Jan Rodemerk1; Ramazan Jabbarli, MD1; Karsten H. Wrede, MD1
1. Department of Neurosurgery, University Hospital Essen, Essen, Germany
PMID: 33226922
DOI: 10.1161/STROKEAHA.120.032514
IN RESPONSE:
We thank Wen et al. for their thoughtful letter in response to our article in Stroke titled: “Pathophysiology of Intracranial Aneurysms: COX-2 Expression, Iron Deposition in Aneurysm Wall, and Correlation with Magnetic Resonance Imaging”.1 We investigated the relationship between expression of COX-2, iron deposition and MRI characteristics of intracranial aneurysm wall structures. Due to anatomic and operative restrictions during microsurgical clipping, most aneurysms were larger than 5 mm.
Drs Wen, Kieran, and Yang recommended a discussion of our study population and raised concerns about the high number of thrombosed aneurysms as well as the change of population in analyzing the MRI characteristics.
Indeed, there was an association between aneurysm size and intraluminal thrombosis in the analyzed cohort. However, the presence of thrombus in aneurysm wall was not limited to the samples from giant aneurysms, as there were only eight giant aneurysms in the cohort. Of note, we assessed the presence of intraluminal thrombosis based on histological analysis and not on radiographic data. Previous histological studies have shown a significantly higher incidence of intraluminal thrombosis compared to MRI alone.2 Moreover, according to a recent publication, almost every instable aneurysm is partially thrombosed. This also includes smaller, asymmetric aneurysms.3 Tulamo et al.4 described the pathophysiological pathway of the thrombus organization in intracranial aneurysms. They concluded that almost every aneurysm develops a thrombus, which in many cases cannot be distinguished from the aneurysm wall.
To address the concerns of selection bias raised by Wen et al., we now performed additional subgroup analyses. At first, we excluded large aneurysms > 20 mm (n = 8). This subgroup presented no correlation between aneurysm size and the appearance of a luminal thrombus (Thrombosed 13.3 ± 5.23 mm [n = 14] vs. non-thrombosed 10.37 ± 4.17 mm [n = 19]; p = 0.11). In contrast, correlations between COX-2 expression and iron deposition (p = 0.05), hypointensities and iron deposition (p = 0.01), as well as COX-2 and rupture event (p = 0.02) remained significant.
In the second subgroup analysis, we only included patients who underwent an MRI examination before their treatment (n = 21). Preoperative acquisition of MRI was restricted mainly due to subarachnoid hemorrhage and therefore this subcohort was significantely smaller. The relationship between COX-2 expression and iron deposition (p = 0.0006) was even more apparent than in the entire cohort. These subgroup analyses further support the drawn conclusions in our study.
It remains extremely difficult to collect data and histopathological samples from small and medium sized aneurysms. Therefore, as stated in our conclusion and also supported by Wen et al., we strongly advocate the establishment of a multicenter registry of histopathologic samples and corresponding MRI data to further investigate the pathophysiology of aneurysm instability.
DISCLOSURES
Outside the submitted work, Dr. Wrede received personal fees from Biogen for expert opinion on aneurysms and vestibular schwannomas.
REFERENCES
1. Rodemerk J, Junker A, Chen B, Pierscianek D, Dammann P, Darkwah Oppong M, Radbruch A, Forsting M, Maderwald S, Quick HH, et al. Pathophysiology of intracranial aneurysms: Cox-2 expression, iron deposition in aneurysm wall, and correlation with magnetic resonance imaging. Stroke. 2020;51:2505-2513
2. Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: Histological analysis of 24 unruptured and 42 ruptured cases. Stroke. 2004;35:2287-2293
3. Frosen J, Cebral J, Robertson AM, Aoki T. Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms. Neurosurg Focus. 2019;47:E21
4. Tulamo R, Frosen J, Hernesniemi J, Niemela M. Inflammatory changes in the aneurysm wall: A review. J Neurointerv Surg. 2018;10:i58-i67