scholarly journals Somatic Mosaicism in the Pathogenesis of de novo Cerebral Arteriovenous Malformations: A Paradigm Shift Implicating the RAS-MAPK Signaling Cascade

2021 ◽  
Vol 50 (2) ◽  
pp. 231-238
Author(s):  
Keyan Peterson ◽  
Stephanie Coffman ◽  
Aqib Zehri ◽  
Anthony Anzalone ◽  
Zhidan Xiang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Vascular Malformation ◽  
Arteriovenous Malformations ◽  
Somatic Mosaicism ◽  
Mapk Signaling ◽  
Signaling Cascade ◽  
Cerebral Arteriovenous Malformations ◽  
Signaling Axis ◽  
Cerebral Avms ◽  
Malformation Syndromes

Cerebral arteriovenous malformations (AVMs) are leading causes of lesional hemorrhagic stroke in both the pediatric and young adult population, with sporadic AVMs accounting for the majority of cases. Recent evidence has identified somatic mosaicism in key proximal components of the RAS-MAPK signaling cascade within endothelial cells collected from human sporadic cerebral AVMs, with early preclinical models supporting a potential causal role for these mutations in the pathogenesis of these malformations. Germline mutations that predispose to deregulation of the RAS-MAPK signaling axis have also been identified in hereditary vascular malformation syndromes, highlighting the key role of this signaling axis in global AVM development. Herein, we review the most recent genomic and preclinical evidence implicating somatic mosaicism in the RAS-MAPK signaling pathway in the pathogenesis of sporadic cerebral AVMs. Also, we review evidence for RAS-MAPK dysregulation in hereditary vascular malformation syndromes and present a hypothesis suggesting that this pathway is central for the development of both sporadic and syndrome-associated AVMs. Finally, we examine the clinical implications of these recent discoveries and highlight potential therapeutic targets within this signaling pathway.

scholarly journals P03.08 Large cerebral arteriovenous malformations management with Volume-staged gamma knife radiosurgery

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii26-iii26
Author(s):  
R M Emad Eldin ◽  
W A Reda ◽  
A M El-Shehaby ◽  
K Abdel Karim ◽  
A Nabeel ◽  
...  
Keyword(s):  
Gamma Knife ◽  
Arteriovenous Malformations ◽  
Gamma Knife Radiosurgery ◽  
Cerebral Arteriovenous Malformations ◽  
Factors Affecting ◽  
Prescription Dose ◽  
The Mean ◽  
Cerebral Avms ◽  
Grade 3

Abstract BACKGROUND Large cerebral arteriovenous malformations (AVM) pose a management dilemma because of the limited success of any single treatment modality by itself. Surgery alone is associated with significant morbidity and mortality. Similarly, embolization alone has limited efficacy. Volume-staged gamma knife radiosurgery (VSGR) has been developed for the treatment of large AVMs, to increase the efficacy and improve safety of treatment of these lesions. The aim of the study was to assess the efficacy and safety of VSGR technique for the treatment of large cerebral AVMs. METHODS The study included patients treated by VSGR between May 2009 and July 2015. All cases had large AVMs (>10 cc). These were 29 patients. RESULTS Twenty-four patients completed radiographic follow up with 15 obliteration cases (62.5%). There was a total of 56 sessions performed. The mean AVM volume was 16 cc (10.1–29.3 cc). The mean prescription dose was 18 Gy (14–22 Gy). The mean follow up duration was 43 months (21–73 months). One patient died during follow up from unrelated cause. Two cases suffered haemorrhage during follow up. Symptomatic edema developed in 5 (17%) patients. The factors affecting obliteration were smaller total volume, higher dose/stage, non-deep location, compact AVM, AVM score less than 3, >18 Gy dose and <15 cc total volume. The factors affecting symptomatic edema were smaller total volume and shorter time between first and last sessions (p 0.012). T2 image changes were affected by SM grade 3 or more (p 0.013) and AVM score 3 or more (p 0.014). CONCLUSION VSGR provides an effective and safe treatment option for large cerebral AVMs. Smaller AVM volume is associated with higher obliteration rate.

scholarly journals Curative Glubran 2 Embolization of Cerebral Arteriovenous Malformations Patient Selection and Initial Results

