Kai U. Frerichs

Local Cerebral Blood Flow during Hibernation, a Model of Natural Tolerance to “Cerebral Ischemia”

The breakdown of cellular homeostasis and progressive neuronal destruction in cerebral ischemia appears to be mediated by a complex network of causes that are intricately interrelated. We have investigated a physiological state existing normally in nature in which mammals appear to tolerate the ordinarily detrimental effects of ischemia with reduced oxygen availability and to resist activation of self-destructive processes, i.e., mammalian hibernation. Ground squirrels (Spermophilus tridecemlineatus) were chronically implanted with arterial and venous catheters and telemetry devices for electroencephalography, electrocardiography, and monitoring of body temperature. The animals were placed in an environmental chamber at an ambient temperature of 5°C. Entrance into hibernation was characterized by a drop in heart rate followed by a gradual decline in body temperature and an isoelectric electroencephalogram. Cold-adapted active animals that were not hibernating served as controls. Cerebral blood flow (CBF) was measured in both groups with the autoradiographic [14C]iodoantipyrine method. Mean (±SD) mass-weighted CBF in the brain as a whole was 62 ± 16 ml/100 g/min (n = 4) in the control group but was reduced to ischemic levels, 7 ± 4 ml/100 g/min (n = 4), in the hibernating animals (p < 0.001). No neuropathological changes were found in similarly hibernating animals aroused from hibernation. Hibernation appears to be actively regulated, and hormonal factors may be involved. The identification and characterization of such factors and of the mechanisms used by hibernating species to increase ischemic tolerance and to blunt the destructive effects of ischemia may enable us to prevent or minimize the loss of homeostatic control during and after cerebral ischemia in other species.

Hibernation in Ground Squirrels Induces State and Species-Specific Tolerance to Hypoxia and Aglycemia: An In Vitro Study in Hippocampal Slices

Hibernation in mammals is associated with a regulated depression of global cellular functions accompanied by reductions of cerebral blood flow that would render the brain profoundly ischemic under normal conditions. Homeostatic control is preserved, however, and brain damage does not occur. We investigated the possibility that hibernation not only confers tolerance to profound hypothermia, but also to hypoxia and aglycemia independent of temperature. Hippocampal slices from ground squirrels Citellus tridecemlineatus in both the active and hibernating states and from rats were subjected to in vitro hypoxia and aglycemia at incubation temperatures of 36°C, 20°C, and 7°C and evaluated histologically. A binary bioassay was used to determine the duration of hypoxia/aglycemia tolerated in each group. At all temperatures, slices from hibernating animals were most tolerant compared with both active squirrels and rats. Slices from active ground squirrels were more tolerant than rat at 20°C and 7°C but not at 36°C indicating a species-specific difference that becomes manifest at lower temperatures. These results indicate that hibernation is associated not only with tolerance to profound hypothermia but also to deprivation of oxygen and glucose. Because tolerance was already demonstrable at the shortest duration of hibernation studied, rapid therapeutic induction of a similar state may be possible. Therefore, identification of the regulatory mechanisms underlying this tolerance may lead to novel neuroprotective strategies.

Evidence for platelet-activating factor as a novel mediator in experimental stroke in rabbits

Platelet-activating factor is a potent mediator of inflammation, which has untoward effects on cerebrovascular and neural elements. While several investigators have reported attenuation of ischemic damage after treatment with antagonists of platelet-activating factor, no study has proved endogenous production of platelet-activating factor in ischemia of the central nervous system. We hypothesized that endogenous production of platelet-activating factor participates in the early pathologic manifestations of deteriorating stroke. In 12 rabbits, we found tissue levels of platelet-activating factor measured by the release of serotonin from washed platelets to be elevated by approximately 20-fold in spinal cord injured by 25 minutes of ischemia and 2 hours of reperfusion (2.80 +/- 0.98 ng/g) compared with that in normal spinal cord (0.15 +/- 0.06 ng/g, p less than 0.01). Given during ischemia to seven rabbits, 10 mg/kg i.p. of a highly selective and potent antagonist of platelet-activating factor (BN 50739) accentuated the early postischemic hyperemia and prevented the delayed hypoperfusion measured by on-line laser-Doppler flowmetry (-35 +/- 7% of baseline [n = 7] without versus 33 +/- 14% with treatment, p less than 0.01) and the edema formation measured as the increase in tissue water content (4.4 +/- 0.7% without [n = 6] versus 2.1 +/- 0.6% with [n = 7]treatment, p less than 0.05) after 2 hours of reperfusion. This neurochemical and pharmacologic evidence emphasizes a new perspective of ischemia-induced phospholipid degradation and suggests an important role for platelet-activating factor in the early manifestations of stroke.

