Abstract
Background
Intracranial blister aneurysms are a rare and an historically difficult to treat subset of aneurysms. They are distinct from typical saccular aneurysms with different pathophysiology and treatment options.
Methods
A prospectively maintained database of subarachnoid hemorrhage patients was queried for those presenting prior to the pandemic (2017–2019), and those presenting during the height of the pandemic in our locality (2021). Aneurysm characteristics and patient demographics associated with rupture risk/formation were collected.
Results
334 aneurysmal subarachnoid hemorrhage patients were reviewed. 86 of these patients presented in 2021, with a statistically significant increase in the proportion of ruptured ICA blister aneurysms as compared to 2017–2019 (7/86, 8% vs 5/248, p = .02). Mean patient age, presenting grade, other aneurysm location proportions, aneurysm size, and incidence of delayed cerebral ischemia were not different between the groups.
Conclusions
Patients presenting with SAH during the height of the SARS-CoV-2 pandemic in 2021 were more likely to have ICA blister type aneurysms.
Keywords: Aneurysm, COVID-19, Subarachnoid hemorrhage
1. Introduction
Intracranial blister aneurysms are a rare and morphologically challenging subset of vascular lesions responsible for.5–2% of all subarachnoid hemorrhages (SAH). [1], [2], [3] The pathophysiology of these aneurysms is incompletely understood. They typically are unrelated to major arterial bifurcations, thin walled, and possess wide-based necks. Open surgical treatment remains challenging and is associated with a high complication rate. [4] Despite long term occlusion rates of up to 77%, there remains no consensus on the best endovascular therapeutic strategy [4], [5].
Severe acute Respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic that has changed the global healthcare landscape. Recent estimates suggest that SAS-CoV-2 continues to infect more than 22 million patients per week globally and has infected 81 million individuals in the United States alone. [6] There is evidence that SARS-CoV-2 is neurovirulent. [7] Additionally, it has been associated with increased rates of ischemic stroke secondary to virus related systemic inflammation. [8], [9] We read with great interest the report of Dodd et al., where the authors described the 10 cases of SARS-CoV-2 associated aneurysmal SAH. In the series they report an abnormally high proportion of dissecting pseudoaneurysms (4/10 cases). [10] We hypothesized that the systemic proinflammatory milieu associated with SARS-CoV-2 infection may raise the incidence of these morphologically distinct and difficult to treat aneurysms.
2. Methods
We retrospectively analyzed our prospectively maintained database of aneurysmal SAH patients at our comprehensive cerebrovascular center to identify individuals presenting during the pre-pandemic period (2017–2019) and during the height of the pandemic in our locality (2021). Mean age, sex, smoking status, illicit drug use, hypertension, presenting Hunt-Hess grade, aneurysm location, aneurysm size, presence of delayed cerebral ischemia (symptomatic vasospasm), and presence of blister morphology were extracted. Blister morphology was defined as a shallow half dome shape, broad base, and origin distinct from vessel branch points of the ICA. The angiography equipment and individuals interpreting the angiograms throughout the study period did not change. Statistical comparisons between presentation groups were made using a 2 tailed t-test for continuous variables and the fisher exact test for categorical variables.
3. Results
We identified 334 patients with aneurysmal SAH: 86 of these patients presented in 2021 during the height of the SARS-CoV-2 pandemic, and 248 of these patients presented prior to the pandemic (2017–2019). ( Table 1 ) summarizes comparative demographic and aneurysm characteristics stratified by time period. There were no statistically significant differences in patient age, smoking status, hypertension, or illicit drug use between presentation periods. There was no significant difference in the proportion of posterior communicating artery, anterior communicating artery, pericallosal, posterior inferior cerebellar artery, or MCA aneurysms between presentation periods. There was no significant difference in mean aneurysm size between the presentation periods (6.6 mm vs 6.1 mm, p = .33). The proportion of patients treated with open or endovascular modalities was not statistically different between presentation periods. There was a statistically significant difference in the proportion of patients who presented with internal carotid artery blister aneurysms (5/248, 2% vs 7/86, 8%, p = .02).
Table 1.
