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).

Intracranial aneurysm risk factors.

see Intracranial aneurysm genetics.

see Intracranial aneurysm pathophysiology.

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 3).

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 4).

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 5).

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 6).

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 7).

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 8).

Toll‑like receptor (TLR) 2/4 serves an important regulatory role in nerve tissue injury. However, the downstream and potential mechanisms remain to be elucidated. The present study was designed to investigate the roles of the TLR2/4‑major myeloid differentiation response gene 88 (MyD88)‑NF‑κB signaling pathway in the development of an intracranial aneurysm. The expression of TLR2, TLR4, and MyD88 in the blood of normal controls and patients with intracranial aneurysms were detected by quantitative PCR and ELISA. Human brain vascular smooth muscle cells were treated by Angiotensin II (Ang II) to evaluate the involvement of the TLR2/4‑MyD88‑NF‑κB signaling pathway in the process. The in vitro experiment was divided into four groups: The control group, an Ang Ⅱ group, an Ang Ⅱ + small interfering (si)RNA control group, and an Ang Ⅱ + TLR2‑group. Cell viability, migration, apoptosis, and expression of TLR2, TLR4, MyD88, NF‑κB, and phosphorylated (p‑)p65 expression was detected. The results demonstrated that the expression of TLR2, TLR4, MyD88, and NF‑κB at mRNA and protein levels in patients with an intracranial aneurysm was significantly higher compared with corresponding protein in normal controls (P&lt;0.05). <em>In vitro</em> experiments demonstrated that Ang Ⅱ treatment increased the cell proliferation and migration rate but reduced the apoptotic rate compared with the control (P&lt;0.05). The expression of TLR2, TLR4, MyD88, NF‑κB, and p‑p65 was significantly increased in the Ang II group (vs. control; P&lt;0.05). By contrast, TLR2‑short interfering RNA reduced the cell proliferation and migration rate and reduced the expression of TLR2, TLR4, MyD88, NF‑κB, and p‑p65 (vs. Ang Ⅱ + short interfering RNA control; P&lt;0.05). In conclusion, the data of the present study indicated that the TLR2/4‑MyD88‑NF‑κB signaling pathway is involved in the intracranial aneurysm pathogenesis 9).


1)

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.
2)

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.
3)

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.
4)

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.
5)

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.
6)

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.
7)

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.
8)

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.
9)

Zhang X, Wan Y, Feng J, Li M, Jiang Z. Involvement of TLR2/4‑MyD88‑NF‑κB signaling pathway in the pathogenesis of intracranial aneurysm. Mol Med Rep. 2021 Jan 26. doi: 10.3892/mmr.2021.11869. Epub ahead of print. PMID: 33655339.

Unruptured intracranial aneurysm treatment

Unruptured intracranial aneurysm treatment

Establishment of drug therapy to prevent rupture of unruptured intracranial aneurysms (IAs) is needed. Previous human and animal studies have gradually clarified candidate drugs for the prevention of intracranial aneurysm rupture. However, because most of these candidates belong to classes of drugs frequently co-administered to prevent cardiovascular diseases, epidemiological studies evaluating these drugs simultaneously should be performed. Furthermore, because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials.

Shimizu et al. performed a cross-sectional study enrolling patients diagnosed with IAs between July 2011 and June 2019. Patients were divided into ruptured or unruptured groups. The drugs investigated were selected according to evidence suggested by either human or animal studies. Univariate and multivariate logistic regression analyses were performed to assess the association of drug treatment with rupture status. They also performed drug-by-drug assessments of the association, including dose-response relationships, with rupture status.

In total, 310 patients with ruptured and 887 patients with unruptured IAs were included. Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38-0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30-0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48-0.93) with ruptured IAs. Moreover, inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipinecilnidipine, and amlodipine among calcium channel blockers, and valsartanazilsartancandesartan, and olmesartan among ARBs. Only non-aspirin non-steroidal anti-inflammatory drugs were positively associated with ruptured IAs (OR, 3.24; 95% CI 1.71-6.13).

The present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for the preventive treatment of unruptured IAs 1).

see Unruptured intracranial aneurysm treatment decision.

In the early 1990’s, endovascular treatment using embolic coils for the treatment of intracranial aneurysms was established. Since then, there has been a significant body of peer-reviewed literature written by medical experts regarding the use, safety, and efficacy of these detachable embolic coils. With the publishing of the ISAT (Intracranial Subarachnoid Aneurysm Trial) trial data in 2005, which compared clinical outcomes of neurosurgical clipping and endovascular coiling, embolic coiling became the preferred method for treatment of the majority of unruptured intracranial aneurysm2).

see Unruptured intracranial aneurysm surgery.

see Unruptured intracranial aneurysm endovascular treatment.


1)

Shimizu K, Imamura H, Tani S, Adachi H, Sakai C, Ishii A, Kataoka H, Miyamoto S, Aoki T, Sakai N. Candidate drugs for preventive treatment of unruptured intracranial aneurysms: A cross-sectional study. PLoS One. 2021 Feb 12;16(2):e0246865. doi: 10.1371/journal.pone.0246865. PMID: 33577580.
2)

Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, Sandercock P; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005 Sep 3-9;366(9488):809-17. PubMed PMID: 16139655.

