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Michael Hugelshofer, Nicola Acciarri, Ulrich Sure, Dimitrios Georgiadis, Ralf W. Baumgartner, Helmut Bertalanffy, and Adrian M. Siegel

Object

Cerebral cavernous malformations (CCMs) are common vascular lesions in the brain, affecting approximately 0.5% of the population and representing 10%–20% of all cerebral vascular lesions. One-quarter of all CCMs affect pediatric patients, and CCMs are reported as one of the main causes of brain hemorrhage in this age group. Symptoms include epileptic seizures, headache, and focal neurological deficits. Patients with symptomatic CCMs can be treated either conservatively or with resection if lesions cause medically refractory epilepsy or other persistent symptoms.

Methods

The authors retrospectively analyzed 79 pediatric patients (41 boys and 38 girls) from 3 different centers, who were surgically treated for their symptomatic CCMs between 1974 and 2004. The mean age of the children at first manifestation was 9.7 years, and the mean age at operation was 11.3 years. The main goal was to compare the clinical outcomes with respect to the location of the lesion of children who preoperatively suffered from epileptic seizures.

Results

Of these patients, 77.3% were seizure free (Engel Class I) after the resection of the CCM. Significant differences in the outcome between children who harbored CCMs at different locations were not found.

Conclusions

Resection seems to be the favorable treatment of symptomatic CCMs not only in adults but also in children.

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Ulrich Sure, Sandra Freman, Oliver Bozinov, Ludwig Benes, Adrian M. Siegel, and Helmut Bertalanffy

Object. Cerebral cavernous malformations (CCMs) have previously been considered as congenital and biologically static malformations. On the other hand, the potential for growth and de novo generation of CCMs have also been reported. It is therefore important to study the proliferative and neoangiogenetic capacity of these lesions.

Methods. The authors studied the surgical specimens of 56 CCMs (23 deep and 33 superficial) obtained from adult patients. The proliferative activity of the endothelium and the neoangiogenetic capacity of these lesions were considered through immunohistochemical anaylsis of proliferating cell nuclear antigen (PCNA), MIB-1, Flk-1, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, and endoglin antibodies.

Positive immunostaining of endothelial cells occurred in 86% of patients for PCNA and in 38% of the cases for MIB-1. The expression of Flk-1 was observed in the endothelium of 71% of the cases, for VEGF in 41%, for HIF-1α in 48.1%, and for endoglin in 63.6% of the cases. The correlation of immunohistochemical and clinical data indicated that VEGF was expressed in significantly less deep-seated lesions when compared with superficial CCMs. Neither the expression of the proliferative markers nor the expression of the angiogenetic antibodies correlated with patient age at surgery, sex, or the number of recent prior hemorrhagic episodes in the patients.

Conclusions. The CCMs from adult patients are active lesions exhibiting endothelial proliferation and neoangiogenesis. According to the data in this study, neoangiogenesis is more prominent in superficial CCMs than in deep-seated CCMs and is not associated with recent prior hemorrhages.

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Zhiyuan Yu, Jun Zheng, Lu Ma, Chao You, and Hao Li

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Kevin N. Strommer, Sebastian Brandner, Ali C. Sarioglu, Ulrich Sure, and Yasuhiro Yonekawa

✓ This case report contains a description of a 61-year-old patient who presented with a progressive truncal ataxia 22 years after complete removal of a small paraganglioma of the cauda equina. Magnetic resonance imaging of the neuraxis revealed a large cystic lesion in the cerebellar midline, three small cortical-to-subcortical nodular tumors in the posterior fossa, and local recurrences of the paraganglioma of the cauda equina. Pathological examination showed the cerebellar midline lesion to be a paraganglioma, most likely a metastasis from the cauda equina localization.

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Yuan Zhu, Qun Wu, Jin-Fang Xu, Dorothea Miller, I. Erol Sandalcioglu, Jian-Min Zhang, and Ulrich Sure

Object

Loss-of-function mutations in CCM genes are frequently detected in familial cerebral cavernous malformations (CCMs). However, the current functional studies of the CCM genes in vitro have been performed mostly in commercially purchased normal cell lines and the results appeared discrepant. The fact that the cerebral vascular defects are rarely observed in CCM gene-deficient animals suggests the requirement of additional pathological background for the formation of vascular lesions. Consistent with these data, the authors assumed that silencing CCM genes in the endothelium derived from CCMs (CCM-ECs) serves as a unique and valuable model for investigating the function of the CCM genes in the pathogenesis of CCMs. To this end, the authors investigated the role and signaling of CCM2 and CCM3 in the key steps of angiogenesis using CCM-ECs.

