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Aneurysmal subarachnoid hemorrhage is a devastating condition causing significant morbidity and mortality. While outcomes from subarachnoid hemorrhage have improved in recent years, there continues to be significant interest in identifying therapeutic targets for this disease. In particular, there has been a shift in emphasis toward secondary brain injury that develops in the first 72 hours after subarachnoid hemorrhage. This time period of interest is referred to as the early brain injury period and comprises processes including microcirculatory dysfunction, blood-brain-barrier breakdown, neuroinflammation, cerebral edema, oxidative cascades, and neuronal death. Advances in our understanding of the mechanisms defining the early brain injury period have been accompanied by improved imaging and nonimaging biomarkers for identifying early brain injury, leading to the recognition of an elevated clinical incidence of early brain injury compared with prior estimates. With the frequency, impact, and mechanisms of early brain injury better defined, there is a need to review the literature in this area to guide preclinical and clinical study.
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Lesões Encefálicas , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/complicações , Incidência , Microcirculação , Barreira Hematoencefálica , Lesões Encefálicas/complicaçõesRESUMO
PURPOSE OF REVIEW: In the USA, around 30% of 795,000 strokes per year are due to proximal large-vessel occlusion, and these are a major cause of death and disability. We review the most recent advances regarding treatment of ischemic stroke amenable to mechanical thrombectomy. RECENT FINDINGS: In the last four years, clinical trial evidence has expanded the time window for successful endovascular treatment to 24 h. Current research is aimed at expanding patient selection to mild strokes, large ischemic cores and occlusions of smaller, more distal blood vessels. Further, we have developed understanding of how to manage blood pressure after thrombectomy and even had promising results for a neuroprotective agent in these patients. Thrombectomy has transformed the treatment of ischemic stroke due to large-vessel occlusion. Recent research has focused on expanding patient candidacy for endovascular treatment and improving medical management to support better neurologic outcomes.
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Procedimentos Endovasculares , AVC Isquêmico , Trombectomia , Humanos , AVC Isquêmico/cirurgiaRESUMO
Primary intraosseous meningiomas (PIMs) are an infrequent variant of meningiomas characterized by hyperostosis and brain compression. En bloc surgical resection of giant PIMs involving critical structures such as venous sinuses or cranial nerves could be associated with significant morbidity. The objective of this report is to demonstrate the safety and feasibility of piecemeal resection of PIMs involving the superior sagittal sinus and frontal sinus. A 54-year-old female with a large 5âcm thick bifrontal primary intra-osseous meningioma encasing the anterior segment of the superior sagittal sinus and frontal sinus underwent a bifrontal craniotomy with piecemeal microsurgical resection of the lesion, complete frontal sinus exoneration, and a synthetic cranioplasty. Clinical outcome was measured by extent of resection, preservation of cortical draining veins and postoperative course. A Simpson grade I resection of the lesion was achieved following piecemeal resection of the giant PIM without clinical or radiographic evidence of venous infarct or injury. The postoperative course was uncomplicated, and the patient was discharged home 3 days after cranioplasty. A complete resection of a giant bifrontal PIM with superior sagittal sinus encasement and frontal sinus involvement can be achieved safely via a piecemeal approach without significant intra-operative morbidity.
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Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Seio Sagital Superior/cirurgia , Craniotomia , Feminino , Humanos , Neoplasias Meníngeas/patologia , Pessoa de Meia-Idade , Crânio/cirurgia , Seio Sagital Superior/patologia , Resultado do TratamentoRESUMO
Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid ß peptide (Aß) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aß-induced vessel dysfunction, but the mechanisms by which insoluble Aß in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.
