Improvement In Neurological Outcome Research Articles

Abstract WP135: Engineered Exosomes With Elevated Mir-27a Improve Neurological Outcome in Ischemic Mice

Background: Augmentation of axonal growth enhances improvement of neurological function after stroke. Our previous in vitro study demonstrated that miR-27a promotes axonal growth of embryonic neurons. The present in vivo study investigated whether exosomes carrying elevated miR-27a (27a-exos) enhance axonal growth and neurological outcome after stroke. Methods and Results: The 27a-exos were isolated from medium of mesenchymal stromal cells (MSCs) transfected with lenti-miR-27 vector. In order to investigate axonal growth and underlying mechanisms, Emx1-Thy1-YFP mice with selective expression of yellow fluorescent protein (YFP) in pyramidal neurons were subjected to the permanent middle cerebral artery occlusion (MCAO). Quantitative RT-PCR analysis showed that compared with exosomes derived from empty-vector transfected MSCs (empty-exos), 27a-exos had 3.7 fold increased miR-27a. 27a-exos (3x10 11 particles) were injected intravenously into mice at 24h after MCAO. Compared with control mice, the empty-exos (n=7) significantly (p<0.05) reduced the foot-fault (5±0.1 vs 11±0.5 in control) and the times to remove adhesive paper (seconds, 47±3 vs 70±4). However, compared with empty-exos, 27a-exos (n=7) further significantly (p<0.05) reduced foot-fault (3.0±0.2) and times to remove the paper (38±1.7). Histopathological and in situ hybridization analysis showed that 27a-exos localized to neurons and significantly (p<0.05) increased miR-27a in Emx1-YFP+ neurons (4±0.7 vs 1 in empty-exos), and augmented (p<0.05) the density of YFP+/pNFH+ axons (7±2 vs 1 in empty-exos). Moreover, 27a-exos substantially decreased the levels of the inhibitory protein Sema6a in the YFP+ axons in peri-infarct areas. Conclusion: Our data suggest that tailored 27a-exos augment the therapeutic effect of exosomes on stroke recovery and that suppression of axonal inhibitory proteins such as Sema6a may contribute to the 27a-exo-enhanced axonal outgrowth to promote neurological recovery post stroke.

Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.

Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.

Abstract 03: High-Dose Intranasal Insulin During CPR Improves Neurological Outcomes in a Rat Model of Cardiac Arrest

Introduction: Post-cardiac arrest brain injury is a major cause of mortality and morbidity. Insulin has well-established CNS neuroprotecive properties mediated by the AKT survival signaling pathway, and known transnasal transport mechanisms make it possible to rapidly achieve therapeutic brain insulin levels after intranasal delivery. Hypothesis: We hypothesize that high-dose intranasal insulin (HD-IN-I) administered during CPR, could improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Methods: Male Long Evans rats were subjected to 8-minute asphyxial cardiac arrest then block randomized to HD-IN-I (1.92 U/g brain wet weight) or placebo (PL) given at the onset of CPR by an experimental operator blinded to treatment. Sham operated rats were used as uninjured controls. For the long-term outcome study (n = 14/group), rats with return of spontaneous circulation (ROSC) were maintained at 37.0 ±0.5 °C for 72 hours and neurologic function was assessed on days 7 - 10. For the mechanistic study (n = 6/group), rats with ROSC were euthanized 30 minutes after ROSC and regional brain homogenates were analyzed by western blot for AKT phosporylation. Results: HD-IN-I during CPR had no statistically significant effect on ROSC rate (93% (13/14) HD-IN-I vs. 86% (12/14) PL, p > 0.05) or 10-day survival (71% (10/14) HD-INI vs. 43% (6/14) PL, p > 0.05). HD-IN-I had no significant impact on serum glucose concentrations. At 10 days post-ROSC, rats in the HD-IN-I group had significantly improved performance on rotarod (latency to fall 87±27 sec HD-IN-I vs. 41±18 sec PL, p < 0.05), Barnes maze (latency to escape box 27±15 sec HD-IN-I vs. 298±5 sec PL, p < 0.05), and passive avoidance (latency to re-enter shock chamber 300±0 sec HD-IN-I vs. 142±46 sec PL, p < 0.05) testing. Hippocampal phosph-AKT/total AKT ratio increased 2-fold in the placebo group and 5.7-fold in the HD-IN-I group relative to shams (p < 0.05). Conclusions: HD-IN-I administered during CPR causes rapid activation of brain AKT survival signaling and improves recovery of neurologic function in a rat cardiac arrest model. Additional studies are warranted to determine dose optimization, therapeutic window and effectiveness in large animal models to advance this novel therapy toward clinical trials.

