[show abstract][hide abstract] ABSTRACT: Neuronal vulnerability to ischemia is dependent on the balance between prosurvival and prodeath cellular signaling. In the latter, it is increasingly appreciated that toxic Ca(2+) influx can occur not only via postsynaptic glutamate receptors, but also through other cation conductances. One such conductance, the Transient receptor potential melastatin type-2 (TRPM2) channel, is a nonspecific cation channel having homology to TRPM7, a conductance reported to play a key role in anoxic neuronal death. The role of TRPM2 conductances in ischemic Ca(2+) influx has been difficult to study because of the lack of specific modulators. Here we used TRPM2-null mice (TRPM2(-/-)) to study how TRPM2 may modulate neuronal vulnerability to ischemia. TRPM2(-/-) mice subjected to transient middle cerebral artery occlusion exhibited smaller infarcts when compared with wild-type animals, suggesting that the absence of TRPM2 is neuroprotective. Surprisingly, field potentials (fEPSPs) recorded during redox modulation in brain slices taken from TRPM2(-/-) mice revealed increased excitability, a phenomenon normally associated with ischemic vulnerability, whereas wild-type fEPSPs were unaffected. The upregulation in fEPSP in TRPM2(-/-) neurons was blocked selectively by a GluN2A antagonist. This increase in excitability of TRPM2(-/-) fEPSPs during redox modulation depended on the upregulation and downregulation of GluN2A- and GluN2B-containing NMDARs, respectively, and on augmented prosurvival signaling via Akt and ERK pathways culminating in the inhibition of the proapoptotic factor GSK3β. Our results suggest that TRPM2 plays a role in downregulating prosurvival signals in central neurons and that TRPM2 channels may comprise a therapeutic target for preventing ischemic damage.
Journal of Neuroscience 10/2013; 33(44):17264-77. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: The allocation of limited healthcare resources poses a constant challenge for clinicians. One everyday example is the prioritization of elective neurosurgical operating room (OR) time in circumstances where cancellations may be encountered. The bioethical framework, Accountability for Reasonableness (A4R) may inform such decisions by establishing conditions that should be met for ethically-justifiable priority setting. Objective: Here, we describe our experience in implementing A4R to guide decisions regarding elective OR prioritization. Methods: The four primary expectations of the A4R process are: (1) relevance, namely achieved by support for the process and criteria for decisions amongst all stakeholders; (2) publicity, satisfied by the effective communication of the results of the deliberation; (3) challengeability through a fair appeals process; and (4) Oversight of the process to ensure that opportunities for its improvement are available. Results: A4R may be applied to inform OR time prioritization, with benefits to patients, surgeons and the institution itself. We discuss various case-, patient-, and surgeon-related factors that may be incorporated into the decision-making process. Furthermore, we explore challenges encountered in the implementation of this process, including the need for timely neurosurgical decision-making and the presence of hospital-based power imbalances. Conclusion: The authors recommend the implementation of a fair, deliberative process to inform priority setting in neurosurgery, as demonstrated by the application of the A4R framework to allocate limited OR time.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 05/2013; 40(3):378-83. · 1.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS: For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS: Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION: Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING: NoNO Inc and Arbor Vita Corp.
The Lancet Neurology 10/2012; 11(11):942-950. · 23.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Over decades, all attempts to translate acute stroke neuroprotectants from discovery in lower-order species to human clinical use have failed. This raised concerns about the predictive validity of preclinical studies in animals for outcomes in human stroke trials. To bridge this translational gap, we used high-order gyrencephalic nonhuman primates subjected to an experimental protocol that mimicked that of a corresponding, separately reported, clinical trial in which the human subjects underwent endovascular cerebral aneurysm repair. Both placebo-controlled studies tested neuroprotection by Tat-NR2B9c, a prospective therapeutic compound, in anesthetized subjects. Embolic strokes were produced by small intra-arterial emboli caused by the endovascular procedure. We show that primates treated with Tat-NR2B9c after the onset of embolic strokes exhibited significantly reduced numbers and volumes of strokes, as visualized by diffusion- and T2-weighted magnetic resonance imaging. These results correctly anticipated the outcome of the corresponding human trial, thus validating this study design as a predictor of neuroprotective efficacy in humans. This strategy may facilitate the evaluation of promising neuroprotectants before undertaking similar studies in human subjects.