Methods

Endothelial cells (ECs) derived from CCMs were isolated, purified, and cultured from the fresh operative specimens of sporadic CCMs (31 cases). The CCM2 and CCM3 genes were silenced by the specific short interfering RNAs in CCM-ECs and in control cultures (human brain microvascular ECs and human umbilical vein ECs). The efficiency of gene silencing was proven by real-time reverse transcriptase polymerase chain reaction. Cell proliferation and apoptosis, migration, tube formation, and the expression of phosphor-p38, phosphor-Akt, and phosphor-extracellular signal-regulated kinase–1 and 2 (ERK1/2) were analyzed under CCM2 and CCM3 silenced conditions in CCM-ECs.

Results

The CCM3 silencing significantly promoted proliferation and reduced apoptosis in all 3 types of endothelium, but accelerated cell migration exclusively in CCM-ECs. Interestingly, CCM2 siRNA influenced neither cell proliferation nor migration. Silencing of CCM3, and to a lesser extent CCM2, stimulated the growth and extension of sprouts selectively in CCM-ECs. Loss of CCM2 or CCM3 did not significantly influence the formation of the tubelike structure. However, the maintenance of tube stability was largely impaired by CCM2, but not CCM3, silencing. Western blot analysis revealed that CCM2 and CCM3 silencing commonly activated p38, Akt, and ERK1/2 in CCM-ECs.

Conclusions

The unique response of CCM-ECs to CCM2 or CCM3 siRNA indicates that silencing CCM genes in CCM-ECs is valuable for further studies on the pathogenesis of CCMs. Using this model system, the authors demonstrate a distinct role of CCM2 and CCM3 in modulating the different processes of angiogenesis. The stimulation of endothelial proliferation, migration, and massively growing and branching angiogenic sprouts after CCM3 silencing may potentially contribute to the formation of enriched capillary-like immature vessels in CCM lesions. The severe impairment of the tube integrity by CCM2, but not CCM3, silencing is associated with the different intracranial hemorrhage rate observed from CCM2 and CCM3 mutation carriers. The activation of p38, ERK1/2, and Akt signal proteins in CCM2- or CCM3-silenced CCM-ECs suggests a possible involvement of these common pathways in the pathogenesis of CCMs. However, the specific signaling mediating the distinct function of CCM genes in the pathogenesis of CCMs needs to be further elucidated.

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Mehdi Chihi, Oliver Gembruch, Marvin Darkwah Oppong, Bixia Chen, Thiemo Florin Dinger, Lennart Barthel, Daniela Pierscianek, Karsten H. Wrede, Neriman Özkan, Ulrich Sure, and Ramazan Jabbarli

OBJECTIVE

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disease. Arterial wall developmental disorders, such as aneurysms, in association with TSC have been well described for extracranial vasculature. The characteristics of intracranial aneurysms (IAs) in TSC have not previously been addressed in the literature. This systematic review was performed to identify and assess the distinct characteristics of IAs in patients with TSC.

METHODS

The authors searched PubMed, Scopus, and Web of Science for publications describing cases of TSC and IA reported before August 7, 2018. They also report 2 cases of IAs in TSC patients treated at their own institution.

RESULTS

Thirty-three TSC patients with a total of 42 IAs were included in this review. Three individuals presented with subarachnoid hemorrhage. The IAs were large or giant in 57.1% and fusiform in 45.2% of the cases. Most of the IAs (61.9%, 26 of 42) originated from the internal carotid artery. There was a higher prevalence of pediatric cases (66.7%) and male patients (63.6%, 21 of 32 individuals with known sex) among the collected series.

CONCLUSIONS

TSC patients with IAs are characterized with a higher proportion of large/giant and fusiform IAs and young age, suggesting rapid aneurysmal growth. Furthermore, there is a distinct location pattern of IAs and an inverse sex ratio than in the healthy population. Large population-based patient registers are required to improve the understanding of epidemiology and pathophysiology of IA formation in TSC.

