- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, United States.
- School of Medicine, University of California Riverside, Riverside, California, United States.
School of Medicine, University of California Riverside, Riverside, California, United States.
DOI:10.25259/SNI_214_2021Copyright: © 2021 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Brian Fiani1, James B. Fowler1, Ryan Arthur Figueras2, Keon Hessamian2, Nathan Mercado2, Olivia Vukcevich2, Manpreet Kaur Singh2. Ruptured cerebral aneurysms in COVID-19 patients: A review of literature with case examples. 26-Apr-2021;12:187
How to cite this URL: Brian Fiani1, James B. Fowler1, Ryan Arthur Figueras2, Keon Hessamian2, Nathan Mercado2, Olivia Vukcevich2, Manpreet Kaur Singh2. Ruptured cerebral aneurysms in COVID-19 patients: A review of literature with case examples. 26-Apr-2021;12:187. Available from: https://surgicalneurologyint.com/surgicalint-articles/10756/
Background: The novel severe acute respiratory syndrome coronavirus 2 is responsible for over 83 million cases of infection and over 1.8 million deaths since the emergence of the COVID-19 pandemic. Because COVID-19 infection is associated with a devastating mortality rate and myriad complications, it is critical that clinicians better understand its pathophysiology to develop effective treatment. Cumulative evidence is suggestive of cerebral aneurysms being intertwined with the hyperinflammatory state and hypercytokinemia observed in severe COVID-19 infections.
Case Description: In case example 1, the patient presents with chills, a mild cough, and sore throat. The patient develops high-grade fever of 39.8° C, decreased oxygen saturation of 93% on room air, and an extensive spontaneous subarachnoid hemorrhage (SAH) in the basal cisterns from a ruptured left posterior communicating artery aneurysm. In case example 2, the patient presents with a positive PCR test for COVID-19 2 weeks prior with spontaneous SAH and found to have a large multilobulated bulbous ruptured aneurysm of the anterior communicating artery. Both patients’ symptoms and high-grade fever are consistent with hypercytokinemia and a hyperinflammatory state, with elevated granulocyte colony-stimulating factor, inducible protein-10, monocyte chemoattractant protein-1, M1P1A, and tumor necrosis factor-α inflammatory mediators found to be elevated in COVID-19 intensive care unit admissions.
Conclusion: COVID-19 effect on cerebral aneurysms requires future studies to clearly delineate correlation, however, hypercytokinemia and a hyperinflammatory state are strongly implicated to cause degenerative vascular changes that may predispose patients to cerebral aneurysm formation, change in size or morphology, and resultant aneurysm rupture.
Keywords: Aneurysm rupture, Cerebral aneurysms, COVID-19, Subarachnoid hemorrhage
To date, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for over 83 million reported cases and over 1.8 million deaths globally since the beginning of the pandemic.[
Although current literature has yet to delineate an exact and definite relationship between COVID-19 and cerebral aneurysm formation/rupture, literature and data of other similar inflammatory states and vascular injury have illuminated several possible explanations of well-described changes observed in other disease processes that can explain COVID-19 pathogenesis. The virus has been reported to bind surface angiotensin-converting enzyme 2 (ACE-2) receptor to enter cells, thus making the virus capable of causing endothelial injury.[
Pathophysiology of cerebral aneurysm
In addition to vessel wall shear stress, the regulation of healthy vasculature involves different cell types and their regulation of local factors, some of which fall out of equilibrium leading to degenerative changes observed in the damaged and weakened vasculature of cerebral aneurysms. Wall shear stress has been linked to the activation of Rac1 and several downstream factors involved in the response to the increased flow and wall shear stress.[
Downstream effector proteins such as monocyte chemoattractant protein-1 (MCP-1) play a major role in the pathogenesis of cerebral aneurysms by recruiting monocytes and macrophages to the area.[
Vascular smooth muscle cells (VSMCs) are critical not only to the normal integrity of the vasculature but also for their role in the pathological development of cerebral aneurysms. VSMCs are highly specialized contractile cells which function to maintain normal vessel morphology and blood pressure.[
Pathophysiologic changes from COVID-19
Cumulative recent evidence suggests that a subgroup of patients with severe COVID-19 infections is observed to have a cytokine storm syndrome. Identification of these patients with hyperinflammatory state and subsequent cytokine storm followed by appropriate treatment with therapeutics that are currently prescribed to treat other diseases may reduce mortality rates of severe COVID-19 infection.[