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Envelhecimento/patologia , Angiopatia Amiloide Cerebral/patologia , Angiopatia Amiloide Cerebral/fisiopatologia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Sistema Vasomotor/fisiopatologia , Acetofenonas/farmacologia , Animais , Apolipoproteínas E/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Angiopatia Amiloide Cerebral/complicações , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Hemorragia Cerebral/complicações , Cricetinae , Óxidos N-Cíclicos/farmacologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Estresse Oxidativo/efeitos dos fármacos , Marcadores de Spin , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/patologiaRESUMO
BACKGROUND AND IMPORTANCE: Gamma Knife radiosurgery is an established technique for non-urgent treatment of various intracranial pathologies. Intra-procedural dislodgement of the stereotactic frame is an uncommon occurrence that could lead to abortion of ongoing treatment and necessitate more invasive treatment strategies. CLINICAL PRESENTATION: In this case report, we describe a novel method for resumption of Gamma Knife treatment after an unplanned intra-procedural interruption. The case example involves a radiosurgical treatment of a Spetzler-Martin grade I arteriovenous malformation. CONCLUSION: Our technique involves integration of scans and coordinate systems from two imaging sessions using the composite isodose line to resolve translational differences, thereby limiting delivery of remaining shots to the untreated region of the lesion. MRI follow-up at 13 months showed a reduction in the nidus size with no evidence of any radiation injury to the surrounding brain parenchyma. We believe this technique will allow care teams to effectively salvage interrupted Gamma Knife procedures and reduce progression to more invasive treatment options.
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Falha de Equipamento , Malformações Arteriovenosas Intracranianas/cirurgia , Complicações Pós-Operatórias/etiologia , Radiocirurgia/efeitos adversos , Idoso , Humanos , Masculino , Complicações Pós-Operatórias/terapia , Radiocirurgia/instrumentação , Radiocirurgia/métodos , Terapia de Salvação/métodosRESUMO
Corpus callosotomy is a palliative surgical procedure for patients with refractory epilepsy. It can be performed through an open approach via a standard craniotomy and the aid of an operating microscope, or alternatively via a mini-craniotomy with endoscope assistance. The extent of callosal disconnection performed varies according to indications and surgeon preference. In this article, we describe both open and endoscopic surgical techniques for anterior and complete corpus callosotomy.
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Corpo Caloso/cirurgia , Epilepsia Resistente a Medicamentos/cirurgia , Endoscopia/métodos , Psicocirurgia/métodos , Criança , Craniotomia/instrumentação , Craniotomia/métodos , Eletroencefalografia , Endoscopia/instrumentação , Humanos , Masculino , Psicocirurgia/instrumentação , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: We and others have shown that soluble amyloid ß-peptide (Aß) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid ß-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. METHODS: To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). RESULTS: We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. CONCLUSIONS: These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid ß-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury.
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Isquemia Encefálica/complicações , Angiopatia Amiloide Cerebral/complicações , Infarto Cerebral/etiologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Angiopatia Amiloide Cerebral/fisiopatologia , Suscetibilidade a Doenças , Masculino , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: Dural arteriovenous fistulas (dAVFs) are usually idiopathic lesions. While individual case reports have documented the occurrence of dAVFs in conjunction with benign meningeal tumors, a detailed characterization of this association is lacking. The objective of this study was to critically examine the relationship between benign meningeal tumors and dAVFs. METHODS: We performed a retrospective review of records at two institutions, identified patients with coexisting benign meningeal tumors and dAVFs at the time of clinical presentation, and examined various clinical, anatomical and radiographic characteristics. RESULTS: Ten patients (4.6%) had coexisting benign meningeal tumors and dAVFs. The most common tumor was meningioma (90%). Nine patients were symptomatic: five from tumor, three from dAVF, and one from both tumor and dAVF. All dAVFs were related to the meningeal tumor. CONCLUSIONS: Benign meningeal tumors may be associated with dAVFs that are either in direct anatomical relation to the tumor or in distant anatomical locations. The increased propensity for development of dAVFs in patients with benign meningeal tumors may be due to multiple factors. Due to this association, additional imaging to exclude dAVFs could be considered in patients with meningeal tumors if exuberant vessels or flow voids are identified on routinely obtained magnetic resonance imaging scans.
