Juergen Konczalla

Time course in the development of cerebral vasospasm after experimental subarachnoid hemorrhage: clinical and neuroradiological assessment of the rat double hemorrhage model.

OBJECTIVE:The “double hemorrhage” model in the rat is frequently used to simulate delayed cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in humans. However, an exact neurological and angiographic characterization of the CVS is not available for this model so far and is provided in the present investigation. Additionally, perfusion weighted imaging (PWI) at 3 tesla magnetic resonance (MR) tomography was implemented to assess the reduction in cerebral blood flow (CBF). METHODS:In a prospective, randomized setting CVS was induced by injection of 0.2 ml autologous blood twice in the cisterna magna of 45 male Sprague-Dawley rats. The surviving animals were examined on Days 2, 3, 5, 7 and 9 and compared to a sham operated control group (n = 9). Rats were neurologically graded between 0 and 3, followed by MRI and selective digital subtraction angiography (DSA). The relative CBF was set in relation to the perfusion of the masseter muscle. RESULTS:The neurological state was significantly worsened on Day 2 (Grade 3), 3 (Grade 3), and 5 (Grade 2) (medians). The relative CBF/muscle BF ratio (2.5 ± 0.8 (SAH) versus 9.2 ± 1.3 (sham) (mean ± SEM) and the basilar artery (BA) diameter (0.15 ± 0.02 mm (SAH) versus 0.32 ± 0.01 mm (sham) were significantly decreased on Day 5. Correlation between relative CBF/muscle BF ratio and BA diameter was 0.70. CONCLUSION:A valid and reproducible CVS simulation was proven by neurological score, DSA, and PWI on Day 5. Furthermore, our data demonstrate the practicability and validity of MR PWI for the monitoring of CVS in a rat SAH model.

Effect of delayed cerebral vasospasm on cerebrovascular endothelin A receptor expression and function

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 ET(A) 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 ET(A) 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 ET(A), 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 ET(A) 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 ET(A) 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 ET(A) receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ET(A) receptor and an endothelium-dependent vasoactive effect after SAH is provided.

Non-aneurysmal non-traumatic subarachnoid hemorrhage: patient characteristics, clinical outcome and prognostic factors based on a single-center experience in 125 patients

BackgroundSubarachnoid hemorrhage (SAH) is mainly caused by ruptured cerebral aneurysms but in up to 15% of patients with SAH no bleeding source could be identified. Our objective was to analyze patient characteristics, clinical outcome and prognostic factors in patients suffering from non-aneurysmal SAH.MethodsFrom 1999 to 2009, data of 125 patients with non-aneurysmal SAH were prospectively entered into a database. All patients underwent repetitive cerebral angiography. Outcome was assessed according to the modified Rankin Scale (mRS) (mRS 0–2 favorable vs. 3–6 unfavorable). Also, patients were divided in two groups according to the distribution of blood in the CT scan (perimesencephalic and non-perimesencephalic SAH).Results106 of the 125 patients were in good WFNS grade (I-III) at admission (85%). Overall, favorable outcome was achieved in 104 of 125 patients (83%). Favorable outcome was associated with younger age (P < 0.001), good admission status (P < 0.0001), and absence of hydrocephalus (P = 0.001).73 of the 125 patients suffered from perimesencephalic SAH, most patients (90%) were in good grade at admission, and 64 achieved favorable outcome.52 of the 125 patients suffered from non-perimesencephalic SAH and 40 were in good grade at admission. Also 40 patients achieved favorable outcome.ConclusionsPatients suffering from non-aneurysmal SAH have better prognosis compared to aneurysm related SAH and poor admission status was the only independent predictor of unfavorable outcome in the multivariate analysis. Patients with a non-perimesencephalic SAH have an increased risk of a worse neurological outcome. These patients should be monitored attentively.

Increased risk of delayed cerebral ischemia in subarachnoid hemorrhage patients with additional intracerebral hematoma.

