Klaus-Peter Stein

Associated Aneurysms in Supratentorial Arteriovenous Malformations: Impact of Aneurysm Size on Haemorrhage

Background: Associated aneurysms (AAs) are presumed to represent an additional risk factor for intracranial haemorrhage from cerebral arterio-venous malformations (AVMs). To date, efforts to capture their natural history, as well as to identify aneurysms with the potential capability of regression after AVM treatment remain incomprehensive. As the aneurysm size represents an important aspect for the treatment indication of incidental saccular aneurysms, this factor has rarely been encountered for the treatment of AAs so far. The present study aims to determine the angiographic and clinical characteristics of AAs with special focus on aneurysm size and their consequences for treatment. Methods: Patients with cerebral AVMs, treated in our department between 1990 and 2013, were analyzed retrospectively. Only patients with supratentorial AVMs and flow-related AAs of the feeding arteries were evaluated. Thus, patients harboring AVMs of the cerebellum and the brain stem and patients with intranidal, venous or remote aneurysms were excluded. Treatment strategies were assessed with special attention on bleeding source and on AA size. Results: In 59 of 409 patients (14%) with supratentorial AVMs, a total of 85 AAs of the feeding arteries were identified. 14 of 59 individuals (24%) presented with multiple AAs. Of 85 AA, 58 aneurysms (68%) were classified as proximal and 27 aneurysms (32%) as distal. The most common location of AAs was the middle cerebral artery (MCA, 39%), followed by the internal carotid artery (ICA, 27%) and the anterior cerebral artery (ACA, 21%). The mean AA size was 4.4 mm ± 3.4 mm. Intracranial haemorrhage was found in 21 of 59 patients (36%) with coexisting AAs. Among these, 10 individuals (17%) suffered from rupture of an AA, accounting for nearly half of all bleedings in this subgroup. Among those patients bearing a single AA, the size of ruptured aneurysms differed significantly from those unruptured (6.6 mm vs. 4.4 mm, p = 0.0046). Nineteen patients (32%) received treatment of 22 AAs, whereas sole AVM treatment was adopted in 26 patients (44%) and conservative management in 14 patients (24%). The main reasons to leave AAs untreated were the small AA size (<5 mm), poor clinical state or treatment denial by the patients. Conclusions: The aneurysm size of AAs in AVM influences the risk of haemorrhage. Therefore, the treatment of larger (diameter ≥5 mm) AAs should be considered, even if a treatment indication of the associated AVM is not given.

Study of angiogenic signaling pathways in hemangioblastoma

Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper‐vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT2‐PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4‐Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core‐components of Dll4‐Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti‐angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor.

Associated Aneurysms in Infratentorial Arteriovenous Malformations: Role of Aneurysm Size and Comparison with Supratentorial Lesions

Background: The natural history and treatment of brain arteriovenous malformations (AVMs) is the object of ongoing debates and discussions. To capture the entirety of these complex lesions, associated vascular pathologies, such as associated aneurysms (AAs), have to be implemented in future risk stratification models, as they are believed to represent additional risk factors for intracranial hemorrhage. The present study aims to determine AA characteristics in posterior fossa AVMs and to compare with AAs accompanying supratentorial AVMs, with special focus on aneurysm size. Methods: Patients with cerebral AVMs, treated in our department between 1990 and 2013, were analyzed retrospectively. Only patients with flow-related AAs of the feeding arteries were evaluated. Thus, patients harboring intranidal, venous or remote aneurysms were excluded. Results: Of 485 patients with cerebral AVM, 76 patients harbored an AVM of the posterior fossa. Among those, 22 individuals exhibited a total of 35 AAs (n = 8 patients with multiple AAs). Most common location of AAs was the posterior inferior cerebellar artery (n = 20, 57%) and mean AA diameter was 7.9 mm (SD 5.5). In the subgroup of patients with a single AA, mean aneurysm size in posterior fossa AVMs was with 7.8 mm (SD 6.0; range 2-25 mm) significantly larger than the mean size of AAs with supratentorial AVMs (4.8 mm, SD 3.0; range 2-20 mm; p = 0.048). Intracranial hemorrhage was found in 18 of 22 patients (82%) with infratentorial AVMs, and of these, 11 patients suffered from aneurysm rupture. In 14 patients bearing a single AA, 8 (57%) had sustained hemorrhage from aneurysm rupture. The mean diameter of AAs was as supposed in the ruptured group with 9.8 mm (SD 6.9; range 4-25 mm) significantly larger than in the unruptured AA group exhibiting a mean of 5.0 mm (SD 3.3; range 2-10 mm; p = 0.038). Patients with posterior fossa AVMs and AAs were significantly older as compared to those patients with supratentorial lesions (57.1, SD 12.6 vs. 45.8 years, SD 15.9 years; p = 0.004), which was also evident in the subgroup of patients with single AAs (55.2, SD 11.7 vs. 45.8 years, SD 14.9 years; p = 0.038). Conclusions: AAs of posterior fossa AVMs are larger in diameter than aneurysms accompanying supratentorial AVMs. AA size influences risk for hemorrhage, which, together with the high number of hemorrhagic events in posterior fossa AVMs, justifies treating these pathologies. The higher age of patients with AVMs of the posterior fossa might be one reason for larger AAs in this cohort, when compared to patients with supratentorial AVMs and AAs.

