Intraarterial Transplantation of Mitochondria After Ischemic Stroke Reduces Cerebral Infarction.

Background-: Transplantation of autologous mitochondria into ischemic tissue may mitigate injury caused by ischemia and reperfusion. Methods-: Using murine stroke models of middle cerebral artery occlusion, we sought to evaluate feasibility of delivery of viable mitochondria to ischemic brain parenchyma. We evaluated the effects of concurrent focused ultrasound activation of microbubbles, which serves to open the blood-brain barrier, on efficacy of delivery of mitochondria. Results-: Following intra-arterial delivery, mitochondria distribute through the stroked hemisphere and integrate into neural and glial cells in the brain parenchyma. Consistent with functional integration in the ischemic tissue, the transplanted mitochondria elevate concentration of adenosine triphosphate in the stroked hemisphere, reduce infarct volume and increase cell viability. Additional of focused ultrasound leads to improved blood brain barrier opening without hemorrhagic complications. Conclusions-: Our results have implications for the development of interventional strategies after ischemic stroke and suggest a novel potential modality of therapy after mechanical thrombectomy.

Impact of histopathological classification of non-functioning adenomas on long term outcomes: comparison of the 2004 and 2017 WHO classifications.

PURPOSE: Outcomes of patients with non-functioning pituitary adenomas categorized using the 2004 and 2017 WHO classification systems are understudied. We report outcomes from the University of Virginia of patients with non-functioning pituitary adenomas categorized using both systems. METHODS: We constructed a database from all 239 patients who underwent resection of a non-functioning pituitary adenoma between 2003 and 2015 and had at least 5 years of follow-up. Pathologic diagnosis was determined under both the 2004 and 2017 WHO classification systems. We compared the rates of recurrence and progression between subtypes using univariate and multivariate Cox regression analyses. RESULTS: Nearly 30% of the tumors in our database were classified as null cell adenomas under the 2004 classification system, whereas only 10% of the tumors were classified as null cell adenomas using the 2017 classification system. Most of these tumors were reclassified as either corticotroph or gonadotroph adenomas. Despite our relatively large cohort and average follow-up of nearly 9 years, we did not detect a significant difference in recurrence and progression between subtypes. CONCLUSIONS: The majority of null cell adenomas diagnosed under the 2004 WHO classification system are reclassified as gonadotroph or corticotroph adenomas under the 2017 WHO classification system. Rates of progression and recurrence between subtypes are not as different as previously believed at our institution and require a larger cohort to further investigate.

Diagnostic, Surgical, and Technical Considerations for Lumbar Interbody Fusion in Patients with Osteopenia and Osteoporosis: A Systematic Review.

OBJECTIVE: Osteoporosis is increasing in incidence as the ageing population continues to grow. Decreased bone mineral density poses a challenge for the spine surgeon. In patients requiring lumbar interbody fusion, differences in diagnostics and surgical approaches may be warranted. In this systematic review, the authors examine studies performing lumbar interbody fusion in patients with osteopenia or osteoporosis and suggest avenues for future study. METHODS: A systematic literature review of the PubMed and MEDLINE databases was performed for studies published between 1986 and 2020. Studies evaluating diagnostics, surgical approaches, and other technical considerations were included. RESULTS: A total of 13 articles were ultimately selected for qualitative analysis. This includes studies demonstrating the utility of Hounsfield units in diagnosis, a survey of surgical approaches, as well as exploring the use of vertebral augmentation and cortical bone screw trajectory. CONCLUSIONS: This systematic review provides a summary of preliminary findings with respect to the use of Hounsfield units as a diagnostic tool, the benefit or lack thereof with respect to minimally invasive approaches, and the question of whether or not cement augmentation or cortical bone trajectory confers benefit in osteoporotic patients undergoing lumbar interbody fusion. While the findings of these studies are promising, the current state of the literature is limited in scope and, for this reason, definitive conclusions cannot be drawn from these data. The authors highlight gaps in the literature and the need for further exploration and study of lumbar interbody fusion in the osteoporotic spine.

Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation.

Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

Anatomical Features of the Deep Cervical Lymphatic System and Intrajugular Lymphatic Vessels in Humans.

