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Activation of the NLRP3/IL-1β/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats

Tadashi Yamaguchi, Takeshi Miyamoto, Eiji Shikata, Izumi Yamaguchi, Kenji Shimada, Kenji Yagi, Yoshiteru Tada, Masaaki Korai, Keiko T. Kitazato, Yasuhisa Kanematsu, and Yasushi Takagi

OBJECTIVE

Subarachnoid hemorrhage (SAH) due to intracranial aneurysm (IA) rupture is often a devastating event. Since the incidence of SAH increases especially in menopause, it is crucial to clarify the detailed pathogenesis of these events. The activation of vascular nucleotide-binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasomes has been studied in ischemic stroke and cardiovascular disease. However, the role of NLRP3 in IA rupture still needs to be explained. The authors sought to test their hypothesis that, under estrogen-deficient conditions, activation of NLRP3 inflammasomes via downregulation of the estrogen receptor (ER) facilitates IA rupture.

METHODS

Ten-week-old female Sprague Dawley rats with and without oophorectomy were subjected to hemodynamic changes and hypertension (OVX+/HT and OVX−/HT, respectively) and fed a high-salt diet. Separately, using human brain endothelial cells (HBECs) and human brain smooth muscle cells (HBSMCs), the authors tested the effect of NLRP3 under estrogen-free conditions and in the presence of estradiol or of ER agonists.

RESULTS

In OVX+/HT rats, the frequency of IA rupture was significantly higher than in OVX−/HT rats (p = 0.03). In the left posterior cerebral artery prone to rupture in OVX+/HT rats, the levels of the mRNAs encoding ERα and Sirt1, but not of that encoding ERβ, were decreased, and the levels of the mRNAs encoding NLRP3, interleukin-1β (IL-1β), and matrix metalloproteinase 9 (MMP-9) were elevated. Immunohistochemical analysis demonstrated that the expression profiles of these proteins correlated with their mRNA levels. Treatment with an ER modulator, bazedoxifene, normalized the expression profiles of these proteins and improved SAH-free survival. In HBECs and HBSMCs under estrogen-free conditions, the depletion of ERα and Sirt1 and the accumulation of NLRP3 were counteracted by exposure to estradiol or to an ERα agonist but not to an ERβ agonist.

CONCLUSIONS

To the authors’ knowledge, this work represents the first demonstration that, in an aneurysm model under estrogen-deficient conditions, the depletion of ERα and Sirt1 may contribute to activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of IAs in the estrogen-deficient rat IA rupture model.

In Journal of Neurosurgery Publish Before Print

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Adverse radiation effect and freedom from progression following repeat stereotactic radiosurgery for brain metastases

Penny K. Sneed, Jason W. Chan, Lijun Ma, Steve E. Braunstein, Philip V. Theodosopoulos, Shannon E. Fogh, Jean L. Nakamura, Lauren Boreta, David R. Raleigh, Benjamin P. Ziemer, Olivier Morin, Shawn L. Hervey-Jumper, and Michael W. McDermott

OBJECTIVE

The authors previously evaluated risk and time course of adverse radiation effects (AREs) following stereotactic radiosurgery (SRS) for brain metastases, excluding lesions treated after prior SRS. In the present analysis they focus specifically on single-fraction salvage SRS to brain metastases previously treated with SRS or hypofractionated SRS (HFSRS), evaluating freedom from progression (FFP) and the risk and time course of AREs.

METHODS

Brain metastases treated from September 1998 to May 2019 with single-fraction SRS after prior SRS or HFSRS were analyzed. Serial follow-up magnetic resonance imaging (MRI) and surgical pathology reports were reviewed to score local treatment failure and AREs. The Kaplan-Meier method was used to estimate FFP and risk of ARE measured from the date of repeat SRS with censoring at the last brain MRI.

RESULTS

A total of 229 retreated brain metastases in 124 patients were evaluable. The most common primary cancers were breast, lung, and melanoma. The median interval from prior SRS/HFSRS to repeat SRS was 15.4 months, the median prescription dose was 18 Gy, and the median duration of follow-up imaging was 14.5 months. At 1 year after repeat SRS, FFP was 80% and the risk of symptomatic ARE was 11%. The 1-year risk of imaging changes, including asymptomatic RE and symptomatic ARE, was 30%. Among lesions that demonstrated RE, the median time to onset was 6.7 months (IQR 4.7–9.9 months) and the median time to peak imaging changes was 10.1 months (IQR 5.6–13.6 months). Lesion size by quadratic mean diameter (QMD) showed similar results for QMDs ranging from 0.75 to 2.0 cm (1-year FFP 82%, 1-year risk of symptomatic ARE 11%). For QMD < 0.75 cm, the 1-year FFP was 86% and the 1-year risk of symptomatic ARE was only 2%. Outcomes were worse for QMDs 2.01–3.0 cm (1-year FFP 65%, 1-year risk of symptomatic ARE 24%). The risk of symptomatic ARE was not increased with tyrosine kinase inhibitors or immunotherapy before or after repeat SRS.

