Burak Kocak, Osman Kizilkilic, Naci Kocer and Civan Islak
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.
Zhiyuan Yu, Jun Zheng, Lu Ma, Chao You and Hao Li
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.
Michael Hugelshofer, Nicola Acciarri, Ulrich Sure, Dimitrios Georgiadis, Ralf W. Baumgartner, Helmut Bertalanffy and Adrian M. Siegel
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.
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.
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.
Resection seems to be the favorable treatment of symptomatic CCMs not only in adults but also in children.
Marvin Darkwah Oppong, Meltem Gümüs, Daniela Pierscianek, Annika Herten, Andreas Kneist, Karsten Wrede, Lennart Barthel, Michael Forsting, Ulrich Sure and Ramazan Jabbarli
Current guidelines for subarachnoid hemorrhage (SAH) include early aneurysm treatment within 72 hours after ictus. However, aneurysm rebleeding remains a crucial complication of SAH. The aim of this study was to identify independent predictors allowing early stratification of SAH patients for rebleeding risk.
All patients admitted to the authors’ institution with ruptured aneurysms during a 14-year period were eligible for this retrospective study. Demographic and radiographic parameters, aneurysm characteristics, medical history, and medications as well as baseline parameters at admission (blood pressure and laboratory parameters) were evaluated in univariate and multivariate analyses. A novel risk score was created using independent risk factors.
Data from 984 cases could be included into the final analysis. Aneurysm rebleeding occurred in 58 cases (5.9%), and in 48 of these cases (82.8%) rerupture occurred within 24 hours after SAH. Of over 30 tested associations, preexisting arterial hypertension (p = 0.02; adjusted odds ratio [aOR] 2.56, 1 score point), aneurysm location at the basilar artery (p = 0.001, aOR 4.5, 2 score points), sac size ≥ 9 mm (p = 0.04, aOR 1.9, 1 score point), presence of intracerebral hemorrhage (p = 0.001, aOR 4.29, 2 score points), and acute hydrocephalus (p < 0.001, aOR 6.27, 3 score points) independently predicted aneurysm rebleeding. A score built upon these parameters (0–9 points) showed a good diagnostic accuracy (p < 0.001, area under the curve 0.780) for rebleeding prediction.
Certain patient-, aneurysm-, and SAH-specific parameters can reliably predict aneurysm rerupture. A score developed according to these parameters might help to identify individuals that would profit from immediate aneurysm occlusion.
Ramazan Jabbarli, Daniela Pierscianek, Karsten Wrede, Philipp Dammann, Marc Schlamann, Michael Forsting, Oliver Müller and Ulrich Sure
The complete clipping of a cerebral aneurysm usually warrants its sustained occlusion, while clip remnants may have far-reaching consequences. The aim of this study is to identify the risk factors for clip remnants requiring retreatment and/or exhibiting growth.
All consecutive patients with primary aneurysm clipping performed at University Hospital of Essen between January 1, 2003, and December 31, 2013, were eligible for this study. Aneurysm occlusion was judged on obligatory postoperative digital subtraction angiography and the need for repeated vascular control. The identified clip remnants were correlated with various demographic and clinical characteristics of the patients, aneurysm features, and surgery-related aspects.
Of 616 primarily clipped aneurysms, postoperative angiography revealed 112 aneurysms (18%) with clip remnants requiring further control (n = 91) or direct retreatment (n = 21). Seven remnants exhibited growth during follow-up, whereas 2 cases were associated with aneurysmal bleeding. Therefore, a total of 28 aneurysms (4.5%) were retreated as clip remnants (range 1 day to 67 months after clipping). In the multivariate analysis, the need for retreatment of clip remnant was correlated with the aneurysm's initial size (> 12 mm; OR 3.22; p = 0.035) and location (anterior cerebral artery > internal carotid artery > posterior circulation > middle cerebral artery; OR 1.85; p = 0.003). Younger age with a cutoff at 45 years (OR 33.31; p = 0.004) was the only independent predictor for remnant growth.