2014 ◽  
Vol 20 (6) ◽  
pp. 722-728 ◽  
Author(s):  
Jie Liu ◽  
Ming Lv ◽  
Xianli Lv ◽  
Hongwei He ◽  
Aihua Liu ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Arteriovenous Malformations ◽  
Gamma Knife Radiosurgery ◽  
Clinical Results ◽  
Hemorrhagic Complication ◽  
Cerebral Arteriovenous Malformations ◽  
Complete Obliteration ◽  
Glubran 2 ◽  
Cerebral Avms

The liquid embolic agents currently used for embolization of cerebral arteriovenous malformations are Onyx and NBCA. Glubran 2, a cyanoacrylate-based synthetic glue, has recently been applied for embolization of cerebral arteriovenous malformations (AVMs). We report the clinical results of selected cerebral AVMs treated with Glubran 2 targeting for curative embolization. Between October 2011 and March 2013, 31 patients with cerebral AVMs were selected for curative embolization with Glubran 2. There were 19 men and 12 women with a mean age of 32 years (range 4–65 years). Initial clinical presentation included hemorrhage in 28 and seizures in three patients. AVM location was frontal in eight patients, parietal in four, occipital in eight temporal in six, cerebellar in two and cerebellar vermis in three patients. Follow-up was performed clinically and with angiography examination at three to six months. Clinical outcomes were evaluated based on the modified Rankin Scale (mRS). A mean of 2.5 (range, 1–12) feeding pedicles were embolized per patient. Complete angiographic obliteration of AVM was achieved in 27 patients. A hemorrhagic complication was observed in one patient, an ischemic complication in one patient and technical complications in four patients. There was no procedure-related disabling neurological deficit or death at discharge. Additional gamma knife radiosurgery was performed in five patients, including one patient with recurrent AVM. All of the patients had favorable clinical outcomes at three to six month follow-up (mRS≤2). The curative embolization technique with Glubran 2 for selected cerebral AVMs achieved a high initial complete obliteration rate with an acceptable complication frequency.

scholarly journals Outcome of Endovascular Treatment of Cerebral Arteriovenous Malformations with Ethylene Vinyl Alcohol Coploymer

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
H E Mohram ◽  
M A Habib ◽  
S H Mourad ◽  
A H Abozeid ◽  
A M M Salem
Keyword(s):  
Arteriovenous Malformations ◽  
Interventional Procedures ◽  
Endovascular Embolization ◽  
Vascular Territory ◽  
Cure Rate ◽  
Cerebral Arteriovenous Malformations ◽  
University Hospitals ◽  
Curative Intent ◽  
Ethylene Vinyl Alcohol ◽  
Cerebral Avms

Abstract Background Cerebral AVMs are very rare lesions, and this rarity contributes to the difficulty of treating them. There is no consensus concerning the method of treatment to be chosen among neurosurgery, radiosurgery or embolization. Onyx embolization could serve as a curative option with accepted morbidity and mortality. The introduction of Onyx and of catheters with detachable tips has no doubt increased the rate of endovascular occlusion, and decreased the risks associated with treatment in our experience. Objective The aim of the study was to assess the outcome of the use of Onyx in the treatment of intracranial AVMs as curative embolization or before neuro- or radiosurgery Patients and Methods This analytical prospective study was conducted on 25 patients who were diagnosed with cerebral arteriovenous malformations and underwent endovascular embolization with EVOH copolymer with curative intent during the study period. Interventional procedures were done in the neuro – endovascular unit, neurosurgery department Ain Shams University Hospitals and associate neuroendovascular unit in El Matarya Teaching Hospital in the period between September 2014 and April 2017. Results Actually comparing these results especially concerning the cure rate along with other studies was somewhat confusing and problematic owing to the diversity in results between studies across the last 15 years. Conclusion For the cases that are not fulfilling these criteria, embolization should be offered as preparing step for other modality of treatment. In our experience, for curative embolization, the AVM should be small sized (&lt; 3 cm), supplied by one vascular territory, with feeders that can tolerate reflux up to 2–3 cm, with clear proximal parts of the draining veins, and not located in deep structures.