Science translational medicine 10/2012; 4(154):154ra133. · 10.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: : Complex intracranial aneurysms and tumors may require high flow cerebral bypasses for safe treatment. All previous studies on such high flow bypasses have been retrospective single institution case series with complication rates and outcomes that may be inherently biased. Here we present results from the first prospective, multicenter international trial on high flow bypasses using the Excimer Laser Assisted Nonocclusive Anastomosis (ELANA) system.
: A total of 8 centers in the US, Canada, and Europe participated in an FDA-IDE trial. All patients required flow replacement or protective bypass for safe treatment of giant/complex aneurysms or tumors; and additionally in Europe, for flow augmentation for bilateral carotid occlusion.
: A total of 46 patients were enrolled, with a mean age of 54.2 (R: 17-76 yrs); 15 males, and 31 females. A subgroup of 35 patients who received a permanent ELANA bypass for anterior circulation aneurysms were analyzed. Bypass patency was 94% immediately postoperatively, and 85% at 7 days. 14% of patients suffered a stroke with neurologic deficits at 30 days post op. Mortality was 6%, with 86% of patients having a modified Rankin score of 2 or better. ELANA related complication rate was 6%.
: The ELANA bypass system can consistently create a saphenous vein EC-IC bypass with no occlusion time, minimizing the risk of ischemia and the need for intraoperative neuro-protective medications. These grafts appear to have an acceptable patency rate in the early postoperative period and can safely be performed in patients with complex intracranial lesions of the anterior cerebral circulation.
[show abstract][hide abstract] ABSTRACT: Despite the discovery of several promising neuroprotective therapies in rodent models of stroke, no therapy other than the fibrinolytics has been found to be effective in human clinical trials. To address potential discrepancies between rodent and human studies, the Stroke Therapy Academic Industry Roundtable (STAIR) committee suggested that nonhuman primates (NHPs) be used for preclinical, translational stroke studies. Due to the paucity of stroke studies in NHPs, few experimental models have been described. Critical factors in designing NHP stroke models include the choice of species, the method of inducing the stroke and the choice of outcome measures. In this review, we describe established NHP models of stroke and discuss factors that may influence model development with a focus on models that may be useful in preclinical studies for neuroprotective drug screening prior to clinical trials.
Journal of the American Society for Experimental NeuroTherapeutics 03/2012; 9(2):371-9. · 5.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: All attempts at treating strokes by pharmacologically reducing the human brain's vulnerability to ischaemia have failed, leaving stroke as a leading cause of death, disability and massive socioeconomic loss worldwide. Over decades, research has failed to translate over 1,000 experimental treatments from discovery in cells and rodents to use in humans, a scientific crisis that gave rise to the prevailing belief that pharmacological neuroprotection is not feasible or practicable in higher-order brains. To provide a strategy for advancing stroke therapy, we used higher-order gyrencephalic non-human primates, which bear genetic, anatomical and behavioural similarities to humans and tested neuroprotection by PSD-95 inhibitors--promising compounds that uncouple postsynaptic density protein PSD-95 from neurotoxic signalling pathways. Here we show that stroke damage can be prevented in non-human primates in which a PSD-95 inhibitor is administered after stroke onset in clinically relevant situations. This treatment reduced infarct volumes as gauged by magnetic resonance imaging and histology, preserved the capacity of ischaemic cells to maintain gene transcription in genome-wide screens of ischaemic brain tissue, and significantly preserved neurological function in neurobehavioural assays. The degree of tissue neuroprotection by magnetic resonance imaging corresponded strongly to the preservation of neurological function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Our findings establish that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic non-human primates treated with PSD-95 inhibitors. Efforts must ensue to translate these findings to humans.