OBJECTIVE Delayed cerebral ischemia (DCI) has a major impact on the outcome of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to assess the influence of an additional intracerebral hematoma (ICH) on the occurrence of DCI. METHODS The authors conducted a single-center retrospective analysis of cases of SAH involving patients treated between 2006 and 2011. Patients who died or were transferred to another institution within 10 days after SAH without the occurrence of DCI were excluded from the analysis. RESULTS Additional ICH was present in 123 (24.4%) of 504 included patients (66.7% female). ICH was classified as frontal in 72 patients, temporal in 24, and perisylvian in 27. DCI occurred in 183 patients (36.3%). A total of 59 (32.2%) of these 183 patients presented with additional ICH, compared with 64 (19.9%) of the 321 without DCI (p = 0.002). In addition, DCI was detected significantly more frequently in patients with higher World Federation of Neurosurgical Societies (WFNS) grades. The authors compared the original and modified Fisher Scales with respect to the occurrence of DCI. The modified Fisher Scale (mFS) was superior to the original Fisher Scale (oFS) in predicting DCI. Furthermore, they suggest a new classification based on the mFS, which demonstrates the impact of additional ICH on the occurrence of DCI. After the different scales were corrected for age, sex, WFNS score, and aneurysm site, the oFS no longer was predictive for the occurrence of DCI, while the new scale demonstrated a superior capacity for prediction as compared with the mFS. CONCLUSIONS Additional ICH was associated with an increased risk of DCI in this study. Furthermore, adding the presence or absence of ICH to the mFS improved the identification of patients at the highest risk for the development of DCI. Thus, a simple adjustment of the mFS might help to identify patients at high risk for DCI.

The Impact of Tracheostomy Timing on Clinical Outcome and Adverse Events in Poor-Grade Subarachnoid Hemorrhage.

Objective: The value of optimal timing of tracheostomy in patients with subarachnoid hemorrhage is controversially debated. This study investigates whether early or late tracheostomy is associated with beneficial outcome or reduced rates of adverse events. Design: Retrospective observational multicentric on patients prospectively inserted into a database. Setting: Neurologic ICUs of one academic hospital and two secondary hospitals in Germany. Patients: Data of all patients admitted to the Goethe University Hospital between 2006 and 2011 with poor-grade subarachnoid hemorrhage were prospectively entered into a database. All patients who underwent tracheostomy were included for analysis. Follow-up was maintained in primary and secondary ICUs. Interventions: Patients underwent tracheostomy upon expected long-term ventilation. Early tracheostomy was defined as performed on days 1–7 and late tracheostomy on days 8–20 after admission. Measurement and Main Results: We compared 148 consecutive patients admitted with poor-grade (World Federation of Neurosurgical Societies, 3–5) subarachnoid hemorrhage. Early tracheostomy was performed in 39 patients and late tracheostomy in 109 patients. In early versus late tracheostomy groups, no significant differences were observed with regard to ICU mortality (7.7% vs 7.3%; p = 0.93) and median modified Rankin Scale after 6 months (3 vs 3; p = 0.94). Of the early group, pneumonia developed in 19 patients, whereas in the late group, pneumonia developed in 75 patients (48.7% vs 68.8%; p = 0.03; odds ratio, 2.32; 95% CI, 1.1–4.9). Six patients of the early group (15.4%) and 36 patients of the late group (33%) suffered from respiratory adverse event (p = 0.04; odds ratio, 2.71; 95% CI, 1.04–7.06). Mechanical ventilation was shorter (17.4 vs 22.3 d; p < 0.05) and decannulation occurred earlier (42 vs 54 d; p = 0.039) in the early tracheostomy group. Conclusions: Tracheostomy within 7 days of critical care admission is a feasible and safe procedure for patients with poor-grade subarachnoid hemorrhage. Early tracheostomy was not associated with an improvement in mortality or neurologic outcome but associated with fewer respiratory adverse events.