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Malformações Vasculares do Sistema Nervoso Central/complicações , Neoplasias Meníngeas/complicações , Meningioma/complicações , Idoso , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Angiografia Cerebral , Embolização Terapêutica , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/terapia , Meningioma/diagnóstico por imagem , Meningioma/terapia , Pessoa de Meia-Idade , Radiocirurgia , Radioterapia Adjuvante , Estudos RetrospectivosRESUMO
The human cerebrovascular system is responsible for maintaining neural function through oxygenation, nutrient supply, filtration of toxins, and additional specialized tasks. While the cerebrovascular system has resilience imparted by elaborate redundant collateral circulation from supportive tertiary structures, it is not infallible, and is susceptible to developing structural vascular abnormalities. The causes of this class of structural cerebrovascular diseases can be broadly categorized as 1) intrinsic developmental diseases resulting from genetic or other underlying aberrations (arteriovenous malformations and cavernous malformations) or 2) extrinsic acquired diseases that cause compensatory mechanisms to drive vascular remodeling (aneurysms and arteriovenous fistulae). Cerebrovascular diseases of both types pose significant risks to patients, in some cases leading to death or disability. The drivers of such diseases are extensive, yet inflammation is intimately tied to all of their progressions. Central to this inflammatory hypothesis is the role of peripheral macrophages; targeting this critical cell type may lead to diagnostic and therapeutic advancement in this area. Here, we comprehensively review the role that peripheral macrophages play in cerebrovascular pathogenesis, provide a schema through which macrophage behavior can be understood in cerebrovascular pathologies, and describe emerging diagnostic and therapeutic avenues in this area.
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Aneurisma Intracraniano , Malformações Arteriovenosas Intracranianas , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico , MacrófagosRESUMO
OBJECTIVE: Despite the adoption of same-day outpatient surgical procedures in some specialties, it remains common practice to admit patients for monitoring after elective endovascular treatment of brain aneurysms to monitor for complications. The necessity of such monitoring has not been fully characterized. Here, the authors reviewed the utilization of imaging during posttreatment hospitalization, a surrogate measure for workup of suspected complications requiring hospital resources, to infer the value of inpatient monitoring after endovascular aneurysm treatment. METHODS: Clinical and angiographic data from eligible patients were retrospectively assessed for demographic characteristics, imaging indications, timing of imaging, and imaging findings. Patients were included if they underwent elective endovascular brain aneurysm treatment, and patients were excluded if significant intraprocedural complications occurred. The recorded imaging modalities included CT, MRI, catheter-based imaging, and ultrasound; plain radiographs were excluded. Multivariable logistic regression analysis was performed to identify predictors of the need for posttreatment imaging. RESULTS: In total, 1229 elective endovascular procedures for brain aneurysm treatment were included. Patients underwent imaging before discharge in 13.4% (165/1229) of cases, with significant findings in 5.0% (61/1229) of cases. The median (interquartile range) time to first posttreatment imaging was 13.2 (4.2-22.8) hours. The need for imaging during posttreatment hospitalization was positively associated with larger aneurysm size (p < 0.05) and negatively associated with underlying cardiovascular disease (p < 0.05). CONCLUSIONS: More than 1 in 8 patients who underwent elective endovascular brain aneurysm treatment required imaging during posttreatment hospitalization, most within the first 24 hours, and 1 in 20 had significant findings. These results suggest the importance of short-term hospitalization after elective endovascular aneurysm treatment.