The current standard practice for the management of COVID-19-positive patients is solely supportive, and the leading cause of mortality in these patients is respiratory failure, secondary to severe acute respiratory distress syndrome (ARDS).[
Inflammation due to neutrophil activation is the key to the development of the hyperinflammatory state in which activation of the protein transcription factor NF-kB mediates foundational changes in DNA transcription.[
Secondary hemophagocytic lymphohistiocytosis (sHLH) is an under acknowledged hyperinflammatory syndrome that shares a similar cytokine profile with severe COVID-19 infections, implying an analogous pathophysiology process (Mehta et al., 2020). Most notably, IL-2, IL-7, granulocyte colony-stimulating factor (GCSF), interferon-γ (IFN-γ), inducible protein 10 (IP-10), MCP-1, macrophage inflammatory protein 1-α (MIP-1α), and TNF-α are the primary mediators of inflammation which are found to be increased in patients with sHLH.[
In consideration of the aforementioned, the hyperinflammatory state and particular hypercytokinemia profile are implicated to be responsible for or at the very least, associated with the mechanism by which severe COVID-19 infection degrades the integrity of the vasculature. Inflammatory states will cause the release of other factors such as endothelin-1, angiotensin-II, and phospholipase A-2 which trigger vasoconstriction of the damaged vessel, increased vascular permeability, and the destruction of microvascular architecture, ultimately amplifying the effects of inflammation and consequent lung damage.[
One final major consideration is the systemic effects of COVID-19 infection. COVID-19 infection occurs through the SARS-CoV-2 virion binding ACE-2, an enzyme critical for regulation of blood pressure and anti-atherosclerotic effects. Consistent with these other findings, SARS-CoV-2-ACE-2 binding has been demonstrated to be responsible for direct damage to the BBB in two separate studies.[
Case example 1
A 52-year-old Hispanic male presented from an outside hospital with head computed tomography (CT) concerning for spontaneous SAH. The patient was initially brought to an outside hospital after he was found unresponsive by his family following a bout of coughing earlier that morning. CPR was initiated for 5 min before EMS arrival, with the patient experiencing a single episode of vomiting and bladder incontinence before regaining consciousness. His family noted that the patient had complaints of chills, a mild cough, and sore throat the night before admission but was otherwise he was in his normal state of health. He had no history of prior tobacco use and otherwise had a medical history significant for hypertension without current pharmacologic treatment. There was no family history of aneurysms or any reported viral prodrome within his family contracts. His baseline modified Rankin scale (MRS) was 0.
On arrival to our institution, the patient had no complaints other than a mild headache and neck pain. Initial vitals were significant for a temperature of 39.8° C, blood pressure 157/95 mmHg, and oxygen saturation of 93% on room air. Clinical examination was notable for some mild confusion, but otherwise there were no cranial nerve deficits or focal findings on clinical exam. A noncontrast head CT demonstrated extensive SAH in the basal cisterns around the midbrain extending into the left Sylvian fissure with mild prominence of the bilateral temporal horns [
An external ventricular drain was placed with an opening pressure 21 mmHg. The patient was intubated before being taken to the neurointerventional suite for treatment. Diagnostic cerebral angiography of the left internal carotid artery (ICA) revealed a dominant left p-comm artery filling the posterior cerebral artery on the left with small aneurysm emanating from the junction of the left ICA and left p-comm artery, pointing posteriorly and inferiorly measuring 4 × 6 × 4 mm [
The patient tolerated the procedure well. He was extubated and taken to the neurological ICU (NICU) in stable condition where he was monitored for complications of SAH. A 10-day course of empiric antibiotics was completed for aspiration pneumonia. Over the course of his stay, his neurological status remained stable, however, he developed progressive hypoxemic respiratory failure and required intubation on hospital day 4 (postbleed day 3). Convalescent plasma and dexamethasone at 6 mg daily were initiated on hospital day 4, while remdesivir was held as the replication phase had passed. His initial high PEEP and FiO2 demands were weaned and he was successfully extubated on hospital day 15 and his ventricular drain removed on hospital day 13. He had no evidence of vasospasm and was downgraded from the ICU on hospital day 16. Clinically at the time of downgrade, the patient was GCS14, e4v4m6, with some intermittent confusion but otherwise appropriate without cranial nerve or any lateralizing motor deficit.