Functional Effects of Levosimendan in Rat Basilar Arteries In Vitro

Levosimendan is a novel calcium sensitizer that is an established treatment for congestive heart failure. In coronary vessels, levosimendan has a vasorelaxant, endothelium-independent effect and an antagonistic effect on endothelin-1 (ET-1). There is also some data for a neuroprotective effect in a traumatic brain injury model, and levosimendan can prevent the reduction of the luminal area of the basilar artery. We considered that patients who suffer heart attack after subarachnoid hemorrhage (SAH) might respond well to levosimendan, which might also be useful to induce hypertension in patients with cerebral vasospasm.However, the functional effects of levosimendan in the cerebrovasculature are unknown. Here, we investigated the functional role of levosimendan on rat basilar artery by assessing vasocontractile reactivity in response to ET-1, sarafotoxin S6c, acetylcholine, sodium nitroprusside, cGMP, and prostaglandin F2α (PGF).Contrary to observations in coronary vessels, levosimendan did not affect the ET-1 system in cerebral arteries; neither ET(A)-receptor-induced contraction nor ET(B)-receptor-dependent relaxation were changed. For the nitric oxide (NO) pathway, only a slight increase was detected. Rather, levosimendan caused significant and dose-dependent relaxation after PGF precontraction.To our knowledge, this is the first report that describes levosimendan-induced functional changes of cerebrovascular contractility and relaxation. Under physiological conditions, levosimendan did not influence ET(A)/ET(B)-receptor signaling or the NO pathway. Interestingly, levosimendan seemed to affect the prostaglandin system and dosedependently reversed PGF- induced contraction. We did not detect a vasospastic potential for levosimedan in cerebral arteries, suggesting that it would be safe for use in SAH patients.

Cerebral vasospasm and delayed cerebral infarctions in 225 patients with non-aneurysmal subarachnoid hemorrhage: the underestimated risk of Fisher 3 blood distribution

Objective Recent data have shown increasing numbers of non-aneurysmal subarachnoid hemorrhage (NASAH). However, data are limited and often only small series have been published. Our objective was to analyze the rate of cerebral vasospasm (CVS), delayed cerebral infarction (DCI), and their influence on the clinical outcome, especially in patients with diffuse Fisher 3 bleeding pattern NASAH (Fi3). Methods Between 1999 and 2014, 225 patients had NASAH. CVS, DCI, and outcome (according to the modified Rankin Scale at 6 months) were analyzed retrospectively. Patients were stratified according to the bleeding type. After univariate analysis a multivariate analysis was performed and NASAH Fi3 was also compared with aneurysmal SAH Fi3. Results Patient characteristics and the outcome of perimesencephalic (PM) and non-PM (NPM) SAH were similar. Excluding Fi3, PM and NPM without Fi3 had similar patient characteristics, clinical course, and outcome. In particular, the Fi3 subgroup had a significantly increased risk of CVS, DCI, unfavorable outcome, hydrocephalus, and death. Early hydrocephalus was associated with Fi3 and intraventricular hemorrhage. The multivariate regression model showed the variables elderly patients, Fi3, and early hydrocephalus as independent and significant predictors for an unfavorable outcome. A further comparison of NASAH Fi3 with aneurysmal SAH Fi3 showed similar characteristics, CVS rate, and mortality. Conclusions Patients with NASAH without a Fi3 bleeding pattern had a similar excellent outcome to patients with PM-SAH. Patients with Fi3 had a high risk for early hydrocephalus, CVS, DCI, and an unfavorable outcome, similar to patients with aneurysmal SAH. After multivariate analysis, early hydrocephalus, elderly patients, and Fi3 were identified as negative prognostic factors. Therefore, patients with Fi3 are at risk and need careful clinical observation.

Crosstalk Between the Angiotensin and Endothelin-System in the Cerebrovasculature

Investigations have shown a multifactorial process as cause for the poor outcome after subarachnoid hemorrhage (SAH), including inflammation, early brain injury, cortical spreading depression, lack of cerebral autoregulation and the cerebral vasospasm (CVS) itself. Losartan may have a beneficial effect after SAH - preventing CVS, restoring cerebral autoregulation, reducing inflammation and early brain injury. Also some data is available for an AT1-receptor-upregulation and upregulated gene expression after subarachnoid hemorrhage, but the functional role of angiotensin on the cerebrovascular contractility is still not completely understood. Therefore, the aim of the present investigation was to detect functional interactions between the AT1-receptor blockade (by losartan) and the endothelin-1 (ET-1) dependent vasoconstriction and vasorelaxation in the basilar artery. To investigate the functional role of losartan on rats basilar artery, changes of the vasoreactivity in an organ bath were determined. Under losartan the ET-1 induced contraction is decreased. After incubation with BQ-788, an ET(B)-receptor antagonist, the lowered contraction is abolished. In precontracted vessels under losartan and BQ-123, an ET(A)-receptor antagonist, ET-1 induced a higher relaxation. AT1-receptor antagonism causes a modulatory effect in ET(B)-receptor-dependent vasorelaxation in the basilar artery. AT1-receptor antagonism due to losartan induces the upregulation of the NO-pathway with a significantly increased relaxation accompanied with enhanced sensitivity of the ET(B)-receptor. Losartan has a dose-dependent antagonistic effect to the ET-1 induced contraction, which seems to ET(B)-receptor dependent. This antagonistic effect could be another beneficial effect after subarachnoid hemorrhage, additionally to the known effects after stroke: preventing CVS, restoring cerebral autoregulation, reducing inflammation and early brain injury.

