroke (6). It is a rare disease, accounting for ~0.5% of all cerebrovascular diseases worldwide (7). Prothrombotic hematological conditions, hormonal (oral contraceptive pill, pregnancy, puerperium, steroids), local factors (skull abnormalities/trauma, compressing mass or infection), systemic illness (dehydration, sepsis, malignancy or connective tissue disorders), or idiopathic causes (7) are all risk factors.
CVST is known to be a multifactorial disease, with at least one risk factor for 85% of the affected adult patients. Risk factors are associated with the Virchow triad of thrombogenesis (lesions of the vessel wall, hypercoagulability, and blood stasis). The most frequent risk factors associated with CVT are prothrombotic conditions. Patients known to have hereditary thrombophilia present with an increased susceptibility to developing any form of thrombosis, CVST included; the most frequent causes are V Leiden factor, polymorphism of G20210A prothrombin and antiphospholipid syndrome, and the rarest risk factors are antithrombin III deficiency, C protein deficiency and S protein deficiency (8).
Previously, a prognosis of CVT was fatal, especially due to tardive or post-mortem identification of the diagnosis. Most patients diagnosed with CVT today have a good prognosis, largely due to improvements in high-performance imaging methods. However, CVT management is notably complicated by SARS-CoV-2 infection. SARS-CoV-2 increases systemic hypercoagulability and thromboembolism and is associated with cerebrovascular diseases, particularly CVT (9).
For confirmation of neurological pathologies, diagnosis is established according to clinical manifestations, objective neurological examinations, paraclinical investigations (biological data analyzed during a patient's stay, and biological material collected to establish hereditary factors for thrombosis), and based on cerebral imaging. The most commonly used imaging methods are CT, native or with angiography, and magnetic resonance imaging (MRI), native or with angiography. Furthermore, the device used was a SIGNA Explorer 1.5 T (GE Healthcare). In order to determine the hereditary thrombosis profile, the test for the identification of mutations associated with thrombophilia, biological material/blood was collected and the equipment used was as follows: For acid DNA isolation a vortex combispin FVL-2400N (Biosan) and a Thermo-Shaker TS-100 centrifuge Hettich Universal 320R (Biosan); for DNA amplification, a Real-Time thermal cycler qTower 2.2 (Analytic Jena); and for hybridization and detection, a Thermo-Shaker PST-60HL (Biosan). The presence of infection with SARS-CoV-2 virus was detected using ARN SARS-CoV-2 testing by reverse transcription-quantitative PCR.
The purpose of neurological treatment is to eliminate the obstacle at the level of the sinus lumen or vessels affected and to stop the progression of a thrombus, to cure the prothrombotic status in order to prevent both venous thrombotic events and relapse (10).
Discussion
These case presentations describe cases of neurological disease in patients associated with SARS-CoV-2 infection hospitalized in the Neurology Section of Constanta County Hospital (Fig. 8). Although the data is limited, observational studies such as these improve our understanding of the evolution of a disease in patients affected by CVT and similar diseases, and its evolution in association with SARS-CoV-2 infection.
In the present report, the cases of two male patients aged 46 and 66, and a female patient aged 41 are presented. When hospitalized, each of these patients presented negative on a PCR test for infection with SARS-CoV-2, but the results of the test changed during hospitalization, along with various localizations of CVT, different risk factors, and distinctly associated pathologies. PCR may miss detection of individuals with SARS-CoV-2 infection, and early sampling minimizes false-negative diagnoses (11). It may be the case that the PCR test was taken too early or taken incorrectly, or the symptoms appeared a period of time after infection, which is why they were diagnosed first with CVST and then with COVID-19(5).
The patients had no direct contact with patients infected with SARS-CoV-2. There was no data on the vaccination status of patients, although this may not be as relevant given numerous reports of individuals infected with COVID-19 following vaccination or prior infection.
The first case described here was that of a male patient, aged 66, with left subacute venous transversal-sigmoid-jugular thrombosis indicated by the native cerebral NMR. The patient's associated risk factors, such as high blood pressure, newly discovered type II diabetes mellitus, and bilateral carotid atheromatosis, appeared in the hereditary thrombosis profile (genotype 5G/5G PAI-1 and haplotype A2/A2 of EPCR) and on the 14th day of hospitalization, the patient tested positive for COVID-19 following a PCR test.