Aneurysmal Sub Arachnoid hemorrhage at University of Pittsburgh Medical Center prior to and During the Covid-19 Pandemic.
| 2017–2019 | 2021 | p | |
|---|---|---|---|
| Cases | 248 | 86 | |
| Mean Age (SD) | 58 (14) | 57 (11) | 0.33 |
| Female Sex | 172/248 (69%) | 61/86 (71%) | 0.89 |
| Relevant Hx | |||
| HTN | 106/248 (43%) | 33/86 (38%) | 0.53 |
| Smoker | 101/248 (41%) | 45/86 (52%) | 0.08 |
| Drug Abuse | 12/248 (5%) | 4/86 (5%) | 1.0 |
| Presenting HH Grade | |||
| I-II | 95/248 (38%) | 31/86 (36%) | 0.80 |
| III | 77/248 (31%) | 27/86 (31%) | 1.0 |
| IV-V | 76/248 (31%) | 28/86 (33%) | 0.79 |
| Aneurysm Location | |||
| ICA non PComm | 11/248 (4%) | 3/86 (3%) | 1.0 |
| PComm | 51/248 (21%) | 14/86 (16%) | 0.43 |
| AComm | 82/248 (33%) | 26/86 (30%) | 0.69 |
| Pericallosal | 10/248 (4%) | 3/86 (3%) | 1.0 |
| MCA Bifurcation | 35/248 (14%) | 10/86 (12%) | 0.71 |
| Vert/PICA | 18/248 (7%) | 10/86 (12%) | 0.25 |
| Basilar Apex | 16/248 (6%) | 5/86 (6%) | 1.0 |
| Others (nonICA Blister) | 20/248 (8%) | 8/86 (9%) | 0.82 |
| ICA Blister Aneurysms | 5/248 (2%) | 7/86 (8%) | 0.02 |
| Mean Size (SD) | 6.6 (3.3) | 6.1 (2.9) | 0.33 |
| Treatment Modality | |||
| Open Surgery | 86/248 (35%) | 33/86 (38%) | 0.60 |
| Endovascular | 162/248 (65%) | 53/86 (62%) | 0.60 |
A comparative summary of blister aneurysm patient demographics and prevalence of post hemorrhagic vasospasm pre and post pandemic is provided in ( Table 2). There was no significant difference between blister aneurysm phenotypes between these two time periods. No patients were diagnosed with active covid during their hospitalization. 6 month modified Rankin Scale was not significantly different between groups. All but two cases in the pre pandemic group were treated with endovascular flow diversion.
Table 2.
Demographics and rates of symptomatic vasospasm in ICA blister aneurysms pre and post pandemic.
| ICA blister aneurysms pre-pandemic (2017–2019) | ICA blister aneurysms during the pandemic (2021) | P Value | |
|---|---|---|---|
| Cases | 5/248 (2%) | 7/86 (8%) | 0.02 |
| Mean Age (SD) | 56.5 (16.8) | 59 (6.96) | 0.68 |
| Smoker | 2/5 (40%) | 2/7 (29%) | 1.00 |
| HTN | 2/5 (40%) | 3/7 (42%) | 1.00 |
| Female Sex | 5/5 (100%) | 4/7 (57%) | 0.21 |
| Symptomatic Vasospasm | 3/5 (60%) | 6/7 (71%) | 0.52 |
| Hunt Hess Grade on Presentation | |||
| 0–2 | 2/5 (40%) | 0/7 (0%) | 0.15 |
| 3 | 0/5 (0%) | 2/7 (29%) | 0.47 |
| 4 | 2/5 (40%) | 2/7 (29%) | 1.0 |
| 5 | 1/5 (20%) | 3/7 (42%) | 0.58 |
| 6 month mRS score | |||
| mRS 0–2 | 3/5 (60%) | 2/7 (29%) | 0.56 |
| mRS 3–5 | 0/5 (0%) | 3/7 (42%) | 0.20 |
| mRS 6 | 2/5 (40%) | 2/7 (29%) | 0.58 |
| Mean Aneurysm Size in mm (SD) | 2.7 (.44) | 2.3 (1.56) | 0.58 |
4. Discussion
In this analysis of aneurysmal SAH patients, we show that those presenting during the height of the SARS-CoV-2 pandemic to our institution (2021) were more likely to have aneurysms with blister morphology. The mechanisms underlying this apparent correlation are unclear, but current estimates suggest that confirmed COVID-19 cases in the Unites States are approaching 100 million. [7] There is likely an even larger proportion of the remaining population that has been asymptomatically infected, or not tested. Patients can develop a maladaptive hyperinflammatory state during SARS-CoV-2 infection as the type I interferon mediated signaling pathways falter, and nF-KB, tnf-alpha, and IL-6 mediated inflammation begins to predominate. [11] The pathophysiology of aneurysmal formation and rupture undoubtedly involves maladaptive inflammation. [12] There is evidence prior to the SARS-CoV-2 pandemic that aspirin alone may blunt this maladaptive inflammation. [13] Interestingly, in a large cohort study of 112,269 patient hospitalized with SARS-CoV-2 low dose aspirin in hospitalized patients has been associated with lower 28 day mortality. [14] The precise mechanisms underlying the increased incidence of blister type aneurysms during the pandemic are unknown.