Abstract 209: Does ECPR for the Younger Patients Who Has Long Downtime Improve Neurological Outcome?

Introduction: It have reported previously that extracorporeal cardiopulmonary resuscitation (ECPR) for out of hospital cardiac arrest should induct within 45 minutes from collapse. However, We often encounter patients with favorable neurological outcome who had longer time interval from collapse to induction of V-A ECMO (Downtime: DT). We analyzed that relation about neurological outcome and DT for patients undergone ECPR. Methods: In this single center retrospective study, from January 2010 to April 2019, we identified 147 patients who underwent ECPR. Of these, 87 patients (59%) had shorter DT (≦45min:Group S), and 60 patients (41%) had longer DT (≧46min:Group L). We compared neurological outcome between two groups. Glasgow-Pittsburgh Cerebral Performance Category (CPC) 1-2 was defined as favorable neurological outcome, CPC3-5 was defined as unfavorable outcome at 3 months. Results were expressed as Median (IQR). Results: Patient characteristics were not different between the two groups. DT were 37 min (32-42: Group S) and 57 min (50-64: Group L). 51 % of the patients in Group S (46 patients) were alive at 3 month, as compared with 35% in Group L (21 patients) (p: 0.05). At the 3 month follow up, Group S had a higher rate of favorable neurological outcome than Group L (39% (34 patients) vs 28% (17 patients) (p:0.18 ). In younger patients (≦65y.o), the rate of favorable neurological outcome were roughly equal in each groups (Group S: 41% (20/48 patients) vs 37% (11/30 patients) ) (p:0.51). Conclusions: Because it is possible younger patients with cardiac arrest had a favorable neurological outcome, even if they had longer DT, it should consider the expanded adaptation of ECPR.

Optimal Hemodynamic Parameter to Predict the Neurological Outcome in Out-of-Hospital Cardiac Arrest Survivors Treated with Target Temperature Management.

Current guidelines suggest the maintenance of systolic blood pressure (SBP) at >90 mmHg and mean arterial pressure (MAP) at >65 mmHg in postcardiac arrest patients. There remains a lack of clarity regarding optimal values and timing of blood pressure parameters associated with the improvement of neurologic outcome. We investigated the association of time-weighted average (TWA) blood pressure parameters with favorable neurological outcome (FO) in postcardiac arrest patients. This was a registry-based observational study with consecutive adult out-of-hospital cardiac arrest (OHCA) survivors who were treated using targeted temperature management (TTM). During 72 hours of TTM period, we abstracted hemodynamic parameters such as SBP, diastolic blood pressure, pulse rate (PR), and MAP. Shock index (SI; PR/SBP) and modified shock index (MSI; PR/MAP) were calculated from each measured hemodynamics. Logistic regression was performed to assess the associations between TWA blood pressure parameters and FO, defined as cerebral performance category 1 or 2 at hospital discharge. Among the 173 patients (median age: 58 years; 64% male), 51 (29.3%) had FO in this study. MAP, SI, and MSI at 6 hours after return of spontaneous circulation (ROSC) showed considerable differences in patients with FO (MAP: 89.1 ± 14.7 vs. 83.6 ± 15.8 mmHg, p = 0.033, SI: 0.7 ± 0.2 vs. 0.9 ± 0.9, p = 0.002, MSI: 1.0 ± 0.3 vs. 1.2 ± 0.3, p ≤ 0.001). Among them, MSI, especially at 6 hours, had the highest area under the curve for prediction of FO (0.685; 95% confidence interval: 0.597-0.772, p < 0.001). Also, MSI <1.0 had a sensitivity of 64.7%, a specificity of 64.2% to predict FO. In comatose survivors of OHCA with TTM, MSI at 6 hours after ROSC had the highest prognostic value for neurologic outcome among blood pressure parameters.