CONCLUSIONS

RE on imaging was common after repeat SRS (30% at 1 year), but the risk of a symptomatic ARE was much less (11% at 1 year). The results of repeat single-fraction SRS were good for brain metastases ≤ 2 cm. The authors recommend an interval ≥ 6 months from prior SRS and a prescription dose ≥ 18 Gy. Alternatives such as HFSRS, laser interstitial thermal therapy, or resection with adjuvant radiation should be considered for recurrent brain metastases > 2 cm.

In Journal of Neurosurgery Publish Before Print

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Association of circumferential aneurysm wall enhancement with recurrence after coiling of unruptured intracranial aneurysms: a preliminary vessel wall imaging study

Takeshi Hara, Toshinori Matsushige, Michitsura Yoshiyama, Yukishige Hashimoto, Shohei Kobayashi, and Shigeyuki Sakamoto

OBJECTIVE

Recent histopathological studies of unruptured intracranial aneurysms (UIAs) have confirmed that aneurysm wall enhancement (AWE) on MR vessel wall imaging (VWI) is related to wall degeneration with in vivo inflammatory cell infiltration. Therefore, pretreatment aneurysm wall status on VWI may be associated with recurrence after endovascular treatment.

METHODS

VWI with gadolinium was performed on 67 consecutive saccular UIAs before endovascular treatment between April 2017 and June 2021. The mean (range) follow-up period after treatment was 24.4 (6–54) months. AWE patterns were classified as circumferential AWE (CAWE), focal AWE (FAWE), and negative AWE (NAWE). The authors retrospectively investigated the relationship between aneurysm recurrence and AWE patterns, as well as conventional risk factors.

RESULTS

Sixty-seven patients with 67 saccular UIAs were eligible for the present study. AWE patterns were as follows: 10 CAWE (14.9%), 20 FAWE (29.9%), and 37 NAWE (55.2%). Follow-up MRA detected aneurysm recurrence in 18 of 69 cases (26.1%). Univariate analysis identified maximum diameter (mean ± SD 5.8 ± 2.2 mm in patients with stable aneurysms vs 7.7 ± 3.8 mm in those with unstable aneurysms, p = 0.02), aspect ratio (1.4 ± 0.5 vs 1.1 ± 0.4, p < 0.01), aneurysm location in posterior circulation (4.1% vs 27.8%, p < 0.01), volume embolization ratio (29.6% ± 7.8% vs 25.2% ± 6.1%, p = 0.02), and AWE pattern (p = 0.04) as significant predictive factors of recurrence. Among the 3 AWE patterns, CAWE was significantly more frequent in the unstable group, but no significant differences in stability of the treated aneurysms were observed with the FAWE and NAWE patterns. In multivariate logistic regression analysis, CAWE pattern (OR 14.2, 95% CI 1.8–110.8, p = 0.01) and volume embolization ratio ≥ 25% (OR 8.6, 95% CI 2.1–34.3, p < 0.01) remained as significant factors associated with aneurysm stability after coiling.

CONCLUSIONS

VWI before coiling provides novel insights into the stability of treated aneurysms. Aneurysms with the CAWE pattern on VWI before coiling may be less stable after treatment.

In Journal of Neurosurgery Publish Before Print

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Compactness index: a radiosurgery outcome predictor for patients with unruptured brain arteriovenous malformations

Po-Wei Huang, Syu-Jyun Peng, David Hung-Chi Pan, Huai-Che Yang, Jo-Ting Tsai, Cheng-Ying Shiau, I-Chang Su, Ching-Jen Chen, Hsiu-Mei Wu, Chung-Jung Lin, Wen-Yuh Chung, Wan-Yuo Guo, Wei-Lun Lo, Shao-Wen Lai, and Cheng-Chia Lee

OBJECTIVE

The goal of the study was to define and quantify brain arteriovenous malformation (bAVM) compactness and to assess its effect on outcomes after Gamma Knife radiosurgery (GKRS) for unruptured bAVMs.

