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CNS (central nervous system) trauma, which is classified as SCI (spinal cord injury) and TBI (traumatic brain injury), is gradually becoming a major cause of accidental death and disability worldwide. Many previous studies have verified that the pathophysiological mechanism underlying cell death and the subsequent neuroinflammation caused by cell death are pivotal factors in the progression of CNS trauma. Simultaneously, EVs (extracellular vesicles), membrane-enclosed particles produced by almost all cell types, have been proven to mediate cell-to-cell communication, and cell death involves complex interactions among molecules. EVs have also been proven to be effective carriers of loaded bioactive components to areas of CNS trauma. Therefore, EVs are promising therapeutic targets to cure CNS trauma. However, the link between EVs and various types of cell death in the context of CNS trauma remains unknown. Therefore, in this review, we summarize the mechanism underlying EV effects, the relationship between EVs and cell death and the pathophysiology underlying EV effects on the CNS trauma based on information in published papers. In addition, we discuss the prospects of applying EVs to the CNS as feasible therapeutic strategies for CNS trauma in the future., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Injuries to the central nervous system (CNS) often lead to severe neurological dysfunction and even death. However, there are still no effective measures to improve functional recovery following CNS injuries. Optogenetics, an ideal method to modulate neural activity, has shown various advantages in controlling neural circuits, promoting neural remapping, and improving cell survival. In particular, the emerging technique of optogenetics has exhibited promising therapeutic methods for CNS injuries. In this review, we introduce the light-sensitive proteins and light stimulation system that are important components of optogenetic technology in detail and summarize the development trends. In addition, we construct a comprehensive picture of the current application of optogenetics in CNS injuries and highlight recent advances for the treatment and functional recovery of neurological deficits. Finally, we discuss the therapeutic challenges and prospective uses of optogenetics therapy by photostimulation/photoinhibition modalities that would be suitable for clinical applications.

Background: Treatment of nerve injuries proves to be a worldwide clinical challenge. Vascularized nerve grafts are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous non-vascularized nerve graft. However, there is no adequate clinical evidence for the beneficial effect of vascularized nerve grafts and they are still disputed in clinical practice., Objective: To systematically review whether vascularized nerve grafts give a superior nerve recovery compared to non-vascularized nerve autografts regarding histological and electrophysiological outcomes in animal models., Material and Methods: PubMed and Embase were systematically searched. The inclusion criteria were as follows: 1) the study was an original full paper which presented unique data; 2) a clear comparison between a vascularized and a non-vascularized autologous nerve transfer was made; 3) the population study were animals of all genders and ages. A standardized mean difference and 95% confidence intervals for each comparison was calculated to estimate the overall effect. Subgroup analyses were conducted on graft length, species and time frames., Results: Fourteen articles were included in this review and all were included in the meta-analyses. A vascularized nerve graft resulted in a significantly larger diameter, higher nerve conduction velocity and axonal count compared to an autologous non-vascularized nerve graft. However, during sensitivity analysis the effect on axonal count disappeared. No significant difference was observed in muscle weight., Conclusion: Treating a nerve gap with a vascularized graft results in superior nerve recovery compared to non-vascularized nerve autografts in terms of axon count, diameter and nerve conduction velocity. No difference in muscle weight was seen. However, this conclusion needs to be taken with some caution due to the inherent limitations of this meta-analysis. We recommend future studies to be performed under conditions more closely resembling human circumstances and to use long nerve defects., Competing Interests: The authors have declared that no competing interests exist.

Thoracolumbar spine trauma can result in potentially life-threatening consequences and requires careful management to ensure good outcomes. The purpose of this chapter is to discuss the anatomy, diagnostic tools, non-operative, and operative treatments important when addressing thoracolumbar trauma., Competing Interests: Disclosure Dr B.F. Stephens is a consultant for Dupuy Synthes Spine and Stryker Spine. All other authors have no disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Craniocervical injuries (CCJs) account for 10% to 30% of all cervical spine trauma. An increasing number of patients are surviving these injuries due to advancements in automobile technology, resuscitation techniques, and diagnostic modalities. The leading injury mechanisms are motor vehicle crashes, falls from height, and sports-related events. Current treatment with urgent rigid posterior fixation of the occiput to the cervical spine has resulted in a substantial reduction in management delays expedites treatment of CCJ injuries. Within CCJ injuries, there is a spectrum of instability, ranging from isolated nondisplaced occipital condyle fractures treated nonoperatively to highly unstable injuries with severely distracted craniocervical dissociation. Despite the evolution of understanding and improvement in the management of cases regarding catastrophic failure to diagnose, subsequent neurologic deterioration still occurs even in experienced trauma centers. The purpose of this article is to review the injuries that occur at the CCJ with the accompanying anatomy, presentation, imaging, classification, management, and outcomes., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The immuno-microenvironment of injured nerves adversely affects mesenchymal stem cell (MSC) therapy for neurotmesis. Magnetic resonance imaging (MRI) can be used noninvasively to monitor nerve degeneration and regeneration. The aim of this study was to investigate nerve repair after MSC transplantation combined with microenvironment immunomodulation in neurotmesis by using multiparametric MRI., Methods: Rats with sciatic nerve transection and surgical coaptation were treated with MSCs combined with immunomodulation or MSCs alone. Serial multiparametric MRI examinations were performed over an 8-week period after surgery., Results: Nerves treated with MSCs combined with immunomodulation showed better functional recovery, rapid recovery of nerve T2, fractional anisotropy and radial diffusivity values, and more rapid restoration of the fiber tracks than nerves treated with MSCs alone., Discussion: Transplantation of MSCs in combination with immunomodulation can exert a synergistic repair effect on neurotmesis, which can be monitored by multiparametric MRI., (© 2020 Wiley Periodicals, Inc.)

