Intracranial aneurysm pathogenesis

Intracranial aneurysm pathogenesis

Until now, the exact etiology of intracranial aneurysms formation remains unclear.

Time-dependent and site-dependent morphological changes and the level of degradation molecules may be indicative of the vulnerability of aneurysm rupture 1).

Miyata et al. proposed the contribution of a structural change in an adventitia, i.e., vasa vasorum formation, to the rupture of IAs 2).

Although some previous reports have demonstrated an association between lipid accumulation and degenerative changes in aneurysm walls in humans, epidemiological studies have failed to identify dyslipidemia as a risk factor for intracranial aneurysm pathogenesis. Thus, Shimizu et al. examined whether an increase in serum cholesterol levels facilitates the progression of intracranial aneurysms in a rat model. Rats were given a high-fat diet (HFD) and subjected to an intracranial aneurysm model. The HFD elevated their serum cholesterol levels. The intracranial aneurysms induced at the anterior cerebral artery-olfactory artery bifurcation were significantly larger in the high-fat group than in the normal-chow group. Histological analysis demonstrated that the loss of medial smooth muscle layers was exacerbated in the high-fat group and indicated the presence of macrophage-derived foam cells in the lesions. In in vitro experiments, the expression levels of the pro-inflammatory genes induced by LPS in RAW264.7-derived foam cells were significantly higher than those in RAW264.7 cells. The combination of these results suggests that increased serum cholesterol levels facilitate degenerative changes in the media and the progression of intracranial aneurysms presumably through foam cell transformation 3).




see Intracranial aneurysm hemodynamics.

In addition to ambiental factors (smoking, excessive alcohol consumption and hypertension), epidemiological studies have demonstrated a familiar influence contributing to the pathogenesis of intracranial aneurysms, with increased frequency in first- and second-degree relatives of people with subarachnoid hemorrhage.

Data suggest that macrophage-derived Matrix metalloproteinase 2 and Matrix metalloproteinase 9, may play an important role in the progression of intracranial aneurysms. The findings will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease 4).

Investigations strongly suggest that the pathophysiology is closely associated with chronic inflammation in vascular walls. Nuclear factor kappaB (NF-kappaB) has a key role in the formation and progression.

Children with Sickle Cell Disease (SCD) are at risk for developing multiple intracranial aneurysms, and a high index of suspicion must be maintained during the interpretation of routine magnetic resonance imaging or angiography of the brain 5).

Dental bacterial DNA can be found using a quantitative polymerase chain reaction in both ruptured and unruptured aneurysm walls, suggesting that bacterial DNA plays a role in the pathogenesis of cerebral aneurysms in general, rather than only in ruptured aneurysms 6).

THSD1 in Intracranial aneurysm pathogenesis

Thrombospondin type-1 domain-containing protein 1 is a protein that in humans is encoded by the THSD1 gene.

The protein encoded by this gene contains a type 1 thrombospondin domain, which is found in thrombospondin, a number of proteins involved in the complement pathway, as well as extracellular matrix proteins. Alternatively spliced transcript variants encoding distinct isoforms have been observed.

As illustrated by THSD1 research, cell adhesion may play a significant role in IA 7).

A study discovered that harmful variants in THSD1 (Thrombospondin type-1 domain-containing protein 1) likely cause intracranial aneurysm and subarachnoid hemorrhage in a subset of both familial and sporadic patients with supporting evidence from two vertebrate models 8).

A report identified THSD1 mutations in familial and sporadic IA patients and shows that THSD1 loss results in cerebral bleeding in 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion 9).



Yamaguchi T, Miyamoto T, Kitazato KT, Shikata E, Yamaguchi I, Korai M, Shimada K, Yagi K, Tada Y, Matsuzaki Y, Kanematsu Y, Takagi Y. Time-dependent and site-dependent morphological changes in rupture-prone arteries: ovariectomized rat intracranial aneurysm model. J Neurosurg. 2019 Sep 13:1-9. doi: 10.3171/2019.6.JNS19777. [Epub ahead of print] PubMed PMID: 31518986.