Cerebral sinus and venous thrombosis in rats induces long-term deficits in brain function and morphology. Evidence for a cytotoxic genesis

The pathophysiology of cerebral venous infarctions is poorly understood, due partially to the lack of a suitable experimental model. Therefore, we developed a model in rats to study acute and long-term changes of brain function and morphology following thrombosis of the superior sagittal sinus. The superior sagittal sinus of rats was exposed, ligated, and injected with thrombogenic material. Thrombosis of the longitudinal sinus and ascending cortical veins was monitored by intravital fluorescence angiography. Histology was studied at 24 h and 4 weeks after thrombosis and changes in intracranial pressure, electroencephalogram (EEG), and tissue impedance were noted. Spontaneous locomotor activity was followed for 4 weeks after thrombosis. The effect of heparin treatment on tissue impedance was evaluated. Thrombosis of the superior sagittal sinus could be regularly induced, although pathological sequelae developed only if ascending veins were affected. Sinus and venous thrombosis was histologically characterized by bilateral, parasagittal infarctions. Thrombosis induction was followed by an increase in intracranial pressure from 4.7 ± 1.6 to 12.8 ± 2.4 mm Hg (n = 4) at 1 h after thrombosis, associated with an exponential rise in tissue impedance to 165 ± 14% (n = 8) of the control. EEG changes were similar to those following global cerebral ischemia and remained pathological for up to 6 months after thrombosis (n = 6). As a permanent behavioral deficit spontaneous locomotor activity was reduced to 60 ± 10% (n = 6) of the control. Finally, the administration of heparin (1 IU/g body weight) after thrombosis induction was found to reverse the pathological tissue impedance response of the brain. In conclusion, involvement of ascending cortical veins following sinus thrombosis appears to be critical for the development of irreversible tissue damage, such as infarction. Changes in intracranial pressure and tissue impedance suggest that the venous thrombosis was followed by brain edema of a predominantly cytotoxic nature. Venous thrombosis led to long-term changes of brain function, as demonstrated by persistent disturbances of the EEG or of the spontaneous locomotor drive. These deficits may be amenable to treatment with heparin.

Treatment of ruptured and unruptured cerebral aneurysms in the USA: a paradigm shift

Background Integration of data from clinical trials and advancements in technology predict a change in selection for treatment of patients with cerebral aneurysm. Objective To describe patterns of use and in-hospital mortality associated with surgical and endovascular treatments of cerebral aneurysms over the past decade. Materials and methods The data are 34 899 hospital discharges with a diagnosis of ruptured or unruptured cerebral aneurysm from 1998 to 2007 identified from the Nationwide Inpatient Sample (NIS). The rates of endovascular coiling and surgical clipping and in-hospital mortality among patients with an aneurysm are examined over a decade by hospital and patient demographic characteristics. Results From 1998 to 2007, 20 134 discharges with a ruptured aneurysm and 14 765 discharges with an unruptured aneurysm were identified. Over this decade, the number of patients discharged with a ruptured aneurysm was stable while the number discharged with an unruptured aneurysm increased significantly. The use of endovascular coiling increased at least twofold for both groups of patient (p<0.001) with the majority of unruptured aneurysms treated with coiling by 2007. Although whites were more likely than non-whites to undergo coiling versus clipping for a ruptured aneurysm (OR=1.30; 95% CI 1.13 to 1.48) and men with unruptured aneurysms were more likely than women to undergo coiling (OR=1.26; 95% CI 1.13 to 1.40), by 2007 differences in treatment selection by gender and racial subgroups were decreased or statistically non-significant. Over time the use of coiling spread from primarily large, teaching hospitals to smaller, non-teaching hospitals. Conclusions The majority of unruptured aneurysms in the USA are now treated with endovascular coiling. Although surgical clipping is used for treatment of most ruptured aneurysms, its use is decreasing over time. Dissemination of endovascular procedures appears widespread across patient and hospital subgroups.