[show abstract][hide abstract] ABSTRACT: Transient receptor potential melastatin 2 (TRPM2) is a calcium permeable non-selective cation channel that functions as a sensor of cellular redox status. Highly expressed within the CNS, we have previously demonstrated the functional expression of these channels in CA1 pyramidal neurons of the hippocampus. Although implicated in oxidative stress-induced neuronal cell death, and potentially in neurodegenerative disease, the physiological role of TRPM2 in the central nervous system is unknown. Interestingly, we have shown that the activation of these channels may be sensitized by co-incident NMDA receptor activation, suggesting a potential contribution of TRPM2 to synaptic transmission. Using hippocampal cultures and slices from TRPM2 null mice we demonstrate that the loss of these channels selectively impairs NMDAR-dependent long-term depression (LTD) while sparing long-term potentiation. Impaired LTD resulted from an inhibition of GSK-3β, through increased phosphorylation, and a reduction in the expression of PSD95 and AMPARs. Notably, LTD could be rescued in TRPM2 null mice by recruitment of GSK-3β signaling following dopamine D2 receptor stimulation. We propose that TRPM2 channels play a key role in hippocampal synaptic plasticity.
[show abstract][hide abstract] ABSTRACT: With increasing application of endovascular therapies worldwide, the management of procedure-related complications has become increasingly important. Of particular interest is the surgical management of complications refractory to endovascular recanalization. Here, we present the unique surgical management of an inadvertent intracranial glue embolus following urgent glue embolization of a maxillofacial arteriovenous malformation. This is the first report to document management of this complication. An arteriotomy was performed and the glue, despite being adhered to the vessel intima, was retrieved in its entirety from the middle cerebral artery (MCA). Following the procedure, the patient developed a new thrombus at the previous glue site, likely related to endothelial injury. With post-operative heparin therapy, the patient recovered to baseline neurological state. This report demonstrates that microsurgical arteriotomy and glue embolectomy of the MCA is feasible, safe and may be useful in the management of complications of inadvertent intracranial glue embolization.
Journal of Clinical Neuroscience 12/2011; 18(12):1733-6. · 1.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: An aneurysm is a focal dilatation of an arterial blood vessel. Luminal forces, such as high blood flow, shear stress and turbulence, are implicated in the pathogenesis of intracranial aneurysms, and luminal characteristics, such as sac size and morphology, are usually essential to the clinical decision-making process. Despite frequent clinical emphasis on the vessel lumen, however, the pathology underlying the formation, growth and rupture of an aneurysm mainly resides in the vessel wall. Research on the morphology and histopathology of the vessel wall reveals that intracranial aneurysms do not constitute a single disease, but are a shared manifestation of a wide range of diseases, each of which has a unique natural history and optimum therapy. This Review classifies intracranial aneurysms by vessel wall pathology, and demonstrates that understanding the morphology and pathology of this structure is important in determining the therapeutic approach. The article concludes that aneurysms represent a symptom of an underlying vascular disease rather than constituting a disease on their own.
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to determine whether neuroprotection is feasible without cerebral blood flow augmentation in experimental permanent middle cerebral artery occlusion.
Rats were subjected to permanent middle cerebral artery occlusion by the suture occlusion method and were treated 1 hour thereafter with a single 5-minute intravenous infusion of the postsynaptic density-95 protein inhibitor Tat-NR2B9c (7.5 mg/kg) or saline (n=8/group). Arterial spin-labeled perfusion-weighted MRI and diffusion weighted MRI were obtained with a 4.7-T Bruker system at 30, 45, 70, 90, 120, 150, and 180 minutes postmiddle cerebral artery occlusion to determine cerebral blood flow and apparent diffusion coefficient maps, respectively. At 24 hours, animals were neurologically scored (0 to 5), euthanized, and the brains stained with 2-3-5-triphenyl tetrazolium chloride to ascertain infarct volumes corrected for edema. Additionally, the effects of Tat-NR2B9c on adenosine 5'-triphosphate levels were measured in vitro in neurons subjected to oxygen-glucose deprivation.