Development of multiple cerebral arteriovenous malformations documented in an adult by serial angiography

2003 ◽  
Vol 98 (1) ◽  
pp. 190-193 ◽  
Author(s):  
Yoshio Miyasaka ◽  
Kuniaki Nakahara ◽  
Hiroshi Takagi ◽  
Hiroyuki Hagiwara
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Angiography ◽  
Arteriovenous Malformations ◽  
Intracerebral Hematoma ◽  
Cerebral Arteriovenous Malformations ◽  
Content Type ◽  
Hematoma Evacuation ◽  
Cerebral Avms ◽  
Fine Print

✓ A 50-year-old woman with a parietal intracerebral hematoma was initially treated by hematoma evacuation. Initial preoperative and follow-up angiograms obtained 6 months later demonstrated no pial arteriovenous malformations (AVMs). She suffered a subarachnoid hemorrhage 8 years later. Results of follow-up cerebral angiography revealed the development of previously undetected multiple cerebral AVMs. This appears to be the first reported case of the development of multiple cerebral AVMs in an adult, demonstrated on serial angiography.

scholarly journals EphB4/ TNFR2/Erk/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation

2019 ◽  
Author(s):  
Yu Zhang ◽  
Chengzhe Yang ◽  
Shaohua Ge ◽  
Limei Wang ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Precursor Cells ◽  
Mapk Signaling Pathway ◽  
Erk Mapk ◽  
Low Concentrations ◽  
Tnf Α ◽  
Signaling Axis ◽  
Positive Effect

Abstract Low concentrations of tumor necrosis factor-alpha and its receptor TNFR2 are both reported to promote osteogenic differentiation of osteoblast precursor cells. Moreover, low concentrations of TNF-α up-regulate the expression of EphB4. However, the molecular mechanisms underlying TNF-α-induced osteogenic differentiation and the roles of TNFR2 and EphB4 have not been fully elucidated. This study showed that with increase in ALP activity, mRNA and protein expression of Runx2, BSP and EphB4, TNFR2 expression was significantly promoted under 0.5 ng/ml TNF-α stimulation in osteoblast precursor cells MC3T3-E1. After TNFR2 was inhibited by gene knockdown with lentivirus-mediated shRNA interference or by a neutralizing antibody against TNFR2, the pro-osteogenic effect of TNF-α was partly reversed, but up-regulation of EphB4 by TNF-α kept unchanged. With EphB4 forward signaling suppressed by a potent inhibitor of EphB4 auto-phosphorylation, NVP-BHG712, TNF-α-enhanced expressions of TNFR2, BSP and Runx2 were significantly decreased. Further investigation into the signaling pathways revealed that TNF-α significantly augmented expression of p-JNK, p-Erk and p-p38, however, only p-Erk expression was significantly inhibited in TNFR2-knockdown cells. In addition, the Erk pathway inhibitor, U0126 (10μM), significantly inhibited the protein levels of Runx2 and BSP when compared with cells treated with TNF-α only. In conclusion, the EphB4, TNFR2 and Erk/MAPK signaling pathway comprise a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation.

Abstract TP446: Noninvasive Evaluation of Cerebral Arteriovenous Malformations by 4D-CT Angiography using 320-detector row CT

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Hiroyuki Tajiri ◽  
Lee Jin ◽  
Toshitaka Tsukiyama ◽  
Yumiko Suzuki
Keyword(s):  
Arteriovenous Malformations ◽  
Average Score ◽  
Noninvasive Evaluation ◽  
Cerebral Arteriovenous Malformations ◽  
Promising Technique ◽  
Conventional Angiography ◽  
Grading Scale ◽  
Martin Grade ◽  
Cerebral Avms

Background and Purpose: Patients with higher Spetzler-Martin grade cerebral arteriovenous malformations (AVMs) are associated with poorer neurologic and clinical outcomes. Four dimensional computed tomography angiography (4D-CTA) is newly and promising technique in the diagnosis of patients with cerebral arteriovenous malformations (AVMs). The purpose of this retrospective study was to investigate the utility of 4D-CTA using whole-brain 320- detector row CT for assessing cerebral AVMs compared with conventional angiography (CA). Materials & Methods: Participants comprised patients admitted to our institution from November 2010 to March 2012 due to cerebral AVMs, who underwent both 4D-CTA and CA within 14days. The diagnosis of AVM was finally confirmed by CA. Two readers reviewed 4D-CTA and CA under consensus regarding detection rate of the AVMs, each component of the AVMs (feeders, nidi, drainers) which was scored using four-point grading scale (excellent=3, good=2, fair=1, poor=0), and the Spetzler-Martin (S-M) grade. Results: During study periods, eleven patients met our criteria. In every case, cerebral AVM was diagnosed by 4D-CTA. The average score for feeders, nidi, and drainers was 2.0, 2.3, and 2.5 in 4D-CTA and 2.4, 2.6, and 2.7 in CA, respectively. The average score of S-M grade was both 2.0, and matched in 11/11 patients. There were no significant differences statistically between two modalities (P<.005). Conclusion: 4D-CTA using 320-detector row CT is a very reliable method and offered diagnostic performance equivalent to CA in detecting and predicting S-M classification of cerebral AVMs.

