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).

Genetics

Pathophysiology

Hemodynamics

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).

References

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)

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.
4)

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.
5)

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.
6)

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.
7)

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.
8)

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.
9)

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.

Intracranial pressure monitoring in children

Intracranial pressure monitoring in children

Protocols for treatment of children with severe traumatic brain injury incorporate intracranial pressure monitoring as part of a comprehensive plan to minimize secondary injuries, using either ICP and/or cerebral perfusion pressure (CPP) as the therapeutic target 1).

At least 500 children enrolled in 9 studies have demonstrated at least some association between ICP and outcome 2) 3) 4) 5) 6) 7) 8) 9) 10).

As a result, most centers adopted ICP monitoring years ago, while some have argued against the need for such an approach 11).

Data suggest that there is a small, yet statistically significant, survival advantage in patients who have ICP monitors and a GCS score of 3. However, all patients with ICP monitors experienced longer hospital length of stay, longer intensive care unit stay, and more ventilator days compared with those without ICP monitors. A prospective observational study would be helpful to accurately define the population for whom ICP monitoring is advantageous 12).

EVD and IP measurements of ICP were highly correlated, although intermittent EVD ICP measurements may fail to identify ICP events when continuously draining cerebrospinal fluid. In institutions that use continuous cerebrospinal fluid diversion as a therapy, a two-monitor system may be valuable for accomplishing monitoring and therapeutic goals 13).


In the search for a reliable, cooperation-independent, noninvasive alternative to invasive intracranial pressure monitoring in children, various approaches have been proposed, but at the present time none are capable of providing fully automated, real-time, calibration-free, continuous and accurate intracranial pressure estimates. Fanelli et al. investigated the feasibility and validity of simultaneously monitored arterial blood pressure(ABP) and middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) waveforms to derive noninvasive ICP (nICP) estimates.

Invasive ICP and ABP recordings were collected from 12 pediatric and young adult patients (aged 2-25 years) undergoing such monitoring as part of routine clinical care. Additionally, simultaneous transcranial Doppler (TCD) ultrasonography-based MCA CBFV waveform measurements were performed at the bedside in dedicated data collection sessions. The ABP and MCA CBFV waveforms were analyzed in the context of a mathematical model, linking them to the cerebral vasculature’s biophysical properties and ICP. The authors developed and automated a waveform preprocessing, signal-quality evaluation, and waveform-synchronization “pipeline” in order to test and objectively validate the algorithm’s performance. To generate one nICP estimate, 60 beats of ABP and MCA CBFV waveform data were analyzed. Moving the 60-beat data window forward by one beat at a time (overlapping data windows) resulted in 39,480 ICP-to-nICP comparisons across a total of 44 data-collection sessions (studies). Moving the 60-beat data window forward by 60 beats at a time (nonoverlapping data windows) resulted in 722 paired ICP-to-nICP comparisons.

Greater than 80% of all nICP estimates fell within ± 7 mm Hg of the reference measurement. Overall performance in the nonoverlapping data window approach gave a mean error (bias) of 1.0 mm Hg, standard deviation of the error (precision) of 5.1 mm Hg, and root-mean-square error of 5.2 mm Hg. The associated mean and median absolute errors were 4.2 mm Hg and 3.3 mm Hg, respectively. These results were contingent on ensuring adequate ABP and CBFV signal quality and required accurate hydrostatic pressure correction of the measured ABP waveform in relation to the elevation of the external auditory meatus. Notably, the procedure had no failed attempts at data collection, and all patients had adequate TCD data from at least one hemisphere. Last, an analysis of using study-by-study averaged nICP estimates to detect a measured ICP > 15 mm Hg resulted in an area under the receiver operating characteristic curve of 0.83, with a sensitivity of 71% and specificity of 86% for a detection threshold of nICP = 15 mm Hg.

This nICP estimation algorithm, based on ABP and bedside TCD CBFV waveform measurements, performs in a manner comparable to invasive ICP monitoring. These findings open the possibility for rational, point-of-care treatment decisions in pediatric patients with suspected raised ICP undergoing intensive care 14).