BACKGROUND: Studies in rodents have re-kindled interest in the study of lymphatics in the central nervous system. Animal studies have demonstrated that there is a connection between the subarachnoid space and deep cervical lymph nodes (DCLNs) through dural lymphatic vessels located in the skull base and the parasagittal area. OBJECTIVE: To describe the connection of the DCLNs and lymphatic tributaries with the intracranial space through the jugular foramen, and to address the anatomical features and variations of the DCLNs and associated lymphatic channels in the neck. METHODS: Twelve formalin-fixed human head and neck specimens were studied. Samples from the dura of the wall of the jugular foramen were obtained from two fresh human cadavers during rapid autopsy. The samples were immunostained with podoplanin and CD45 to highlight lymphatic channels and immune cells, respectively. RESULTS: The mean number of nodes for DCLNs was 6.91 ± 0.58 on both sides. The mean node length was 10.1 ± 5.13 mm, the mean width was 7.03 ± 1.9 mm, and the mean thickness was 4 ± 1.04 mm. Immunohistochemical staining from rapid autopsy samples demonstrated that lymphatic vessels pass from the intracranial compartment into the neck through the meninges at the jugular foramen, through tributaries that can be called intrajugular lymphatic vessels. CONCLUSIONS: The anatomical features of the DCLNs and their connections with intracranial lymphatic structures through the jugular foramen represent an important possible route for the spread of cancers to and from the central nervous system; therefore, it is essential to have an in-depth understanding of the anatomy of these lymphatic structures and their variations.

Systematic Review of Functional Mapping and Cortical Reorganization in the Setting of Arteriovenous Malformations, Redefining Anatomical Eloquence.

Objective: The goal of this study was to systematically review functional mapping and reorganization that takes place in the setting of arteriovenous malformations (AVMs) and its potential impact on grading and surgical decision making. Methods: A systematic literature review was performed using the PubMed database for studies published between 1986 and 2019. Studies assessing brain mapping and functional reorganization in AVMs were included. Results: Of the total 84 articles identified in the original literature search, 12 studies were ultimately selected. This includes studies evaluating the impact of cortical reorganization on patient outcomes and factors impacting and triggering cortical reorganization in AVM. Conclusion: These studies demonstrate the utility of preoperative brain mapping and acknowledgment of functional reorganization in the setting of AVMs. While these findings led to alterations in Spetzler-Martin grading and subsequent surgical decision making, it remains unclear the clinical utility of this information when assessing patient outcomes. While promising, more research is required before recommendations can be made regarding functional brain mapping and cortical reorganization with respect to AVM surgery involving eloquent brain tissue.

Early obliteration of pediatric brain arteriovenous malformations after stereotactic radiosurgery: an international multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs. METHODS: The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared. RESULTS: The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation. CONCLUSIONS: Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.

From Bench to Bedside, the Current State of Oncolytic Virotherapy in Pediatric Glioma.

Glioma continues to be a challenging disease process, making up the most common tumor type within the pediatric population. While low-grade gliomas are typically amenable to surgical resection, higher grade gliomas often require additional radiotherapy in conjunction with adjuvant chemotherapy. Molecular profiling of these lesions has led to the development of various pharmacologic and immunologic agents, although these modalities are not without great systemic toxicity. In addition, the molecular biology of adult glioma and pediatric glioma has been shown to differ substantially, making the application of current chemotherapies dubious in children and adolescents. For this reason, therapies with high tumor specificity based on pediatric tumor cell biology that spare healthy tissue are needed. Oncolytic virotherapy serves to fill this niche, as evidenced by renewed interest in this domain of cancer therapy. Initially discovered by chance in the early 20th century, virotherapy has emerged as a viable treatment option. With promising results based on preclinical studies, the authors review several oncolytic viruses, with a focus on molecular mechanism and efficacy of these viruses in tumor cell lines and murine models. In addition, current phase I clinical trials evaluating oncolytic virotherapy in the treatment of pediatric glioma are summarized.

Arteriovenous malformation presenting with epilepsy: a multimodal approach to diagnosis and treatment.

