Cerebral vasospasm after subarachnoid hemorrhage from intracranial aneurysm rupture in SARS-CoV-2 positive patients. A retrospective review from two Bulgarian hospitals

Abstract Intracranial aneurysms are acquired lesions resulting from hemodynamic stress on the vascular wall. Their rupture usually presents as a subarachnoid hemorrhage (SAH) with a high mortality rate. Cerebral vasospasm follows, which leads in many cases to delayed brain ischemia and even death. We aimed to explore the relationship between cerebral perfusion and coronavirus disease (COVID-19) in aneurysmal SAH. We analyzed 42 cases that underwent treatment for proven SAH due to ruptured cerebral aneurysms between January 2020 and December 2021. The patients were treated adhering to a standard protocol. The cerebral vasospasm was assessed by measuring the difference in the mean arterial pressure of the carotid artery relative to the internal cerebral artery (Lindegaard’s ratio) by transcranial Doppler ultrasound for 12 consecutive days. Twenty-three patients showed no signs of an acute respiratory syndrome associated with COVID-19 but tested positive for the SARS-coronavirus 2 (SARS-CoV-2). The control group included 19 SARS-CoV-2 negative cases. The mean age was 59.7 ± 8.4 years (range 44-72), with 29 males and 13 females. The mean arterial pressure was without a significant difference of 89.3 ± 3.3 to 89.7 ± 3.7 mmHg in SARS-CoV-2 negative to positive patients. When viral infection was evident, we observed a higher Lindegaard’s ratio of 2.12 ± 0.36 than the control, with a value of 1.43 ± 0.33 (p < 0.01). Thus, brain perfusion was 32.5% better in negative patients. We suggest that SARS-CoV-2 positive patients, without acute COVID-19, are more likely to have worse brain perfusion after SAH from cerebral aneurysm rupture.


Introduction
Intracranial aneurysms are acquired lesions resulting from hemodynamic stress on the vascular wall, which are most often localized in the area of the bifurcations of the cerebral arteries in their cistern segments. In about 85% of cases, they engage the anterior part of the circle of Willis. The aneurysms are most common in the anterior vascular complex with the anterior communicating artery (30%), followed by the internal carotid artery with the posterior communicating artery (25%) and bifurcation of the middle cerebral artery (20%). The rest affects the vertebrobasilar system. In about 20% of cases, multiple aneurysms could be found [1].
The rupture of a brain aneurysm usually presents as a subarachnoid hemorrhage (SAH). Patients describe the sudden headache, which is an initial symptom, as the strongest in their life. Furthermore, the typical blood localization is often associated with intraparenchymal, subdural or intraventricular collections with the corresponding clinical manifestations. Consequences of such acute neurological severe conditions are high mortality and severe disability in a significant proportion of patients [2]. A lightning headache without evidence for hemorrhage is also observed, often responsive to drug treatment. The cause might be aneurysmal expansion, thrombosis or intramural bleeding without rupture [3].
Secondary to aneurysmal SAH is cerebral vasospasm, which often leads to delayed brain ischemia and even death. This complication may also follow other pathologies associated with intracranial subarachnoid hemorrhages like rupture of arteriovenous malformations, head trauma, brain surgery and endovascublar procedures [4,5]. The term vasospasm COVID-19; aneurysmal subarachnoid hemorrhage; Lindegaard's ratio; transcranial Doppler ultrasound; cerebrovascular vasospasm; acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in 1951 from Ecker and can be considered in the context of clinical and radiographic findings [6].
Radiographic vasospasm is an arterial lumen reduction with a delay in contrast filling and decreased blood flow. The most reliable and accurate method for detecting and evaluating this phenomenon is conventional angiography. However, it is invasive and carries risks, proven in many studies [7]. The approach to confirm the diagnosis relies on previous or subsequent angiographies showing the same vessel of average diameter. The angiographic vasospasm after SAH has an incidence of about 50% [8]. A non-invasive method is transcranial Doppler (TCD) ultrasound, which measures the blood flow velocity in the major branches of the anterior circle of Willis [9]. Clinically symptomatic vasospasm after SAH leads to the so-called delayed ischemic neurological deficit. It is characterized by auto-and allodisorientation and/or a suppressed level of consciousness, sometimes with focal neurological deficits, including speech disorders or muscle weakness.
A growing number of reports associate certain nervous system manifestations with the coronavirus disease 2019 (COVID-19), which is an emerging and rapidly evolving pandemic situation. At the end of November 2021, the World Health Organization (WHO) confirmed 260 867 011 cases with 5 200 267 deaths worldwide. From clinical observations and studies, there is increasing data that infection with SARS-CoV-2 leads not only to pneumatological complications but also systemic inflammatory reactions and neurological symptoms [10,11]. Moreover, nervous system manifestations were significantly more common in severe compared with mild disease [12]. Among the florid clinical presentation, evidence of diffuse endothelial inflammation was reported in a series of patients with COVID-19 [13]. With the inducted coagulopathies, studies demonstrate that acute ischemic infarcts and intracranial hemorrhages dominate imaging features in brain involvement [14].
The study aimed to explore and analyze the relationship between cerebral perfusion and the effect of SARS-CoV-2 infection in patients with aneurysmal subarachnoid hemorrhage.