Background: The Nigerian Academy of Neurological Surgeons in 2019 resolved to standardize the practice of neurosurgery in Nigeria. It set up committees to standardize the various aspects of neurosurgery, such as neurotrauma, pediatrics, functional, vascular, skull base, brain tumor, and spine. The Committee on Neurotrauma convened and resolved to study most of the available protocols and guidelines in use in different parts of the world., Objective: To formulate a standard protocol for the practice of neurotrauma care within the Nigerian locality., Methods: The Committee split its membership into 3 subcommittees to cover the various aspects of the Neurotrauma Guidelines, such as neurotrauma curriculum, standard neurotrauma management protocols, and neurotrauma registry. Each subcommittee was to research on available models and formulate a draft for Nigerian neurotrauma., Results: All the 3 subcommittees had their reports ready on schedule. Each concurred that neurotrauma is a major public health challenge in Nigeria. They produced 3 different drafts on the 3 thematic areas of the project. The subcommittees are: 1. Subcommittee on Fellowship, Training and Research Curriculum; 2. Subcommittee on Standard Protocols and Management Guidelines; and 3. Subcommittee of the Nigerian Neurotrauma Registry., Conclusion: The committee concluded that a formal protocol for neurotrauma care is long overdue in Nigeria for the standardization of all aspects of neurotrauma. It then recommended the adoption of these guidelines by all institutions offering services in Nigeria using the management protocols, opening a registry, and mounting researches on the various aspects of neurotrauma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Increasing evidence suggests that large-volume infusions of 0.9% sodium chloride (NaCl) for resuscitation are associated with hyperchloremic metabolic acidosis, renal vasoconstriction, and increased risk of acute kidney injury (AKI). Patients with neurological injury may require hypertonic NaCl for therapeutic hypernatremia, treatment of cerebral salt wasting, hyponatremia, or elevated intracranial pressure. Consequently, this increased exposure to chloride may result in an increased risk for development of AKI. Objective: The primary aim of this study was to describe the risk for development of AKI in neurologically injured patients receiving large volumes of intravenous hypertonic NaCl. Methods: This single-center, retrospective study looked at neurologically injured patients who received hypertonic NaCl and sodium acetate. Data were collected to assess renal function, hyperchloremia, and acidemia. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive association between the amount of daily and overall chloride exposure and development of AKI. Results: A total of 301 patients were screened, and of those, 142 were included. Of the 142 patients included, 13% developed AKI, and 38% developed hyperchloremia. Additionally, 32% of patients were switched from NaCl to sodium acetate after an average of 3.4 ± 1.5 days of NaCl therapy. The ROC curve demonstrated that if patients received greater than 2055 mEq of chloride over 7 days, they were more likely to develop AKI (sensitivity 72%, specificity 70%; P = 0.002; area under the curve = 0.7). Conclusion and Relevance: Neurologically injured patients receiving hypertonic sodium therapy with a high chloride load are at risk of developing hyperchloremia and AKI.

Introduction: Patients with neurocritical injuries account for 10-16 % of pediatric intensive care unit (PICU) admissions and frequently require neuromonitoring., Objective: To describe the current status of neuromonitoring in Argentina., Methods: Survey with 37 questions about neuromonitoring without including patients' data. Period: April-June 2017., Results: Thirty-eight responses were received out of 71 requests (14 districts with 11 498 annual discharges). The PICU/hospital bed ratio was 21.9 (range: 4.2-66.7). Seventy-four percent of PICUs were public; 61 %, university-affiliated; and 71 %, level I. The availability of monitoring techniques was similar between public and private (percentages): intracranial pressure (95), electroencephalography (92), transcranial Doppler (53), evoked potentials (50), jugular saturation (47), and bispectral index (11). Trauma was the main reason for monitoring., Conclusion: Except for intracranial pressure and electroencephalography, neuromonitoring resources are scarce and active neurosurgery availability is minimal. A PICU national registry is required., Competing Interests: None, (Sociedad Argentina de Pediatría.)

The objective of this proof-of-concept study was to demonstrate the targeted delivery of erythropoietin (EPO) using magnetically guided magnetic nanoparticles (MNPs).MNPs consisting of a ferric-ferrous mixture (FeCl3·6H2O and FeCl2·4H2O) were prepared using a co-precipitation method. The drug delivery system (DDS) was manufactured via the spray-drying technique using a nanospray-dryer. The DDS comprised 7.5 mg sodium alginate, 150 mg MNPs, and 1000 IU EPO.Scanning electron microscopy revealed DDS particles no more than 500 nm in size. Tiny particles on the rough surfaces of the DDS particles were composed of MNPs and/or EPO, unlike the smooth surfaces of the only alginate particles. Transmission electron microscopy showed the tiny particles from 5 to 20 nm in diameter. Fourier-transform infrared spectroscopy revealed DDS peaks characteristic of MNPs as well as of alginate. Thermal gravimetric analysis presented that 50% of DDS weight was lost in a single step around 500°C. The mode size of the DDS particles was approximately 850 nm under in vivo conditions. Standard soft lithography was applied to DDS particles prepared with fluorescent beads using a microchannel fabricated to have one inlet and two outlets in a Y-shape. The fluorescent DDS particles reached only one outlet reservoir in the presence of a neodymium magnet. The neurotoxicity was evaluated by treating SH-SY5Y cells in 48-well plates (1 × 10 cells/well) with 2 μL of a solution containing sodium alginate (0.075 mg/mL), MNPs (1.5 mg/mL), or sodium alginate + MNPs. A cell viability assay kit was used to identify a 93% cell viability after MNP treatment and a 94% viability after sodium alginate + MNP treatment, compared with the control. As for the DDS particle neurotoxicity, a 95% cell viability was noticed after alginate-encapsulated MNPs treatment and a 93% cell viability after DDS treatment, compared with the control.The DDS-EPO construct developed here can be small under in vivo conditions enough to pass through the lung capillaries with showing the high coating efficiency. It can be guided using magnetic control without displaying significant neurotoxicity in the form of solution or particles.

