Gerrit Alexander Schubert

Acute Hypoperfusion Immediately after Subarachnoid Hemorrhage: A Xenon Contrast-Enhanced CT Study

The acute neurological deficit present immediately after subarachnoid hemorrhage (SAH) correlates with overall outcome. Only limited data are available to quantify changes in cerebral perfusion in this acute phase, and this study sought to characterize those changes within the first 12 h post-SAH. Xenon contrast-enhanced CT scanning was performed in 17 patients (Hunt and Hess grade [HH] 1-3, n = 9; HH 4-5, n = 8) within 12 h after SAH. Cerebral blood flow (CBF) was analyzed in all cortical and central vascular regions of interest (ROI), as well as infratentorial ROI. Hemodynamic stress distribution (central/cortical ROI) was also calculated. Asymptomatic patients without perfusion deficits served as controls (n = 5), and Glasgow Outcome Scale score (GOS) was determined 3 months after the event. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were within normal limits in all patients. CBF was significantly reduced in all patients with SAH (34 mL/100 g x min) compared to controls (67 mL/100 g x min; p < 0.001). Patients in better clinical condition (HH 1-3) presented with significantly less reduction of CBF (41 mL/100 g x min) compared to patients with more severe hemorrhage (HH 4-5: 24 mL/100 g x min; p < 0.001), and had better outcomes. Changes in perfusion were more pronounced in supratentorial than in infratentorial ROI. Hemodynamic stress distribution was most pronounced in patients with higher HH grade (p < 0.05). The first 12 h after SAH are characterized by persistent, severe reduction of CBF, which in turn correlates with HH grade, but is independent of ICP or CPP. Acute peripheral vasospasm of the microvasculature, not detectable by conventional angiography, may account for this early phase of prolonged hypoperfusion.

Characterization of Direct and Indirect Cerebral Revascularization for the Treatment of European Patients with Moyamoya Disease

Background: The best revascularization strategy for moyamoya disease (MMD) remains unknown. Our aim was to characterize angiographic revascularization effects of a bilateral standardized revascularization approach, consisting of superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and encephalomyosynangiosis (EMS) on one hemisphere and single EMS on the contralateral hemisphere of each patient, and to compare the effects of both revascularization strategies on cerebral hemodynamics. Methods: In 30 patients (18 females/12 males, age 8–63 years), standardized revascularization was performed. Digital subtraction angiography was performed preoperatively and at 7 days, 6 months and 12 months postoperatively. STA-MCA and EMS functions were graded I (poor), II (medium) or III (extensive) according to angiographic aspects. In 20 patients, cerebrovascular reserve capacity (CVRC) was assessed pre- and postoperatively (at 12 months) using xenon CT. Results: After 12 months, STA-MCA/EMS function was grade 1 in 40/40%, grade 2 in 27/26%, and grade 3 in 27/10% of hemispheres, respectively. Twelve months after surgery, single EMS showed grade I in 37%, grade II in 27%, and grade III in 20% of hemispheres. Combined revascularization improved CVRC significantly compared to preoperative measurement (preoperative: 16.5 ± 34.6% vs. postoperative: 60.8 ± 64.22%; p < 0.05). Single EMS did not improve CVRC significantly (preoperative: 21.8 ± 35.9% vs. postoperative: 34.8 ± 63.0%; p < 0.05). Conclusions: Combined and indirect revascularization may be successfully applied in a bilateral standardized approach. STA-MCA/EMS is superior to single EMS in restoring CVRC in adult MMD patients.

Hypothermia Reduces Early Hypoperfusion and Metabolic Alterations during the Acute Phase of Massive Subarachnoid Hemorrhage: A Laser-Doppler-Flowmetry and Microdialysis Study in Rats

