Gregory J. Zipfel

The changing landscape of ischaemic brain injury mechanisms.

Thrombolysis has become established as an acute treatment for human stroke. But despite multiple clinical trials, neuroprotective strategies have yet to be proved effective in humans. Here we discuss intrinsic tissue mechanisms of ischaemic brain injury, and present a perspective that broadening of therapeutic targeting beyond excitotoxicity and neuronal calcium overload will be desirable for developing the most effective neuroprotective therapies.

Critical Care Management of Patients Following Aneurysmal Subarachnoid Hemorrhage: Recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference

Subarachnoid hemorrhage (SAH) is an acute cerebrovascular event which can have devastating effects on the central nervous system as well as a profound impact on several other organs. SAH patients are routinely admitted to an intensive care unit and are cared for by a multidisciplinary team. A lack of high quality data has led to numerous approaches to management and limited guidance on choosing among them. Existing guidelines emphasize risk factors, prevention, natural history, and prevention of rebleeding, but provide limited discussion of the complex critical care issues involved in the care of SAH patients. The Neurocritical Care Society organized an international, multidisciplinary consensus conference on the critical care management of SAH to address this need. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. A jury of four experienced neurointensivists was selected for their experience in clinical investigations and development of practice guidelines. Recommendations were developed based on literature review using the GRADE system, discussion integrating the literature with the collective experience of the participants and critical review by an impartial jury. Recommendations were developed using the GRADE system. Emphasis was placed on the principle that recommendations should be based not only on the quality of the data but also tradeoffs and translation into practice. Strong consideration was given to providing guidance and recommendations for all issues faced in the daily management of SAH patients, even in the absence of high quality data.

Brain tissue responses to ischemia

The brain is particularly vulnerable to ischemia. Complete interruption of blood flow to the brain for only 5 minutes triggers the death of vulnerable neurons in several brain regions, whereas 20–40 minutes of ischemia is required to kill cardiac myocytes or kidney cells. In part, the prominent vulnerability of brain tissue to ischemic damage reflects its high metabolic rate. Although the human brain represents only about 2.5% of body weight, it accounts for 25% of basal metabolism, a metabolic rate 3.5 times higher even than that of the brains of other primate species. In addition, central neurons have a near-exclusive dependence on glucose as an energy substrate, and brain stores of glucose or glycogen are limited. However, over the last 15 years, evidence has emerged indicating that energetics considerations and energy substrate limitations are not solely responsible for the brain’s heightened vulnerability to ischemia. Rather, it appears that the brain’s intrinsic cell-cell and intracellular signaling mechanisms, normally responsible for information processing, become harmful under ischemic conditions, hastening energy failure and enhancing the final pathways underlying ischemic cell death in all tissues, including free radical production, activation of catabolic enzymes, membrane failure, apoptosis, and inflammation. Since these common pathways are explored in other accompanying JCI Perspectives, we will emphasize the role of injury-enhancing signaling mechanisms specific to the central nervous system (CNS) and discuss potential therapeutic approaches to interrupting these mechanisms. Refinement of glutamate receptor antagonist approaches. A major limitation in past clinical trials of glutamate receptor antagonists has been dose ceilings imposed by drug side effects. Not unexpectedly, interfering with the brain’s major excitatory transmitter system can lead to alterations in motor or cognitive function (prominent with NMDA antagonists), or sedation (prominent with AMPA antagonists). It seems plausible that the therapeutic index of NMDA antagonist therapy might be improved by the utilization of subtype-selective agents, such as ifenprodil, an antagonist selective for the NR2B subtype of NMDA receptors. NR2B receptors are preferentially expressed in forebrain relative to hindbrain, so blocking these receptors may produce greater neuroprotection in forebrain with less interference with motor function than subtype-unselective NMDA antagonists. In addition, ifenprodil inhibition of NR2B receptors increases with increasing agonist stimulation, a “use dependency” that might increase drug effect at overactivated synapses relative to normal synapses (46). The neuroprotective efficacy of NMDA antagonist therapy might also be enhanced by combination with AMPA or kainate receptor antagonists, both to increase overall antiexcitotoxic efficacy on ischemic neurons, as well as specifically to extend protection to GABAergic neurons expressing Ca2+-permeable AMPA receptors, and oligodendrocytes. Indeed, failure to rescue GABAergic neurons while successfully rescuing nearby excitatory neurons might lead to an increase in local circuit excitation and seizure activity in stroke survivors. High-level pan-blockade of both NMDA and AMPA receptors could have problematic side effects, for example, respiratory depression, but these difficulties might be surmountable through the use of subtype-selective drugs. An alternative approach to blocking NMDA and AMPA receptors concurrently might be to reduce glutamate release, for example, through hypothermia or reduction of circuit excitability with GABA agonists or blockers of voltage-gated Na+ channels. Zinc-directed therapies. While current putative antiexcitotoxic therapies have focused on glutamate receptor activation and resultant Ca2+ overload, the pathological role of neuronal Zn2+ overload suggests additional targets for therapeutic intervention. Indeed, variable reduction of toxic Zn2+ influx may underlie some of the inconsistent beneficial effects of voltage-gated Ca2+-channel antagonists observed in animal models of transient global ischemia (47). Further delineation of the precise routes responsible for toxic Zn2+ may permit greater reduction in this toxic Zn2+ overload. Another possible approach would be to reduce Zn2+ release from nerve terminals. In settings where ischemia is anticipated, it may even prove possible to accomplish this via acute dietary zinc reduction, as anecdotal evidence in humans has suggested that such reduction profoundly disturbs brain function, likely due to reduction of transmitter Zn2+ release (48). Further off, one can envision strategies for modifying neuronal Zn2+ transporters to improve the extrusion or sequestration of intracellular Zn2+, or for upregulating intracellular Zn2+-binding proteins such as metallothioneins. Combination therapies. Recent implication of apoptosis in the pathogenesis of ischemic neuronal death raises an unsettling possibility that current efforts to block NMDA receptor-mediated Ca2+ influx may go too far, achieving the desired reduction of toxic calcium overload and excitotoxicity in some neurons, but then promoting apoptosis in other neurons through Ca2+ starvation (4). It is plausible that different neurons might sustain different levels of [Ca2+]i at different times, with neurons further from the ischemic core or at later time points after ischemia onset sustaining less calcium influx than counterparts in the acute ischemic core. These neurons may be damaged badly enough to trigger apoptosis, but their [Ca2+]i levels may fall below the “set point” optimal for promoting survival (49), such that broad and sustained NMDA receptor blockade promotes apoptosis, reducing the benefits to be had by attenuating calcium overload in other neurons. If this scenario proves valid, it may be possible to enhance the benefits and reduce the dangers of NMDA antagonists by concurrently administering antiapoptotic treatments. Dual inhibition of excitotoxic necrosis and ischemic apoptosis has shown promise in two experimental studies to date. Coadministration of the NMDA antagonist dextrophan with cycloheximide produced greater than 80% reduction in infarct volume following transient focal ischemia in rats, better than either agent alone (50); and Ma et al. (51) observed neuroprotective synergy between MK-801 and the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.FMK) on both infarct size and therapeutic window. The combination of antiexcitotoxic strategies with thrombolysis has also been shown to provide additive protection in a rodent model of embolic stroke (52). On theoretical grounds, antioxidant drugs might be especially valuable in reducing reperfusion-induced injury, for example in association with thrombolytic therapy, or the deleterious component of certain growth factor actions.

Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain

The amyloid-β peptide (Aβ) plays a central pathophysiological role in Alzheimers disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentration.

Clinical Features and Outcome in North American Adults With Moyamoya Phenomenon

Background and Purpose— To describe baseline clinical features and outcomes of adults with moyamoya phenomenon treated at a single North American institution. Methods— We identified 34 adults with moyamoya phenomenon by review of angiographic records. Clinical presentation and baseline stroke risk factors were obtained by chart review. Follow-up was obtained prospectively. A 5-year Kaplan-Meier stroke risk was calculated. Results— The median age was 42 (range 20 to 79) years. Twenty-five were women. The initial symptom was ischemia, hemorrhage, or asymptomatic in 24, 7, and 3 patients, respectively. Twenty-two had bilateral involvement and 12 had unilateral moyamoya vessels. Baseline stroke risk factors were similar between groups. The median follow-up in 31 living patients was 5.1 (range 0.2 to 19.6) years. Fourteen patients were treated with surgical revascularization (20 total hemispheres). In medically treated symptomatic hemispheres, the 5-year risk of recurrent ipsilateral stroke was 65% after the initial symptom and 27% after angiographic diagnosis. Patients with bilateral involvement presenting with ischemic symptoms were at the highest risk of subsequent stroke (n=17, 5-year risk of stroke with medical treatment after first symptom of 82%). In surgically treated hemispheres, the 5-year risk of perioperative or subsequent ipsilateral stroke or death was 17%. This was significantly different compared with medical treatment after first symptom (P=0.02) but not after angiographic diagnosis. Conclusion— Moyamoya phenomenon in North American adults is associated with a high risk of recurrent stroke, particularly those with bilateral involvement and ischemic symptoms. These data suggest a potential benefit with surgery if diagnosis could be made earlier.

Vascular contributions to cognitive impairment and dementia including Alzheimer's disease

Scientific evidence continues to demonstrate the linkage of vascular contributions to cognitive impairment and dementia such as Alzheimers disease. In December, 2013, the Alzheimers Association, with scientific input from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute from the National Institutes of Health, convened scientific experts to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimers disease and related dementia. This manuscript summarizes the meeting and the resultant discussion, including an outline of next steps needed to move this area of research forward.

Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo.