The size and location of the aneurysm are the main risk factors for clip remnants requiring retreatment. Because of the risk for growth, younger individuals (< 45 years old) with clip remnants require a long-term (> 5 years) vascular follow-up.
Clinical trial registration no: DRKS00008749 (Deutsches Register Klinischer Studien)
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
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.
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.
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.
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.
Ulrich Sure, Nick Butz, Jürgen Schlegel, Adrian M. Siegel, Jörg P. Wakat, Hans D. Mennel, Siegfried Bien and Helmut Bertalanffy
Object. To date, both arteriovenous malformations (AVMs) and cavernomas have been considered to be congenital malformations. A recent survey of the literature has shown the potential for de novo generation of both familial and sporadic cavernomas as well as AVMs. Therefore, it was of interest to determine the biological behavior of these lesions in detail.
Methods. The proliferative and angiogenic capacities of the endothelium of 13 cavernomas and 25 AVMs obtained in patients recently treated (1997–1998) at one institution were studied. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA), MIB-1, and vascular endothelial growth factor (VEGF) and its receptor Flk-1 was performed using standard staining procedures. Positive immunostaining of the nuclei of endothelial cells was observed in specimens of both AVMs and cavernomas for PCNA (80% of AVMs and 85% of cavernomas), and Flk-1 (80% of AVMs and 31% of cavernomas). Endothelial expression of VEGF in the 18 incompletely embolized AVMs was found in 72% of cases but only in 28% of the seven cases in which patients did not undergo endovascular treatment; it was found in 38% of cavernomas. Endothelial expression of MIB-1 was found in 12% of AVMs but in no cavernomas.
Conclusions. These results indicate that there is endothelial proliferation as well as neoangiogenesis in cerebral cavernomas and AVMs. The increased level of angiogenesis in only partially obliterated AVMs underscores the need for radical and complete occlusion of cerebral AVMs to avoid recurrences and further risks of morbidity.
Yuan Zhu, Christian Peters, Monika Hallier-Neelsen, Dorothea Miller, Axel Pagenstecher, Helmut Bertalanffy and Ulrich Sure
Cerebral cavernous malformations (CCMs) are the most common vascular malformation of the central nervous system and involve dysregulated angiogenesis. However, the underlying mechanism of this disease is poorly understood. Phosphatase and tensin homolog (PTEN) plays a crucial role in regulating angiogenesis. The authors attempted to determine whether PTEN is involved in the pathological angiogenesis of CCM.
The authors used Western blot analysis and immunohistochemical methods to detect the expression of PTEN, PCNA, and P-Akt in the surgical specimens of CCMs and controls. The function of PTEN in cell proliferation was studied after PTEN silencing in endothelial cultures by using the short interfering RNA technique.
Western blot analysis showed significant reduction of PTEN protein expression in CCMs compared with control brain tissue (p < 0.01). Immunohistochemical analysis confirmed PTEN insufficiency in 33% of vascular endothelia of CCMs, which was significantly higher than that of controls (2%, p < 0.01). Furthermore, PTEN insufficiency occurred more frequently in multiple CCMs (44%) and in small lesions (39%) than in single CCMs (28%, p < 0.05) and large lesions (30%, p < 0.05), respectively, suggesting a potential role of PTEN in the progression of the lesions. Of note, a negative correlation was observed between the expression of PTEN and PCNA in CCM endothelial cells. However, Akt was not constitutively activated in CCMs. Using cultured endothelial cells, the authors demonstrated that PTEN silencing by short interfering RNA increased Akt activation, PCNA expression, and cell proliferation (p < 0.001). Surprisingly, the PTEN silencing–mediated increase in endothelial proliferation was not reversed by the PI3K inhibitor wortmannin.
In this study, the authors report for the first time a significant PTEN insufficiency in CCM vessels associated with endothelial proliferation. The in vitro study provides direct evidence for a pivotal role of PTEN in regulating endothelial proliferation, most likely through a PI3K-independent pathway. The authors suggest that PTEN insufficiency is potentially involved in CCM by stimulating angiogenesis.