METHODS

Unsupervised machine learning with fuzzy c-means clustering was used to differentiate the tissue constituents of bAVMs on T2-weighted MR images. The percentages of vessel, brain, and CSF were quantified. The proposed compactness index, defined as the ratio of vasculature tissue to brain tissue, categorized bAVM morphology into compact, intermediate, and diffuse types according to the tertiles of this index. The outcomes of interest were complete obliteration and radiation-induced changes (RICs).

RESULTS

A total of 209 unruptured bAVMs treated with GKRS were retrospectively included. The median imaging and clinical follow-up periods were 49.2 and 72.3 months, respectively. One hundred seventy-three bAVMs (82.8%) achieved complete obliteration after a median latency period of 43.3 months. The rates of RIC and permanent RIC were 76.1% and 3.8%, respectively. Post-GKRS hemorrhage occurred in 14 patients (6.7%), resulting in an annual bleeding risk of 1.0%. Compact bAVM, smaller bAVM volume, and exclusively superficial venous drainage were independent predictors of complete obliteration. Diffuse bAVM morphology, larger bAVM volume, and higher margin dose were independently associated with RICs.

CONCLUSIONS

The compactness index quantitatively describes the compactness of unruptured bAVMs. Moreover, compact bAVMs may have a higher obliteration rate and a smaller risk of RICs than diffuse bAVMs. This finding could help guide decision-making regarding GKRS treatment for patients with unruptured bAVMs.

In Journal of Neurosurgery Publish Before Print

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Editorial. Indications for arachnoid cyst surgery

Cormac O. Maher

In Journal of Neurosurgery: Pediatrics Publish Before Print

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Letter to the Editor. Estimation of date and time of injury using coagulation and fibrinolytic parameters

Takashi Araki and Hiroyuki Yokota

In Journal of Neurosurgery: Pediatrics Publish Before Print

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Letter to the Editor. Holmes tremor and hydrocephalus: a sign of global rostral midbrain dysfunction syndrome

Lelio Guida, Thomas Blauwblomme, Giuseppe Cinalli, Stéphanie Puget, and Christian Sainte-Rose

In Journal of Neurosurgery: Pediatrics Publish Before Print

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Letter to the Editor. Overlapping confidence intervals

Joseph Piatt

In Journal of Neurosurgery Publish Before Print

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Letter to the Editor. The “wrap” on Tarlov cysts

Rudolph J. Schrot

In Journal of Neurosurgery: Spine Publish Before Print

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Prognostic impact of the multimodal treatment approach in patients with C19MC-altered embryonal tumor with multilayered rosettes

Masahiro Sugawa, Kohei Fukuoka, Makiko Mori, Yuki Arakawa, Yutaka Tanami, Sumihito Nobusawa, Junko Hirato, Atsuko Nakazawa, Jun Kurihara, and Katsuyoshi Koh

OBJECTIVE

Embryonal tumor with multilayered rosettes (ETMR) is one of the childhood central nervous system tumors with the poorest prognosis; thus, establishing an optimal treatment strategy is essential, However, because of the low incidence and molecular heterogeneity of the tumor, the optimal treatment has not yet been determined. In this study the authors evaluated the prognostic impact of a multimodal treatment approach in patients with ETMR.

METHODS

The authors evaluated 4 patients with ETMR at their institution who showed varied clinical features and also conducted clinical characterization and prognostic analysis of previously reported cases of the ETMR-presenting locus 19q13.42 with a chromosome 19 microRNA cluster (C19MC) amplification, which is known to be a diagnostic hallmark of the tumor.

RESULTS

Of the 4 patients with ETMR in the authors’ institution, in 1 case the patient’s tumor showed a neuroblastoma-like appearance without multilayered rosettes; however, the diagnosis was confirmed by the presence of amplified C19MC. From a clinical standpoint, 2 patients who underwent gross-total resection (GTR) of the tumor and chemotherapy followed by high-dose chemotherapy (HDC) had long-term complete remission with or without local irradiation. In the multivariate analysis of 43 cases with C19MC-altered ETMR reported in the literature, HDC and local irradiation were significantly correlated with better event-free survival (HR 0.17, p = 0.0087; HR 0.17, p = 0.010) and overall survival (OS) (HR 0.29, p = 0.023; HR 0.28, p = 0.019), respectively. GTR was also correlated with better OS (HR 0.40, p = 0.039).

CONCLUSIONS

This case series demonstrated pathological and clinical heterogeneity among ETMR cases and the diagnostic importance of the molecular genetic approach among embryonal tumors, particularly during infancy. Based on the results of the analysis of molecularly uniformed ETMR cases, multimodal treatment may play a significant role in the prognosis of these tumors.

In Journal of Neurosurgery: Pediatrics Publish Before Print