The Extended Lateral Supraorbital Approach and Extradural Anterior Clinoidectomy Through a Frontopterio-Orbital Window : Technical Note and Pilot Surgical Series

BACKGROUND: Lateral approaches to treat anterior cranial fossa lesions have evolved since the first frontotemporal approach described by Dandy in 1918. We describe a less invasive approach to perform extradural anterior clinoidectomy through a lateral supraorbital (LSO) approach for anterior circulation aneurysms and anterolateral skull base lesions. METHODS: The extended LSO approach involves performing a standard lateral supraorbital craniotomy followed by drilling of the sphenoid wing and lateral wall of the orbit through the frontal bony opening of the LSO approach, without any temporal extension of the craniotomy. This creates a frontopterio-orbital window exposing the periorbita; superior, medial, and anterior aspect of the temporal dura mater; and superior orbital fissure. After unroofing the superior orbital fissure, the meningo- orbital fold is cut, and the temporal dura mater is peeled from the lateral wall of the cavernous sinus to expose the anterior clinoid process allowing a standard opening of the optic canal and anterior clinoidectomy. RESULTS: The extended LSO approach and extradural anterior clinoidectomy allowed access to 4 sphenoid wing/anterior clinoidal meningiomas, 5 anterior circulation aneurysms, 2 temporomesial lesions, and 1 orbital/cavernous sinus abscess. Postoperatively, 2 patients had transient hemiparesis, 2 patients had transient third nerve palsy, and 1 patient had minimal visual field deterioration. All patients had a modified Rankin Scale score CONCLUSION: The extended LSO approach opens a new route (frontopterio-orbital window) to perform extradural anterior clinoidectomy safely and increases surgical exposure, angles, and operability of a less invasive keyhole craniotomy (LSO approach) to treat anterior cranial fossa lesions.Peer reviewe

Dependence of NMDA/GSK-3β Mediated Metaplasticity on TRPM2 Channels at Hippocampal CA3-CA1 Synapses

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

The impact of postsynaptic density 95 blocking peptide (Tat-NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate-induced epileptogenesis

Antiepileptogenic agents that prevent the development of epilepsy following a brain insult remain the holy grail of epilepsy therapeutics. We have employed a label‐free proteomic approach that allows quantification of large numbers of brain‐expressed proteins in a single analysis in the mouse (male C57BL/6J) kainate (KA) model of epileptogenesis. In addition, we have incorporated two putative antiepileptogenic drugs, postsynaptic density protein‐95 blocking peptide (PSD95BP or Tat‐NR2B9c) and a highly selective inducible nitric oxide synthase inhibitor, 1400W, to give an insight into how such agents might ameliorate epileptogenesis. The test drugs were administered after the induction of status epilepticus (SE) and the animals were euthanized at 7 days, their hippocampi removed, and subjected to LC‐MS/MS analysis. A total of 2,579 proteins were identified; their normalized abundance was compared between treatment groups using ANOVA, with correction for multiple testing by false discovery rate. Significantly altered proteins were subjected to gene ontology and KEGG pathway enrichment analyses. KA‐induced SE was most robustly associated with an alteration in the abundance of proteins involved in neuroinflammation, including heat shock protein beta‐1 (HSP27), glial fibrillary acidic protein, and CD44 antigen. Treatment with PSD95BP or 1400W moderated the abundance of several of these proteins plus that of secretogranin and Src substrate cortactin. Pathway analysis identified the glutamatergic synapse as a key target for both drugs. Our observations require validation in a larger‐scale investigation, with candidate proteins explored in more detail. Nevertheless, this study has identified several mechanisms by which epilepsy might develop and several targets for novel drug development

A dual-center validation of the PIRAMD scoring system for assessing the severity of ischemic Moyamoya disease

Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD) is a recently proposed imaging-based scoring system that incorporates the severity of disease and its impact on parenchymal hemodynamics in order to better support clinical management and evaluate response to intervention. In particular, PIRAMD may have merit in identifying symptomatic patients that may benefit most from revascularization. Our aim was to validate the PIRAMD scoring system

Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015

The 2015 update of the Canadian Stroke Best Practice Recommendations Hyperacute Stroke Care guideline highlights key elements involved in the initial assessment, stabilization, and treatment of patients with transient ischemic attack (TIA), ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and acute venous sinus thrombosis. The most notable change in this 5th edition is the addition of new recommendations for the use of endovascular therapy for patients with acute ischemic stroke and proximal intracranial arterial occlusion. This includes an overview of the infrastructure and resources required for stroke centers that will provide endovascular therapy as well as regional structures needed to ensure that all patients with acute ischemic stroke that are eligible for endovascular therapy will be able to access this newly approved therapy; recommendations for hyperacute brain and enhanced vascular imaging using computed tomography angiography and computed tomography perfusion; patient selection criteria based on the five trials of endovascular therapy published in early 2015, and performance metric targets for important time-points involved in endovascular therapy, including computed tomography-to-groin puncture and computed tomography-to-reperfusion times. Other updates in this guideline include recommendations for improved time efficiencies for all aspects of hyperacute stroke care with a movement toward a new median target door-toneedle time of 30 min, with the 90th percentile being 60 min. A stronger emphasis is placed on increasing public awareness of stroke with the recent launch of the Heart and Stroke Foundation of Canada FAST signs of stroke campaign; reinforcing the public need to seek immediate medical attention by calling 911; further engagement of paramedics in the prehospital phase with prehospital notification to the receiving emergency department, as well as the stroke team, including neuroradiology; updates to the triage and same-day assessment Conflict of interest: Leanne K. Casaubon: Medtronic (as an independent study patient assessor for a cardiac TAVI study); NoNO Inc. as site PI for the Frontier study of NA-1 neuroprotective in stroke; Covidien as an advisory board member. Jean-Martin Boulanger: conference speaker for BI Novartis, Sanofi Aventis, Merck, Merz, Allergan, Pfizer, Bayer, Boehringer Ingelheim. Gord Gubitz: speaker for Bayer, Boehringer Ingleheim, and BMS Pfizer. Dr. Michael D. Hill: Heart and Stroke Foundation of Alberta Board Chair, salary award holder; Vernalis Group Ltd and Merck Ltd Consultant; Hoffmann-LaRoche Canada, provided drug for clinical trial, consultancy and CME lecturer; Coviden, research grant holder; Servier Canada, CME lecturer (funds donated to charity); BMS Canada, consultancy (funds donated to charity); Alberta Innovates Health Solutions, program grant award; principal investigator, ESCAPE trial. Brian Moses: speaker for AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi Aventis, and Servier; speaker and advisory board member for BMS, Eli Lilly, Merck, NovoNordisk, Pfizer; advisory board member for Medtronic. Funding: The development of the Canadian Stroke Best Practice Recommendations is funded in their entirety by the Heart and Stroke Foundation, Canada. No funds for the development of these guidelines come from commercial interests, including pharmaceutical and medical device companies. All members of the recommendation writing groups and external reviewers are volunteers and do not receive any remuneration for participation in guideline development, updates, and reviews. All participants complete a conflict of interest declaration prior to participation. of patients with transient ischemic attack; updates to blood pressure recommendations for the hyperacute phase of care for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The goal of these recommendations and supporting materials is to improve efficiencies and minimize the absolute time lapse between stroke symptom onset and reperfusion therapy, which in turn leads to better outcomes and potentially shorter recovery times

Molecular mechanisms of calcium-dependent excitotoxicity

Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central nervous system ischemia, trauma, and other neurological disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate, the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates a number of postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx or efflux. This leads to a disturbance of the intracellular ionic environment, the best characterized feature of which is the influx of sodium, chloride, and Ca2+. An excess of Ca2+ ions then activates intracellular Ca2+-dependent signaling cascades that eventually lead to neuronal cell death. Despite intensive research in the field of Ca2+-dependent neurotoxicity the precise molecular mechanisms leading to cell death remain poorly understood. In particular, the question of the precise relationship between Ca2+ loading and neurotoxicity has been controversial. Many glutamate receptors are clustered and localized at the postsynaptic density. Recently, increasing knowledge of the molecular composition of the postsynaptic density has allowed us to extend our understanding of the molecular mechanisms of Ca2+ dependent excitotoxicity and to propose that distinct, membrane receptor-specific, neurotoxic signaling pathways transduce Ca2+-dependent excitotoxicity. These findings may have significant implications in the search for precisely targeted therapeutic drugs for a range of neurological disorders

Targeting NMDA receptors in stroke: new hope in neuroprotection

Abstract NMDA (N-methyl-d-aspartate) receptors (NMDARs) play a central role in excitotoxic neuronal death caused by ischemic stroke, but NMDAR channel blockers have failed to be translated into clinical stroke treatments. However, recent research on NMDAR-associated signaling complexes has identified important death-signaling pathways linked to NMDARs. This led to the generation of inhibitors that inhibit these pathways downstream from the receptor without necessarily blocking NMDARs. This therapeutic approach may have fewer side effects and/or provide a wider therapeutic window for stroke as compared to the receptor antagonists. In this review, we highlight the key findings in the signaling cascades downstream of NMDARs and the novel promising therapeutics for ischemic stroke

Impact of cytoplasmic calcium buffering on the spatial and temporal characteristics of intercellular calcium signals in astrocytes

The impact of calcium buffering on the initiation and propagation of mechanically elicited intercellular Ca2+waves was studied using astrocytes loaded with different exogenous, cell membrane-permeant Ca2+chelators and a laser scanning confocal or video fluorescence microscope. Using an ELISA with a novel antibody to BAPTA, we showed that different cell-permeant chelators, when applied at the same concentrations, accumulate to the same degree inside the cells. Loading cultures with BAPTA, a high Ca2+affinity chelator, almost completely blocked calcium wave occurrence. Chelators having lower Ca2+affinities had lesser affects, as shown in their attenuation of both the radius of spread and propagation velocity of the Ca2+wave. The chelators blocked the process of wave propagation, not initiation, because large [Ca2+]iincreases elicited in the mechanically stimulated cell were insufficient to trigger the wave in the presence of high Ca2+affinity buffers. Wave attenuation was a function of cytoplasmic Ca2+buffering capacity; i.e., loading increasing concentrations of low Ca2+affinity buffers mimicked the effects of lesser quantities of high-affinity chelators. In chelator-treated astrocytes, changes in calcium wave properties were independent of the Ca2+-binding rate constants of the chelators, of chelation of other ions such as Zn2+, and of effects on gap junction function. Slowing of the wave could be completely accounted for by the slowing of Ca2+ion diffusion within the cytoplasm of individual astrocytes. The data obtained suggest that alterations in Ca2+buffering may provide a potent mechanism by which the localized spread of astrocytic Ca2+signals is controlled.</jats:p