Outcome after hemorrhage following Gamma Knife surgery for cerebral arteriovenous malformations

2009 ◽  
Vol 110 (5) ◽  
pp. 1003-1009 ◽  
Author(s):  
Manish Kumar Kasliwal ◽  
Shashank Sharad Kale ◽  
Aditya Gupta ◽  
Narayanam Anantha Sai Kiran ◽  
Manish Singh Sharma ◽  
...  
Keyword(s):  
Gamma Knife ◽  
Arteriovenous Malformations ◽  
Venous Drainage ◽  
Venous Hypertension ◽  
Gamma Knife Surgery ◽  
New Delhi ◽  
Cerebral Arteriovenous Malformations ◽  
Complete Obliteration ◽  
Cerebral Avms ◽  
Risk Of Hemorrhage

Object Although the effects of Gamma Knife surgery (GKS) on the risk of hemorrhage are poorly understood, a certain subset of patients does suffer bleeding after GKS. This study was undertaken to analyze the outcome of patients sustaining hemorrhage after GKS; it is the most feared complication of radiosurgical management of cerebral arteriovenous malformations (AVMs). Methods Between May 1997 and June 2006, 494 cerebral AVMs in 489 patients were treated using a Leksell Gamma Knife Model B, and follow-up evaluations were conducted until June 2007 at the All India Institute of Medical Sciences in New Delhi. Fourteen patients who sustained a hemorrhage after GKS formed the study group. In most of these patients conservative management was chosen. Results The mortality rate was 0% and there was a 7% risk of sustaining a severe deficit following rebleeding after GKS. None of the patients sustained rebleeding after complete obliteration. Patients with Spetzler-Martin Grade III or less had increased chances of hemorrhage after GKS (p < 0.002). The presence of deep venous drainage, aneurysm, venous hypertension, or periventricular location on angiography was common in patients with hemorrhage after GKS. Conclusions The risk of hemorrhage that remains following GKS for cerebral AVMs is highest in the 1st year after treatment. The present study showed a relatively good outcome even in cases with hemorrhage following GKS, with no deaths and minimal morbidity, further substantiating the safety and efficacy of the procedure.

Staged radiosurgery for extra-large cerebral arteriovenous malformations: method, implementation, and results

2008 ◽  
Vol 109 (Supplement) ◽  
pp. 65-72 ◽  
Author(s):  
Wen-Yuh Chung ◽  
Cheng-Ying Shiau ◽  
Hsiu-Mei Wu ◽  
Kang-Du Liu ◽  
Wan-Yuo Guo ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Arteriovenous Malformations ◽  
High Signal ◽  
Minor Bleeding ◽  
Cerebral Arteriovenous Malformations ◽  
Presenting Symptoms ◽  
Second Stage ◽  
The Mean ◽  
Cerebral Avms

Object The effectiveness and safety of radiosurgery for small- to medium-sized cerebral arteriovenous malformations (AVMs) have been well established. However, the management for large cerebral AVMs remains a great challenge to neurosurgeons. In the past 5 years the authors performed preplanned staged radiosurgery to treat extra-large cerebral AVMs. Methods An extra-large cerebral AVM is defined as one with nidus volume > 40 ml. The nidus volume of cerebral AVM is measured from the dose plan—that is, as being the volume contained within the best-fit prescription isodose. From January 2003 to December 2007, the authors treated 6 patients with extra-large AVMs by preplanned staged GKS. Staged radiosurgery is implemented by rigid transformation with translation and rotation of coordinates between 2 stages. The average radiation-targeted volume was 60 ml (range 47–72 ml). The presenting symptoms were seizure in 4 patients and a bleeding episode in 2. One patient had undergone a previous craniotomy and evacuation of hematoma. The mean interval between the 2 radiosurgical sessions was 6.9 months (range 4.5–9.1 months). The prescribed marginal dose given to the nidus volume in each stage ranged from 16 to 18.6 Gy. The expected marginal dose of total nidus was 17–19 Gy. Regular follow-up MR imaging was performed every 6 months. The mean follow-up period was 28 months (range 12–54 months). Results Most of the patients exhibited clinical improvement: relief of headache and reduced frequency of seizure attack. All patients had significant regression of nidus observed on MR imaging follow-up. Two patients had angiogram-confirmed complete obliteration of the nidus 45 and 60 months after the second-stage radiosurgical session. One patient experienced minor bleeding 8 months after the second-stage radiosurgery with mild headache. She had satisfactory recovery without clinical neurological deficit after conservative treatment. Conclusions These preliminary results indicate that staged radiosurgery is a practical strategy to treat patients with extra-large cerebral AVMs. It takes longer to obliterate the AVMs. The observed high signal T2 changes after the radiosurgery appeared clinically insignificant in 6 patients followed up for an average of 28 months. Longer follow-up is necessary to confirm its long-term safety.

