Unpacking the Role of Extracellular Vesicles in Ischemic and Hemorrhagic Stroke: Pathophysiology and Therapeutic Implications.

Stroke is a leading cause of death and disability worldwide. Inflammation and microvascular dysfunction have been associated with brain injury and long-term disability after both ischemic and hemorrhagic stroke. Recent studies have suggested a potential role of extracellular vesicles (EVs) as a link underlying these pathogenic processes. EVs are cell-derived particles enveloped by a lipid bilayer, containing proteins, lipids, and nucleic acids. From a functional standpoint, EVs can facilitate intercellular communication, including across the blood-brain barrier (BBB). Recent advances in EV research have shown a preferential release of EVs from specific cell types in the context of stroke, some of which were associated with increased neuroinflammation, microvascular dysfunction, and neuronal cytotoxicity while others offered a degree of neuroprotection. However, one historic challenge in the studies of EVs in stroke is the lack of consistent definitions and methods to analyze EVs, only recently updated in the MISEV2018 guidelines. Given limitations and complexity in the treatment of stroke, particularly delivery of therapeutics across the BBB, increasing attention has been paid towards manipulating EVs as one vehicle that can permit targeted therapeutic delivery to the central nervous system. These discoveries point towards a future where a better understanding of EVs will advance our knowledge of stroke-associated mechanisms of cerebral and systemic injury and contribute to the development of novel treatments. Here, we review the role that EVs play in ischemic and hemorrhagic stroke.

Clinical and radiographic benefits of skipping C7 instrumentation in posterior cervicothoracic fusion: a retrospective analysis.

Background: C7 instrumentation during posterior cervicothoracic fusion can be challenging because it requires additional work of either placing side connectors to a single rod or placing two rods. Our clinical observations suggested that skipping instrumentation at C7 in a multi-level posterior cervicothoracic fusion will result in minimal intraoperative complications and decreased blood-loss while still maintaining sagittal balance parameters of cervical fusion. The objective of this study is to determine the clinical and radiographic outcomes of skipping C7 instrumentation compared to instrumenting the C7 vertebra in posterior cervicothoracic fusion. Methods: This is a retrospective chart review of 314 consecutive patients who underwent multilevel posterior cervical fusion (PCF) at our institution. Out of 314 patients, 19 were instrumented at C7 serving as the control group, while the remaining 295 patients were not. Evaluation of efficacy was based on intraoperative complications, operative time, estimated blood loss (EBL), significant long-term complications, and radiographic evidence of fusion. Results: Skipping the C7 level resulted in a significant reduction in EBL (488±576 vs. 822±1,137; P=0.007); however, operative time was similar between groups (174±95 vs. 184±86 minutes; P=0.844). Complications were minimal in both groups and not statistically significant. Radiographic analysis revealed C7 bridge patients had a significantly increased postoperative sagittal vertical axis (SVA) (29.3±13.1 vs. 20.2±3.1 mm; P=0.008); however, there was no significant difference between groups in SVA correction (-0.3±16.2 vs. -16.1±16.0 mm; P=0.867), T1 slope correction (3.4°±9.9° vs. 3.2°±5.5°; P=0.127), or cervical cobb angle correction (-5.7°±14.2° vs. -7.0°±12.2°; P=0.519). There were no significant long-term complications in either group. Conclusions: Skipping instrumentation at C7 in a multilevel posterior cervicothoracic fusion is associated with significantly reduced operative blood loss without loss of radiographic correction. This study demonstrates the clinical benefits of skipping C7 instrumentation in posterior cervicothoracic fusion with maintenance of radiographic correction parameters.

Utility of neuromuscular blockade reversal in the evaluation of acute neurosurgical patients: A retrospective case-series.