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Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Aneurisma Intracraniano , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/cirurgia , Estudos Retrospectivos , Procedimentos Endovasculares/métodos , Resultado do Tratamento , Implante de Prótese Vascular/métodos , Hospitalização , Hospitais , Procedimentos Cirúrgicos Eletivos , Fatores de RiscoRESUMO
OBJECTIVE: The number of cerebrovascular (CV) surgeons has grown with the rise of endovascular neurosurgery. However, it is unclear whether the number of CV surgeon-scientists has concomitantly increased. With increasing numbers of CV neurosurgeons in the US workforce, the authors analyzed associated changes in National Institutes of Health (NIH) and Neurosurgery Research and Education Foundation (NREF) funding trends for CV surgeons over time. METHODS: Publicly available data were collected on currently practicing academic CV surgeons in the US. Inflation-adjusted NIH funding between 2009 and 2021 was surveyed using NIH RePORTER and Blue Ridge Institute for Medical Research data. The K12 Neurosurgeon Research Career Development Program and NREF grant data were queried for CV-focused grants. Pearson R correlation, chi-square analysis, and the Mann-Whitney U-test were used for statistical analysis. RESULTS: From 2009 to 2021, NIH funding increased: in total (p = 0.0318), to neurosurgeons (p < 0.0001), to CV research projects (p < 0.0001), and to CV surgeons (p = 0.0018). During this time period, there has been an increase in the total number of CV surgeons (p < 0.0001), the number of NIH-funded CV surgeons (p = 0.0034), and the percentage of CV surgeons with NIH funding (p = 0.370). Additionally, active NIH grant dollars per CV surgeon (p = 0.0398) and the number of NIH grants per CV surgeon (p = 0.4257) have increased. Nevertheless, CV surgeons have been awarded a decreasing proportion of the overall pool of neurosurgeon-awarded NIH grants during this time period (p = 0.3095). In addition, there has been a significant decrease in the number of K08, K12, and K23 career development awards granted to CV surgeons during this time period (p = 0.0024). There was also a significant decline in the proportion of K12 (p = 0.0044) and downtrend in early-career NREF (p = 0.8978) grant applications and grants awarded during this time period. Finally, NIH-funded CV surgeons were more likely to have completed residency less recently (p = 0.001) and less likely to have completed an endovascular fellowship (p = 0.044) as compared with non-NIH-funded CV surgeons. CONCLUSIONS: The number of CV surgeons is increasing over time. While there has been a concomitant increase in the number of NIH-funded CV surgeons and the number of NIH grants awarded per CV surgeon in the past 12 years, there has also been a significant decrease in CV surgeons with K08, K12, and K23 career development awards and a downtrend in CV-focused K12 and early-career NREF applications and awarded grants. The latter findings suggest that the pipeline for future NIH-funded CV surgeons may be in decline.
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Background: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints. Materials and methods: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient's hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH. Discussion: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH. Trial registration: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.
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Introduction: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. 3,10,13 However, the effects of taVNS on cardiovascular dynamics in critically ill patients like those with SAH have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population 5 . Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study. Methods: In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored rapidly responsive cardiovascular biomarkers in patients exhibiting clinical improvement. Results: We found that repetitive taVNS did not significantly alter heart rate, corrected QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity from 5-10 days after initial treatment, as compared to the sham treatment. Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than 1 point in their Modified Rankin Score at the time of discharge. Conclusions: Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment. Trial registration: NCT04557618.