Final infarct volume was decreased by 30.3% in the Tat-NR2B9c-treated animals compared with controls (P=0.028). There was a significant improvement in 24 hours neurological scores in the Tat-NR2B9c group compared with controls, 1.8±0.5 and 2.8±1.0, respectively (P=0.021). Relative to controls, Tat-NR2B9c significantly attenuated diffusion-weighted imaging lesion growth and preserved the diffusion-weighted imaging/perfusion-weighted imaging mismatch (ischemic penumbra) without affecting cerebral blood flow in the ischemic core or penumbra. Tat-NR2B9c treatment of primary neuronal cultures resulted in 26% increase in cell viability and 34% greater adenosine 5'-triphosphate levels after oxygen-glucose deprivation.
Preservation of adenosine 5'-triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a postsynaptic density-95 protein inhibitor.
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to evaluate in symptomatic moyamoya patients the effect of surgical revascularization on impaired cerebrovascular reactivity (CVR) and its relationship to clinical outcome.
Brain revascularization was performed using a direct superficial temporal artery to middle cerebral artery bypass or indirect encephalo-dural-arterial synangiosis. CVR was measured pre- and 3 months postoperatively using blood oxygen level-dependent MRI during iso-oxic hypercapnic changes in end-tidal carbon dioxide. Outcomes were assessed by MRI, clinical examination, and modified Rankin Scale scores.
Fifty-five hemispheres were revascularized in 39 patients (superficial temporal artery to middle cerebral artery in 47, encephalo-dural-arterial synangiosis in 8). Surgery reversed CVR impairment in 52 hemispheres (94.5%) and in 36 of 39 patients (92.3%; Fisher exact test, P<0.001), and this was predictive of a patent extracranial-intracranial bypass. New, clinically silent perioperative hemorrhages, cortical foci of ischemia, or new white matter T2 hyperintensities were detected after 11 surgeries (20%), but no new lesions arose after 3 postoperative months. One patient had a clinical perioperative stroke (1.8%). In clinical follow-up, 37 of 39 patients (95%) had stable or improved modified Rankin Scale scores and 2 patients (5.1%) worsened. No patients with patent bypasses or CVR improvements exhibited new clinical symptoms, but failure of CVR improvement corresponded to a poorer long-term outcome (Fisher exact test, P<0.001).
Cerebral revascularization surgery is a safe and effective treatment for reversing preoperative CVR defects and may prevent recurrence of preoperative symptoms. Moreover, CVR measurements may be useful in long-term follow-up and for predicting bypass patency.
[show abstract][hide abstract] ABSTRACT: Cerebral proliferative angiopathy (CPA) has been morphologically distinguished from classically appearing brain arteriovenous malformations (AVMs) by exhibition of functional brain parenchyma that is intermingled with abnormal vascular channels. The presence of oligemia in this intralesional brain tissue may suggest ischemia, which is not detected in classic brain AVMs. The authors hypothesized that patients with CPA would exhibit a greater impairment of cerebrovascular reserve in neuronal tissue surrounding the true nidus compared with those with brain AVMs.
Four patients with CPA, 10 patients with brain AVMs and seizures, and 12 young healthy individuals were studied. The 4 patients with CPA underwent blood oxygen level-dependent MR imaging examinations while applying normoxic step changes in end-tidal CO(2) to obtain quantitative cerebrovascular reactivity measurements.
Patients with a CPA lesion exhibited severely impaired perilesional cerebrovascular reserve in comparison with patients with brain AVMs and seizures (0.10 ± 0.03 vs 0.16 ± 0.03, respectively; p < 0.05), and young healthy individuals (0.10 ± 0.03 vs 0.21 ± 0.06, respectively; p < 0.01).
This study demonstrated severely impaired cerebrovascular reserve in the perilesional brain tissue surrounding the abnormal vessels of patients with CPA. This finding may provide an additional means to distinguish CPA from classic brain AVMs.