Miyata H, Imai H, Koseki H, Shimizu K, Abekura Y, Oka M, Kawamata T, Matsuda T, Nozaki K, Narumiya S, Aoki T. Vasa vasorum formation is associated with rupture of intracranial aneurysms. J Neurosurg. 2019 Aug 16:1-11. doi: 10.3171/2019.5.JNS19405. [Epub ahead of print] PubMed PMID: 31419795.

Shimizu K, Miyata H, Abekura Y, Oka M, Kushamae M, Kawamata T, Mizutani T, Kataoka H, Nozaki K, Miyamoto S, Aoki T. High-Fat Diet Intake Promotes the Enlargement and Degenerative Changes in the Media of Intracranial Aneurysms in Rats. J Neuropathol Exp Neurol. 2019 Jul 24. pii: nlz057. doi: 10.1093/jnen/nlz057. [Epub ahead of print] PubMed PMID: 31340038.

Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N. Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke. 2007 Jan;38(1):162-9. Epub 2006 Nov 22. PubMed PMID: 17122420.

Saini S, Speller-Brown B, Wyse E, Meier ER, Carpenter J, Fasano RM, Pearl MS. Unruptured Intracranial Aneurysms in Children With Sickle Cell Disease: Analysis of 18 Aneurysms in 5 Patients. Neurosurgery. 2015 Feb 12. [Epub ahead of print] PubMed PMID: 25710108.

Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Lehtimäki T, Oksala N, Öhman JE. Bacterial DNA findings in ruptured and unruptured intracranial aneurysms. Acta Odontol Scand. 2016 May;74(4):315-20. doi: 10.3109/00016357.2015.1130854. Epub 2016 Jan 18. PubMed PMID: 26777430.

Xu Z, Rui YN, Hagan JP, Kim DH. Intracranial Aneurysms: Pathology, Genetics, and Molecular Mechanisms. Neuromolecular Med. 2019 May 4. doi: 10.1007/s12017-019-08537-7. [Epub ahead of print] Review. PubMed PMID: 31055715.

Rui YN, Xu Z, Fang X, Menezes MR, Balzeau J, Niu A, Hagan JP, Kim DH. The Intracranial Aneurysm Gene THSD1 Connects Endosome Dynamics to Nascent Focal Adhesion Assembly. Cell Physiol Biochem. 2017;43(6):2200-2211. doi: 10.1159/000484298. Epub 2017 Oct 25. PubMed PMID: 29069646.

Santiago-Sim T, Fang X, Hennessy ML, Nalbach SV, DePalma SR, Lee MS, Greenway SC, McDonough B, Hergenroeder GW, Patek KJ, Colosimo SM, Qualmann KJ, Hagan JP, Milewicz DM, MacRae CA, Dymecki SM, Seidman CE, Seidman JG, Kim DH. THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage. Stroke. 2016 Dec;47(12):3005-3013. Epub 2016 Nov 15. Erratum in: Stroke. 2017 Aug;48(8):e240. PubMed PMID: 27895300; PubMed Central PMCID: PMC5134902.

Anterior Communicating Artery Aneurysm Risk Factors

Anterior Communicating Artery Aneurysm Risk Factors

Age, hypertension, heart disease, diabetes mellitus, cerebral atherosclerosis, aneurysms located at the internal carotid artery (ICA) and aneurysm neck width (N) correlated negatively with rupture risk. Aneurysms located at the anterior communicating artery, bifurcation, irregularity, with a daughter sac, aneurysm height, maximum size, aspect ratio (AR), height-to-width ratio and bottleneck factor were significantly and positively correlated with rupture risk 1).