The second case described a female patient, aged 41, with thrombosis in the right superior frontal subacute cortical tardive-vein, superior sagittal sinus, sinuses' confluent, sigmoid sinuses, and transverse on the right side; partially the right internal jugular vein was indicated on native NMR and angiography. The patient's associated risk factors such as uterine fibrosis, treatment with oral contraceptives, chronic tabagism, acute syphilis, severe posthemorrhagic hypochromic microcitary anemia, dyslipidemia and presented modifications at the hereditary thromboliphic profile [composed heterozygote for C677T and A1298C of MTHFR mutations, homozygote for 4G of PAI-1 mutation and haplotype A1/A1 (H1/H1) of EPCR]. On the 10th day of hospitalization, the patient was positive for COVID-19 infection following a PCR test.
The third case was a male patient, aged 46, who had thrombosis of the transverse and sagittal sinuses and in some bilateral frontal and parietal superior cortical veins in the CT native and contrast substance CT. The patient presented with SARS-CoV-2 infection on the 9th day of hospitalization. He presented with risk factors, such as high blood pressure, asthma, acute renal failure, and syndrome of hepatic cytolysis. The evolution of this patient's disease was not favorable, as he developed a vascular coma, and cardiac and respiratory arrest during hospitalization.
CVST presents as one of three clinical syndromes: Isolated intracranial high blood pressure (characterized by headaches, papillary edema, and visual problems), focal syndrome (accompanied by convulsions reported in 39.3%, paresis in 37.2%, and aphasia in 19.1% of cases), and encephalopathy (characterized by the alteration of the mental state, extended neurological signs, and coma). Risk factors include a genetic predisposition to thrombophilia, which can be determined in patients with CVST by assessing C protein deficit and S protein deficit (12), antithrombin III and factor V Leiden levels, and mutations of the G20210A prothrombin gene. Other risk factors, which may explain an increased predisposition to CVST in women more than in men, may be due to use of oral contraceptives, pregnancy, and puerperium. Among the risk factors, there are also focal infections at the level of the head, neck, and sinuses, or malign infections, particularly in older patients (12). However, a previous study indicated that up to 12.5% of cases did not present with any associated risks. Therefore, the lack of an associated risk suggests that the infection with SARS-CoV-2 virus acted as a potential etiological factor in the development of CVST (12).
In the study by Cavalcanti et al (13), three patients (<41 years old) were infected with SARS-CoV-2 virus and cerebral vein sinus thrombosis. One patient in the study presented with thrombosis in both the superficial and profound venous systems. Another patient showed involvement of the right sinus, Galen vein and internal cerebral veins. The third patient had thrombosis in the profound spinal veins. Additionally, two of these patients experienced hemorrhagic venous heart attacks. On average, the time from the onset of symptoms indicating SARS-CoV-2 infection to a thrombotic event was 7 days, with a range of 2 to 7 days. It is worth noting that one of the patients had recently been diagnosed with diabetic ketoacidosis, while another patient was using oral contraceptives. All three patients had an unfavorable evolution and eventually succumbed to their conditions. Even though COVID-19 is severe and its primary effect is acute respiratory distress, cardiac disorders, acute renal disorders and thromboembolic events are increasingly being reported (13). The association between profound cerebral thrombosis and potentially fatal complications may complicate the initial clinical presentation of a patient infected with COVID-19. The cases presented herein offer us a new perspective on the fact that such cases display insights regarding the proofs accumulated according to which COVID-19 contributes to hypercoagulation and therefore increases the risk of mortality (13).
In the present study, the third case was an uncommon manifestation of catastrophic CVT in a relatively young patient who had previously only presented with asthma and was infected with SARS-CoV-2, with an unfavorable outcome, leading to exitus. In the study by Cavalcanti et al (13), in the case of symptomatic CVT with a recent COVID-19 infection, one patient presented the same risk factor as case 2 in the present study, the use of oral contraceptives; COVID-19 infection was almost certainly a risk factor synergistic in both studies. Based on the given statement, it can be understood that in the present study, the third case described an uncommon manifestation of catastrophic cerebral venous thrombosis (CVT) in a relatively young patient. This patient had previously only been diagnosed with asthma and was also infected with SARS-CoV-2. Unfortunately, the outcome for this patient was unfavorable, leading to death (exitus).
The statement then refers to a study conducted by Cavalcanti et al (13), where a similar risk factor was observed in a patient with symptomatic CVT and recent COVID-19 infection. Specifically, in both the present study (case 2) and the study by Cavalcanti et al, the use of oral contraceptives was identified as a shared risk factor. Additionally, it suggests that COVID-19 infection likely acted as a synergistic risk factor in both cases, indicating that the combination of COVID-19 and oral contraceptive use may have contributed to the development of CVT.