Treatment of complex neurovascular lesions: an interdisciplinary angio suite approach

Objective: The objective of this study was to analyse our initial experience using an interdisciplinary angio suite approach to neurosurgical treatment of complex neurovascular lesions and expound technical feasibility and possible applications. Subjects: Six out of 451 patients with cranial or spinal neurovascular lesions were surgically treated in the angio suite (biplane angiographic system) during a 28-month observation period. Clinical baseline data, radiological and intraoperative findings as well as clinical and radiological outcome were assessed. Results: A ventral spinal perimedullary arteriovenous malformation, a ventral spinal perimedullary fistula, two diffuse frontal dural arteriovenous fistulas, a multifocal temporal arteriovenous malformation and a partially embolized fronto-temporo-basal dural arteriovenous fistula were successfully treated with angiographically confirmed complete occlusion and unimpaired neurological condition of the patients at the 12-month follow up. Conclusion: This study demonstrates the feasibility of this approach and points out possible indications, namely ventrally located spinal lesions and diffuse, deep seated cranial lesions.

Surgical management of intradural spinal cord tumors in children and young adults: A single-center experience with 50 patients.

Background: Intradural spinal cord tumors (IDSCTs) in children and young adults are rare diseases. This present study is aimed to demonstrate our experience with a large series of children and young adults with IDSCT. Methods: A total of 50 patients aged <20 years with IDSCT treated in our department between 1990 and 2010 were included in the study. Clinical, histological, and radiological findings, treatment strategies, and clinical outcome were retrospectively assessed. Depending on the relation to the spinal cord, IDSCT were dichotomized into intramedullary SCT (IMSCT) and extramedullary SCT (EMSCT). The functional outcome was evaluated with the Frankel score assessing the longest available follow-up period. Results: Mean age was 10.3 years (range 6 months–19 years). IDSCT surgery was performed in 44 patients (88%). A common first symptom in patients with EMSCT was neck and back pain (41%), whereas monoparesis of arms (43%) were often seen in patients with IMSCT. The main duration of the symptoms was longer in patients with IMSCT. The postoperative functional outcome was generally comparable to the preoperative functional condition, while better for EMSCT (P < 0.01). The functional outcome at last follow-up correlated significantly with the preoperative Frankel score (P < 0.002). Conclusion: Due to the mostly mild impact of the surgery on the functional outcome, the surgical treatment of IDSCT in children and young patients can be uniquely advocated.

Downregulation of programmed cell death 10 is associated with tumor cell proliferation, hyperangiogenesis and peritumoral edema in human glioblastoma

BackgroundNeovascularization and peritumoral edema are hallmarks of glioblastoma (GBM). Programmed cell death 10 (PDCD10) plays a pivotal role in regulating apoptosis, neoangiogenesis and vessel permeability and is implicated in certain tumor signaling pathways. However, little is known about PDCD10 in GBM. We aimed to investigate the expression pattern of PDCD10 and to identify the association of its expression with some molecular and clinical parameters in human GBM.MethodsmRNA and protein expression of PDCD10 were examined respectively by real-time RT-PCR and Western blotting in GBM (n = 27), astrocytoma grade II (n = 13) and control (n = 11). The protein level of p-Akt and GFAP was detected by Western blot. Double-imunofluorecent staining was performed to reveal the cellular expression profile of PDCD10. Brain edema and microvascular density (MVD) were respectively analyzed based on pre-operative MRI and after laminin immnostaining. MGMT promoter methylation was detected by methylation specific PCR.ResultsmRNA and protein levels of PDCD10 were significantly downregulated in GBM, concomitantly accompanied by the activation of Akt. PDCD10 immunoreactivity was absent in proliferating tumor cells, endothelial cells and GFAP-positive cells, but exclusively present in the hypoxic pseudopalisading cells which underwent apoptosis. Moreover, loss of PDCD10 was associated with a higher MVD and a more severe peritumoral edema but not with MGMT promoter methylation in GBM.ConclusionWe report for the first time that PDCD10 expression is downregulated in GBM, which is associated with the activation of Akt signaling protein. PDCD10 is potentially implicated in tumor proliferation and apoptosis, hyperangiogenesis and peritumoral edema in GBM.