OBJECTIVE: Sugammadex reversal of neuromuscular blocking agents (NMBAs) is usually performed postoperatively. A scarcity of literature exists exploring sugammadex use for timely neurological examination of neurosurgical patients. NMBAs, like rocuronium, are used in the Emergency Department during intubation and their unpredictable duration of action often impedes timely and accurate assessment of patient neurological status. We aim to explore the role of sugammadex in evaluating patients in need of acute neurosurgical care. METHODS: Retrospective assessment of patients presenting with traumatic brain injury or intracranial hemorrhage was conducted at our level 1 trauma center. Patients of interest were those for whom sugammadex reversal of rocuronium neuromuscular blockade, from intubating doses, was pursued to ensure timely neurologic assessment. Nine patients were identified for whom GCS pre-/post-sugammadex, rocuronium dosing, elapsed time between rocuronium administration and reversal, and clinical course data were retrieved. RESULTS: Arrival GCS was 5.2 ± 3.2, with intubation accomplished within 10 ± 2.5 min of presentation. Rocuronium dosing was consistent between patients, average single dose of 1.2 ± 0.3 mg/kg. Lingering neuromuscular blockade ranged from 28 to 132 min (87.3 ± 34.3 min). All patients exhibited a GCS of 3 T upon initial neurosurgical evaluation, prior to reversal. Post-reversal GCS rose to 6.0 T ± 2.2. Sugammadex facilitated more accurate clinical decision making in 8 of 9 patients, including prevention of unnecessary invasive procedures. Two of 9 patients were eventually discharged home or to a rehabilitation facility. CONCLUSIONS: Rocuronium neuromuscular blockade can linger beyond pharmacokinetic predictions, thus delaying timely and precise neurologic assessment. Our data suggests sugammadex may be a useful addition to the clinician's armamentarium for acute neurologic assessment in the neurosurgical population. Sugammadex may impact clinical decision-making in certain patients and allow for more informed decision-making by families and physicians alike. Prospective studies are needed to definitively assess the impact of sugammadex on outcomes in acute neurosurgical settings.

Generational Changes in Lumbar Spinal Canal Dimensions: Findings from a Sample U.S. Population.

OBJECTIVE: Evaluation of lumbar canal dimensions in a Chicago population born in 2 different decades. METHODS: This is a retrospective chart review analyzing computed tomography reconstruction from patients born between 1940 and 1949 (older group) and 1970 and 1979 (younger group). The cross-sectional area (CSA) and anterior-posterior diameter (APD) of the lumbar bony canal was measured at each lumbar level at the level of the pedicle. RESULTS: Our study includes 918 patients, 372 in the young group and 546 in the older group. Older patients have significantly larger CSA and APD at all lumbar levels compared with younger patients. Further, CSA and APD comparisons between ethnicities demonstrate significant differences between individuals of Caucasian, Asian, Hispanic, African American, and Other ethnicities. Lastly, there were no differences in CSA or APD compared with factors known to affect bone health (smoking, steroid use, osteoporosis, cancer history). CONCLUSIONS: As seen in European cohorts, our data suggest that patients born in the 1940s have both larger canal area and larger anterior-posterior diameter compared with the younger generation. These data suggest that significant differences exist between ethnicities. These differences highlight the importance of studying normal anatomical dimensions within different geographical populations and the importance of studying non-modifiable factors as they relate to spinal dimensions and spine patients. Furthermore, spinal canal growth seems to be negatively influenced in younger generations, a rather unexpected but worrying finding.

Activated Mesenchymal Stem Cells Induce Recovery Following Stroke Via Regulation of Inflammation and Oligodendrogenesis.

Background Brain repair mechanisms fail to promote recovery after stroke, and approaches to induce brain regeneration are scarce. Mesenchymal stem cells (MSC) are thought to be a promising therapeutic option. However, their efficacy is not fully elucidated, and the mechanism underlying their effect is not known. Methods and Results The middle cerebral artery occlusion model was utilized to determine the efficacy of interferon-γ-activated mesenchymal stem cells (aMSCγ) as an acute therapy for stroke. Here we show that treatment with aMSCγ is a more potent therapy for stroke than naive MSC. aMSCγ treatment results in significant functional recovery assessed by the modified neurological severity score and open-field analysis compared with vehicle-treated animals. aMSCγ-treated animals showed significant reductions in infarct size and inhibition of microglial activation. The aMSCγ treatment suppressed the hypoxia-induced microglial proinflammatory phenotype more effectively than treatment with naive MSC. Importantly, treatment with aMSCγ induced recruitment and differentiation of oligodendrocyte progenitor cells to myelin-producing oligodendrocytes in vivo. To elucidate the mechanism underlying high efficacy of aMSCγ therapy, we examined the secretome of aMSCγ and compared it to that of naive MSC. Intriguingly, we found that aMSCγ but not nMSC upregulated neuron-glia antigen 2, an important extracellular signal and a hallmark protein of oligodendrocyte progenitor cells. Conclusions These results suggest that activation of MSC with interferon-γ induces a potent proregenerative, promyelinating, and anti-inflammatory phenotype of these cells, which increases the potency of aMSCγ as an effective therapy for ischemic stroke.

