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).


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.

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.

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.

Pituitary Surgery During Covid-19

Pituitary Surgery During Covid-19

see Precautions for endoscopic transnasal skull base surgery during the COVID-19 pandemic

During the Covid-19 pandemic, every hospital has had to change its internal organization. The nature of the transsphenoidal corridor exposes the pituitary surgery team to an increased risk of virus exposure 1).

It was reported that the aerosolization and mucosal involvement increase the risk of viral transmission during operation. Therefore, transcranial is a safer surgical approach during the COVID-19 pandemic.

Nine cases of pituitary adenomas have presented with urgent manifestations. The endoscopic endonasal approach was performed in eight patients, while a craniotomy was selected for a recurrent pituitary adenoma. Pre- and postoperative thorough clinical evaluations with chest CT scans were performed. Other strict infection control measures have been applied.

In 8 weeks duration starting from the past days of February 2020, we have operated on four females and five males of pituitary adenomas. Visual deterioration was the main presenting symptom. The driving factor for surgery was saving vision in eight patients. Fortunately, the postoperative course was uneventful for all patients. No suspected COVID-19 infection has been reported in any patient or health-care team except one patient. In our city, PCR test was routinely not available 2).

A retrospective cohort study was conducted of all patients who underwent high-priority endoscopic nasal surgery or anterior skull base surgery between 23rd March and 15th June 2020 at University Hospitals Birmingham NHS Trust.

Twenty-four patients underwent endonasal surgery during the study period, 12 were males and 12 were females. There was no coronavirus-related morbidity in any patient.

This observational study found that it is possible to safely undertake urgent endonasal surgery; the nosocomial risk of coronavirus disease 2019 can be mitigated with appropriate peri-operative precautions 3).

A 21-year old male, who required urgent surgery because of progressive visual disturbance due to giant pituitary adenoma. On brain MRI with contrast, it was revealed an extra-axial tumor extending anteriorly over planum sphenoidal with the greatest diameter was 5.34 cm. A transcranial approach was chosen to resect the tumor. Near-total removal of the tumor was achieved without damaging the vital neurovascular structure. The visual acuity was improved and no significant postoperative complication. Pathology examination revealed pituitary adenoma.

Transcranial surgery for pituitary adenoma is still an armamentarium in neurosurgical practice, especially in the COVID-19 pandemic to provide a safer surgical approach 4).

The goal of a paper of Penner et al. is to illustrate the feasibility of pituitary region surgery during the SARS-CoV-2 pandemic.

After two negative COVID tests were obtained, three patients with macro GH-secreting tumors, and two patients with micro ACTH-secreting tumors resistant to medical treatment underwent surgery during the pandemic. During the surgery, every patient was treated as if they were positive.

Neither operator nor patient has developed COVID symptoms. The two neurosurgeons performing the operations underwent two COVID swabs, which resulted in negative.

Pituitary surgery is high-risk non-urgent surgery. However, the method described has so far been effective and is safe for both patients and healthcare providers 5).

The impact of COVID-19 on pituitary surgery. ANZ J Surg. 2020 Apr 25. doi: 10.1111/ans.15959. [Epub ahead of print] PubMed PMID: 32336017 6).

A 47-year-old male COVID-19 positive patient presented to the Emergency Department with a left frontal headache that culminated with diplopia, left eye ptosis, and left visual acuity loss after 5 days. Transsphenoidal hypophysectomy was uneventfully performed, and the patient was discharged from the hospital on postoperative day four. It additionally describes in detail the University of Mississippi Medical Center airway management algorithm for patients infected with the novel coronavirus who need emergent surgical attention 7).

A 72-year-old woman who required urgent endonasal transsphenoidal surgery (eTSS) because of progressive visual field disturbance due to pituitary adenoma, in whom we conducted reverse-transcriptase-polymerase-chain-reaction (RT-PCR) for COVID-19 and chest CT before eTSS. We took care of her by following the rule for suspected infection patient and safely completed her treatment without medical staff infection. Under COVID-19 pandemic state, essentially careful management including RT-PCR test and chest CT should be taken for the high infection risk surgeries to avoid the outbreak through the hospital. And the cost of the RT-PCR test for the patients should be covered by the government budget 8).


Quillin JW, Oyesiku NM. Status of Pituitary Surgery During the COVID-19 Pandemic. Neurol India. 2020 May-Jun;68(Supplement):S134-S136. doi: 10.4103/0028-3886.287685. PMID: 32611904.

Arnaout MM, Bessar AA, Elnashar I, Abaza H, Makia M. Pituitary adenoma surgeries in COVID-19 era: Early local experience from Egypt. Surg Neurol Int. 2020 Oct 29;11:363. doi: 10.25259/SNI_472_2020. PMID: 33194296; PMCID: PMC7655998.

Naik PP, Tsermoulas G, Paluzzi A, McClelland L, Ahmed SK. Endonasal surgery in the coronavirus era – Birmingham experience. J Laryngol Otol. 2020 Nov 4:1-4. doi: 10.1017/S0022215120002364. Epub ahead of print. PMID: 33143753; PMCID: PMC7729149.