Management of Patients with Primary Intramedullary Spinal Cord Glioblastoma.

BACKGROUND Primary intramedullary spinal cord glioblastomas are very rare tumors of the spinal cord. They imply a very poor prognosis because complete surgical resection is not possible as the result of the infiltrative growth of these tumors. The aim of this study is to present our data achieved with an aggressive multimodality treatment. METHODS We retrospectively reviewed our clinical database. All patients with histologically proven intramedullary spinal cord glioblastoma treated in our department were included in this study. RESULTS Four patients with intramedullary spinal cord glioblastoma were identified between 2006 and 2015, all of whom were female. Mean age at the time of surgery was 33.5 years (range 14-50 years). Tumors were located in the cervical region in 2 patients and in the thoracic region in 2 patients. All 4 patients underwent microsurgical biopsy of the tumor. After surgery, all patients received radiation and temozolomide treatment. One patient underwent additional therapy with Bevacizumab, another patient received Rapamycin and Sunitinib, and the third patient received Chlorethyl-cyclohexyl-nitroso-urea and Etoposide as additional therapy after tumor regrowth. Tumor progression occurred in a mean time of 18.2 months (6-32 months). In this series, all patients died as the result of progression of the malignancy; median survival after diagnosis was 32.5 months. CONCLUSIONS The surgical outcome of intramedullary spinal cord glioblastoma still remains poor. Severe disability and amelioration of the neurologic status lead to reduced quality of life; however, an aggressive multimodal and interdisciplinary treatment for the disease may be associated with longer survival.

Alteration of the cerebrovascular function of endothelin B receptor after subarachnoidal hemorrhage in the rat.

The substantial role of endothelin-1 (ET-1) in the development of cerebral vasospasm (CVS) after subarachnoidal hemorrhage (SAH) has been demonstrated by numerous experimental and, recently, clinical investigations. Whether the expression or function of the ET(B) receptor is altered in CVS is still unclear, however. The aim of the present study was, therefore, to characterize the cerebroarterial ET(B) receptor function during CVS. Experimental CVS was induced by the rat double-hemorrhage model. Reduction of the cerebral blood flow (CBF) was confirmed by magnetic resonance perfusion-weighted imaging. Animals were sacrificed on days 3 (d3) and 5 (d5) after CVS induction. The basilar arteries (BA) were dissected, cut into ring segments, and prepared for measurement of isometric force in an organ bath. Concentration-effect curves (CECs) were constructed by cumulative application of ET-1, acetylcholine (Ach), or sarafotoxin S6c (S6c). Segments with (E+) endothelial function were used. CECs were compared by the maximum effect (Emax), the pD2, and the shift calculated on the pD2 level. The pD2 is the negative decadic logarithm of the concentration producing the half maximal effect (−log10EC50). After SAH, the relative regional CBF in the d3 and d5 groups was reduced to 63% and 32%, respectively, of the CBF in controls. ET-1 induced a dose-dependent contraction of segments with and segments without CVS. In E+ segments, the Emax for ET-1 was not significantly changed after SAH (mean values [ ± SEM] of 104% ± 4% for the control group, 106% ± 4% for the d3 group, and 104% ± 3% for the d5 group). The CECs, however, were significantly shifted to the left versus the control by factors of 2.4 in the d3 group and 3.6 in the d5 group. Relaxation by S6c was significantly reduced after SAH (Emax: 73% ± 11% in the control group, 21% ± 13% in the d3 group, and 13% ± 8% in the d5 group), whereas relaxation associated with Ach was not significantly changed (Emax: 45% ± 7% in the control group, 56% ± 6% in the d3 group, and 43% ± 6% in the d5 group). Significant contraction by S6c was not observed in E+ and E − segments in any of the study groups. The present data indicate the loss of the ET(B) receptor–mediated relaxation of the cerebral arteries in cases of CVS, which is independent of the endothelial nitric oxide synthase level.