In the central nervous system (CNS), neuronal functionality is highly dependent on mitochondrial integrity and activity. In the context of a damaged or diseased brain, mitochondrial dysfunction leads to reductions in ATP levels, thus impairing ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial ability to generate ATP may be a basic premise to restore neuronal functionality. Recently, emerging data in rodent and human studies suggest that mitochondria and its components are surprisingly released into extracellular space and potentially transferred between cells. Transferred mitochondria may support oxidative phosphorylation in recipient cells. In this mini-review, we (a) survey recent findings in cell to cell mitochondrial transfer and the presence of cell-free extracellular mitochondria and its components, (b) review experimental details of how to detect extracellular mitochondria and mitochondrial transfer in the CNS, (c) discuss strategies and tissue sources for mitochondria isolation, and (d) explore exogenous mitochondrial transplantation as a novel approach for CNS therapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries., (Copyright © 2019 Yates, Anthony, Ruitenberg and Couch.)

The basis for assessing thoracolumbar vertebral body fractures are two established classification systems. Important, especially in terms of further treatment, is the distinction between osteoporotic and healthy bones. The AO Spine classification offers a comprehensive tool for healthy bones to reliably specify the morphological criterias (alignment, integrity of the intervertebral disc, fragment separation, stenosis of the spinal canal). In addition to the fracture morphology, the OF classification for osteoporotic fractures includes patient-specific characteristics to initiate adequate therapy. In general an adequate pain therapy is required for early rehabilitation. While in the bone healthy population, physiotherapy reduces the risk of muscle deconditioning, in the osteoporotic population it additionally serves to prevent subsequent fractures. Unlike osteoporotic patients, bone healthy patients with vertebral fractures should not undergo a corset/orthosis treatment., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To characterize the marketplace for direct-to-consumer (DTC) unproven stem cell-based interventions (SCBI) for neurologic diseases and injuries using crowdfunding data., Methods: Search terms were developed from previous empirical studies of DTC businesses and the International Classification of Diseases-11 for neurologic diseases and used to query GoFundMe's internal search engine. Campaigns initiated November 2017-2018 and seeking SCBI for neurologic diseases and injuries (n = 1,030) were reviewed to identify the number of donors, number of Facebook shares, recipient location, funding pledged, funding requested, underlying neurologic condition, treatment location, and treatment facility name., Results: A total of 1,030 crowdfunding campaigns for SCBI for neurologic diseases and injuries requested $33,449,979 and received $5,057,069 from 38,713 donors. The most common neurologic condition identified was multiple sclerosis (MS) (n = 404, 35.5%). Of campaigns naming specific destination facilities (n = 392), the most common clinical settings identified were the Stem Cell Institute in Panama City, Panama (n = 91, 23.2%), StemGenex in San Diego, California (n = 44, 11.2%), and Clinica Ruiz in Puebla, Mexico (n = 36, 9.2%)., Conclusions: MS dominated the total number of crowdfunding campaigns. Most campaigns were linked to individuals from regions geographically proximal to destination facilities advertising SCBI for particular neurologic diseases. Most of the clinical destinations were located in comparatively high-income countries such as the United States, Mexico, and Panama. These findings provide considerable insight into the DTC marketplace for SCBI. Analysis of crowdfunding campaigns can be used to develop more targeted patient education initiatives and health policies related to domestic and international travel for unproven SCBI., (© 2019 American Academy of Neurology.)

Nerous system diseases, both central and peripheral, bring an incredible burden onto patients and enormously reduce their quality of life. Currently, there are still no effective treatments to repair nerve lesions that do not have side effects. Stem cell-based therapies, especially those using dental stem cells, bring new hope to neural diseases. Dental stem cells, derived from the neural crest, have many characteristics that are similar to neural cells, indicating that they can be an ideal source of cells for neural regeneration and repair. This review summarizes the neural traits of all the dental cell types, including DPSCs, PDLCs, DFCs, APSCs and their potential applications in nervous system diseases. We have summed up the advantages of dental stem cells in neural repair, such as their neurotrophic and neuroprotective traits, easy harvest and low rejective reaction rate, among others. Taken together, dental stem cells are an ideal cell source for neural tissue regeneration and repair., (© 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

Acute nerve injuries are routinely encountered in multisystem trauma patients. Advances in surgical treatment of nerve injuries now mean that good outcomes can be achieved. Despite this, old mantras associated with management of nerve injuries, including "wait a year to see if recovery occurs" and "there's nothing we can do", persist. Practicing by these mantras places these patients at a disadvantage. Changes begin to occur in the nerve, neuromuscular junction, and muscle from the moment a nerve injury occurs. These changes can become irreversible approximately 18 to 24 months following denervation. Thus, it is a race to reestablish a functional nerve-muscle connection before these irreversible changes. Good outcomes rely on appropriate acute management and avoiding delays in care. Primary nerve surgery options include direct primary repair, nerve graft repair, and nerve transfer. Acute management of nerve injuries proceeds according to the rule of 3's and requires early cooperation between trauma surgeons who recognize the nerve injury and consultant nerve surgeons. Care of patients with acute traumatic nerve injuries should not be delayed. Awareness of current management paradigms among trauma surgeons will help facilitate optimal upfront management. With the ever-expanding surgical options for management of these injuries and the associated improvement of outcomes, early multidisciplinary approaches to these injuries have never been more important. Old mantras must be replaced with new paradigms to continue to see improvements in outcomes for these patients. The importance of this review is to raise awareness among trauma surgeons of new paradigms for management of traumatic nerve injuries.