The Safety of Dedicated-Team Catheter-Based Diagnostic Cerebral Angiography in the Era of Advanced Noninvasive Imaging

BACKGROUND AND PURPOSE: Given the current high quality and usefulness of noninvasive cerebrovascular imaging, invasive angiographic evaluation of the cerebrovascular system is justified if the procedural risk for a neurologic complication is far below the anticipated benefit. The purpose of this study was to evaluate the safety of diagnostic cerebral angiography provided by a dedicated neurointerventional team in a high-volume university hospital. MATERIALS AND METHODS: A consecutive cohort of 1715 patients undergoing diagnostic cerebral angiography at our institution from 2000 to 2008 was retrospectively assessed for incidence of stroke or TIA related to cerebral angiography. In the subgroup of patients (n = 40) who serendipitously underwent DWI within the first 30 days after cerebral angiography, the presence of new DWI hyperintensities found in territories explored during angiography was tabulated. Complications related to the catheter technique and sheath placement were also studied. RESULTS: No stroke or permanent neurologic deficit was seen in any of the 1715 patients undergoing diagnostic neuroangiography. One patient experienced a TIA. Nonneurologic complications without long-term sequelae occurred in 9 patients. Two patients had punctate areas of restricted diffusion in territories that had been angiographically explored. CONCLUSIONS: Within a high-volume neurointerventional practice, the risk for neurologic complications related to catheter-based diagnostic cerebral angiography can approach zero. As the absolute number of invasive diagnostic procedures diminishes with time, diagnostic cerebral angiography remains a useful tool while providing a foundation for neuroendovascular interventions, and should preferably be performed in institutions with high-volume operators also capable of managing unanticipated complicating adverse events.

Ascorbate and glutathione regulation in hibernating ground squirrels

Ground squirrels withstand up to 90% reductions in cerebral blood flow during hibernation as well as rapid reperfusion upon periodic arousals from torpor. Metabolic suppression likely plays a primary adaptive role which allows hibernating species to tolerate such phenomena. However, several other aspects of hibernation physiology are also consistent with tolerance to dramatic fluctuations in cerebral blood flow, suggesting that multiple neuroprotective adaptations may work in concert during hibernation. The purpose of the present work was to study the dynamics of the low molecular weight antioxidants, ascorbate and glutathione (GSH), during hibernation. Alterations in concentrations of ascorbate during hibernation and arousal in two species of hibernating ground squirrels suggest that it could play a protective role during hibernation or arousal. Samples were collected during the hibernation season from arctic ground squirrels (AGS; Spermophilus parryii) and 13-lined ground squirrels (TLS; S. tridecemlineatus) during prolonged torpor and in squirrels that did not hibernate or had not been hibernating for several weeks. We determined antioxidant levels in plasma, cerebrospinal fluid (CSF), and in frontal cortex, hippocampus and cerebellum using high-performance liquid chromatography (HPLC). Plasma ascorbate concentrations increased dramatically (3-4-fold) in both species during hibernation and rapidly returned to prehibernation levels upon arousal. By contrast, plasma GSH concentrations fell slightly or remained stable during hibernation. Ascorbate levels in the CSF doubled in hibernating AGS (not determined in TLS), while brain ascorbate content fell slightly (10-15%) in both species. Substantial increases in plasma and CSF ascorbate concentrations suggest that this antioxidant could play a protective role during hibernation and reperfusion upon arousal from hibernation.