Noninvasive quantitative measures of the peripapillary retinal structure by SD-OCT were correlated with invasively measured intracranial pressure. Optical coherence tomographic parameters showed promise as surrogate, noninvasive measures of intracranial pressure, outperforming other conventional clinical measures. Spectral-domain OCT of the peripapillary region has the potential to advance current treatment paradigms for elevated intracranial pressure in children 15).

References

1)

Adelson PD, Bratton SL, Carney NA, Chesnut RM, du Coudray HE, Goldstein B, Kochanek PM, Miller HC, Partington MP, Selden NR, Warden CR, Wright DW; American Association for Surgery of Trauma; Child Neurology Society; International Society for Pediatric Neurosurgery; International Trauma Anesthesia and Critical Care Society; Society of Critical Care Medicine; World Federation of Pediatric Intensive and Critical Care Societies. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Chapter 19. The role of anti-seizure prophylaxis following severe pediatric traumatic brain injury. Pediatr Crit Care Med. 2003 Jul;4(3 Suppl):S72-5. PubMed PMID: 12847355.
2)

Alberico AM, Ward JD, Choi SC, Marmarou A, Young HF. Outcome after severe head injury. Relationship to mass lesions, diffuse injury, and ICP course in pediatric and adult patients. J Neurosurg. 1987;67(5):648–656.
3)

Barzilay Z, Augarten A, Sagy M, Shahar E, Yahav Y, Boichis H. Variables affecting outcome from severe brain injury in children. Intensive Care Med. 1988;14(4):417–421.
4)

Chambers IR, Treadwell L, Mendelow AD. Determination of threshold levels of cerebral perfusion pressure and intracranial pressure in severe head injury by using receiver-operating characteristic curves: an observational study in 291 patients. J Neurosurg. 2001;94(3):412–416.
5)

Downard C, Hulka F, Mullins RJ, Piatt J, Chesnut R, Quint P, Mann NC. Relationship of cerebral perfusion pressure and survival in pediatric brain-injured patients. J Trauma. 2000;49(4):654–658. discussion 658-659.
6)

Eder HG, Legat JA, Gruber W. Traumatic brain stem lesions in children. Childs Nerv Syst. 2000;16(1):21–24.
7)

Esparza J, J MP, Sarabia M, Yuste JA, Roger R, Lamas E. Outcome in children with severe head injuries. Childs Nerv Syst. 1985;1(2):109–114.
8)

Kasoff SS, Lansen TA, Holder D, Filippo JS. Aggressive physiologic monitoring of pediatric head trauma patients with elevated intracranial pressure. Pediatr Neurosci. 1988;14(5):241–249.
9)

Michaud LJ, Rivara FP, Grady MS, Reay DT. Predictors of survival and severity of disability after severe brain injury in children. Neurosurgery. 1992;31(2):254–264.
10)

Shapiro K, Marmarou A. Clinical applications of the pressure-volume index in treatment of pediatric head injuries. J Neurosurg. 1982;56(6):819–825.
11)

Salim A, Hannon M, Brown C, Hadjizacharia P, Backhus L, Teixeira PG, Chan LS, Ford H. Intracranial pressure monitoring in severe isolated pediatric blunt head trauma. Am Surg. 2008 Nov;74(11):1088-93. PubMed PMID: 19062667.
12)

Alkhoury F, Kyriakides TC. Intracranial Pressure Monitoring in Children With Severe Traumatic Brain Injury: National Trauma Data Bank-Based Review of Outcomes. JAMA Surg. 2014 Jun;149(6):544-8. doi: 10.1001/jamasurg.2013.4329. PubMed PMID: 24789426.
13)

Exo J, Kochanek PM, Adelson PD, Greene S, Clark RS, Bayir H, Wisniewski SR, Bell MJ. Intracranial pressure-monitoring systems in children with traumatic brain injury: combining therapeutic and diagnostic tools. Pediatr Crit Care Med. 2011 Sep;12(5):560-5. doi: 10.1097/PCC.0b013e3181e8b3ee. PubMed PMID: 20625341; PubMed Central PMCID: PMC3670608.
14)