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

Objective: This article reviews the clinical results that can be obtained after repair of a traumatic peripheral nerve injury in the pediatric population., Methods: A systematic review of the published literature has been made., Results: Functional outcome after major nerve injuries is sometimes disappointing in adults. However, children have been reported to experience much better functional results after nerve repair than adults. Moreover, recovery generally is faster in children. The superior capacity of children's central nervous system to adapt to external or internal environmental changes (neural plasticity) and the shorter recovery distance from the axon repair site to the target muscle are claimed to be crucial determinants of their favorable outcomes. Moreover, even in the pediatric population, it has been demonstrated that functional results are better the younger the patient is, including better clinical results in those injured in early childhood (< 6 years old) than in those injured in adolescence. Other favorable prognostic factors include the type of nerve injury (with complete transections doing less well than crush injuries) and the timing of surgery (with better outcomes after early repairs)., Conclusions: All efforts should be done to repair in a timely and adequate fashion traumatic peripheral nerve injuries in children, as the results are good.

Stem cell transplantation is a promising strategy to treat brain injuries. However, cell-based therapies are limited because poor local cell engraftment. Here, we present a polylactic acid (PLA) scaffold to support mesenchymal stem cells (MSCs) delivery in stroke. We isolated bone marrow MSCs from adult C57/Bl6 mice, cultured them on PLA polymeric rough microfibrous (PRM) scaffolds obtained by rotary jet spinning, and transplanted over the brains of adult C57/Bl6 mice, carrying thermocoagulation-induced cortical stroke. No inflammatory response to PRM was found. MSCs transplantation significantly reduced the area of the lesion and PRM delivery increased MSCs retention at the injury site. In addition, PRM upregulated α6-integrin and CXCL12 production, which may be the cause for greater cell retention at the lesion site and may provide additional benefit to MSCs transplantation procedures. We conclude that PRM scaffolds offer a promising new system to deliver stem cells to injured areas of the brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Human mesenchymal stromal stem cells (hMSCs) hold regenerative medicine potential due to their availability, in vitro expansion readiness, and autologous feasibility. For neural repair, hMSCs show translational value in research on stroke, spinal cord injury (SCI), and traumatic brain injury. It is pivotal to establish multimodal in vitro systems to investigate molecular mechanisms underlying neural actions of hMSCs. Here, we describe a platform protocol on how to set up organotypic co-cultures of hMSCs (alone or polymer-scaffolded) with explanted adult rat dorsal root ganglia (DRGs) to determine neural injury and recovery events for designing implants to counteract neurotrauma sequelae. We emphasize in vitro hMSC propagation, polymer scaffolding, hMSC stemness maintenance, hMSC-DRG interaction profiling, and analytical formulas of neuroinflammation, trophic factor expression, DRG neurite outgrowth and tropic tracking, and in vivo verification of tailored implants in rodent models of SCI. © 2018 by John Wiley & Sons, Inc., (© 2018 John Wiley & Sons, Inc.)

Object: In patients with focal nerve injury and neuropathic pain cutting the nerve to obtain permanent pain reduction can be considered. Surgery is indicated only if a diagnostic nerve block provides temporary pain relief. We evaluated the predictive value of a block on the outcome of surgery., Methods: In total, three blocks were performed at two week intervals. Patients were blinded to injections containing lidocaine 1% and a placebo was included. Surgery was offered regardless of the effect of the blocks. Twenty-four patients received 72 blocks. Sixteen patients opted for surgery, 5 patients refrained from surgery, and in 3 the blocks provided permanent pain relief. The predictive ability of the block on the outcome of surgery was assessed by calculating the area under a Receiver Operating Characteristic curve (AUC)., Results: The AUC of the first lidocaine block was 0.35 with a 95% confidence interval from 0.077 to 0.62. At 95% confidence (two-sided), the AUC is less than 0.62, and hence the predictive ability of the block was poor. The outcome of the second lidocaine block and saline block did not change the conclusion of the first block., Conclusions: We conclude that the use of blocks to select patients for surgery should be critically appraised., Perspective: A pain relieving response to one open block is currently considered mandatory before patients with focal nerve injury and neuropathic pain are offered surgery. Blinded blocks including a placebo show that responses for selection should be carefully interpreted because they may not be as predictive as generally presumed., Competing Interests: The authors have declared that no competing interests exist.

Objective: In clinical diagnosis and treatment, the occurrence of hypocalcemia during severe nervous system damage is not uncommon but is easily neglected so that delayed treatment, further injurie and even death. It can provide theoretical support for the evaluation of the early identification in calcium ion imbalance and the development of standard calcium ion monitoring program for patients with critical disease by integrating the clinical symptoms induced by low blood calcium based on severe nervous system injury and analyzing the correlation among them.