Morbidity and mortality of subarachnoid hemorrhage (SAH) are correlated with the severity of the patients acute neurological deficit. This initial presentation has been attributed to cerebral hypoperfusion in the acute phase, and we investigated the impact of moderate hypothermia on the early changes in perfusion and metabolism following massive experimental SAH. SAH was induced in 61 anesthetized rats by rapid injection of 0.5 mL of arterial blood into the cisterna magna. In normothermia (NT), animals were kept at 37 degrees C, while in the primary hypothermia (pHT) group, temperature was lowered to 32 degrees C prior to SAH, and in the secondary hypothermia (sHT) group, cooling was started immediately after SAH. From 30 min prior to 180 min after SAH, Laser-Doppler-flowmetry (LDF) probes allowed online recording of cerebral blood flow (CBF) while parenchymal dialysate was collected by microdialysis probes within the frontoparietal cortex. In NT, the acute phase was characterized by impaired autoregulation and prolonged hypoperfusion. In pHT and sHT, autoregulation was preserved and acute hypoperfusion rapidly improved. SAH also caused a highly significant reduction in glucose in NT only. pHT significantly reduced accumulation of lactate, glutamate, and aspartate. Comparable trends were present for histidine, GABA, and taurine, while glutamine consumption was ameliorated. Early perfusion deficits caused by acute hypoperfusion and disruption of cerebral autoregulation can be ameliorated by hypothermia. Also, the acute phase of experimental SAH is characterized by glucose depletion, lactate accumulation, and release of excitatory amino acids, which can be influenced favorably by hypothermia.

Hypothermia reduces cytotoxic edema and metabolic alterations during the acute phase of massive SAH: a diffusion-weighted imaging and spectroscopy study in rats.

Acute changes in cerebral perfusion and metabolism after subarachnoid hemorrhage (SAH) have been shown to contribute significantly to acute brain injury. The purpose of this study was to examine the effects of moderate hypothermia on the acute changes after massive experimental SAH as evaluated by diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS). SAH in rats was induced by injection of 0.5 mL of arterial blood. Normothermic animals (NT, n = 10) were kept at 37.0 +/- 0.2 degrees C, while temperature was lowered to 32.0 +/- 0.2 degrees C in the primary hypothermia group (pHT, n = 10) prior to SAH and in the secondary hypothermia group (sHT, n = 10) immediately after SAH. DWI and MRS were performed from 30 min prior up to 3 h after injury. The apparent diffusion coefficient (ADC) was measured in cortical and hippocampal regions of interest (ROIs). MRS included lactate, N-acetyl aspartate (NAA), and creatine in a central voxel. DWI showed a generalized, significant decline in ADC after SAH in NT. Significant change in ADC in pHT was absent, and accelerated recovery for animals in sHT was noted. MRS analysis revealed significant lactate accumulation to 204 +/- 40% from baseline only in NT, while sHT was characterized by a transient, less pronounced increase of lactate (159 +/- 11%) and lactate in pHT did not change significantly (117 +/- 11%). NAA did not change significantly when compared to baseline or between groups for NT, pHT, or sHT. Creatine rose significantly to 166 +/- 27% in NT after the insult, indicating increased metabolic stress which was absent in pHT (106 +/- 8%) and sHT (124 +/- 18%). Hypothermia can ameliorate early development of cytotoxic edema, lactate accumulation, and a general metabolic stress response after SAH, even when started after the insult. Our study indicates that a potentially beneficial influence on metabolism and cerebral perfusion in this crucial phase is practicable and might hold the key to further improve outcome in SAH.

Hypothermia as a neuroprotective strategy in subarachnoid hemorrhage: a pathophysiological review focusing on the acute phase

Abstract Aneurysmal subarachnoid hemorrhage (SAH) remains a very prevalent challenge in neurosurgery associated with a high morbidity and mortality due to the lack of specific treatment modalities. The prognosis of SAH patients depends primarily on three factors: (i) the severity of the initial bleed, (ii) the endovascular or neurosurgical procedure to occlude the aneurysm and (iii) the occurrence of late sequelae, namely delayed ischemic neurological deficits due to cerebral vasospasm. While neurosurgeons and interventionalists have put significant efforts in minimizing periprocedural complications and a multitude of investigators have been devoted to the research on chronic vasopasm, the acute phase of SAH has not been studied in comparable detail. In various experimental studies during the past decade, hypothermia has been shown to reduce neuronal damage after ischemia, traumatic brain injury and other cerebrovascular diseases. Clinically, only some of these encouraging results could be reproduced. This review analyses results of studies on the effects of hypothermia on SAH with special respect to the acute phase in an experimental setting. Based on the available data, some considerations for the application of mild to moderate hypothermia in patients with subarachnoid hemorrhage are given.