Ethics statement
All procedures performed in studies involving human participants were in line with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethical Boards of University Hospitals "St. Ivan Rilski" and "St. Anna" Sofia, Bulgaria. Written informed consent was obtained from all patients during the treatment.

Patients
We conducted a retrospective analysis on 42 patients who underwent treatment for ruptured cerebral aneurysms in the acute stage. Local governmental pandemic regulations included real-time RT-PCR assay targeting RNA-dependent RNA polymerase (RdRp), envelope (E) and nucleocapsid (N) genes of SARS-CoV-2 for every patient that was admitted to our facility taken at the time of hospitalization. Laboratoryconfirmed positive patients were referred to a dedicated neurointensive care COVID-19 unit. We employed a control group of SARS-CoV-2 negative patients with aneurysmal subarachnoid hemorrhage due to a rupture of an aneurysm. These patients were selected to radiologically and clinically match the same inclusion criteria with the SARS-CoV-2 positive group.
The study includes cases between January 2020 and December 2021 in the Department of Neurosurgery of St. Ivan Rilski" University Hospital and University Hospital "St. Anna", Sofia, Bulgaria. Postoperative care and observation then followed in the Department of Anesthesiology and Intensive Care of both hospitals. All medical records were evaluated, including the ASA, Fisher, and Hunt&Hess scores. Patients with Fisher grade I (no SAH detected) or IV (intracerebral and/or intraventricular hemorrhage regardless of SAH), as well as Hunt&Hess grades IV and V, were not included in the study [15,16].
Patients were monitored daily via TCD (Philips CX50 Ultrasound System), and their Lindegaard's ratios (LR) were calculated. Briefly, the examination requires a temporal window to expose the anterior circulation. We determine the velocity at the internal carotid (ICA) and medial cerebral artery (MCA), thus LR = V MCA /V ICA . This ratio is used to assess the presence and severity of vasospasm in the MCA [17]. All patients received an intravenous infusion of calcium channel blocker (nimodipine), adhering to a standard treatment protocol. Routinely, all of them were kept in normovolemia (defined as central venous pressure 8-12 cmH20 and normal hematocrite) with mean arterial pressure around or above 90 mmHg with vasopressor when necessary. Normal blood oxygenation and saturation was maintained as well.

Data analysis
Statistical analyses were completed using SPSS (version 23, IBM Corp., Armonk, NY, USA). A descriptive analysis of the consecutive time points measurements of LR, mean arterial pressure (MAP), and glasgow coma scale (gCS) was done. Data are presented as mean values with standard deviation (±SD). Comparison of means of LR between SARS-CoV-2 positive and SARS-CoV-2 negative patients was done by using independent samples t-test. We considered differences as statistically significant at the p < 0.05 level.

Results
Twenty-three patients were PCR positive for SARS-CoV-2 (without acute respiratory syndrome associated with COVID-19) and had proven aneurysmal SAH. Another 19 were PCR negative cases. Table 1 presents a summary of the demographic and clinical characteristics of both groups. The mean hospital stay was 12.4 days (range 6-46 days). Out of the 42 patients, four died during observation. Three of them were PCR positive for the virus. All fatal cases were Hunt&Hess grade III with multiple comorbidities and severe vasospasm. Statistically significant correlations between factors, however, were not found. None of the patients in the study had evidence of vasospasm past day 11 as measured via TCD.
The gCS points and MAP values (89.3 ± 3.3 vs. 89.7 ± 3.7 mmHg in SARS-CoV-2 negative vs. positive patients) were similar in the two groups in the corresponding period. On the other hand, we observed a significantly higher LR of 2.12 ± 0.36 in SARS-CoV-2 positive patients compared to 1.43 ± 0.33 in the controls, p < 0.01 (Table 2 and Figure 1). The neurological impairment and the corresponding Hunt&Hess grading showed no strong association with the presence and severity of vasospasm.