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Philipp Dammann, Markus Barth, Yuan Zhu, Stefan Maderwald, Marc Schlamann, Mark E. Ladd, and Ulrich Sure

High-resolution susceptibility weighted MR imaging at high field strength provides excellent depiction of venous structures, blood products, and iron deposits, making it a promising complementary imaging modality for cerebral cavernous malformations (CCMs). Although already introduced in 1997 and being constantly improved, susceptibility weighted imaging is not yet routine in clinical neuroimaging protocols for CCMs. In this article, the authors review the recent literature dealing with clinical and scientific susceptibility weighted imaging of CCMs to summarize its prospects and drawbacks and provide their first experience with its use in ultra–high field (7-T) MR imaging.

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Alejandro N. Santos, Laurèl Rauschenbach, Marvin Darkwah Oppong, Bixia Chen, Annika Herten, Michael Forsting, Ulrich Sure, and Philipp Dammann

OBJECTIVE

Treatment indications for patients with brainstem cavernous malformations (BSCMs) remain difficult and controversial. Some authors have tried to establish classification tools to identify eligible candidates for surgery. Authors of this study aimed to validate the performance and replicability of two proposed BSCM grading systems, the Lawton-Garcia (LG) and the Dammann-Sure (DS) systems.

METHODS

For this cross-sectional study, a database was screened for patients with BSCM treated surgically between 2003 and 2019 in the authors’ department. Complete clinical records, preoperative contrast-enhanced MRI, and a postoperative follow-up ≥ 6 months were mandatory for study inclusion. The modified Rankin Scale (mRS) score was determined to quantify neurological function and outcome. Three observers independently determined the LG and the DS score for each patient.

RESULTS

A total of 67 patients met selection criteria. Univariate and multivariate analyses identified multiple bleedings (p = 0.02, OR 5.59), lesion diameter (> 20 mm, p = 0.007, OR 5.43), and patient age (> 50 years, p = 0.019, OR 4.26) as predictors of an unfavorable postoperative functional outcome. Both the LG (AUC = 0.72, p = 0.01) and the DS (AUC = 0.78, p < 0.01) scores were robust tools to estimate patient outcome. Subgroup analyses confirmed this observation for both grading systems (LG: p = 0.005, OR 6; DS: p = 0.026, OR 4.5), but the combined use of the two scales enhanced the test performance significantly (p = 0.001, OR 22.5).

CONCLUSIONS

Currently available classification systems are appropriate tools to estimate the neurological outcome after BSCM surgery. Future studies are needed to design an advanced scoring system, incorporating items from the LG and the DS score systems.

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Marvin Darkwah Oppong, Kathrin Buffen, Daniela Pierscianek, Annika Herten, Yahya Ahmadipour, Philipp Dammann, Laurèl Rauschenbach, Michael Forsting, Ulrich Sure, and Ramazan Jabbarli

OBJECTIVE

Clinical data on secondary hemorrhagic complications (SHCs) in patients with aneurysmal subarachnoid hemorrhage (SAH) are sparse and mostly limited to ventriculostomy-associated SHCs. This study aimed to elucidate the incidence, risk factors, and impact on outcome of SHCs in a large cohort of SAH patients.

METHODS

All consecutive patients with ruptured aneurysms treated between January 2003 and June 2016 were eligible for this study. Patients’ charts were reviewed for clinical data, and imaging studies were reviewed for radiographic data. SHCs were divided into those associated with ventriculostomy and those not associated with ventriculostomy, as well as into major and minor bleeding forms, depending on clinical impact.

RESULTS

Sixty-two (6.6%) of the 939 patients included in the final analysis developed SHCs. Ventriculostomy-associated bleedings (n = 16) were independently predicted by mono- or dual-antiplatelet therapy after aneurysm treatment (p = 0.028, adjusted odds ratio [aOR] = 10.28; and p = 0.026, aOR = 14.25, respectively) but showed no impact on functional outcome after SAH. Periinterventional use of thrombolytic agents for early effective anticoagulation was the only independent predictor (p = 0.010, aOR = 4.27) of major SHCs (n = 38, 61.3%) in endovascularly treated patients. In turn, a major SHC was independently associated with poor outcome at the 6-month follow-up (modified Rankin Scale score > 3). Blood thinning drug therapy prior to SAH was not associated with SHC risk.

CONCLUSIONS

SHCs present a rare sequela of SAH. Antiplatelet therapy during (but not before) SAH increases the risk of ventriculostomy-associated bleedings, but without further impact on the course and outcome of SAH. The use of thrombolytic agents for early effective anticoagulation carries relevant risk for major SHCs and poor outcome.