A significant clinical challenge in the surgery of peripheral nervous system injured via accidents and natural disease is development of biomimetic grafts which could potentially promote nerve repair and regeneration. Although various engineered neural tissue scaffolds have been proposed to support the neural cell functions, they have not been able to instantaneously mimic the whole characteristics of endogenous microenvironment. In this study, we proposed a three-layered tubular scaffold which could provide appropriate electrical, mechanical and biological properties for peripheral nerve engineering. While the inter layer was graphene (Gr) embedded alginate-polyvinyl alcohol (AP-Gr) fibrous scaffold with well-defined anisotropy, the outer layer was double network scaffold of polycaprolactone fumarate (PCLF) and eggshell membrane (ESM). These two layers were attached together using a polycaprolactone (PCL) fibrous membrane, a middle layer, via a simple melting process. Results showed that while the electrical conductivity of the three-layered scaffold was similar to that of AP-Gr fibrous layer, the strength of the three-layered scaffold was significantly improved compared to AP-Gr and ESM-PCLF (1.5 and 1.1 times, respectively) attributed to well attachment of the two layers. As a proof-of-concept, PC12 cell attachment, proliferation, and alignment were studied on the developed three-layered scaffold. The majority of the cells (55%) aligned (<20°) along the major axis of fibers features. Furthermore, electrical stimulation revealed positive effect on the alignment of PC12 cells and change in the cell morphology. With the ease of fabrication and mechanical robustness, the three-layered scaffold of AP-Gr and ESM-PCLF might be utilized as a versatile system for the engineering of peripheral nerve tissue.

Cell transplantation is an ambitious, but arguably realistic, therapy for repair of the nervous system. Cell delivery is a major challenge for clinical translation, especially given the apparently inhibitory astrogliotic environment in degenerated tissue. However, astrogliotic tissue also contains endogenous structural and biochemical cues that can be harnessed for functional repair. Minimizing damage to these cues during cell delivery could enhance cell integration. This theory is supported by studies with an auditory astrocyte scar model, in which cells delivered onto the surface of the damaged nerve were more successfully integrated in the host than those injected into the tissue. We consider the application of this less invasive approach for nerve injury and its potential application to some neurodegenerative disorders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Trauma to either the central or peripheral nervous system (PNS) often leads to significant loss of function and disability in patients. This high rate of long-term disability is due to the overall limited regenerative potential of nervous tissue, even though the PNS has more regenerative potential than the central nervous system (CNS). The supporting glial cells in the periphery, Schwann cells, are part of the reason for the improved recovery observed in the PNS. In the CNS, the glial populations, astrocytes and oligodendrocytes (OLs), do not have as much potential to promote regeneration and are at times inhibitory to neuronal growth. In particular, the inhibitory roles astrocytes play following trauma has led to a historical focus on neurons and OLs instead of astrocytes. Recently, this focus has shifted as new, regenerative astrocyte phenotypes have been described. From these observations, glial cells clearly play critical roles in native recovery pathways in both the CNS and PNS. This makes the ability to manipulate both transplanted and native glial cell phenotypes a potentially successful strategy to improve nerve injury outcomes. This review focuses on factors that cause glial cells to adopt repair phenotypes and biomaterials that manipulate and/or harness these glial phenotypes.

Neurological injury is the primary lethal mechanism of injury in children, and the primary etiology of long-term disability after trauma. Laboratories and clinical/translational teams have sought to develop stem/progenitor cell therapies to improve recovery in a clinical setting in which there is no significant reparative option. While none of these treatments are currently standard therapeutics, phase IIb clinical trials are underway in both adults and children in severe traumatic brain injury (TBI) and phase I/IIa trials in spinal cord injury. This review will characterize the cell therapy strategies: cell replacement and tissue integration vs. immunomodulation/enhanced endogenous tissue repair. TBI is somewhat different from other central nervous system injuries (spinal cord injury and stroke), in that TBI is a diffuse injury, whereas spinal cord injury and stroke are anatomically discrete. Importantly, this drives cell therapy approaches, as TBI is less apt to be treatable with a local cell replacement intervention. More localized injuries may be more amenable to local approaches and cell replacement to bridge focal gaps. This review focuses on a few reports in the field that highlight areas of progress, but is not intended to be a comprehensive survey of the state of regenerative medicine for neurological injuries.

Peripheral nerve injury affects 2.8% of trauma patients with severe cases often resulting in long-lived permanent disability, despite nerve repair surgery. Autologous Schwann cell (SC) therapy currently provides an exciting avenue for improved outcomes for these patients, particularly with the possibility to derive SCs from easily-accessible adult skin. However, due to current challenges regarding the efficient expansion of these cells, further optimization is required before they can be seriously considered for clinical application. Here, a microcarrier-based bioreactor system is proposed as a means to scale-up large numbers of adult skin-derived SCs for transplantation into the injured nerve. Bioprocessing parameters that allow for the expansion of adult rodent SCs have been identified, whilst maintaining similar rates of proliferation (as compared to static-grown SCs), expression of SC markers, and, importantly, their capacity to myelinate axons following transplant into the injured sciatic nerve. The same bioprocessing parameters can be applied to SCs derived from adult human skin, and like rodent cells, they sustain their proliferative potential and expression of SC markers. Taken together, this dataset demonstrates the basis for a scalable bioprocess for the production of SCs, an important step towards clinical use of these cells as an adjunct therapy for nerve repair. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Examine the association of a daily palliative care needs checklist on outcomes for family members of patients discharged from the neurosciences intensive care unit (neuro-ICU)., Methods: We conducted a prospective, longitudinal cohort study in a single, thirty-bed neuro-ICU in a regional comprehensive stroke and level 1 trauma center. One of two neuro-ICU services that admit patients to the same ICU on alternating days used a palliative care needs checklist during morning work rounds. Between March and October, 2015, surveys were mailed to family members of patients discharged from the neuro-ICU., Results: Nearly half of surveys (n = 91, 48.1%) were returned at a median of 4.7 months. At the time of survey completion, mean Modified rankin scale score (mRS) of neuro-ICU patients was 3.1 (SD 2). Overall ratings of quality of care were relatively high (82.2 on a 0-100 scale) with 32% of family members meeting screening criteria for depressive syndrome. The primary outcome measuring family satisfaction, consisting of eight items from the Family Satisfaction in the ICU questionnaire, did not differ significantly between families of patients from either ICU service nor did family ratings of depression (PHQ-8) and post-traumatic stress (PCL-17)., Conclusions: Among families of patients discharged from the neuro-ICU, the daily use of a palliative care needs checklist had no measurable effect on family satisfaction scores or long-term psychological outcomes. Further research is needed to identify optimal interventions to meet the palliative care needs specific to family members of patients treated in the neuro-ICU.