Differences in simple morphological variables in ruptured and unruptured middle cerebral artery aneurysms

OBJECT Management of unruptured intracranial aneurysms remains controversial in neurosurgery. The contribution of morphological parameters has not been included in the treatment paradigm in a systematic manner or for any particular aneurysm location. The authors present a large sample of middle cerebral artery (MCA) aneurysms that were assessed using morphological variables to determine the parameters associated with aneurysm rupture. METHODS Preoperative CT angiography (CTA) studies were evaluated using Slicer software to generate 3D models of the aneurysms and their surrounding vascular architecture. Morphological parameters examined in each model included 5 variables already defined in the literature (aneurysm size, aspect ratio, aneurysm angle, vessel angle, and size ratio) and 3 novel variables (flow angle, distance to the genu, and parent-daughter angle). Univariate and multivariate statistical analyses were performed to determine statistical significance. RESULTS Between 2005 and 2008, 132 MCA aneurysms were treated at a single institution, and CTA studies of 79 aneurysms (40 ruptured and 39 unruptured) were analyzed. Fifty-three aneurysms were excluded because of reoperation (4), associated AVM (2), or lack of preoperative CTA studies (47). Ruptured aneurysms were associated with larger size, greater aspect ratio, larger aneurysm and flow angles, and smaller parent-daughter angle. Multivariate logistic regression revealed that aspect ratio, flow angle, and parent-daughter angle were the strongest factors associated with ruptured aneurysms. CONCLUSIONS Aspect ratio, flow angle, and parent-daughter angle are more strongly associated with ruptured MCA aneurysms than size. The association of parameters independent of aneurysm morphology with ruptured aneurysms suggests that these parameters may be associated with an increased risk of aneurysm rupture. These factors are readily applied in clinical practice and should be considered in addition to aneurysm size when assessing the risk of aneurysm rupture specific to the MCA location.

Stent usage in the treatment of intracranial aneurysms: past, present and future

As endovascular approaches to intracranial aneurysm (IA) treatment continue to evolve, the use of intracranial stents has advanced from an infrequent adjunct to potential curative monotherapy. Early results of endovascular therapy for IAs have clearly underscored large aneurysm size, low coil packing density and wide aneurysm neck as factors limiting successful long term obliteration. Intracranial stents were originally introduced as adjuncts to mitigate these limitations by facilitating tighter coil packing and preventing coil herniation. As evidence of their utility as flow diversion devices and as catalysts for aneurysm neck remodeling surfaced, their potential as standalone therapy was realised and is currently under close scrutiny. Here we review the evolution of stents in the treatment of IAs, from balloon expandable stents, to self-expanding stents, to the exciting advances in monotherapeutic flow diverting stents, amalgamating occlusion rates and reviewing complication rates.

Aspirin and Aneurysmal Subarachnoid Hemorrhage

OBJECTIVE Recent evidence has suggested a potential beneficial effect of aspirin on the risk of aneurysm rupture. This benefit must be weighed against its potential adverse effects as an antiplatelet agent in the setting of acute aneurysmal subarachnoid hemorrhage (SAH). METHODS A total of 747 consecutive patients with cerebral aneurysms were reviewed, comparing demographics, aneurysm features, presenting clinical and radiographic grades, vasospasm, and outcome at 1 year between patients with aneurysmal SAH taking aspirin on presentation and those who were not. RESULTS The rate of hemorrhagic presentation was significantly greater in patients not taking aspirin (40% vs. 28%; P = 0.016). Among 274 patients presenting with aneurysmal SAH, there was no significant difference in presenting clinical (Hunt and Hess) and radiographic (Fisher) grade between patients taking aspirin and those who were not. There was also no significant difference in the rate of subsequent angiographic and delayed cerebral ischemia. Multivariate analysis of outcome at 1 year found only increasing age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.12), Hunt and Hess grade (OR 3.01, 95% CI 1.81-5.03), and associated hypertension (OR 3.30, 95% CI 1.39-7.81) to be statistically significant risk factors for poor outcome (death or dependence), whereas aspirin use was not associated with poor outcome (OR 1.19, 95% CI 0.35-4.09; P = 0.78). CONCLUSIONS In the present study, patients taking aspirin had a lower rate of hemorrhagic presentation. In addition, taking aspirin did not adversely impact presenting clinical grade or radiographic grade, vasospasm, and outcome in the setting of aneurysmal SAH.