Journal of Neurosurgery Pediatrics 09/2011; 8(3):310-5. · 1.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: To promote functional recovery after CNS injuries, it is crucial to develop strategies that enhance both neuronal survival and regeneration. Here, we report that caspase-6 is upregulated in injured retinal ganglion cells and that its inhibition promotes both survival and regeneration in these adult CNS neurons. Treatment of rat retinal whole mounts with Z-VEID-FMK, a selective inhibitor of caspase-6, enhanced ganglion cell survival. Moreover, retinal explants treated with this drug extended neurites on myelin. We also show that caspase-6 inhibition resulted in improved ganglion cell survival and robust axonal regeneration following optic nerve injury in adult rats. The effects of Z-VEID-FMK were similar to other caspase inhibitory peptides including Z-LEHD-FMK and Z-VAD-FMK. In searching for downstream effectors for caspase-6, we identified caspase-8, whose expression pattern resembled that of caspase-6 in the injured eye. We then showed that caspase-8 is activated downstream of caspase-6 in the injured adult retina. Furthermore, we investigated the role of caspase-8 in RGC apoptosis and regenerative failure both in vitro and in vivo. We observed that caspase-8 inhibition by Z-IETD-FMK promoted survival and regeneration to an extent similar to that obtained with caspase-6 inhibition. Our results indicate that caspase-6 and caspase-8 are components of a cellular pathway that prevents neuronal survival and regeneration in the adult mammalian CNS.
Journal of Neuroscience 07/2011; 31(29):10494-505. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic deficiencies in regional blood flow lead to cerebral cortical thinning without evidence of gross tissue loss at the same time as potentially negatively impacting on neurological and cognitive performance. This is most pronounced in patients with severe occlusive cerebrovascular disease in whom affected brain areas exhibit "steal physiology," a paradoxical reduction of cerebral blood flow in response to a global vasodilatory stimulus intended to increase blood flow. We tested whether surgical brain revascularization that eliminates steal physiology can reverse cortical thinning.
We identified 29 patients from our database who had undergone brain revascularization with pre- and postoperative studies of cerebrovascular reactivity using blood oxygen(ation) level-dependent MRI and whose preoperative study exhibited steal physiology without MRI-evident structural abnormalities. Cortical thickness in regions corresponding to steal physiology, and where applicable corresponding areas in the normal hemisphere, were measured using Freesurfer software.
At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere (n=30). Mean cortical thickness in the revascularized regions increased by 5.1% (from 2.40 ± 0.03 to 2.53 ± 0.03; P<0.0001).
Successful regional revascularization and reversal of steal physiology is followed by restoration of cortical thickness.
[show abstract][hide abstract] ABSTRACT: Brainstem arteriovenous malformations are challenging lesions, and benefits of treatment are uncertain.
To study the clinical course of Brainstem arteriovenous malformations and the influence of treatments on outcome.
We reviewed a prospective series of 31 brainstem arteriovenous malformations. Demographic, morphological, and clinical characteristics were recorded. Factors determining initial and final outcomes (modified Rankin Scale), results of treatments (cure rates, complications), and disease course were analyzed.
Brainstem arteriovenous malformations were symptomatic and bled in 93% and 61% of cases, respectively. Examination was abnormal and initial modified Rankin Scale score was < 3 in 71% and 86% of patients, respectively. The average follow-up time was 6.2 years, and 26% of patients rebled (5.9 %/y). Treatment modalities included conservative, radiosurgical, endovascular, surgical, and multimodality treatment in 13%, 58%, 35%, 16%, and 26% of cases, respectively. The obliteration rate was 60% overall and 39% after radiosurgery, 40% after embolization, and 75% after microsurgery, with respective complication-free cure rates of 71%, 50%, and 0%. Overall procedural mortality and morbidity were 2.3% and 18.6%, respectively. Final modified Rankin Scale score was < 3 in 77% of cases. Neurological deterioration (35%) was related to treatment complications in 74% of cases with a negative impact of surgery (P = .04), palliative embolization (odds ratio = 16), and multimodality treatments (odds ratio = 24). Radiosurgery was inversely associated with worsening (odds ratio = 0.06).
Brainstem arteriovenous malformations require individualized treatment decisions. Single-modality treatments with a reasonable chance of complete cure and low complication rate (such as radiosurgery) should be favored.