Arteriovenous malformation (AVM) presenting with epilepsy significantly impacts patient quality of life, and it should be considered very much a seizure disorder. Although hemorrhage prevention is the primary treatment aim of AVM surgery, seizure control should also be at the forefront of therapeutic management. Several hemodynamic and morphological characteristics of AVM have been identified to be associated with seizure presentation. This includes increased AVM flow, presence of long pial draining vein, venous outflow obstruction, and frontotemporal location, among other aspects. With the advent of high-throughput image processing and quantification methods, new radiographic attributes of AVM-related epilepsy have been identified. With respect to therapy, several treatment approaches are available, including conservative management or interventional modalities; this includes microsurgery, radiosurgery, and embolization or a combination thereof. Many studies, especially in the domain of microsurgery and radiosurgery, evaluate both techniques with respect to seizure outcomes. The advantage of microsurgery lies in superior AVM obliteration rates and swift seizure response. In addition, by incorporating electrophysiological monitoring during AVM resection, adjacent or even remote epileptogenic foci can be identified, leading to extended lesionectomy and improved seizure control. Radiosurgery, despite resulting in reduced AVM obliteration and prolonged time to seizure freedom, avoids the risks of surgery altogether and may provide seizure control through various antiepileptic mechanisms. Embolization continues to be used as an adjuvant for both microsurgery and radiosurgery. In this study, the authors review the latest imaging techniques in characterizing AVM-related epilepsy, in addition to reviewing each treatment modality.

Local Peroxynitrite Impairs Endothelial Transient Receptor Potential Vanilloid 4 Channels and Elevates Blood Pressure in Obesity.

BACKGROUND: Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The recognition that Ca2+ signaling in endothelial cells promotes vasodilation has led to the hypothesis that endothelial Ca2+ signaling is compromised during obesity, but the underlying abnormality is unknown. In this regard, transient receptor potential vanilloid 4 (TRPV4) ion channels are a major Ca2+ influx pathway in endothelial cells, and regulatory protein AKAP150 (A-kinase anchoring protein 150) enhances the activity of TRPV4 channels. METHODS: We used endothelium-specific knockout mice and high-fat diet-fed mice to assess the role of endothelial AKAP150-TRPV4 signaling in blood pressure regulation under normal and obese conditions. We further determined the role of peroxynitrite, an oxidant molecule generated from the reaction between nitric oxide and superoxide radicals, in impairing endothelial AKAP150-TRPV4 signaling in obesity and assessed the effectiveness of peroxynitrite inhibition in rescuing endothelial AKAP150-TRPV4 signaling in obesity. The clinical relevance of our findings was evaluated in arteries from nonobese and obese individuals. RESULTS: We show that Ca2+ influx through TRPV4 channels at myoendothelial projections to smooth muscle cells decreases resting blood pressure in nonobese mice, a response that is diminished in obese mice. Counterintuitively, release of the vasodilator molecule nitric oxide attenuated endothelial TRPV4 channel activity and vasodilation in obese animals. Increased activities of inducible nitric oxide synthase and NADPH oxidase 1 enzymes at myoendothelial projections in obese mice generated higher levels of nitric oxide and superoxide radicals, resulting in increased local peroxynitrite formation and subsequent oxidation of the regulatory protein AKAP150 at cysteine 36, to impair AKAP150-TRPV4 channel signaling at myoendothelial projections. Strategies that lowered peroxynitrite levels prevented cysteine 36 oxidation of AKAP150 and rescued endothelial AKAP150-TRPV4 signaling, vasodilation, and blood pressure in obesity. Peroxynitrite-dependent impairment of endothelial TRPV4 channel activity and vasodilation was also observed in the arteries from obese patients. CONCLUSIONS: These data suggest that a spatially restricted impairment of endothelial TRPV4 channels contributes to obesity-induced hypertension and imply that inhibiting peroxynitrite might represent a strategy for normalizing endothelial TRPV4 channel activity, vasodilation, and blood pressure in obesity.

Kickstand Rod Technique for Correcting Coronal Imbalance in Adult Scoliosis: 2-Dimensional Operative Video.

Restoration of spinal alignment and balance is a major goal of adult scoliosis surgery. In the past, sagittal alignment has been emphasized and was shown to have the greatest impact on functional outcomes. However, recent evidence suggests the impact of coronal imbalance on pain and functional outcomes has likely been underestimated.1,2 In addition, iatrogenic coronal imbalance may be common and frequently results from inadequate correction of the lumbosacral fractional curve.2,3 The "kickstand rod" is a recently described technique to achieve and maintain significant coronal-plane correction.4 Also, of secondary benefit, the kickstand rod may function as an accessory supplemental rod to offload stress and bolster primary instrumentation. This may reduce occurrence of rod fracture (RF) or pseudarthrosis (PA).5 Briefly, this technique involves positioning the kickstand rod on the side of coronal imbalance (along the major curve concavity or fractional curve convexity in our video demonstration). The kickstand rod spans the thoracolumbar junction proximally to the pelvis distally and is secured with an additional iliac screw placed just superior to the primary iliac screw. By using the iliac wing as a base, powerful distraction forces can reduce the major curve to achieve more normal coronal balance. This operative video illustrates the technical nuances of utilizing the kickstand rod technique for correction of severe lumbar scoliosis and coronal malalignment in a 60-yr-old male patient. Alignment correction was achieved and maintained without evidence of RF/PA after nearly 6 mo postoperatively. The patient gave informed consent for surgery and to use imaging for medical publication.