The brain, due to intensive cellular processes and maintenance of electrochemical gradients, is heavily dependent on a constant supply of energy. Brain injury, and critical illness in general, induces a state of increased metabolism and catabolism, which has been proven to lead to poor outcomes. Of all the biochemical interventions undertaken in the ICU, providing nutritional support is perhaps one of the most undervalued, but potentially among the safest, and most effective interventions. Adequate provisions of calories and protein have been shown to improve patient outcomes, and guidelines for the nutritional support of the critically ill patient are reviewed. However, there are no such specific guidelines for the critically ill patient with neurological injury. Patients with primary or secondary neurological disorders are frequently undernourished, while data suggest this population would benefit from early and adequate nutritional support, although comprehensive clinical evidence is lacking. We review the joint recommendations from the Society for Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition, as they pertain to neurocritical care, and assess the recommendations for addressing nutrition in this patient population.

Purpose of Review: This article discusses neurologic complications resulting from environmental injuries and the treatment modalities for these conditions., Recent Findings: Recent advances include improved management of altitude sickness. Relatively uncommon conditions, such as keraunoparalysis (lightning-induced paralysis) and high-pressure neurologic syndrome, are areas of ongoing study., Summary: Environmental injuries may be associated with serious neurologic sequelae. This article reviews thermal and electrical injuries as well as injuries related to aviation, altitude, and diving. Recognition of signs and symptoms of such complex injuries and exposures will permit accurate diagnoses and improved outcomes.

Introduction: Since its discovery as a major CNS-abundant protein 25 years ago, Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has emerged as an important enzyme in regulating brain protein metabolism, by coupling to the proteasome pathway of protein degradation. Areas covered: UCH-L1 is implicated in both familial and sporadic Parkinson disease and other chronic neurodegenerative diseases. Also, UCH-L1 has been recently emerging as a biofluid-based biomarker for various forms of acute neurotrauma and CNS injury. Expert opinion: The loss of UCH-L1 activity coupled with the gain of proteinopathy function are linked to neurodegeneration such as Parkinsonism and Alzheimer's disease. In addition, certain post-translational modifications of UCH-L1 might promote the conversion of the cytosolic UCH-L1(C) to the membrane-associated UCH-L1(M) form, which seems to play a role in alpha-synucleinopathy formation. Thus, targeting the conversion of UCH-L1(C) to the UCH-L1(M) form might be the key to developing therapies for neurodegenerative diseases linked to UCH-L1. In parallel, UCH-L1 is also emerging as a promising neuron-derived biomarker for traumatic brain injury, ischemic and homographic stroke, pediatric hypoxic-ischemic encephalopathy, spinal cord injury, epileptic seizure and cardiac arrest. This shows that UCH-L1 has strong potential as a robust and universal biomarker target for various forms of CNS injury.

Culinary and medicinal mushrooms have been appreciated since prehistoric times as valuable resources for food and medicine. Edible mushrooms represent an untapped source of nutraceuticals and valuable palatable food. Long considered tonics, they are now treasured as functional foods that can improve human health and quality of life. Numerous studies have provided insights into the neuroprotective effects of edible mushrooms, which are attributed to their antioxidant, antineuroinflammatory, and cholinesterase inhibitory properties, and their ability to prevent neuronal death. Here we review the recent literature on the role of culinary and medicinal mushrooms in the management of neurodegenerative diseases and neurotrauma. We highlight some of the molecular mechanisms for how these alternative medicines provide health benefits that could help us to harness their neuroprotective effects.

Background: Although relatively uncommon, neurological deficits following hip and knee arthroplasty can have permanent and debilitating consequences. This study was conducted to quantify the effectiveness of an educational curriculum aimed at standardizing the identification of and acute response to postoperative neurological deficits in the inpatient setting, specifically with respect to improvements in clinician knowledge, confidence levels, and communication skills., Methods: A multidisciplinary committee at a single, high-volume academic institution created an algorithm delineating the appropriate clinical actions and escalation procedures in the setting of a postoperative neurological deficit for each clinical practitioner involved in care for patients who undergo arthroplasty. An educational curriculum composed of online learning modules and an in-person "boot camp" featuring simulations with standardized patients was developed, along with assessments of clinician knowledge, confidence levels, and communication skills. Nurses, physical therapists, physician assistants, residents, fellows, and attending surgeons were encouraged to participate. The intervention spanned a 5-month period in 2015 with a mean time of 18.4 weeks between baseline assessments and the time of the latest follow-up., Results: Online modules were completed by 322 individuals, boot camp was completed by 70 individuals, and latest assessments were completed by 38 individuals. The percentage correct on the knowledge assessment increased from 74.5% before the learning modules to 89.5% immediately after (p < 0.001) but degraded over time such that there was no significant difference between baseline and the latest follow-up scores (p = 0.11). Over the course of the boot camp, physician assistants and residents successfully performed approximately 91% of the indicated actions on the scoring rubric; physical therapists and nurses successfully performed 78%. Scores on the communication skills assessment showed a significant mean increase (p = 0.02) over the course of the intervention from 30.32 to 32.50, and the mean self-assessed confidence survey scores increased by 16.7%, from 7.2 to 8.4 (p < 0.001)., Conclusions: A multimodality educational curriculum aimed at quality improvement can produce significant knowledge improvements, but these gains may not be maintained over time without further instruction. Gains in confidence and communication skills appear to be more long-lasting.