The initial report of blister type aneurysms of the internal carotid artery by Takahashi et al. describes the extremely thin neck and mild amount of associated atherosclerosis distinct from a vessel bifurcation. [15] Very few studies have reported on the histological characteristics of these aneurysm given their tendency for intraoperative bleeding. Consistent among the few specimens that have been collected from live patients during surgery are dense layers of fibrosis throughout the anatomic layers of the vessel, distinct from the collagen deposition and smooth muscle cell hypertrophy seen in traditional saccular aneurysms at vessel wall bifurcations. [16] It has been postulated that hemodynamic stress is associated with the formation of blister aneurysms given their traditional location along the dorsal carotid wall, an area of high wall sheer stress. [17] Vessel bifurcations, however, are also an area of high wall sheer stress, suggesting an alternative etiologic mechanism distinct from those at play during traditional saccular aneurysm formation. It is plausible that the proinflammatory milieu in the SARS-CoV-2 exposed individual could, in addition to traditional risk factors for aneurysm formation, predispose individuals to develop blood blister like aneurysms. Future histopathological analysis of these difficult to treat lesions should characterize the cellular and molecular mediators of inflammation present in these lesions.
It is clear that patients with blister type aneurysms tend to present as higher grade. In comparison 94% of patients in the initial International Subarachnoid Aneurysm Trial (ISAT) presented in good neurologic condition (World Federation of Neurosurgical Societies, WFNS) grades 1–3. Moreover, our data suggests that these patients’ trend towards poor outcomes on average at follow up, while only 23.7% of treated patients in ISAT had a modified Rankin scale of three or greater. [18] It is also possible that there is a delayed treatment seeking effect of the COVID-19 pandemic which may have shifted the apparent prevalence of patients with certain pathologies.
Our investigation is limited by our inability to account for pre-ictal covid exposure and the retrospective nature of the study. Moreover, our institutional policy was to test only those individuals who are symptomatic on arrival to the hospital. However, given the 100 million confirmed cases as of the writing of this manuscript, and likely many more asymptomatically infected/non-tested individuals, there is an inevitably high rate of baseline SARS-CoV-2 exposure in 2021.
5. Conclusion
In a large retrospective analysis of patients with aneurysmal SAH during the peak of the COVID-19 pandemic, an increased proportion of individuals presented with blister-like aneurysm morphology. The mechanisms underlying this correlation remain unclear but may be explained by maladaptive inflammation in those exposed to the SARS-CoV-2 virus. Future studies should explore the inflammatory microenvironment of these difficult to treat vascular lesions.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Joseph S Hudson: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Supervision; Validation; Visualization; Writing – review & editing, David McCarthy: Formal analysis; Investigation, Ali Alattar: Formal analysis; Investigation, Zain Mehdi: Investigation, Michael Lang: Data curation, Paul A Gardner: Data curation,; Writing – review & editing, George Zenonos: Data curation, Robert Friedlander: Supervision, Bradley Gross: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Supervision; Validation; Visualization; Writing – review & editing.
Biography
Joseph Scott Hudson, MD, joined the University of Pittsburgh Department of Neurological Surgery residency program in July 2019 after graduating with research distinction from the University of Iowa Carver College of Medicine. He also received his undergraduate degree from the University of Iowa with honors in biology, a minor in chemistry, and high distinction. During his undergraduate education, he became heavily involved in the Department of Neurosurgery at the University of Iowa Hospitals and Clinics. His work under the mentorship of David Hasan, MD, in cerebrovascular neurosurgery included basic science investigations into the pathogenesis of intracranial aneurysms, device development, and neurovascular imaging development. During medical school, Dr. Hudson received research support from the Neurosurgery Research and Education Foundation (NREF) as a medical student fellow, subsequently receiving the 2016 NREF best medical student abstract award. His research has led to numerous peer reviewed publications, abstracts, and oral presentations at national neurosurgical conferences. Dr. Hudson is an elected member of the Alpha Omega Alpha medical honor society. Dr. Hudson was born in Waterloo, Iowa. He was raised in Cedar Falls, Iowa and Plankstadt, Germany. His hobbies outside of neurosurgery include spending time with family and friends, golf, professional and collegiate sports, snow skiing, travel, and water sports. Dr. Hudson’s publications can be reviewed through the National Library of Medicine’s publication database.