Combined Treatment with Hydrophilic and Lipophilic Statins Improves Neurological Outcomes Following Experimental Cardiac Arrest in Mice.

Global ischemia due to cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) causes significant neuronal damage in vulnerable areas in the brain. Currently, a majority of patients eventually die after successful CPR due to neurological injury. Statins have pleiotropic effects including anti-inflammatory and/or antioxidant responses. These pleiotropic effects can have a beneficial role in the post-CPR phase. We tested whether two different types of statins, hydrophilic pravastatin and lipophilic simvastatin, attenuated neurological injury following CA/CPR. The efficacy of pravastatin and simvastatin combination treatment was also assessed. Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 8-min CA/CPR were randomized into four groups: control, 2mg/kg pravastatin, 20mg/kg simvastatin, or a combination of 3mg/kg pravastatin and 10mg/kg simvastatin. Neurobehavioral assessment and histological analyses were performed to assess overall general health condition and neuronal injury, respectively. Combination treatment with pravastatin and simvastatin significantly reduced neuronal injury in the striatum and hippocampus, reduced cerebral edema, and improved general health at 4days after CA/CPR. Combination statin treatment upregulated endothelial nitric oxide synthase mRNA in the brain. Pravastatin alone, but not simvastatin alone, improved general health after CA/CPR. Pravastatin was less potent than simvastatin at reducing neuronal injury in the brain. Combination treatment with two different types of statins at the correct dose may be a promising approach to neuroprotection following CA/CPR.

273 Modified Shock Index and Neurologic Outcome During Treated Target Temperature Management in Out-of-Hospital Cardiac Arrest Survivors

Current guidelines suggest the maintenance of systolic blood pressure (SBP) at >90mmHg and mean arterial pressure (MAP) at >65mmHg in post-cardiac arrest patients. There remains a lack of clarity regarding optimal values and timing of blood pressure parameters associated with the improvement of neurologic outcome. We investigated the association of time-weighted average blood pressure parameters with favorable neurological outcome (FO) in post-cardiac arrest patients.

A Single Injection of Docosahexaenoic Acid Induces a Pro-Resolving Lipid Mediator Profile in the Injured Tissue and a Long-Lasting Reduction in Neurological Deficit after Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) can lead to life-changing neurological deficits, which reflect the fast-evolving secondary injury post-trauma. There is a need for acute protective interventions, and the aim of this study was to explore in an experimental TBI model the neuroprotective potential of a single bolus of a neuroactive omega-3 fatty acid, docosahexaenoic acid (DHA), administered in a time window feasible for emergency services. Adult mice received a controlled cortical impact injury (CCI) and neurological impairment was assessed with the modified Neurological Severity Score (mNSS) up to 28 days post-injury. DHA (500 nmol/kg) or saline were injected intravenously at 30 min post-injury. The lipid mediator profile was assessed in the injured hemisphere at 3 h post-CCI. After completion of behavioral tests and lesion assessment using magnetic resonance imaging, over 7 days or 28 days post-TBI, the tissue was analyzed by immunohistochemistry. The single DHA bolus significantly reduced the injury-induced neurological deficit and increased pro-resolving mediators in the injured brain. DHA significantly reduced lesion size, the microglia and astrocytic reaction, and oxidation, and decreased the accumulation of beta-amyloid precursor protein (APP), indicating a reduced axonal injury at 7 days post-TBI. DHA reduced the neurofilament light levels in plasma at 28 days. Therefore, an acute single bolus of DHA post-TBI, in a time window relevant for acute emergency intervention, can induce a long-lasting and significant improvement in neurological outcome, and this is accompanied by a marked upregulation of neuroprotective mediators, including the DHA-derived resolvins and protectins.