Hypothermia Reduces Acute Vasospasm Following SAH in Rats

Subarachnoid hemorrhage (SAH) due to rupture of an aneurysm results in acute brain injury manifesting itself clinically as an acute neurologic deficit. Depending on the severity of the bleeding, the patients are classified according to clinical grading scales. This classification allows estimation of individual prognosis, as the extent of acute injury constitutes the crucial parameter for outcome following SAH. This statement has only recently been confirmed by Proust et al. [8], who reported a favorable outcome after Hunt and Hess grades IV and V in only 10% of cases.

Clazosentan, an endothelin receptor antagonist, prevents early hypoperfusion during the acute phase of massive experimental subarachnoid hemorrhage: a laser Doppler flowmetry study in rats

OBJECT Acute cerebral hypoperfusion and early disturbances in cerebral autoregulation after subarachnoid hemorrhage (SAH) have been demonstrated repeatedly and have been shown to contribute significantly to acute and secondary brain injury. Acute vasoconstriction has been identified as a major contributing factor. Although increasing evidence implicates endothelin (ET)-1 in the development of cerebral vasospasm, its role in the acute phase after SAH has not yet been investigated. The purpose of this study was to further determine the role of ET in the first minutes to hours after massive experimental SAH induced by prophylactic treatment with the ET receptor antagonist clazosentan. METHODS Subarachnoid hemorrhage was induced in 22 anesthetized rats by injection of 0.5-ml arterial, nonheparinized blood into the cisterna magna over the course of 60 seconds. In addition to monitoring intracranial pressure (ICP) and mean arterial blood pressure, laser Doppler flowmetry (LDF) probes were placed stereotactically over the cranial windows to allow online recording of cerebral blood flow (CBF) starting 30 minutes prior to SAH and continuing for 3 hours after SAH. The control group (Group A, 11 rats) received vehicle saline solution via a femoral catheter before SAH, and a second group (Group B, 11 rats) was treated prophylactically with clazosentan, an ET(A) receptor antagonist. Treatment was started 30 minutes prior to bolus injection (1 mg/kg body weight), immediately followed by a continuous infusion of 1 mg/kg body weight/hr until the end of the experiment. RESULTS Induction of SAH in the rats caused an immediate increase in ICP, which led to an acute decrease in cerebral perfusion pressure (CPP). Perfusion, as measured with LDF, was found to have decreased relative to baseline by 30 +/-20% in the control group and 20 +/-9% in the clazosentan-treated group. Intracranial pressure and CPP recovered comparably in both groups thereafter within minutes. Control animals demonstrated prolonged hypoperfusion with a loss of autoregulation independent of CPP changes, finally approaching 80% of baseline values toward the end of the experiment. The authors observed that clazosentan did not influence peracute CPP-dependent hypoperfusion, but prevented continuous CBF reduction. Laser Doppler flowmetry perfusion readings remained depressed in control animals at 73 +/-19% of baseline in comparison with 106 +/-25% of baseline in clazosentan-treated animals (p = 0.001). CONCLUSIONS The first hours after a massive experimental SAH can be characterized by a CPP-independent compromise in cerebral perfusion. Prophylactic treatment with the ET receptor antagonist clazosentan prevented hypoperfusion. It is known that in the first days after SAH, a reduction in CBF correlates clinically to high-grade SAH. Although research currently focuses on delayed vasospasm, administration of vasoactive drugs in the acute phase of SAH may reverse perfusion deficits and improve patient recovery.

Proposal for a new grading of Moyamoya disease in adult patients.

Background: Moyamoya disease (MMD) is graded based on digital subtraction angiography (DSA) with limited clinical applications. The aim was to identify clinically relevant parameters that may be used to develop a novel MMD grading system. Methods: In 40 MMD patients bilateral revascularization surgery was performed. Clinical data including DSA, MRI and regional cerebral blood flow studies were assessed. χ2 test corrected for dependency of measurements at the same subject and analysis of receiver operating characteristics were used to identify key parameters. Grading system included: DSA (stenosis/occlusion = 1 point; stenosis/occlusion + intracranial compensation = 2 points; stenosis/occlusion + intracranial compensation + extra-intracranial compensation = 3 points), MRI (no sign of ischemia = 0 points; signs of ischemia = 1 point) and cerebrovascular reserve capacity (CVRC > –5% = 0 points; CVRC < –5% = 2 points). MMD grade I referred to 1–2 points, grade II to 3–4 and grade III to 5–6 points. Results: DSA, MRI and CVRC were dependent factors associated with the occurrence of clinical symptoms. Receiver operating characteristics analysis indentified the grading system as superior to each single parameter in predicting clinical symptoms. Fourteen hemispheres were graded as mild (grade I), 35 as moderate (grade II) and 31 as severe (grade III); 21% of grade I, 63% of grade II and 93% of grade III hemispheres were clinically symptomatic. Conclusions: The proposed grading system allows to stratify for clinical symptomatology in MMD patients. Future studies will have to investigate its value for assessing clinical symptoms and treatment risks.