Additionally, the study by Hameed et al (9) also included one patient who had used oral contraceptives. Another similarity of our study and the case report by Cavalcanti et al (13) is the fact that the patients from both studies received antibiotic treatments. A similarity between our study and the studies by Cavalcanti et al (13) and Hameed et al (9) consisted of the fact that in the present study, at least one patient exhibited dehydration, which is known to be a contributor to the pathology of COVID-19.
Mowla et al (5) presented a case series of 13 individuals with symptomatic CVT and concurrent COVID-19 infection from Iran, Singapore, and the United States. The mean age of the SARS-CoV-2 positive patients was substantially greater than that of the CVST-positive patients in the control sample. Their patients exhibited a much lower prevalence of recognized CVST risk factors than the general population. That is, the older age and considerably fewer risk factors for CVST in comparison to the non-SARS-CoV-2 infected comparison group suggested that SARS-CoV-2 infection may have served as a precursor for CVST. The statement suggests that in the comparison group, the patients infected with SARS-CoV-2 were older and had fewer risk factors for CVST compared to the non-SARS-CoV-2 infected group. This observation indicates that SARS-CoV-2 infection may have acted as a potential precursor or trigger for the development of CVST, considering that the infected group had an older age and fewer established risk factors for the condition.
Hameed et al (9) studied 20 cases with symptomatic CVT and recent COVID-19 infection from Pakistan, Egypt, Singapore, and the United Arab Emirates. In the same study, the most frequent neurological manifestations were headaches and seizures. Although mortality was high, survivors had a favorable functional neurological result.
The novelty of the present study compared with previous studies, comes from the fact that our patients were also tested for their hereditary thrombosis profile and the test revealed gene mutations. Furthermore, the patients were previously relatively healthy (one patient had asthma and the other was diagnosed at admission with diabetes type 2) and did not have any pathological antecedents in this area; thus, the COVID-19 infection was almost certainly an additive risk factor. It is also noteworthy as, in contrast to previous studies, in the present study, the patients were admitted due to their neurological symptoms and the COVID-19 infection was detected later. In the study of Hameed et al (9), CVT was a presenting characteristic in 65% of patients, whereas 35% of patients developed CVT when receiving treatment for COVID-19 infection. Additionally, in the study of Mowla et al (5), only one patient was asymptomatic at presentation; thus, another novelty of the present study is that the patients were asymptomatic at presentation, but CVST was present and apparent.
Additionally, in patients with severe COVID-19, rapid clinical deterioration or exacerbation could be associated with a neurological event, possibly CVST, adding to the disease's high fatality rate. Furthermore, physicians may consider SARS-CoV-2 infection as a differential diagnosis when dealing with patients who exhibited these neurological symptoms simultaneously during the COVID-19 pandemic in order to avoid a late diagnosis or misdiagnosis. Furthermore, accurate epidemiological data and pathophysiological results are necessary to aid future therapeutic management.
In summary, the present case series provides cases to exemplify that COVID-19 may serve as a significant contributor to hypercoagulation, thus increasing the potential lethality of the disease. Increased recognition of this uncommon but possibly curable consequence of COVID-19 infection is thus recommended, particularly given that the present is the only such study assessing COVID-19 infection in patients with CVT from Romania and South-East Europe, to the best of our knowledge.
In conclusion, patients with COVID-19 are at an increased risk of stroke, especially in the first 10 days after infection. A particular form of stroke is presented by CVT; the pathophysiological mechanisms presented are immune systemic processes, a cytokine storm leading to increased blood viscosity, and thrombogenesis within the state of hypercoagulability, at the same time producing inflammation marked by the increase of prothrombotic factors.
Recent data collected from research and studies supports that there is an increase in neurological pathologies, such as thrombotic complications of the sinuses and cerebral vessels for patients confirmed to be infected with SARS-CoV-2. Risk factors for CVT include infections, oral contraceptives, pregnancy, hematological disorders, mechanical or traumatic factors, autoimmune inflammatory disorders or even malign pathologies. Coexistent risk factors and age are well-defined risk factors for the development of CVT. Moreover, an association of the infection with SARS-CoV-2 virus for these patients may involve the onset of a procoagulant cascade and the evolution of the clinical status of the patient.