Epinephrine during resuscitation of traumatic cardiac arrest and increased mortality: a post hoc analysis of prospective observational study

BackgroundThe beneficial effect of epinephrine during resuscitation from out-of-hospital cardiac arrest (OHCA) has been inconclusive, and potential harm has been suggested, particularly in trauma victims. Although no significant improvement in neurological outcomes has been found among resuscitated patients using epinephrine, including trauma patients, the use of epinephrine is recommended in the Advanced Trauma Life Support protocol. Given that the use of vasopressors was reported to be associated with increased mortality in patients with massive bleeding, the undesirable effects of epinephrine during the resuscitation of traumatic OHCA should be elucidated. We hypothesised that resuscitation with epinephrine would increase mortality in patients with OHCA following trauma.MethodsThis study is a post-hoc analysis of a prospective, multicentre, observational study on patients with OHCA between January 2012 and March 2013. We included adult patients with traumatic OHCA who were aged ≥15 years and excluded those with missing survival data. Patient data were divided into epinephrine or no-epinephrine groups based on the use of epinephrine during resuscitation at the hospital. Propensity scores were developed to estimate the probability of being assigned to the epinephrine group using multivariate logistic regression analyses adjusted for known survival predictors. The primary outcome was survival 7 days after injury, which was compared among the two groups after propensity score matching.ResultsOf the 1125 adults with traumatic OHCA during the study period, 1030 patients were included in this study. Among them, 822 (79.8%) were resuscitated using epinephrine, and 1.1% (9/822) in the epinephrine group and 5.3% (11/208) in the no-epinephrine group survived 7 days after injury. The use of epinephrine was significantly associated with decreased 7-day survival (odds ratio = 0.20; 95% CI = 0.08–0.48; P < 0.01), and this result was confirmed by propensity score-matching analysis, in which 178 matched pairs were examined (adjusted odds ratio = 0.11; 95% CI = 0.01–0.85; P = 0.02).ConclusionsThe relationship between the use of epinephrine during resuscitation and decreased 7-day survival was found in patients with OHCA following trauma, and the propensity score-matched analyses validated the results. Resuscitation without epinephrine in traumatic OHCA should be further studied in a randomised controlled trial.

The Anti-inflammatory Compound Candesartan Cilexetil Improves Neurological Outcomes in a Mouse Model of Neonatal Hypoxia.

Recent studies suggest that mild hypoxia-induced neonatal seizures can trigger an acute neuroinflammatory response leading to long-lasting changes in brain excitability along with associated cognitive and behavioral deficits. The cellular elements and signaling pathways underlying neuroinflammation in this setting remain incompletely understood but could yield novel therapeutic targets. Here we show that brief global hypoxia-induced neonatal seizures in mice result in transient cytokine production, a selective expansion of microglia and long-lasting changes to the neuronal structure of pyramidal neurons in the hippocampus. Treatment of neonatal mice after hypoxia-seizures with the novel anti-inflammatory compound candesartan cilexetil suppressed acute seizure-damage and mitigated later-life aggravated seizure responses and hippocampus-dependent learning deficits. Together, these findings improve our understanding of the effects of neonatal seizures and identify potentially novel treatments to protect against short and long-lasting harmful effects.