Fanelli A, Vonberg FW, LaRovere KL, Walsh BK, Smith ER, Robinson S, Tasker RC, Heldt T. Fully automated, real-time, calibration-free, continuous noninvasive estimation of intracranial pressure in children. J Neurosurg Pediatr. 2019 Aug 23:1-11. doi: 10.3171/2019.5.PEDS19178. [Epub ahead of print] PubMed PMID: 31443086.
15)

Swanson JW, Aleman TS, Xu W, Ying GS, Pan W, Liu GT, Lang SS, Heuer GG, Storm PB, Bartlett SP, Katowitz WR, Taylor JA. Evaluation of Optical Coherence Tomography to Detect Elevated Intracranial Pressure in Children. JAMA Ophthalmol. 2017 Apr 1;135(4):320-328. doi: 10.1001/jamaophthalmol.2017.0025. PubMed PMID: 28241164; PubMed Central PMCID: PMC5470406.

Primary Intracranial Solitary Fibrous Tumor

Primary Intracranial Solitary Fibrous Tumor

Intracranial solitary fibrous tumors (ISFTs) are rare mesenchymal neoplasms originating in the meninges and constitute a heterogeneous group of rare spindle-cell tumors that include benign and malignant neoplasms of which hemangiopericytoma is nowadays considered a cellular phenotypic variant. ISFT usually shows benign or indolent clinical behavior 1).

Primary Intracranial Solitary Fibrous Tumor (SFT) involving the central nervous system (CNS) was first reported in 1996 by Carneiro et al, who described 7 cases of meningeal SFT that could be distinguished from fibrous meningioma on morphologic and immunohistochemical grounds 2).

Since then, more than 60 cases of CNS SFT including the meninges and the spinal cord have been described in the pertinent literature.

For its rarity and resemblance to other more common brain tumors, such as meningioma and hemangiopericytomas, intracranial SFT (ISFT) is often poorly recognized and remains a diagnostic challenge.

Although there are no pathognomonic imaging findings, some imaging features, such as the “black-and-white mixed” pattern on T2-weighted images and marked heterogeneous enhancement, might be helpful in the diagnosis of intracranial solitary fibrous tumor

A 62-year-old man with headache and memory disturbance for 2 years. A, Noncontrast CT shows a heterogenous hyperattenuated multilobulated tumor in left middle cranial fossa. B, Contrast-enhanced CT, intense but inhomogeneous contrast enhancement is noted. C, T1-weighted axial MR image, a large lobulated mass is seen in the left paraclinoid portion to the tentorium. D, T2-weighted axial MR image reveals 2 different signal intensity portions of the mass, hyposignal intensity and hypersignal intensity to gray matter. E and F, Gadolinium-enhanced T1-weighted axial and coronal MR images show marked and heterogenous enhancement. The tumor is partially implanted on the surface of the tentorium (arrows). Memory disturbance might be because of the mass effect on the limbic system. G, Selective injection of the left internal carotid artery (capillary phase); the tumor is supplied at its periphery by pial branches. H, Selective injection of the left external carotid artery; there is tumor blushing with dysplastic dilation of the tumor vessels. There is no demonstrable significant arteriovenous shunt or early venous drainage. 3).

Case reports

Yamaguchi et al. reported a very rare case of intracranial SFT in a 55-year-old woman who presented with gait disturbance and numbness in bilateral upper limbs from three months prior to visiting the hospital. Head MRI revealed a homogeneously enhancing mass lesion located primarily in the fourth ventricle extending into the spinal canal and left foramen of Luschka, with a maximum diameter of 60 mm. Notably, this tumor presented spontaneous partial regression during waiting planned surgery without therapy, including chemotherapy and radiotherapy. This patient underwent a midline suboccipital craniotomy and resection of the tumor. Interestingly, there was no attachment to the dura mater of the posterior cranial fossa and the lesion was only attached to the dorsal part of the medulla oblongata.