The anterior communicating artery (AcomA) junction is the most common location for cerebral aneurysms. This might because of increased vascular wall shear stress due to the complex structure of the junction. The aim of a study of İdil Soylu et al. was to investigate the effect of morphological parameters in the development of anterior Communicating Artery Aneurysms. This retrospective study was approved by the institutional ethics committee. A retrospective analysis of the hospital database was performed to identify patients with AcomA aneurysms. Patients with normal computed tomography angiography (CTA) examinations were enrolled in the study as the control group. The control group was similar to the patient group in gender and age. Morphological parameters (vessel diameters, vessel diameter ratios, and vessel angles) on the same side (ipsilateral) and on the opposite side (contralateral) of the patients with aneurysm, and morphological parameters of the control group were compared. A total of 171 subjects were involved in the study (86 patients with aneurysms and 85 patients in the control group). Multivariate regression analysis revealed that the ipsilateral A1-A2 angle (OR: 0.932; 95% CI: 0.903-0.961; p < 0.001), the ipsilateral A1/A2 vessel diameter ratio (OR: 27.725; 95% CI: 1.715-448.139; p = 0.019), and the contralateral internal carotid artery (ICA)/A1 ratio (OR: 11.817; 95% CI: 2.617-53.355; p = 0.001) were significant morphological predictors for developing an aneurysm. An increased contralateral ICA/A1 ratio, an increased ipsilateral A1/A2 vessel diameter ratio, and a narrow bifurcation angle are significant predictors for developing an aneurysm. Therefore, in patients with clinical risk factors these parameters may be interpreted as additional morphological risk factors for developing an aneurysm 2).

An asymmetry of the A1 segment of the anterior cerebral artery is an assumed risk factor for the development of anterior communicating artery aneurysms (ACoAAs).

In clinic, it’s very common to find out the unequal development of section A1 of anteromedial brain artery. The resulting hemodynamic changes are considered to be one of the main reasons for the formation of anterior communicating artery aneurysms 3).

An asymmetry of the A1 segment of the anterior cerebral artery (A1SA) was identified on digital subtraction angiography studies from 127 patients (21.4%) and was strongly associated with ACoAA (p < 0.0001, OR 13.7). An A1SA independently correlated with the occurrence of ACA infarction in patients with ACoAA (p = 0.047) and in those without an ACoAA (p = 0.015). Among patients undergoing ACoAA coiling, A1SA was independently associated with the severity of ACA infarction (p = 0.023) and unfavorable functional outcome (p = 0.045, OR = 2.4).

An A1SA is a common anatomical variation in SAH patients and is strongly associated with ACoAA. Moreover, the presence of A1SA independently increases the likelihood of ACA infarction. In SAH patients undergoing ACoAA coiling, A1SA carries the risk for severe ACA infarction and thus an unfavorable outcome. Clinical trial registration no.: DRKS00005486 ( 4).

Findings in a study of Matsukawa et al. demonstrated that the anterior projection of an ACoA aneurysm may be related to rupturing. The authors would perhaps recommend treatment to patients with unruptured ACoA aneurysms that have an anterior dome projection, a bleb(s), and a size ≥ 5 mm 5)



Wang GX, Zhang D, Wang ZP, Yang LQ, Yang H, Li W. Risk factors for ruptured intracranial aneurysms. Indian J Med Res. 2018 Jan;147(1):51-57. doi: 10.4103/ijmr.IJMR_1665_15. PubMed PMID: 29749361; PubMed Central PMCID: PMC5967217.

İdil Soylu A, Ozturk M, Akan H. Can vessel diameters, diameter ratios, and vessel angles predict the development of anterior communicating artery aneurysms: A morphological analysis. J Clin Neurosci. 2019 Jul 26. pii: S0967-5868(19)30755-6. doi: 10.1016/j.jocn.2019.07.024. [Epub ahead of print] PubMed PMID: 31358430.

Okamoto S, Itoh A. Craniotomy side for neck clipping of the anterior communicating aneurysm via the pterional approach. No Shinkei Geka. 2002;30:285–291.

Jabbarli R, Reinhard M, Roelz R, Kaier K, Weyerbrock A, Taschner C, Scheiwe C, Shah M. Clinical relevance of anterior cerebral artery asymmetry in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2017 Nov;127(5):1070-1076. doi: 10.3171/2016.9.JNS161706. Epub 2016 Dec 23. PubMed PMID: 28009232.