Case example 2
A 61-year-old Hispanic male was transferred from an outside facility when he was found by his wife after falling in the bathroom earlier that morning. At the outside institution, he reportedly had a GCS of 8 (unknown breakdown) and was for declining mental status. CT head demonstrated prominent SAH in the basal cisterns [
On arrival to our institution, he was afebrile, with BP 164/100 mmHg and saturating 100% on 40% FiO2. Clinically, he was intubated with a GCS of 8T (e2vTm5), with a prosthetic right eye but otherwise with intact cranial nerves. He was localizing to pain in his left upper extremity and withdrawing in all other extremities. Laboratory values were significant for leukocytosis of 18.0 10e9/L and sodium 135 mEq/L. Liver function test and coagulation were within normal limits. A right frontal ventriculostomy was placed and he was started on levetiracetam, nimodipine, and high-dose rosuvastatin for vasospasm protection.
On postbleed day 1, he was taken to the interventional suite for coiling. Diagnostic angiography of the left ICA revealed a large multilobulated bulbous aneurysm of the anterior communicating artery [
Postprocedure, the patient returned intubated to the ICU with a stable neurological examination. He was successfully extubated on hospital day 2 and spiked a fever on hospital day 5–38.4°C, but otherwise remained afebrile during his hospital course. Ventricular drain weaning was unsuccessful and a right frontal ventriculoperitoneal shunt was placed on hospital day 20. He was downgraded from the ICU on hospital day 22 with no evidence of vasospasm. Clinically, he was a GCS of 14, e4v4m6. He would intermittently converse but remained confused. Cranial nerves were intact and he would intermittently follow simple commands in all extremities with no lateralizing motor deficits.
With the onset of the SARS-CoV-2 pandemic, the novel virus leaves much to discover between COVID-19 and ruptured cerebral aneurysms. Further studies should be performed to evaluate the incidence of cerebral aneurysms in the COVID-19 population compared to general population or non-COVID-19 population to assert if there are any statistically significant differences. Large retrospective studies at institutions that have access to database logging will be required to follow trends and analyze the data. Finding patients with pre- and post-COVID-19 inoculation would also prove useful to detect if the ruptured cerebral aneurysms were present beforehand or there was any change in size or morphology after becoming infected.
The immune response in COVID-19 infection is a likely culprit in the predisposition to cerebral aneurysm formation or changes in size, morphology, and tendency to rupture through NF-Kb expression causing markedly increased cytokine release, “cytokine storm,” induced ARDS and sHLH. Severe COVID-19 cases may benefit from IL-6 pathway inhibition, as a retrospective study of COVID-19 patients found nonsurvivors to have elevated IL-6 and serum ferritin levels.[
The direct impact of COVID-19 on cerebral aneurysm formation and rupture is still unclear, however, certain biochemical inflammatory processes could be the link. We have identified two case examples. The patient in case example 1 presented to our institution due to SAH secondary to ruptured p-comm aneurysm. The patient had no family history of aneurysms and had no significant risk factors other than hypertension. He tested positive for COVID-19 on inpatient testing.
In the second case example, the patient presented to the hospital with declining mental status and CT confirmed prominent SAH in the basal cisterns. The patient had tested positive for COVID-19 2 weeks prior, thus one could speculate that his anterior communicating aneurysm could be a symptom of his COVID-19 infection. Although seemingly asymptomatic during initial infection, the patient had severe leukocytosis, thus indicating serious COVID-19 infection. Serious infection is implicated in arterial vasculature damage. However, the patient also had a severe hypertension history, which also may have contributed to aneurysm rupture.
The inflammatory response from COVID-19 induces hypercytokinemia and therefore has been implicated to degrade the integrity of the cerebral vasculature and predispose individuals to cerebral aneurysm formation, rupture, and ICH. Therefore, these case examples along with the literature review highlight important areas for future studies on COVID-19-associated hyperinflammatory state, pathophysiology, and effective treatment. At current time, most of the link between COVID-19 and cerebral aneurysm formation, changes, or rupture are speculation and long-term retrospective studies will be needed to assess for certainty.
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