Safety and Efficacy of Skipping C7 Instrumentation in Posterior Cervicothoracic Fusion.

OBJECTIVE: To analyze the safety and efficacy of skipping instrumentation at the C7 vertebra during posterior cervicothoracic fusions. METHODS: This is a retrospective chart review of 53 patients who underwent multilevel posterior cervical fusion between 2010 and 2015. Of 53 patients, 7 patients were instrumented at C7, serving as the control group, whereas the remaining 46 patients were not. Evaluation of efficacy was based on intraoperative complications, operative time, estimated blood loss, significant long-term complications, and radiographic evidence of fusion. RESULTS: Skipping the C7 level resulted in a significant reduction in estimated blood loss (321 ± 214 mL in the C7 bridge group vs. 531 ± 365 mL in the control group) and an insignificant, but decreased, reduction in operative time (155 ± 70 minutes in the C7 bridge group vs. 194 ± 66 minutes in the control group). Two intraoperative complications were noted in the C7 group, and 1 intraoperative complication was noted in the control group. In addition, patients skipped at C7 maintained sagittal balance with fusion rates similar to control patients at follow-up. No significant long-term complications were found in both groups. CONCLUSIONS: Skipping C7 in a multilevel posterior cervicothoracic fusion demonstrates significantly reduced estimated blood loss and faster operative times compared with the control group. In addition, postoperative assessment yielded similar rates of fusion in both groups. Serious negative outcomes of skipping C7 were not found in this retrospective study. Our study results illustrate the clinical benefits of skipping instrumentation at C7 to minimize surgical risk in patients undergoing posterior cervical fusion across the cervicothoracic junction.

Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer's Disease Patients.

Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin+Sox2+ neural progenitor cells (NPCs) and DCX+ neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin+ cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX+PCNA+ cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX+PCNA+ cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.

Cytosolic Phospholipase A2 Facilitates Oligomeric Amyloid-ß Peptide Association with Microglia via Regulation of Membrane-Cytoskeleton Connectivity.

Cytosolic phospholipase A2 (cPLA2) mediates oligomeric amyloid-ß peptide (oAß)-induced oxidative and inflammatory responses in glial cells. Increased activity of cPLA2 has been implicated in the neuropathology of Alzheimer's disease (AD), suggesting that cPLA2 regulation of oAß-induced microglial activation may play a role in the AD pathology. We demonstrate that LPS, IFNγ, and oAß increased phosphorylated cPLA2 (p-cPLA2) in immortalized mouse microglia (BV2). Aß association with primary rat microglia and BV2 cells, possibly via membrane-binding and/or intracellular deposition, presumably indicative of microglia-mediated clearance of the peptide, was reduced by inhibition of cPLA2. However, cPLA2 inhibition did not affect the depletion of this associated Aß when cells were washed and incubated in a fresh medium after oAß treatment. Since the depletion was abrogated by NH4Cl, a lysosomal inhibitor, these results suggested that cPLA2 was not involved in the degradation of the associated Aß. To further dissect the effects of cPLA2 on microglia cell membranes, atomic force microscopy (AFM) was used to determine endocytic activity. The force for membrane tether formation (Fmtf) is a measure of membrane-cytoskeleton connectivity and represents a mechanical barrier to endocytic vesicle formation. Inhibition of cPLA2 increased Fmtf in both unstimulated BV2 cells and cells stimulated with LPS + IFNγ. Thus, increasing p-cPLA2 would decrease Fmtf, thereby increasing endocytosis. These results suggest a role of cPLA2 activation in facilitating oAß endocytosis by microglial cells through regulation of the membrane-cytoskeleton connectivity.

T-1 pedicle subtraction osteotomy for the treatment of rigid cervical kyphotic deformity: report of 4 cases.