Objective: To evaluate the correlation between the treatment, the characteristics of the lesions and the clinical outcome of patients with traumatic injuries to the craniocervical junction., Methods: This was a retrospective study of patients treated conservatively or surgically between 2010 and 2013 with complete data sets., Results: We analyzed 37 patients, 73% were men with mean age of 41.7 years. Of these, 32% were submitted to initial surgical treatment and 68% received conservative treatment. Seven (29%) underwent surgery subsequently. In the surgical group, there were seven cases of odontoid type II fractures, two cases of fracture of posterior elements of the axis, one case of C1-C2 dislocation with associated fractured C2, one case of occipitocervical dislocation, and one case of combined C1 and C2 fractures, and facet dislocation. Only one patient had neurological déficit that improved after treatment. Two surgical complications were seen: a liquoric fistula and one surgical wound infection (reaproached). In the group treated conservatively, odontoid fractures (eight cases) and fractures of the posterior elements of C2 (five cases) were more frequent. In two cases, in addition to the injuries of the craniocervical junction, there were fractures in other segments of the spine. None of the patients who underwent conservative treatment presented neurological deterioration., Conclusion: Although injuries of craniocervical junction are relatively rare, they usually involve fractures of the odontoid and the posterior elements of the axis. Our results recommend early surgical treatment for type II odontoid fractures and ligament injuries, the conservative treatment for other injuries., Objetivo: Avaliar a correlação entre o tratamento, as características das lesões e o resultado clínico em pacientes com lesões traumáticas na junção craniocervical., Métodos: Estudo retrospectivo de pacientes maiores de 18 anos tratados de forma conservadora ou cirúrgica, entre 2010 e 2013., Resultados: Foram analisados 37 pacientes, 73% eram do sexo masculino e a média de idade foi de 41,7 anos. Inicialmente 32% dos pacientes foram submetidos a tratamento cirúrgico, e 68% foram submetidos a tratamento conservador. Sete pacientes (29%) do grupo conservador foram submetidos posteriormente à cirurgia. No grupo cirúrgico, houve sete casos de fratura de odontóide tipo II, dois casos de fratura de elementos posteriores do áxis, um caso de luxação C1-C2, um caso de deslocamento occipito-cervical e um caso de fraturas de C1 e C2 e luxação facetária. Um paciente apresentava déficit neurológico, melhorando após o tratamento. Houve duas complicações pós-cirúrgicas, uma fístula liquórica e uma infecção de ferida operatória (reabordada). No grupo conservador, predominaram as fraturas do odontóide (oito) e dos elementos posteriores de C2 (cinco). Em dois casos, havia também fraturas em outros segmentos da coluna. Nenhum dos pacientes deste grupo apresentou deterioração neurológica., Conclusão: As lesões da junção craniocervical são raras, sendo mais frequentes as fraturas do odontóide e dos elementos posteriores do áxis. Nossos resultados recomendam o tratamento cirúrgico precoce para os pacientes com fraturas do odontóide tipo II e lesões ligamentares, e tratamento conservador para os demais pacientes., Competing Interests: none.

Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery. The development of adjunctive strategies that broadly support plasticity to facilitate the benefits of rehabilitative interventions has the potential to improve treatment of a wide range of neurological disorders. Recently, stimulation of the vagus nerve in conjunction with rehabilitation has emerged as one such potential targeted plasticity therapy. Vagus nerve stimulation (VNS) drives activation of neuromodulatory nuclei that are associated with plasticity, including the cholinergic basal forebrain and the noradrenergic locus coeruleus. Repeatedly pairing brief bursts of VNS sensory or motor events drives robust, event-specific plasticity in neural circuits. Animal models of chronic tinnitus, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and post-traumatic stress disorder benefit from delivery of VNS paired with successful trials during rehabilitative training. Moreover, mounting evidence from pilot clinical trials provides an initial indication that VNS-based targeted plasticity therapies may be effective in patients with neurological diseases and injuries. Here, I provide a discussion of the current uses and potential future applications of VNS-based targeted plasticity therapies in animal models and patients, and outline challenges for clinical implementation.

Recent research has suggested that the growth of central nervous system (CNS) axons during development is mediated through the PI3K/Akt/mammalian target of rapamycin (mTOR) intracellular signalling axis and that suppression of activity in this pathway occurs during maturity as levels of the phosphatase and tensin homologue (PTEN) rise and inhibit PI3K activation of mTOR, accounting for the failure of axon regeneration in the injured adult CNS. This hypothesis is supported by findings confirming that suppression of PTEN in experimental adult animals promotes impressive axon regeneration in the injured visual and corticospinal motor systems. This review focuses on these recent developments, discussing the therapeutic potential of a mTOR-based treatment aimed at promoting functional recovery in CNS trauma patients, recognising that to fulfil this ambition, the new therapy should aim to promote not only axon regeneration but also remyelination of regenerated axons, neuronal survival and re-innervation of denervated targets through accurate axonal guidance and synaptogenesis, all with minimal adverse effects. The translational challenges presented by the implementation of this new axogenic therapy are also discussed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Traumatic injuries to the nervous system lead to a common clinical problem with a quite high incidence and affect the patient’s quality of life. Based on a major challenge not yet addressed by current therapeutic interventions for these diseases, a novel promising field of neural tissue engineering has emerged, grown, and attracted increasing interest. This review provides a brief summary of the recent progress in the field, especially in combination with the research experience of the author’s group. Several important aspects related to tissue engineered nerves, including the theory on their construction, translation into the clinic, improvements in fabrication technologies, and the formation of a regenerative environment, are delineated and discussed.Furthermore, potential research directions for the future development of neural tissue engineering are suggested.