Discussion
A report on COVID-19 patients from Wuhan, PR China, stated that 36% of them had neurological manifestations, 6% had acute cerebrovascular events. These accidents events are more common in critically ill patients with comorbidities, corroborating a multifactorial mechanism for their occurrence [11]. To avoid such factors, e.g. hypoxemia related to perfusion abnormalities due to pulmonary vascular shunting [18] and impairment of oxygen coupling to hemoglobin [19], we included only patients with mild disease in our study. We did not observe mortality directly related to the viral illness in clinical means. However, Chougar et al. [20] reported MRI findings in 58.9% of patients with newly developed neurological symptoms in the course of COVID-19. Kremer et al. [21] even observed perfusion abnormalities in all cases with a severe infection on oxygen therapy and neurologic manifestation. In our study, brain MRI was not performed mainly due to logistical reasons.
To our knowledge, SARS-CoV-2 has a complex effect on a primary severe condition such as aneurysmal   subarachnoid hemorrhage. There are different mechanisms of action associated with hypoxemia, coagulation impairment, endothelial inflammation and indirect alterations due to multiple-organ dysfunction [22,23]. Furthermore, SAH is also complicated with fever and pulmonary changes, which are hardly differentiated from finding the viral disease [24]. Now, most medical centers have postponed elective surgery to free resources for patients with COVID-19. However, some emergent surgical and endovascular interventions are inevitable for life-threatening conditions such a SAH. Early and aggressive actions reduce morbidity and mortality [25], but in the current pandemic situation, the right timing and treatment approach, in general, is still unknown. We established that patients with higher MAP and negative PCR SARS-CoV-2 tests had better brain perfusion, respectively higher LR. Patients in the PCR positive group without acute COVID-19 symptoms had worse brain perfusion in almost the same MAP. None of the available clinical studies demonstrate a relationship between anesurysmal SAH and increased risk or severity of vasospasm due to COVID-19. However, to date, many patients with SARS-CoV-2 infection have a cytokine storm syndrome. The pathophysiological consequences lead to the release of endothelin-1, angiotensin-II, phospholipase A-2 and other factors, which, in turn, induce vasoconstriction of the affected vessel, increased vascular permeability, and the destruction of microvascular architecture, thus aggravating the effects of inflammation and damage of multiple organs. Identification of this state and the appropriate treatment may reduce the morbidity and mortality rates [26]. Fiani et al. [27] hypothesized a relationship between inflammation and deterioration of the vascular integrity, which suggests that certain changes in the vessels are responsible for precipitating cerebral aneurysm formation and rupture. One proposed explanation for such a connection is that the proinflammatory cytokines and cytotoxic cells result in endothelial injury. This loss of integrity in the vasculature due to the cumulative effects of ischemia, rigorous vasoconstriction of the damaged vessels and resultant increase in shear wall stress, release of proteases and reactive oxygen species, which all occur during states of hyperinflammation, makes a predisposition not only to an aneurysm rupture but also to a vasoconstriction and delayed secondary brain ischemia. In addition, COVID-19 occurs through the SARS-CoV-2 virion binding ACE-2, an enzyme critical for regulation of blood pressure. Consistent with this, binding to the discussed enzyme has been demonstrated to be responsible for direct damage to the blood-brain barrier [28].
Nguen et al. [29] proposed that in COVID-19 cases, early discussion and pre-planning of potential treatment approaches for possible cerebral vasospasm are recommended. Due to the viral infection, SAH patients with concomitant symptomatic hypoxia and/or respiratory failure may not tolerate medical therapy for delayed cerebral ischemia such as hypervolemia or induced hypertension therapy. According to the authors [29], the use of vasopressor agents alone for blood pressure augmentation without volume resuscitation may be warranted. They add that patients with cardiac involvement of COVID-19 may need ionotropic support and yet may not tolerate their pro-arrhythmogenic effects. We agree that treatment strategies directed to vasospasm may need to be individualized based on the clinical condition. They include calcium antagonists for vasodilation, arterial pressure control and oxygenation support but avoidance of excessive infusions.
A report from Northwestern Memorial Hospital, Chicago, IL, USA, describes TCD ultrasonography as a noninvasive method for microemboli detection in patients without SAH but with confirmed COVID-19 [30]. However, in our SARS-CoV-2 positive group, no single patient was detected by TCD with microemboli during the treatment in ICU.
One of the possible mechanisms by which the new coronavirus (SARS-CoV-2) could induce brain damage is the impairment of cerebrovascular hemodynamics (CVH) and intracranial compliance (ICC) [31].

Conclusions
Our observations suggest that patients without COVID-19 but with positive SARS-CoV-2 test are more likely to have worse brain perfusion after subarachnoid hemorrhage from cerebral aneurysm rupture in the Bulgarian population. It is necessary to cover a larger group of patients in the future to prove the statistical significance of the obtained results.

Disclosure statement
All authors declare no conflict of interest regarding the topic of this paper.

Funding
There was no external funding associated with the research presented in this paper.

Data availability statement
The data that support the findings of this study are available upon reasonable request from the corresponding author, DM. The data are not publicly available due to their containing information that could compromise the privacy of research participants.

Ethical approval
All procedures performed in studies involving human participants were following the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.