Cervical kyphotic deformity represents a difficult to treat pathology often arising from multiple factors including, but not limited to, traumatic injuries, degenerative changes, and ankylosing spondylitis. Furthermore, treatment of these deformities becomes increasingly difficult with any preexisting instrumentation. Currently, several options exist to treat these severe deformities, with the Smith-Petersen osteotomy and C-7 pedicle subtraction osteotomy being the most frequently used approaches. However, these techniques come with significant risk to the patient including nerve root injury as well as compression of the vertebral arteries. The authors here report on a series of 4 patients with rigid cervical deformity who underwent T-1 pedicle subtraction osteotomy. The authors review the relevant literature and provide a novel, less risky, and potentially more corrective approach for treating cervical deformities.

Pica in a Child with Anterior Cingulate Gyrus Oligodendroglioma: Case Report.

The anterior cingulate gyrus (ACG) is a continued focus of research as its exact role in brain function and vast connections with other anatomical locations is not fully understood. A review of the literature illustrates the role the ACG likely plays in cognitive and emotional processing, as well as a modulating role in motor function and goal-oriented behaviors. While lesions of the cingulate gyrus are rare, each new case broadens our understanding of its role in cognitive neuroscience and higher order processing. The authors present the case of an 8-year-old boy with a 1-month history of staring spells, agitated personality, and hyperphagia notable for the consumption of paper, who was found to have a 3-cm tumor in the left ACG. Following surgical resection of the tumor, his aggressive behavior and pica were ameliorated and the patient made an uneventful recovery, with no evidence of recurrence over the last 6 years since surgical resection. Here we discuss a unique behavioral presentation of pica, along with a review of the current literature, to illustrate functions of the ACG relevant to the location of the lesion.

Corticosteroid Treatment for Metastatic Spinal Cord Compression: A Review.

STUDY DESIGN: Narrative review. OBJECTIVE: Metastatic spinal cord compression (MSCC) is a very frequent complication among cancer patients. Presenting commonly as nocturnal back pain, MSCC typically progresses to lower extremity paresis, loss of ambulatory capabilities, and paraplegia. In addition to standard treatment modalities, corticosteroid administration has been utilized in preclinical and clinical settings as adjunctive therapy to reduce local spinal cord edema and improve clinical symptoms. This article serves as a review of existing literature regarding corticosteroid management of MSCC and seeks to provide potential avenues of research on the topic. METHODS: A literature search was performed using PubMed in order to consolidate existing information regarding dexamethasone treatment of MSCC. Of all search results, 7 articles are reviewed, establishing the current understanding of metastatic spine disease and dexamethasone treatment in both animal models and in clinical trials. RESULTS: Treatment with high-dose corticosteroids is associated with an increased rate of potentially serious systemic side effects. For this reason, definitive guidelines for the use of dexamethasone in the management of MSCC are unavailable. CONCLUSIONS: It is still unclear what role dexamethasone plays in the treatment of MSCC. It is evident that new, more localizable therapies may provide more acceptable treatment strategies using corticosteroids. Looking forward, the potential for more targeted, localized application of the steroid through the use of nanotechnology would decrease the incidence of adverse effects while maintaining the drug's efficacy.

Spinal Compression Fracture Management: A Review of Current Treatment Strategies and Possible Future Avenues.

STUDY DESIGN: Narrative review. OBJECTIVE: Despite the numerous treatment options for vertebral compression fractures, a consensus opinion for the management of patients with these factures has not been established. This review is meant to provide an up-to-date overview of the most common treatment strategies for compression fractures and to suggest possible routes for the development of clearer treatment guidelines. METHODS: A comprehensive database search of PubMed was performed. All results from the past 30 years were obtained and evaluated based on title and abstract. The full length of relevant studies was analyzed for level of evidence, and the strongest studies were used in this review. RESULTS: The major treatment strategies for patients with compression fractures are conservative pain management and vertebral augmentation. Despite potential adverse effects, medical management, including nonsteroidal anti-inflammatory drugs, calcitonin, teriparatide, and bisphosphonates, remains the first-line therapy for patients. Evidence suggests that vertebral augmentation, especially some of the newer procedures, have the potential to dramatically reduce pain and improve quality of life. At this time, balloon-assisted kyphoplasty is the procedure with the most evidence of support. CONCLUSIONS: Based on current literature, it is evident that there is a lack of standard of care for patients with vertebral compression fractures, which is either due to lack of evidence that a procedure is successful or due to serious adverse effects encountered with prolonged treatment. For a consensus to be reached, prospective clinical trials need to be formulated with potential new biomarkers to assess efficacy of treatment strategies.