Clinical utility of arterial spin labeling imaging in disorders of the nervous system.

Neuroimaging is an indispensable tool in the workup and management of patients with neurological disorders. Arterial spin labeling (ASL) is an imaging modality that permits the examination of blood flow and perfusion without the need for contrast injection. Noninvasive in nature, ASL provides a feasible alternative to existing vascular imaging techniques, including angiography and perfusion imaging. While promising, ASL has yet to be fully incorporated into the diagnosis and management of neurological disorders. This article presents a review of the most recent literature on ASL, with a special focus on its use in moyamoya disease, brain neoplasms, seizures, and migraines and a commentary on recent advances in ASL that make the imaging technique more attractive as a clinically useful tool.

The role of contrast-enhanced ultrasound in neurosurgical disease.

Contrast-enhanced ultrasound (CEUS) is a relatively new imaging modality in the realm of neurosurgical disease. CEUS permits the examination of blood flow through arteries, veins, and capillaries via intravascular contrast agents and allows vascular architectural mapping with extreme sensitivity and specificity. While it has established utility in other organ systems such as the liver and kidneys, CEUS has not been studied extensively in the brain. This report presents a review of the literature on the neurosurgical applications of CEUS and provides an outline of the imaging modality's role in the diagnosis, evaluation, and treatment of neurosurgical disease.

Enhanced recovery after surgery in intramedullary and extramedullary spinal cord lesions: perioperative considerations and recommendations.

Enhanced recovery after surgery (ERAS) is an evidence-based approach developed to ameliorate the patient recovery process following surgical procedures. Employing a multimodal, multidisciplinary approach, ERAS implements strategies and treatment paradigms that have been shown to improve patient outcomes, reduce hospital length of stay, and ultimately reduce healthcare costs. With a substantial body of the literature supporting the implementation of ERAS in other surgical specialties, ERAS has only recently made its foray into spine surgery. Despite this, current studies are limited to spinal deformity and degenerative disease, with limited data regarding spinal cord surgery. This is due in part to the complex nature and rarity of spinal cord lesions, making the establishment of a formal ERAS protocol difficult. In developing an ERAS protocol, there must be a consensus on what factors are important to consider and implement. To address this, we reviewed the most recent advances in intramedullary and extramedullary spinal cord surgery in order to identify elements that influence patient outcomes. Using this information, the authors provide evidence-based recommendations with the intent of introducing a framework for future ERAS protocols with respect to treating spinal cord lesions.

The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture.

The pathogenesis of intracranial aneurysms remains complex and multifactorial. While vascular, genetic, and epidemiological factors play a role, nascent aneurysm formation is believed to be induced by hemodynamic forces. Hemodynamic stresses and vascular insults lead to additional aneurysm and vessel remodeling. Advanced imaging techniques allow us to better define the roles of aneurysm and vessel morphology and hemodynamic parameters, such as wall shear stress, oscillatory shear index, and patterns of flow on aneurysm formation, growth, and rupture. While a complete understanding of the interplay between these hemodynamic variables remains elusive, the authors review the efforts that have been made over the past several decades in an attempt to elucidate the physical and biological interactions that govern aneurysm pathophysiology. Furthermore, the current clinical utility of hemodynamics in predicting aneurysm rupture is discussed.

Enhanced recovery after spine surgery: a systematic review.

OBJECTIVEEnhanced recovery after surgery (ERAS) is a multidimensional approach to improving the care of surgical patients using subspecialty- and procedure-specific evidence-based protocols. The literature provides evidence of the benefits of ERAS implementation, which include expedited functional recovery, decreased postoperative morbidity, reduced costs, and improved subjective patient experience. Although extensively examined in other surgical areas, ERAS principles have been applied to spine surgery only in recent years. The authors examine studies investigating the application of ERAS programs to patients undergoing spine surgery.METHODSThe authors conducted a systematic review of the PubMed and MEDLINE databases up to November 20, 2018.RESULTSTwenty full-text articles were included in the qualitative analysis. The majority of studies were retrospective reviews of nonrandomized data sets or qualitative investigations lacking formal control groups; there was 1 protocol for a future randomized controlled trial. Most studies demonstrated reduced lengths of stay and no increase in rates of readmissions or complications after introduction of an ERAS pathway.CONCLUSIONSThese introductory studies demonstrate the potential of ERAS protocols, when applied to spine procedures, to reduce lengths of stay, accelerate return of function, minimize postoperative pain, and save costs.

