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Hartmut Vatter, Juergen Konczalla, Stefan Weidauer, Christine Preibisch, Michael Zimmermann, Andreas Raabe, and Volker Seifert

Object

The key role in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) is increasingly assigned to endothelin (ET)-1. Constriction of the cerebrovasculature by ET-1 is mainly mediated by the ETA receptor but is putatively altered during the development of cerebral vasospasm. Therefore, the aim in the present study was to characterize these alterations, with the emphasis on the ETA receptor.

Methods

Cerebral vasospasm was induced using the rat double-hemorrhage model and proven by perfusion weighted magnetic resonance imaging. Rats were killed on Day 5 after SAH, and immunohistochemical staining for ETA receptors was performed. The isometric force of basilar artery ring segments with (E+, control group) and without (E−, SAH group) endothelial function was measured. Concentration effect curves (CECs) for ET-1 were constructed by cumulative application in the absence and presence of the selective ETA receptor antagonist clazosentan (10−8 or 10−7 M).

Results

The CEC for E+ segments was significantly shifted to the left after SAH by a factor of 3.7, whereas maximum contraction was unchanged. In E− segments, the CECs were not shifted during cerebral vasospasm but the maximum contraction was significantly enhanced. The inhibitory potency of clazosentan yielded a pA2 value of 8.6 ± 0.2. Immunohistochemical staining of the smooth-muscle layer showed no significant increase of ETA receptor expression, but positive staining occurred in the endothelial space after SAH.

Conclusions

The present data indicate an enhanced contractile effect of the smooth-muscle ETA receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ETA receptor and an endothelium-dependent vasoactive effect after SAH is provided.

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Peter Vajkoczy, Bernhard Meyer, Stefan Weidauer, Andreas Raabe, Claudius Thome, Florian Ringel, Volker Breu, Peter Schmiedek, and the other Study Participants

Objective

The goal of this study was to investigate the safety and tolerability of the novel endothelin A (ETA) receptor antagonist clazosentan in patients with subarachnoid hemorrhage (SAH) and its potential to reduce the incidence and severity of cerebral vasospasm following surgical clipping of the aneurysm.

Methods

This Phase IIa multicenter study had two parts: a double-blind, randomized Part A (some patients given clazosentan [0.2 mg/kg/hr] and others given placebo), in which statistical inference was performed, and an open-label Part B (patients with established vasospasm given clazosentan [0.4 mg/kg/hr for 12 hours followed by 0.2 mg/kg/hr]) for exploratory purposes only. Primary end points were the incidence and severity of angiographic vasospasm on Day 8 after SAH and the safety and tolerability of the drug.

Thirty-four patients (Hunt and Hess Grades III and IV and Fisher Grade ≥3) were recruited and 32 (15 in the clazosentan group and 17 in the placebo group) were retained in the intent-to-treat population; 19 patients entered Part B. In Part A, treatment with clazosentan resulted in a reduced incidence of angiographically evident cerebral vasospasm (40% compared with 88% of patients, p = 0.008). In addition, the severity of vasospasm was reduced in the clazosentan group (p = 0.012). In Part B of the study, in 50% of assessable patients who were initially treated with placebo reversal of vasospasm was observed following the initiation of clazosentan therapy. The incidence of new infarctions was 15% in the clazosentan group and 44% in the placebo group (p = 0.130). There was no adverse event pattern indicating a specific organ toxicity of clazosentan.

Conclusions

This study indicates that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal SAH with the incidence and severity of adverse events comparable to that of placebo.

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Elke Hattingen, Catriona Good, Stefan Weidauer, Sebastian Herminghaus, Peter Raab, Gerhard Marquardt, Andreas Raabe, Volker Seifert, and Friedhelm E. Zanella

Object. The goal of this study was to evaluate a novel form of brain surface representation that allows simple, reliable mapping of the surface neuroanatomy for the preoperative evaluation of the spatial relationship between a focal lesion and the precentral gyrus.

Methods. High-resolution three-dimensional (3D) magnetic resonance (MR) imaging data sets were postprocessed using a curved multiplanar reformatting technique to create brain surface reformatted (BSR) images. These BSR images were reconstructed in less than 5 minutes and demonstrated the entire central sulcus with adjacent surface structures in one view. Two experienced neuroradiologists determined the localization of lesions near the central sulcus in 27 patients on standard MR images in three orthogonal planes and on BSR images. In addition, these observers judged whether the lesions were easy or difficult to localize on standard MR and BSR images, and whether diagnoses based on these methods were certain or doubtful. Anatomical localization based on BSR images was compared with that based on functional MR (fMR) images or intraoperative mapping of motor function. The BSR images yielded a perfect concordance with the fMR images and intraoperative mapping (Cohen κ 1.0) and optimal diagnostic accuracy in localizing perirolandic lesions (both sensitivity and specificity were 100%). Localization was judged to be easy for 48 of 54 diagnoses based on BSR images compared with 26 of 54 based on standard MR images. Diagnoses were assessed as certain for 52 cases based on BSR images and 34 cases based on standard MR images.

Conclusions. Brain surface reformatted imaging improves the diagnostic accuracy of standard anatomical MR imaging for localizing superficial brain lesions in relation to the precentral gyrus. The complementary use of this technique with standard two-dimensional imaging is supported by the fast and simple postprocessing technique and may provide useful information for preoperative surgical planning.

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Jürgen Beck, Andreas Raabe, Heiner Lanfermann, Joachim Berkefeld, Richard Du Mesnil De Rochemont, Friedhelm Zanella, Volker Seifert, and Stefan Weidauer

Object

The aim of this study was to analyze the effects and outcome of transluminal balloon angioplasty (TBA) on brain tissue perfusion by using combined perfusion- and diffusion-weighted (PW/DW) magnetic resonance (MR) imaging in patients with cerebral vasospasm after subarachnoid hemorrhage.

Methods

Ten consecutive patients with cerebral vasospasm treated using TBA were included in this prospective study. Hemodynamically relevant vasospasm was diagnosed using a standardized PW/DW MR imaging protocol. Digital subtraction angiography was used to confirm vasospasm, and TBA was performed to dilate vasospastic arteries. The PW/DW imaging protocol was repeated after TBA. The evaluation of the passage of contrast medium after standardized application using the bolus tracking method allowed for the calculation of the time to peak (TTP) before and after TBA.

Tissue at risk was defined based on perfusion delays in individual vessel territories compared with those in reference territories. In cases with proximal focal vasospasm, TBA could dilate spastic arteries. Follow-up PW/DW MR imaging showed the disappearance of, or a decrease in, the mismatch. A TBA-induced reduction in the perfusion delay of 6.2 ± 1 seconds (mean ± standard error of the mean) to 1.5 ± 0.45 seconds resulted in the complete prevention of infarction; a reduction in the delay of 6.2 ± 2.7 to 4.1 ± 1.9 seconds resulted in the preservation of those brain tissue parts having only small infarcts in the vessel territories. Without TBA, however, the perfusion delay remained or even increased (11.1 ± 3.7 seconds), and the complete infarction of a territory occurred.

Conclusions

Angioplasty of vasospastic arteries leads to hemodynamic effects that can be quantified using PW/DW MR imaging. In cases of a severe PW/DW imaging mismatch successful TBA improved tissue perfusion and prevented cerebral infarction. The clinical significance of PW/DW MR imaging and the concept of tissue at risk is shown by cerebral infarction in vessels not accessible by TBA.