Very small intracranial aneurysm

Very small intracranial aneurysm

Very small intracranial aneurysm (VSIA) (< 3 mm).

Ruptured VSIA group has higher percentage of females and lower aspect ratio than ruptured non-VSIA group. Further studies regarding the characteristics of ruptured and unruptured VSIA patients is required for assistance in clinical decision related to treatment of VSIA group before the aneurysm sac rupture 1).

The most common site of rupture of very small aneurysm was the anterior communicating artery (ACoA). Rupture of small and very small aneurysms is unpredictable, and treatment may be considered in selected high-risk patients according to factors such as young age, ACoA location, and hypertension 2).

Treatment of very small unruptured intracranial aneurysms (VSUIAs, defined as ≤3 mm) can be indicated in selected circumstances. The feasibility and outcomes of endovascular therapy for VSUIAs have been recently published; however, the efficacy and complication rate of surgical clipping has not been reported in any large series to date.

In a study, 183 patients (128 women, mean age 51.3 years) were treated with 190 procedures for a total of 228 aneurysms. Most were anterior circulation aneurysms (n = 215). The majority were directly clipped (n = 222, 97.4%), with coagulation or wrapping in the remainder. After 1 reoperation for incomplete clipping, postoperative imaging of 225 aneurysms confirmed complete occlusion in 221 (98.2%), 1 neck remnant (0.44%), and 3 partial occlusions (1.3%). Mortality was 0%. Early postoperative neurological deficit developed in 12 patients (6.6%); posterior circulation location was a significant risk factor for early neurological deficit (P < .001). Middle cerebral artery aneurysms had the lowest rate of postoperative deficits at 1.5% (P = .023). After the initial 30-day perioperative period, all deficits related to treatment of posterior circulation aneurysms recovered; overall neurological morbidity decreased to 2.7% with no mortality.

VSUIA clipping is highly effective and is associated with a low morbidity rate. For VSUIAs selected for treatment, our data support surgical clipping as the modality of choice 3).


Aneurysms treated with a Pipeline Embolization Device in vessels less than 2.5 mm between June 2012 and August 2014 were included. They evaluated risk factors, family history of aneurysms, aneurysm characteristics, National Institute of Health Stroke Scale (NIHSS), and modified Rankin scale (mRS) on admission and angiography and clinical outcome at discharge, 6 months, and 1 year.

They included seven patients with a mean age of 65 years. The parent vessel size ranged from 1.5 to 2.3 mm; mean 1.9 mm. Location of the aneurysms was as follows: two aneurysms centered along the pericallosal artery (one left, one right), one on the right angular artery, one aneurysm at the anterior communicating artery (ACom), one at the ACom-right A2 anterior cerebral artery (ACA), one at the lenticulostriate artery, and one at the A1-A2 ACA artery. Aneurysms ranged from 1 to 12 mm in diameter. All aneurysms were treated with a single Pipeline™ Embolization Device (PED). No peri- or post-procedural complications or mortality occurred. The patients were discharged with no change in NIHSS or mRS score. Angiographic follow-up was available in six patients. Angiography showed complete aneurysm occlusion in all. NIHSS and mRS remained unchanged at follow-up.

The preliminary results show that flow diversion technology is an effective and safe therapy for aneurysms located on small cerebral arteries. Larger studies with long-term follow-up are needed to validate our promising results 4).


1)

Park GT, Kim JH, Jung YJ, Chang CH. Characteristics of patients with ruptured very small intracranial aneurysm sized less than 3 mm. J Cerebrovasc Endovasc Neurosurg. 2020 Oct 22. doi: 10.7461/jcen.2020.E2020.07.001. Epub ahead of print. PMID: 33086456.
2)

Lee GJ, Eom KS, Lee C, Kim DW, Kang SD. Rupture of Very Small Intracranial Aneurysms: Incidence and Clinical Characteristics. J Cerebrovasc Endovasc Neurosurg. 2015 Sep;17(3):217-22. doi: 10.7461/jcen.2015.17.3.217. Epub 2015 Sep 30. PubMed PMID: 26526401; PubMed Central PMCID: PMC4626345.
3)

Bruneau M, Amin-Hanjani S, Koroknay-Pal P, Bijlenga P, Jahromi BR, Lehto H, Kivisaari R, Schaller K, Charbel F, Khan S, Mélot C, Niemela M, Hernesniemi J. Surgical Clipping of Very Small Unruptured Intracranial Aneurysms: A Multicenter International Study. Neurosurgery. 2016 Jan;78(1):47-52. doi: 10.1227/NEU.0000000000000991. PubMed PMID: 26317673.
4)

Puri AS, Massari F, Asai T, Marosfoi M, Kan P, Hou SY, Howk M, Perras M, Brooks C, Clarencon F, Gounis MJ, Wakhloo AK. Safety, efficacy, and short-term follow-up of the use of Pipeline™ Embolization Device in small (<2.5mm) cerebral vessels for aneurysm treatment: single institution experience. Neuroradiology. 2015 Dec 23. [Epub ahead of print] PubMed PMID: 26700827.
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