One-stage combined anterior-posterior surgery for thoracic and lumbar spinal tuberculosis

Context: Surgical intervention is imperative when spinal tuberculosis (TB) is accompanied by severe spinal damage or kyphotic deformity. As one-stage anterior-only or posterior-only surgery for thoracic and lumbar spinal TB has many disadvantages, combined anterior-posterior surgery was proposed to be a more effective strategy. Objective: To examine the clinical outcomes of one-stage combined anterior-posterior surgery for patients with spinal TB. Design: Retrospective investigation design. Setting: All patients were enrolled at the Hangzhou Red Cross Hospital between August 2002 and October 2014. Participants: Sixty-seven patients with thoracic and lumbar spinal TB were studied. Interventions: All patients were treated with one-stage surgery using a combined anterior-posterior approach. Outcome measures: The patients were evaluated preoperatively and postoperatively by measuring their neurological function using the visual analogue scale (VAS) and the Frankel grades, and spinal deformity using the Cobb angle and radiological examinations. All patients were followed up for at least 11 months and up to 96 months. Results: There was a significant postoperative improvement in neurological outcomes, according to VAS scores and Frankel grades. Kyphotic angles were corrected significantly and were maintained during the final follow-up. Bone fusion was achieved within 4–7 months. Conclusion: One-stage surgical treatment via a combined anterior-posterior approach is an effective and feasible method for treating spinal TB.

Abstract WP134: Calcium Release-activated Calcium Channel Inhibition Improves Neurological Outcome and Suppresses Inflammation in Female Mice Following Cerebral Ischemic Injury

Purpose: Calcium release-activated calcium (CRAC) channels activate microglia via store-operated Ca 2+ entry. We previously reported that the specific CRAC channel inhibitor (CM-EX-137) had neuroprotective effects in a model of experimental stroke due to suppression of microglial activation in male mice. However, it is well known that sex differences can influence stroke outcome as well as immune responses. Whether CRAC channel inhibition in female mice is similarly neuroprotective is unknown. The purpose of this study is to determine whether female mice respond similarly CRAC channel inhibition in a stroke model Subjects and Methods: C57/BL6 female mice, aged 2 months were subjected to distal middle cerebral artery occlusion (dMCAO) were treated with CM-EX-137 (5mg/kg IP; dMCAO-CM) or vehicle control (dMCAO-vehicle) daily for 3d. Stroke surgeries were carried out during the same phase of the estrus cycle (diestrus) to avoid potential confounds due to varying estrogen levels. These groups were also compared to sham groups. CM-EX-137 was injected immediately after occlusion and at 24 &amp; 48h. Brains were extracted 3d post dMCAO. Neurological functions were evaluated before surgery, and 1 &amp; 3d later. Lesion size was estimated from cresyl violet stains. Microglia and astrocyte activation were assessed using immunohistochemistry. Results: Neurological function at both 24 and 72 h post ischemia were significantly improved in dMCAO-CM group, compared with dMCAO-vehicle group (n=7/group; p&lt;0.001). CM-EX-137 also significantly reduced infarct volume at 3dafter dMCAO (p&lt;0.001). CM-EX-137 inhibited microglial/monocyte/macrophage activation (p&lt;0.001; isolectin B4, CD68) and led to decreased iNOS positive cells (p&lt;0.01). CM-EX-137 also decreased expression of CRAC channel components STIM1 and Orai1 on CD68+ macrophages (p&lt;0.001). However, GFAP staining indicated that CM-EX-137 had no effect on astrocyte activation. Conclusion: CRAC channel inhibition reduce inflammatory responses and improve neurological outcome following experimental stroke in female animals. These results are in line with those that we observed in male mice. Thus, CRAC channel inhibition seems to be similarly effective and anti-inflammatory in both genders in a stroke model.

Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) leads to cellular loss, destabilization of membranes, disruption of synapses and altered brain connectivity, and increased risk of neurodegenerative disease. A significant and long-lasting decrease in phospholipids (PLs), essential membrane constituents, has recently been reported in plasma and brain tissue, in human and experimental TBI. We hypothesized that supporting PL synthesis post-injury could improve outcome post-TBI. We tested this hypothesis using a multi-nutrient combination designed to support the biosynthesis of PLs and available for clinical use. The multi-nutrient, Fortasyn® Connect (FC), contains polyunsaturated omega-3 fatty acids, choline, uridine, vitamins, cofactors required for PL biosynthesis, and has been shown to have significant beneficial effects in early Alzheimer's disease. Male C57BL/6 mice received a controlled cortical impact injury and then were fed a control diet or a diet enriched with FC for 70 days. FC led to a significantly improved sensorimotor outcome and cognition, reduced lesion size and oligodendrocyte loss, and it restored myelin. It reversed the loss of the synaptic protein synaptophysin and decreased levels of the axon growth inhibitor, Nogo-A, thus creating a permissive environment. It decreased microglia activation and the rise in ß-amyloid precursor protein and restored the depressed neurogenesis. The effects of this medical multi-nutrient suggest that support of PL biosynthesis post-TBI, a new treatment paradigm, has significant therapeutic potential in this neurological condition for which there is no satisfactory treatment. The multi-nutrient tested has been used in dementia patients and is safe and well tolerated, which would enable rapid clinical exploration in TBI.

Targeted Temperature Management at 33°C or 36°C Produces Equivalent Neuroprotective Effects in the Middle Cerebral Artery Occlusion Rat Model of Ischemic Stroke.

Targeted temperature management (TTM, 32°C to 36°C) is one of the most successful achievements in modern resuscitation medicine. It has become standard treatment for survivors of sudden cardiac arrest to minimize secondary brain damage. TTM at 36°C is just as effective as TTM at 33°C and is actually preferred because it reduces adverse TTM-associated effects. TTM also likely has direct neuroprotective effects in ischemic brains in danger of stroke. It remains unclear, however, whether higher temperature TTM is equally effective in protecting the brain from the effects of stroke. Here, we asked whether TTM at 36°C is as effective as TTM at 33°C in improving outcomes in a middle cerebral artery occlusion (MCAO) model of ischemic stroke. After dividing rats randomly into MCAO, MCAO+33°C TTM, MCAO+36°C TTM, and sham groups, we subjected all of them except for the sham group to MCAO for 3 h (for the behavioral tests) or 4 h (for all other biochemical analyses). We found TTM protocols at both 33°C and 36°C to produce comparable reductions of infarct volumes in the MCAO territory and equally attenuate the extracellular release of high mobility group box 1 in postischemic brains. Both the TTM conditions prevent the mRNA induction of a major pro-inflammatory cytokine, tissue necrosis factor-α, in the ischemic penumbra region. Finally, both the TTM protocols produce similar improvements in neurological outcomes in rats, as measured by a battery of behavior tests 21 h after the start of reperfusion. These data acquired in a rat MCAO model suggest TTM at 36°C has excellent therapeutic potential for improving clinical outcomes for patients with acute ischemic stroke.

Surgical Management of Moderate Basal Ganglia Intracerebral Hemorrhage: Comparison of Safety and Efficacy of Endoscopic Surgery, Minimally Invasive Puncture and Drainage, and Craniotomy

To date, no standard surgical procedure has been proven effective for intracerebral hemorrhage (ICH), particularly deep hematomas. This retrospective study evaluated the effectiveness and safety of endoscopic surgery, minimally invasive puncture and drainage, and craniotomy for treating moderate basal ganglia ICH. Patients with basal ganglia ICH (N= 177) were divided into 3 groups based on therapeutic intervention as follows: endoscopic surgery group (n= 61), minimally invasive puncture and drainage group (n= 60), and craniotomy group (n= 56). Patient characteristics at admission were recorded. Operative time; blood loss during operation; evacuation rate; postoperative complications secondary to perihematomal edema, including rebleeding, infectious meningitis, pulmonary infection, gastrointestinal bleeding, and epilepsy; mortality; and Glasgow Outcome Scale scores were compared among the 3 groups. Minimally invasive puncture and drainage was the least traumatic procedure and had the shortest operative time, but it could not remove the hematoma quickly; moreover, it had the highest rebleeding rate. Craniotomy was effective in removing the hematoma but resulted in marked trauma and had the highest incidence of pulmonary infection. Endoscopic surgery was safer and more effective than the other 2 surgical methods, with greater improvement in neurologic outcomes and no change in mortality. Minimally invasive neuroendoscopic management has the advantages of direct vision, efficient hematoma evacuation, and relatively good results. Endoscopic surgery may be a more promising approach for the treatment of moderate basal ganglia ICH.