Spontaneous Resolution of Spinal Epidural Hematoma Resulting from Domestic Child Abuse: Case Report.

Nonaccidental head injury, as seen in domestic child abuse cases, is often associated with spinal injury, and spinal subdural hematoma is the most frequent diagnosis. While spinal epidural hematomas are a rare occurrence, the incidence of spontaneous epidural hematomas occurring in nonaccidental head injury patients is even lower. Epidural hematomas often result in acute focal neurological deficits necessitating emergent neurosurgical intervention. In patients without focal neurological deficits, conservative management may allow for spontaneous resolution of the epidural hematoma. The authors present the case of a 2-year-old boy with a large spinal epidural hematoma resulting after an event of nonaccidental injury, specifically, domestic child abuse. This patient exhibited no focal neurological deficits and was managed conservatively without surgical clot evacuation. On a follow-up visit, repeat imaging studies demonstrated a stable resolution of spinal epidural hematoma, providing further support for the safety of conservative management in these patients.

Intramedullary spinal cord tumors: a review of current and future treatment strategies.

Intramedullary spinal cord tumors have low incidence rates but are associated with difficult treatment options. The majority of patients with these tumors can be initially treated with an attempted resection. Unfortunately, those patients who cannot undergo gross-total resection or have subtotal resection are left with few treatment options, such as radiotherapy and chemotherapy. These adjuvant treatments, however, are associated with the potential for significant adverse side effects and still leave patients with a poor prognosis. To successfully manage these patients and improve both their quality of life and prognosis, novel treatment options must be developed to supplement subtotal resection. New research is underway investigating alternative therapeutic approaches for these patients, including directed, localized drug delivery and nanomedicine techniques. These and other future investigations will hopefully lead to promising new therapies for these devastating diseases.

Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory.

Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via ß-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer's disease.

Improvement in venous outflow following superior sagittal sinus decompression after a gunshot wound to the head: case report.

The most commonly described indications for surgical management of closed depressed skull fractures are hematoma evacuation and repair of extensive cosmetic deformity. Venous sinus injury, which occurs in a subset of depressed skull fractures, is not typically listed as an indication for surgical treatment due to the potential for major venous hemorrhage associated with surgery near these structures. However, if patients exhibit signs and symptoms of intracranial hypertension and radiographic findings demonstrate sinus compromise, surgical elevation of the depressed skull fragments is indicated. The authors present the case of a 25-year-old woman with a depressed skull fracture secondary to a gunshot wound with symptomatic compromise in venous outflow of the posterior one-third of the superior sagittal sinus. The patient was treated with surgical decompression via bilateral craniectomy along with intracranial pressure-lowering medical therapy and had almost full resolution of her presenting symptoms with documented improvement in flow through the superior sagittal sinus. While the use of surgical treatment for these types of injuries is highly debated, the authors demonstrate here that safe, effective surgical management of these patients is possible and that surgical decompression should always be considered in the case of symptomatic venous sinus flow obstruction.

Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here.

This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.

Composite tissue allotransplantation and dysregulation in tissue repair and regeneration: a role for mesenchymal stem cells.

Vascularized composite tissue allotransplantation is a rapidly evolving area that has brought technological advances to the forefront of plastic surgery, hand surgery, and transplant biology. Composite tissue allografts (CTAs) may have profound functional, esthetic, and psychological benefits, but carry with them the risks of life-long immunosuppression and the inadequate abilities to monitor and prevent rejection. Allografts may suffer from additional insults further weakening their overall benefits. Changes in local blood flow, lack of fully restored neurologic function, infection, inflammation with subsequent dysregulated regenerative activity, and paucity of appropriate growth factors may all be involved in reducing the potential of CTAs and therefore serve as new therapeutic targets to improve outcomes. Strategies involving minimized immunosuppression and pro-regenerative therapy may provide a greater path to optimizing long-term CTA function. One such strategy may include mesenchymal stem cells (MSCs), which can provide unique anti-inflammatory and pro-regenerative effects. Insights gained from new studies with MSCs on composite allografts, advances in tissue regeneration reported in other MSC-based clinical studies, as well as consideration of newly described capacities of MSCs, may provide new regenerative based strategies for the care of CTAs.