Hypoperfusion in the Acute Phase of Subarachnoid Hemorrhage

PURPOSE Acute disruption of cerebral perfusion and metabolism is a well-established hallmark of the immediate phase after subarachnoid hemorrhage (SAH). It is thought to contribute significantly to acute brain injury, but despite its prognostic importance, the exact mechanism and time course is largely unknown and remains to be characterized. METHODS We investigated changes in cerebral perfusion after SAH in both an experimental and clinical setting. Using an animal model of massive, experimental SAH (n=91), we employed Laser-Doppler flowmetry (LDF), parenchymal microdialysis (MD; n=61), Diffusion-weighted imaging (DWI) and MR spectroscopy (MRS; n=30) to characterize the first hours after SAH in greater detail. The effect of prophylactic treatment with hypothermia (HT; 32°C) and an endothelin-A (ET-A) receptor antagonist (Clazosentan) was also studied. In a group of patients presenting with acute SAH (n=17) we were able to determine cerebral blood flow (CBF) via Xenon-enhanced computed tomography (XeCT) within 12 h after the ictus. RESULTS The acute phase after SAH is characterized both experimentally and clinically by profound and prolonged hypoperfusion independent from current intracranial pressure (ICP), indicating acute vasospasm. Experimentally, when treated with hypothermia or a ET-A receptor antagonist prophylactically, acute hypoperfusion improved rapidly. DWI showed a generalized, significant decline of the apparent diffusion coefficient (ADC) after SAH, indicating cytotoxic edema which was not present under hypothermia. SAH causes a highly significant reduction in glucose, as well as accumulation of lactate, glutmate and aspartate (MD and MRS). HT significantly ameliorated these metabolic disturbances. CONCLUSION Acute vasospasm, cytotoxic edema and a general metabolic stress response occur immediately after experimental SAH. Prophylactic treatment with hypothermia or ET-A antagonists can correct these disturbances in the experimental setting. Clinically, prolonged and ICP-independent hypoperfusion was also confirmed. As the initial phase is of particular importance regarding the neurological outcome and is amenable to beneficial intervention, the acute stage after SAH demands further investigation and warrants the exploration of measures to improve the immediate management of SAH patients.

Perfusion Characteristics of Moyamoya Disease: An Anatomically and Clinically Oriented Analysis and Comparison

Background and Purpose— Moyamoya disease (MMD) is characterized by unique angiographic features of collateralization. However, a detailed quantification as well as comparative analysis with cerebrovascular atherosclerotic disease (CAD) and healthy controls have not been performed to date. Methods— We reviewed 67 patients with MMD undergoing Xenon-enhanced computed tomography, as well as 108 patients with CAD and 5 controls. In addition to cortical, central, and infratentorial regions of interest, particular emphasis was put on regions that are typically involved in MMD (pericallosal territory, basal ganglia). Cerebral blood flow (CBF), cerebrovascular reserve capacity (CVRC), and hemodynamic stress distribution were calculated. Results— MMD is characterized by a significant, ubiquitous decrease in CVRC and a cortical but not pericallosal decrease in CBF when compared with controls. Baseline perfusion is maintained within the basal ganglia, and hemodynamic stress distribution confirmed a relative preservation of central regions of interest in MMD, indicative for its characteristic proximal collateralization pattern. In MMD and CAD, cortical and central CBF decreased significantly with age, whereas CVRC and hemodynamic stress distribution are relatively unaffected by age. No difference in CVRC of comparable regions of interest was seen between MMD and CAD, but stress distribution was significantly higher in MMD, illustrating the functionality of the characteristic rete mirabilis. Conclusions— Our data provide quantitative support for a territory-specific perfusion pattern that is unique for MMD, including central preservation of CBF compared with controls and patients with CAD. This correlates well with its characteristic feature of proximal collateralization. CVRC and hemodynamic stress distribution seem to be more robust parameters than CBF alone for assessment of disease severity.