Golden N, Niryana W, Awyono S, Eka Mardhika P, Bhuwana Putra M, Stefanus Biondi M. Transcranial approach as surgical treatment for giant pituitary adenoma during COVID 19 pandemic – What can we learn?: A case report. Interdiscip Neurosurg. 2021 Feb 25:101153. doi: 10.1016/j.inat.2021.101153. Epub ahead of print. PMID: 33654658; PMCID: PMC7906516.

Penner F, Grottoli S, Lanotte MMR, Garbossa D, Zenga F. Pituitary surgery during Covid-19: a first-hand experience and evaluation [published online ahead of print, 2020 Jul 10]. J Endocrinol Invest. 2020;10.1007/s40618-020-01354-x. doi:10.1007/s40618-020-01354-x

Mitchell RA, King JA, Goldschlager T, Wang YY. The impact of COVID-19 on pituitary surgery. ANZ J Surg. 2020 Apr 25. doi: 10.1111/ans.15959. [Epub ahead of print] PubMed PMID: 32336017.

Santos CDSE, Filho LMDCL, Santos CAT, Neill JS, Vale HF, Kurnutala LN. Pituitary tumor resection in a patient with SARS-CoV-2 (COVID-19) infection. A case report and suggested airway management guidelines. Braz J Anesthesiol. 2020 Mar-Apr;70(2):165-170. doi: 10.1016/j.bjane.2020.05.003. Epub 2020 Jun 10. PMID: 32834194; PMCID: PMC7283047.

Akai T, Maruyama K, Takakura H, Yamamoto Y, Morinaga Y, Kuroda S. Safety management in urgent endonasal trans-sphenoidal surgery for pituitary adenoma during the COVID-19 pandemic in Japan – A case report. Interdiscip Neurosurg. 2020 Dec;22:100820. doi: 10.1016/j.inat.2020.100820. Epub 2020 Jul 10. PMID: 32835016; PMCID: PMC7347482.

National Trauma Data Bank

National Trauma Data Bank

The National Trauma Data Bank (NTDB), also called the American College of Surgeons National Trauma Data Bank, is a compilation of information about traumatic injuries and outcomes in the United States. Hospital emergency rooms and other institutions such as trauma centers which are participants submit data and receive in return access to reports analyzing data about both their own operations and trauma medicine in the United States as a whole.

Annual reports, an annual report, and a pediatric report, which includes demographic information is issued. Access to data sets is available to researchers who apply and are approved.

The National Trauma Data Bank® (NTDB®) National Sample Program (NSP) is a national probability sample of 100 Level I and II trauma centers in the United States. The goal of the NTDB NSP is to enhance current injury information by providing nationally representative baseline estimates of trauma care to meet the needs of trauma care assessment, clinical outcomes research, and injury surveillance. This program is supported by the Centers for Disease Control and Prevention and the American College of Surgeons (ACS).

The NTDB National Sample is a unique and powerful database that includes information on trauma patients, such as admission and discharge status; patient demographics (for example, gender, age, race); injury and diagnosis (i.e., mechanism, e-code, ICD-9 or AIS code); procedure codes; injury severity scores (i.e., the Injury Severity Score, Glasgow Coma Scale); and outcome variables (for example, length of stay, intensive care unit days, payment method).

The National Trauma Data Bank was used to identify patients with spinal cord injury. The primary objective was to determine the association between center type, transfer, and surgical intervention. A secondary objective was to determine the association between center type, transfer, and surgical timing. Multivariable logistic regression models were fit on surgical intervention and timing of the surgery as binary variables, adjusting for relevant clinical and demographic variables.

There were 11,744 incidents of spinal cord injury identified. A total of 2,883 patients were transferred to a Level I center and 4,766 presented directly to a Level I center. Level I center refers to a level I trauma center. Those who were admitted directly to a level I center had a higher odds of receiving surgery (odds ratio, 1.703; 95% confidence interval, 1.47-1.97; p < 0.001), but there was no significant difference in terms of timing of surgery. Patients transferred into a level I center were also more likely to undergo surgery than those at a level II/III/IV center, although this was not significant (odds ratio, 1.213; 95% confidence interval, 0.099-1.48; p = 0.059).

Patients with traumatic spinal cord injury admitted to a Level I trauma center were more likely to have surgery, particularly if they were directly admitted to a Level I center. A study of Williamson et al. provides insights into a large US sample and sheds light on opportunities for improving pre-hospital care pathways for patients with traumatic SCI, to provide timely and appropriate care and achieve the best possible outcomes 1)


Williamson T, Hodges S, Yang LZ, Lee HJ, Gabr M, Ugiliweneza B, Boakye M, Shaffrey CI, Goodwin CR, Karikari IO, Lad S, Abd-El-Barr M. Impact of US hospital center and interhospital transfer on spinal cord injury management: An analysis of the National Trauma Data Bank. J Trauma Acute Care Surg. 2021 Jun 1;90(6):1067-1076. doi: 10.1097/TA.0000000000003165. PMID: 34016930.
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