Background and Purpose— In light of recent evidence suggesting that an upregulation of K+ efflux mediated by outward delayed rectifier (IK) channels promotes central neuronal apoptosis, we sought to test the possibility that blockers of IK channels might be neuroprotective against hypoxia/ischemia-induced neuronal death. Methods— Membrane currents were recorded with the use of patch clamp recordings in cultured murine cortical neurons. Protective effects of K+ channel blockers were examined in rats subjected to transient middle cerebral artery occlusion followed by 14-day reperfusion. Results— The K+ channel blocker tetraethylammonium (TEA) (5 mmol/L) selectively blocked IK without affecting N-methyl-d-aspartate receptor–mediated current or voltage-gated Ca2+ currents. Both TEA and a lipophilic K+ channel blocker, clofilium, attenuated neuronal apoptosis induced by hypoxia in vitro and infarct volume induced by ischemia in vivo. Conclusions— These data are consistent with the idea that K+ channel–mediated K+ efflux may contribute to ischemia-triggered apoptosis and suggest that preventing excessive K+ efflux through K+ channels may constitute a therapeutic approach for the treatment of stroke.

Cerebrovascular Dysfunction in Amyloid Precursor Protein Transgenic Mice : Contribution of Soluble and Insoluble Amyloid-β Peptide, Partial Restoration via γ-Secretase Inhibition

The contributing effect of cerebrovascular pathology in Alzheimers disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-β peptide (Aβ), the same peptide found in neuritic plaques of AD, may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble Aβ but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Aβ can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble Aβ on vessel function. We found that (1) vascular impairment was present in both young and older Tg2576 mice; (2) a strong correlation between CAA severity and vessel reactivity exists; (3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of Aβ improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Aβ cause cerebrovascular dysfunction, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.

CRANIAL DURAL ARTERIOVENOUS FISTULAE: ASYMPTOMATIC CORTICAL VENOUS DRAINAGE PORTENDS LESS AGGRESSIVE CLINICAL COURSE

OBJECTIVECranial dural arteriovenous fistulae (dAVF) with cortical venous drainage (CVD) (Borden Types 2 and 3) are reported to carry a 15% annual risk of intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit (NHND). The purpose of this study was to compare the clinical course of Type 2 and 3 dAVFs that present with ICH or NHND with those that do not. METHODSTwenty-eight patients with Type 2 or 3 dAVFs were retrospectively evaluated. CVD was classified as asymptomatic (aCVD) if patients presented incidentally or with pulsatile tinnitus or orbital phenomena. CVD was classified as symptomatic (sCVD) if patients presented with ICH or NHND. Occurrence of new ICH or new or worsening NHND between diagnosis and disconnection of CVD or last follow-up (if not disconnected) was noted. Overall frequency of events was compared using Fishers exact test. Cumulative, event-free survival was compared using Kaplan-Meier analysis with log-rank testing. RESULTSOf 17 patients with aCVD, 1 (5.9%) developed ICH and none experienced NHND or death during the median 31.4-month follow-up period. Of 11 patients with sCVD, 2 (18.2%) developed ICH and 3 (27.3%) experienced new or worsened NHND over the median 9.7-month follow-up period. One of these patients subsequently died. Overall frequency of ICH or NHND was significantly lower in patients with aCVD versus sCVD (P = 0.022). Respective annual event rates were 1.4 versus 19.0%. aCVD patients had significantly higher cumulative event-free survival (P = 0.0016). CONCLUSIONCranial dAVFs with aCVD may have a less aggressive clinical course than those with sCVD.

Cranial dural arteriovenous fistulas: modification of angiographic classification scales based on new natural history data

This article presents a modification to the existing classification scales of intracranial dural arteriovenous fistulas based on newly published research regarding the relationship of clinical symptoms and outcome. The 2 commonly used scales, the Borden-Shucart and Cognard scales, rely entirely on angiographic features for categorization. The most critical anatomical feature is the identification of cortical venous drainage (CVD; Borden-Shucart Types II and III and Cognard Types IIb, IIa + b, III, IV, and V), as this feature identifies lesions at high risk for future hemorrhage or ischemic neurological injury. Yet recent data has emerged indicating that within these high-risk groups, most of the risk for future injury is in the subgroup presenting with intracerebral hemorrhage or nonhemorrhagic neurological deficits. The authors have defined this subgroup as symptomatic CVD. Patients who present incidentally or with symptoms of pulsatile tinnitus or ophthalmological phenomena have a less aggressive clinical course. The authors have defined this subgroup as asymptomatic CVD. Based on recent data the annual rate of intracerebral hemorrhage is 7.4-7.6% for patients with symptomatic CVD compared with 1.4-1.5% for those with asymptomatic CVD. The addition of asymptomatic CVD or symptomatic CVD as modifiers to the Borden-Shucart and Cognard systems improves their accuracy for risk stratification of patients with high-grade dural arteriovenous fistulas.