Early Surgical Decompression Improves Neurological Outcome after Complete Traumatic Cervical Spinal Cord Injury: A Meta-Analysis.

In patients with traumatic spinal cord injury (tSCI) a distinction in surgical urgency is made on the basis of the severity of the initial neurological injury. The optimal timing of surgical decompression, as well as its impact on neurological recovery, is as of yet undetermined. This study addresses neurological improvement after early and late surgery for complete and incomplete cervical tSCI. A systematic search retrieved 15 publications of observational studies reporting outcome measurements after surgery in 1126 patients with cervical tSCI from PubMed and Embase databases. Surgery was considered early within 24 h, and late thereafter. An improvement of at least two grades on the American Spinal Injury Association (ASIA) scale was considered clinically meaningful. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Improvement rates were summarized using individual patient data in a Bayesian random effects model and compared for those with complete and incomplete tSCI after early and late surgery. In patients with complete cervical tSCI (n = 422), improvement was more frequent after early surgery than after late surgery (respectively, 22.6%, 95% credibility interval [CI]: 16.6-28.7% and 10.4%, 95% CI: 5.6-15.8%; odds ratio [OR] 2.6 [95% CI: 1.4-5.1]). Whereas in patients with incomplete cervical tSCI (n = 636), improvement was similar between early and late surgery (respectively 30.4%, 95% CI: 19.8-41.6% and 32.5%, 95% CI: 21.4-45.8%; OR 0.9 [95% CI: 0.4-1.9]). These data suggest a paradigm shift in the treatment of patients with complete cervical tSCI, as surgical decompression within 24 h is more frequently associated with clinically meaningful improvement. In incomplete cervical tSCI, neurological outcome is similar between early and late surgery.

Awake Craniotomy for Resection of Brain Metastases: A Systematic Review

Surgery for brain metastases aims to reduce mass effect and achieve local control through maximizing resection. There is increasing recognition that awake craniotomy (AC) is especially relevant for resection of brain metastases in eloquent areas. This study seeks to examine the neurologic outcomes of using AC for brain metastases resection. A systematic search for studies examining the role of AC in patients with brain metastases was conducted via PubMed without limitations on the year of publication, language, or study design, using the following search terms: (cerebral OR brain) and (metastases OR tumor) and (awake OR intraoperative OR eloquent OR supramarginal). Studies were included if patients underwent AC for resection of brain metastases and data on pre- and postoperative neurologic function were available. Seven studies published between 2001 and 2017 with 104 patients who underwent 107 ACs were identified. Gross total resection was achieved in 61% of patients, supramarginal resection was achieved in 32%, and subtotal resection was achieved in 7%. Immediately after operation, 73% of patients experienced no change or improvement in neurologic outcomes, whereas 27% experienced worsening. In the long term, 96% of those with postoperative worsening of function experienced improvements in neurologic function. Most patients experienced improvements in neurologic function immediately after AC, and most patients that experienced short-term worsening of neurologic function after the procedure showed excellent recovery. AC should be considered as a technique to optimize outcomes in brain metastases in eloquent areas.

Scalable synthesis and validation of PAMAM dendrimer-N-acetyl cysteine conjugate for potential translation.

Dendrimer‐N‐acetyl cysteine (D‐NAC) conjugate has shown significant promise in multiple preclinical models of brain injury and is undergoing clinical translation. D‐NAC is a generation‐4 hydroxyl‐polyamidoamine dendrimer conjugate where N‐acetyl cysteine (NAC) is covalently bound through disulfide linkages on the surface of the dendrimer. It has shown remarkable potential to selectively target and deliver NAC to activated microglia and astrocytes at the site of brain injury in several animal models, producing remarkable improvements in neurological outcomes at a fraction of the free drug dose. Here we present a highly efficient, scalable, greener, well‐defined route to the synthesis of D‐NAC, and validate the structure, stability and activity to define the benchmarks for this compound. This newly developed synthetic route has significantly reduced the synthesis time from three weeks to one week, uses industry‐friendly solvents/reagents, and involves simple purification procedures, potentially enabling efficient scale up.