Matsukawa H, Uemura A, Fujii M, Kamo M, Takahashi O, Sumiyoshi S. Morphological and clinical risk factors for the rupture of anterior communicating artery aneurysms. J Neurosurg. 2013 May;118(5):978-83. doi: 10.3171/2012.11.JNS121210. Epub 2012 Dec 14. PubMed PMID: 23240701.

Giant middle cerebral artery aneurysm

Giant middle cerebral artery aneurysm

Giant middle cerebral artery aneurysm (size > 2.5 cm)

Case reports

Bendok et al. presented the case of a 61-year-old female who was brought to the emergency room after she had partial complex seizures. CT and MRI of the brain revealed a right temporal lobe mass which was initially thought to be a tumor. The patient was therefore referred to us for further management. The round nature of the lesion raised suspicion for an aneurysm. A CT angiography was performed followed by a diagnostic conventional cerebral angiogram and confirmed the presence of a giant thrombosed aneurysm 1).

A video case illustrates key surgical steps required in safe management of a giant recurrent previously coiled MCA aneurysm. The patient described in this case was a 68-year old male who presented with a sudden onset severe headache and dizziness. The patient had a history of a prior coil embolization of a 12 mm left middle cerebral artery aneurysm at an outside hospital. Imaging demonstrated recurrence of now a giant left middle cerebral artery aneurysm with coil compaction and left temporal lobe edema. MRI further demonstrated thrombus in the aneurysm and aneurysm wall enhancement concerning for impending rupture. Given the aneurysm size, imaging features and mass effect, the aneurysm was treated with microsurgical clipping. This case is valuable to the literature with a clear video case illustration of aneurysm dome excision, aneurysm endarterectomy and picket fence aneurysm neck reconstruction. Aneurysm dome excision is critical for treatment of giant aneurysms causing mass effect and was only used in this case as thrombus and coil mass did not allow for direct clipping across the neck without compromise of the MCA M2 branch. Hence, this video highlights key technical tenets, such as safe thrombus removal and adequate cleaning of the endoluminal surface and preparedness for bypass in challenging cases 2).

A 64-year-old woman who suffered subarachnoid hemorrhage in 2005. She was treated with coiling of the aneurysm at an outside institution. She presented to the clinic with headaches and was found on angiography to have giant recurrence of the aneurysm. To allow adequate exposure for clipping, Arko et al. performed the surgery through a cranio-orbito-zygomatic (COZ) skull base approach, which is demonstrated. The surgery was performed in an operating room/angiography hybrid suite allowing for high quality intraoperative angiography. The technique and room flow are also demonstrated. The video can be found here: 3).


Left pterional craniotomy for thrombectomy and clipping of ruptured left MCA giant aneurysm

Cranio-orbito-zygomatic approach of a giant MCA aneurysm in a hybrid angio/OR suite



Bendok BR, Abi-Aad KR, Rahme R, Turcotte EL, Welz ME, Patra DP, Hess R, Kalen B, Krishna C, Batjer HH. Tulip Giant Aneurysm Amputation and “Shingle Clip Cut Clip” Technique for Microsurgical Reconstruction of a Giant Thrombosed Middle Cerebral Artery Aneurysm. World Neurosurg. 2019 Aug 2. pii: S1878-8750(19)32108-4. doi: 10.1016/j.wneu.2019.07.192. [Epub ahead of print] PubMed PMID: 31377441.

Glauser G, Piazza M, Choudhri O. Aneurysm Dome Excision and Picket Fence Clip Reconstruction of a Previously Coiled Recurrent Giant MCA Aneurysm: Technical Nuances. World Neurosurg. 2019 Apr 1. pii: S1878-8750(19)30913-1. doi: 10.1016/j.wneu.2019.03.233. [Epub ahead of print] PubMed PMID: 30947002.

Arko L, Quach E, Sukul V, Desai A, Gassie K, Erkmen K. Cranio-orbito-zygomatic approach for a previously coiled/recurrent giant MCA aneurysm in a hybrid angio/OR suite. Neurosurg Focus. 2015 Jul;39(VideoSuppl1):V8. PubMed PMID: 26132625.
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