The introduction of evidence based medicine de-emphasised clinical experience and so-called "background information" and stressed the importance of evidence gained from clinical research when making clinical decisions. For many years randomised controlled trials have been seen to be the only way to advance clinical practice, however, applying this methodology in the context of severe trauma can be problematic. In addition, it is increasingly recognised that considerable clinical experience is required in order to critically evaluate the quality of the evidence and the validity of the conclusions as presented. A contemporary example is seen when considering the role of decompressive craniectomy in the management of neurotrauma. Although there is a considerable amount of evidence available attesting to the efficacy of the procedure, considerable clinical expertise is required in order to properly interpret the results of these studies and the implications for clinical practice. Given these limitations the time may have come for a redesign of the traditional pyramid of evidence, to a model that re-emphasises the importance of "background information" such as pathophysiology and acknowledges the role of clinical experience such that the evidence can be critically evaluated in its appropriate context and the subsequent implications for clinical practice be clearly and objectively defined., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across "gaps" in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration.

Purpose: Craniocervical arterial dissections (CCADs) represent a preventable cause of acute ischemic stroke (AIS). Our objective was to describe clinical presentation, imaging features, treatment strategies, and report clinical and imaging outcomes of CCADs at a large pediatric tertiary referral center., Methods: Electronic medical records were queried using variations of the word dissection for patients under 25 years of age with neuroimaging over a 13-year period. Medical and imaging records were reviewed to identify carotid, vertebral, or intracranial dissections. Demographics, presenting symptoms, presence of AIS, mechanism of injury, dissection location, dissection treatment, and complications stemming from treatment were collected. Clinical outcome was classified according to modified Rankin Scale (mRS) score. Imaging follow-up was obtained until the dissection healed or stabilized., Results: A total 6,289 patients met initial search criteria. Of the 42 (0.7%) patients with CCADs, 23 (54.8%) had internal carotid artery (ICA) dissections, and 17 (40.5%) had vertebrobasilar (VB) dissections. More females had ICA dissections (p = 0.002), and more males had VB dissections (p = 0.01). CCADs associated with traumatic presentation occurred in 34 patients (81.0%), while 8 (19.0%) were spontaneous. Good outcomes (mRS 0-3) were noted for 36 patients, and 5 had poor outcomes (mRS 4-6). In the 17 patients with vessel occlusion, 50.0% had partial or complete recanalization at a mean follow-up of 23.9 months., Conclusions: CCAD is commonly related to trauma and presents with AIS. The majority of patients experience good clinical outcome. Recanalization of initial vessel occlusion occurs in half of cases at 2 years.

Upper motoreuron lesions (UML) affects people of all ages and conditions and is a major cause of disability in the young. Whereas active exercise is recognised as paramount to restore the lost motor functions, passive mobilisation of the affected limbs is regarded as a means to safeguard muscular tissue properties during a period of disuse and lack of voluntary control, which often characterises the acute and sub-acute phases. The purpose of the present work is to study the cortical reactivity in UML patients who are treated for two weeks with a robotic passive ankle mobiliser, and the clinical effects of this treatment. The rationale is that, if passive mobilisation can affect positively the functional reorganisation at a cortical level, it could be proposed as a suitable tool to maintain afferentation and guide central nervous remapping, thus bridging the period of time when active exercise is impossible due to acute paresis. Preliminary results on 7 patients (aged 15.35±4.36) showed that this therapy is very well tolerated and suggest that its application could specifically improve ankle PROM and plantarflexor muscle length. EEG data showed improved desynchronisation in at least one frequency band in 3 patients of the study, thus confirming the effects of passive mobilisation on the cortical re-organisation of some patients having UML.

Purpose of Review: Sports neurology is an emerging area of subspecialty. Neurologists and non-neurologists evaluating and managing individuals participating in sports will encounter emergencies that directly or indirectly involve the nervous system. Since the primary specialty of sports medicine physicians and other practitioners involved in the delivery of medical care to athletes in emergency situations varies significantly, experience in recognition and management of neurologic emergencies in sports will vary as well. This article provides a review of information and elements essential to neurologic emergencies in sports for the practicing neurologist, although content may be of benefit to readers of varying background and expertise., Recent Findings: Both common neurologic emergencies and less common but noteworthy neurologic emergencies are reviewed in this article. Issues that are fairly unique to sports participation are highlighted in this review. General concepts and principles related to treatment of neurologic emergencies that are often encountered unrelated to sports (eg, recognition and treatment of status epilepticus, increased intracranial pressure) are discussed but are not the focus of this article. Neurologic emergencies can involve any region of the nervous system (eg, brain, spine/spinal cord, peripheral nerves, muscles). In addition to neurologic emergencies that represent direct sports-related neurologic complications, indirect (systemic and generalized) sports-related emergencies with significant neurologic consequences can occur and are also discussed in this article., Summary: Neurologists and others involved in the care of athletes should consider neurologic emergencies in sports when planning and providing medical care.