Anticoagulation reversal in vitamin K antagonist-associated intracerebral hemorrhage: a systematic review.

The effect of rapid anticoagulation reversal on mortality and functional outcome in vitamin K antagonist-associated intracerebral hemorrhage (VKA-ICH) is uncertain. Given the approval of idarucizumab for dabigatran reversal and pending approval for andexanet alfa for reversal of factor Xa inhibitors, a systematic appraisal of the effectiveness of reversal for VKA-ICH would provide a bench mark for current practice. We performed PubMed searches and reviewed current guidelines. Using pre-specified inclusion and exclusion criteria, studies were reviewed by two physicians independently. Data elements abstracted included study design, sample size, inclusion and exclusion criteria; patient characteristics at presentation; time to presentation and therapy; dose and timing of warfarin reversal agents; functional outcome and mortality. Studies were assessed for risk of bias. Twenty-one studies met the selection criteria. The overall quality of the studies was poor with small sample size for the majority and all studies being either case series or retrospective observational in design. Inclusion criteria were not uniform. Interpretation of the effectiveness of vitamin K antagonist reversal on functional outcome was not feasible due to lack of standard protocols in the management of VKA-ICH including choice, dose, and timing of reversal agent, timing of subsequent INR monitoring, and decision for repeat imaging. Confounding by indication, lack of universal reporting of functional outcome, and use of varied scales for the endpoint further limited a summary interpretation. Despite availability of reversal agents, mortality and morbidity remain high following VKA-ICH. Evidence for improvement in neurological outcome is limited.

SIRT2 Inhibition Confers Neuroprotection by Downregulation of FOXO3a and MAPK Signaling Pathways in Ischemic Stroke.

Sirtuin 2 (SIRT2) is a family member of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases which appears to have detrimental roles in an array of neurological disorders such as Parkinson's disease (PD) and Huntington's disease (HD). In light of the recently emerging roles of sirtuins in normal physiology and pathological conditions such as ischemic stroke, we investigated the role of SIRT2 in ischemic stroke-induced neuronal cell death. Primary cortical neurons were subjected to oxygen-glucose deprivation (OGD) under in vitro ischemic conditions, and subsequently tested for the efficacy of SIRT2 inhibitors AK1 and AGK2 in attenuating apoptotic cell death caused by OGD. We have also evaluated the effect of SIRT2 inhibition in C57BL/6 mice subjected to 1h middle cerebral artery occlusion (MCAO) followed by 24h reperfusion, which is a model for ischemic reperfusion injury in vivo. Significant reductions in apoptotic cell death were noted in neurons treated with AK1 or AGK2, as evidenced by reduced cleaved caspase-3 and other apoptotic markers such as Bim and Bad. In addition, downregulation of phosphorylated-AKT and FOXO3a proteins of the AKT/FOXO3a pathway, as well as a marked reduction of JNK activity and its downstream target c-Jun, were also observed. When tested in animals subjected to MCAO, the neuroprotective effects of AGK2 in vivo were evidenced by a substantial reduction in ipsilateral infarct area and a significant improvement in neurological outcomes. A similar reduction in the levels of pro-apoptotic proteins in the infarct tissue, as well as downregulation of AKT/FOXO3a and JNK pathway, were also noted. In summary, the current study demonstrated the neuroprotective effects of SIRT2 inhibition in ischemic stroke, and identified the downregulation of AKT/FOXO3a and MAPK pathways as intermediary mechanisms which may contribute to the reduction in apoptotic cell death by SIRT2 inhibition.