Although the location of the SFT in the fourth ventricle is rare, SFT should be considered as one of the differential diagnosis of fourth ventricle tumors. In addition, this case indicates that SFT in the fourth ventricle may regress on occasion spontaneously without a precisely known cause for this spontaneous partial regression 4).


Torazawa et al., encountered a case of small solitary fibrous tumor in the optic canal causing rapid visual deterioration. The radiographic findings of pre-operative imaging studies were compatible with those of meningioma; however, unlike meningioma, bleeding from the tumor was very profuse during the operation. The endoscopic transnasal approach was effective for handling the highly vascularized tumor in this delicate region, and gross total removal was achieved with postoperative gradual improvement in his visual function. Nevertheless, the tumor recurred after six months, and re-resection was performed with using the same surgical corridor, followed by adjuvant radiotherapy.

Endoscopic transnasal surgery is a valuable option for aggressive lesions in the optic canal. Although the efficacy of radiotherapy for SFT remains controversial, it should be considered when the tumor shows progressive features 5).


A 63-year-old female patient who had confused mentality, without other neurological deficit. The brain MRI showed an ovoid mass in the right frontal lobe. The tumor was surgically removed grossly and totally, and the pathologic diagnosis was SFT. At 55 months after the surgery, the tumor recurred at the primary site and at an adjacent area. A second operation was thus done, and the tumor was again surgically removed grossly and totally. The pathologic diagnosis was the same as the previous, but the Ki-67 index was elevated. Ten months later, two small recurring tumors in the right frontal skull base were found in the follow-up MRI. It was decided that radiation therapy be done, and MRI was done again 3 months later. In the follow-up MRI, the size of the recurring mass was found to have decreased, and the patient did not manifest any significant symptom. Follow-up will again be done 18 months after the second surgery 6).

References

1)

Aljohani HT, Chaussemy D, Proust F, Chibbaro S. Intracranial solitary fibrous tumor/hemangiopericytoma: Report of two cases and literature review. Int J Health Sci (Qassim). 2017 Jul-Sep;11(3):69-70. PubMed PMID: 28936155; PubMed Central PMCID: PMC5604277.
2)

Carneiro SS, Scheithauer BW, Nascimento AG, Hirose T, Davis DH. Solitary fibrous tumor of the meninges: a lesion distinct from fibrous meningioma. A clinicopathologic and immunohistochemical study. Am J Clin Pathol. 1996 Aug;106(2):217-24. PubMed PMID: 8712177.
3)

Weon YC, Kim EY, Kim HJ, Byun HS, Park K, Kim JH. Intracranial solitary fibrous tumors: imaging findings in 6 consecutive patients. AJNR Am J Neuroradiol. 2007 Sep;28(8):1466-9. PubMed PMID: 17846192.
4)

Yamaguchi J, Motomura K, Ohka F, Aoki K, Tanahashi K, Hirano M, Nishikawa T, Shimizu H, Wakabayashi T, Natsume A. Spontaneous tumor regression of intracranial solitary fibrous tumor originating from the medulla oblongata: A case report and literature review. World Neurosurg. 2019 Jul 18. pii: S1878-8750(19)31958-8. doi: 10.1016/j.wneu.2019.07.052. [Epub ahead of print] PubMed PMID: 31326640.
5)

Torazawa S, Shin M, Hasegawa H, Otani R, Ueki K, Saito N. Endoscopic transnasal resection of solitary fibrous tumor in the optic canal. World Neurosurg. 2018 May 16. pii: S1878-8750(18)31003-9. doi: 10.1016/j.wneu.2018.05.050. [Epub ahead of print] PubMed PMID: 29777894.
6)

Kim JH, Yang KH, Yoon PH, Kie JH. Solitary Fibrous Tumor of Central Nervous System: A Case Report. Brain Tumor Res Treat. 2015 Oct;3(2):127-31. doi: 10.14791/btrt.2015.3.2.127. Epub 2015 Oct 30. PubMed PMID: 26605270; PubMed Central PMCID: PMC4656890.
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