References
- 1.Abe M. tabuchi kazuo, yokohama, Hiroaki et al. Blood blisterlike aneurysms of the internal carotid artery. J. Neurosurg. 1998;89:419–424. doi: 10.3171/jns.1998.89.3.0419. [DOI] [PubMed] [Google Scholar]
- 2.Ogawa A., Suzuki M., Ogasawara K., et al. Aneurysms at non branching sites in the supraclinoid portion of the internal carotid artery: Internal carotid artery trunk aneurysms. Neurosurgery. 2000;47:578–583. doi: 10.1097/00006123-200009000-00008. [DOI] [PubMed] [Google Scholar]
- 3.Owen C., Montemurro N., Lawton M.T. Blister aneurysms of the internal carotid artery: microsurgical results and management strategy. Neurosurgery. 2017;80:235–247. doi: 10.1227/NEU.0000000000001259. [DOI] [PubMed] [Google Scholar]
- 4.Ricciardi L., Trungu S., Scerrati A., et al. Surgical treatment of intracranial blister aneurysms: a systematic review. Clin. Neurol. Neurosurg. 2021;202 doi: 10.1016/j.clineuro.2021.106550. ([Epub ahead of print]) [DOI] [PubMed] [Google Scholar]
- 5.Scerrati A., Visani J., Flacco M.E., et al. Endovascular treatment of ruptured intracranial aneurysms: a systematic review and meta-analysis. ANJR Am. J. Neuroradiol. 2021;42(3):538–545. doi: 10.3174/ajnr.A6924. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Johns Hopkins University. Coronavirus resource center. Published 2021. Accessed May 10, 2022. 〈http://coronavirus.jhu.edu〉.
- 7.Lima M., Siokas V., Aloizou A., et al. Unraveling the possible routes of SARS-CoV-2 invasion into the central nervous system. Curr. Treat. Options Neurol. 2020;22(11):37. doi: 10.1007/s11940-020-00647-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hess D.C., Eldahshan W., Rutkowski, et al. Covid-19 related stroke. Transl. Stroke Res. 2020;11:322–325. doi: 10.1007/s12975-020-00818-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chavada V., Chaurasia B., Fiorindi A., et al. Ischemic stroke and SARS-CoV-2 Infection: the bidirectional pathology and risk morbidities. Neurol. Int. 2022;14:391–405. doi: 10.3390/neurolint14020032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Dodd W., Jabbour P., Sweid A., et al. Aneurysmal subarachnoid hemorrhage in patients with coronavirus disease 2019 (COVID 19): A Case series. World Neurosurg. 2021;153:e259–e264. doi: 10.1016/j.wneu.2021.06.092. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hadjadj J., Yatim N., Barnabei L., et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369(6504):718–724. doi: 10.1126/science.abc6027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hudson J.S., Hoyne D.S., Hasan D.M. Inflammation and human cerebral aneurysms: current and future treatment prospects. Future Neurol. 2013;8(6) doi: 10.2217/fnl.13.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hudson J.S., Marincovich A.J., Roa J.A., et al. Aspirin and Intracranial Aneurysms. Stroke. 2019;50(9):2591–2596. doi: 10.1161/STROKEAHA.119.026094. [DOI] [PubMed] [Google Scholar]
- 14.Chow J., Rahnavard A., Gomberg-Maitland M. et al. Association of Early Aspirin use with in-hospital mortality in patients with moderate covid-19. JAMA Netw Open. 5(3): e223890. [DOI] [PMC free article] [PubMed]
- 15.Takahashi A., Fujiwara S., Mizoi K., et al. Surgical treatment of chimame (blood blister) like aneurysm at the C2 portion of the internal carotid artery. Surg. Cereb. Stroke. 1988;16:72–77. [Google Scholar]
- 16.Lee S., Kwak Y., Oh C., et al. Pathogenesis of dorsal internal carotid artery wall aneurysms based on histopathological examination and microscopic configuration. J. Clin. Neurosci. 2018;58:181–186. doi: 10.1016/j.jocn.2018.08.002. [DOI] [PubMed] [Google Scholar]
- 17.Nakagawa F., Kobayashi S., Takemae T., et al. Aneurysms protruding from the dorsal wall of the internal carotid artery. J. Neurosurg. 1986;65:303–308. doi: 10.3171/jns.1986.65.3.0303. [DOI] [PubMed] [Google Scholar]
- 18.Molyneux A., Kerr R., Stratton I., et al. International subarachnoid trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. Lancet. 2002;360(9342):1267–1274. doi: 10.1016/s0140-6736(02)11314-6. [DOI] [PubMed] [Google Scholar]