Extracranial-intracranial bypass approach to cerebral revascularization: a historical perspective.

While the majority of cerebral revascularization advancements were made in the last century, it is worth noting the humble beginnings of vascular surgery throughout history to appreciate its progression and application to neurovascular pathology in the modern era. Nearly 5000 years of basic human inquiry into the vasculature and its role in neurological disease has resulted in the complex neurosurgical procedures used today to save and improve lives. This paper explores the story of the extracranial-intracranial approach to cerebral revascularization.

Neoplastic Cerebral Aneurysm from Metastatic Lung Adenocarcinoma with Neuroendocrine Features.

BACKGROUND: Neoplastic cerebral aneurysms are exceedingly rare. We describe a case of a ruptured, distal middle cerebral artery aneurysm as the presenting symptom leading to the identification of metastatic lung cancer. CASE DESCRIPTION: The patient underwent an uncomplicated surgical trapping and ligation of the aneurysm. Histopathologic examination of the aneurysm confirmed the neoplastic cerebral aneurysm was due to a metastatic lung adenocarcinoma with neuroendocrine features. The patient subsequently underwent stereotactic radiosurgery to the resection cavity. CONCLUSIONS: Neoplastic cerebral aneurysms are rare, and there are insufficient data to support specific guidelines for management. This case is novel as the patient received adjuvant stereotactic radiosurgery to the operative bed, as well as systemic chemotherapy, and has maintained good functional status as of last follow-up at 6 months.

Case Report: Facial Nerve Bifurcation Noted During Resection of Vestibular Schwannoma.

BACKGROUND AND IMPORTANCE: Resection of cerebellopontine angle tumors is challenging because the proximity of the facial nerve puts it at risk of inadvertent injury and subsequent dysfunction. It is critical to consider variations in anatomy and be aware of the potential deviations in the course of the nerve in order to avoid damage. CLINICAL PRESENTATION: We present a case of a facial nerve bifurcation identified during resection of a vestibular schwannoma. CONCLUSION: This is the only reported case of proximal facial nerve bifurcation. We review what is known about variations in proximal facial nerve anatomy, the rates of facial nerve injury after schwannoma resection, and the importance of neuromonitoring in identifying the nerve and predicting function postoperatively. Ultimately, understanding possible anatomic variations in the nerve is critical to minimize iatrogenic injury during surgery.

Endovascular treatment for cerebral vasospasm following aneurysmal subarachnoid hemorrhage: predictors of outcome and retreatment.

OBJECTIVE: Although endovascular therapy has been widely adopted for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), its effect on clinical outcomes remains incompletely understood. The aims of this retrospective cohort study are to evaluate the outcomes of endovascular intervention for post-aSAH vasospasm and identify predictors of functional independence at discharge and repeat endovascular vasospasm treatment. METHODS: We assessed the baseline and outcomes data for patients with aSAH who underwent endovascular vasospasm treatment at our institution, including intra-arterial (IA) vasodilator infusion and angioplasty. Statistical analyses were performed to determine factors associated with good outcome at discharge (modified Rankin Scale 0-2) and repeat endovascular vasospasm treatment. RESULTS: The study cohort comprised 159 patients with a mean age of 52 years. Good outcome was achieved in 17% of patients at discharge (26/150 patients), with an in-hospital mortality rate of 22% (33/150 patients). In the multivariate analysis, age (OR 0.895; p=0.009) and positive smoking status (OR 0.206; p=0.040) were negative independent predictors of good outcome. Endovascular retreatment was performed in 34% (53/156 patients). In the multivariate analysis, older age (OR 0.950; p=0.004), symptomatic vasospasm (OR 0.441; p=0.046), initial treatment with angioplasty alone (OR 0.096; p=0.039), and initial treatment with combined IA vasodilator infusion and angioplasty (OR 0.342; p=0.026) were negative independent predictors of retreatment. CONCLUSION: We found a modest rate of functional independence at discharge in patients with aSAH who underwent endovascular vasospasm treatment. Older patients and smokers had worse functional outcomes at discharge. Initial use of angioplasty appears to decrease the need for subsequent retreatment.