scholarly journals Neurological morbidity and mortality associated with the endovascular treatment of cerebral arteriovenous malformations before and during the Onyx era

2015 ◽  
Vol 122 (6) ◽  
pp. 1492-1497 ◽  
Author(s):  
R. Webster Crowley ◽  
Andrew F. Ducruet ◽  
M. Yashar S. Kalani ◽  
Louis J. Kim ◽  
Felipe C. Albuquerque ◽  
...  
Keyword(s):  
Endovascular Treatment ◽  
Arteriovenous Malformations ◽  
Morbidity And Mortality ◽  
Neurological Deficits ◽  
Embolic Agent ◽  
Cerebral Arteriovenous Malformations ◽  
Neurological Morbidity ◽  
Martin Grade ◽  
The Mean ◽  
Cerebral Avms

OBJECT The widespread implementation of the embolic agent Onyx has changed the endovascular management of cerebral arteriovenous malformations (AVMs). Recent data suggest that outcomes following embolization and resection may have worsened in the Onyx era. It has been hypothesized that there may be increased complications with Onyx embolization and increased surgical aggressiveness in patients treated with Onyx. In this study the authors analyzed their institutional experience with the endovascular treatment of cerebral AVMs prior to and after the introduction of Onyx to determine factors associated with periprocedural neurological morbidity and mortality. METHODS A retrospective review was performed of all patients with cerebral AVMs undergoing embolization at the Barrow Neurological Institute from 1995 to 2012. RESULTS Endovascular treatment of 342 cerebral AVMs was performed over 446 treatment sessions (mean age 37.8 years, range 1–83 years). Clinical presentation included hemorrhage in 47.6%, seizures in 21.9%, headaches in 11.1%, and no symptoms in 10% of cases. The endovascular pretreatment strategy was preoperative in 78.9%, preradiosurgery in 9.1%, palliative in 5.3%, targeted in 4.4%, and curative in 2.3%. The median Spetzler-Martin grade was III. The mean number of arteries embolized was 3.5 (range 0–13 arteries), and the mean number of treatment sessions was 1.3 (range 1–4 sessions). Onyx was used in 105 AVMs (30.7%), and N-butyl cyanoacrylate (NBCA) without Onyx was used in 229 AVMs (67%). AVMs treated with Onyx had a higher mean number of arterial pedicles embolized than did NBCA cases (4.3 ± 2.7 vs 3.2 ± 2.4, respectively; p < 0.001) and a greater number of sessions (1.5 ± 0.7 vs 1.2 ± 0.5, respectively; p < 0.05). Unexpected immediate postprocedural permanent neurological deficits were present in 9.6% of AVMs, while transient deficits were present in 1.8%. There was 1 death (0.3%). Spetzler-Martin grade was not associated with differences in outcome, as permanent neurological deficits were observed in 12%, 9%, 13%, 11%, and 13% of AVMs for Spetzler-Martin Grades I–V, respectively (p = 0.91). The use of Onyx compared with NBCA was not associated with differences in periprocedural morbidity (p = 0.23). This lack of a difference persisted even when controlling for number of arteries and sessions (p = 0.14). Sex was not associated with differences in outcome. CONCLUSIONS Permanent and transient postprocedural neurological deficits were noted in 9.6% and 1.8% of all cases, respectively. AVM grade was not associated with endovascular outcome. Despite the greater number of sessions required and arteries embolized for Onyx cases, there was no statistically significant difference in the risk of neurological deficits following cerebral AVM embolization with Onyx and NBCA.

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