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Background: Inflammation contributes to morbidity following subarachnoid hemorrhage (SAH). Transauricular vagus nerve stimulation (taVNS) offers a noninvasive approach to target the inflammatory response following SAH. Methods: In this prospective, triple-blinded, randomized, controlled trial, twenty-seven patients were randomized to taVNS or sham stimulation. Blood and cerebrospinal fluid (CSF) were collected to quantify inflammatory markers. Cerebral vasospasm severity and functional outcomes (modified Rankin Scale, mRS) were analyzed. Results: No adverse events occurred. Radiographic vasospasm was significantly reduced (p = 0.018), with serial vessel caliber measurements demonstrating a more rapid return to normal than sham (p < 0.001). In the taVNS group, TNF-α was significantly reduced in both plasma (days 7 and 10) and CSF (day 13); IL-6 was also significantly reduced in plasma (day 4) and CSF (day 13) (p < 0.05). Patients receiving taVNS had higher rates of favorable outcomes at discharge (38.4% vs 21.4%) and first follow-up (76.9% vs 57.1%), with significant improvement from admission to first follow-up (p = 0.014), unlike the sham group (p = 0.18). The taVNS group had a significantly lower rate of discharge to skilled nursing facility or hospice (p = 0.04). Conclusion: taVNS is a non-invasive method of neuro- and systemic immunomodulation. This trial supports that taVNS following SAH can mitigate the inflammatory response, reduce radiographic vasospasm, and potentially improve functional and neurological outcomes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04557618.
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OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ-pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5-9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.
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Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Glioma/radioterapia , Paclitaxel/uso terapêutico , Análise de Variância , Animais , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Quimioterapia Combinada , Feminino , Géis/uso terapêutico , Humanos , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Análise de Sobrevida , TemozolomidaRESUMO
OBJECT: In this paper the authors' goal was to review the clinical features and outcome of patients with intracranial dural arteriovenous fistulas (DAVFs) who presented with hemorrhage. METHODS: A retrospective study of 28 patients with DAVFs who presented with intracranial hemorrhage to 2 separate institutions was performed. The information reviewed included clinical presentation, location and size of hemorrhage, angiographic features, treatment, and clinical and radiologically documented outcomes. Clinical and radiological follow-up were available in 27 of 28 patients (mean follow-up 17 months). RESULTS: The vast majority of patients were male (86%), and the most common presenting symptom was sudden-onset headache. All DAVFs had cortical venous drainage, and about one-third were associated with a venous varix. The most common location was tentorial (75%). Treatment ranged from endovascular (71%), surgical (43%), Gamma Knife surgery (4%), or a combination of modalities. The majority of fistulas (75%) were completely obliterated, and most patients experienced excellent clinical outcome (71%, modified Rankin Scale score of 0 or 1). There were no complications in this series. CONCLUSIONS: Case series, including the current one, suggest that the vast majority of patients who present with intracranial hemorrhage from a DAVF are male. The most common location for DAVFs presenting with hemorrhage is tentorial. Excellent outcomes are achieved with individualized treatment, which includes various therapeutic strategies alone or in combination. Despite the hemorrhagic presentation, almost two-thirds of patients experience a full recovery with no or minimal residual symptoms.
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Malformações Vasculares do Sistema Nervoso Central/complicações , Embolização Terapêutica/métodos , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/terapia , Resultado do Tratamento , Idoso , Angiografia Cerebral , Feminino , Humanos , Hemorragias Intracranianas/diagnóstico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Delayed cerebral ischemia (DCI) is an important contributor to poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. We previously showed that volatile anesthetics such as isoflurane, sevoflurane and desflurane provided robust protection against SAH-induced DCI, but the impact of a more commonly used intravenous anesthetic agent, propofol, is not known. The goal of our current study is to examine the neurovascular protective effects of propofol on SAH-induced DCI. Twelve-week-old male wild-type mice were utilized for the study. Mice underwent endovascular perforation SAH or sham surgery followed one hour later by propofol infusion through the internal jugular vein (2 mg/kg/min continuous intravenous infusion). Large artery vasospasm was assessed three days after SAH. Neurological outcome assessment was performed at baseline and then daily until animal sacrifice. Statistical analysis was performed via one-way ANOVA and two-way repeated measures ANOVA followed by the Newman-Keuls multiple comparison test with significance set at p < 0.05. Intravenous propofol did not provide any protection against large artery vasospasm or sensory-motor neurological deficits induced by SAH. Our data show that propofol did not afford significant protection against SAH-induced DCI. These results are consistent with recent clinical studies that suggest that the neurovascular protection afforded by anesthetic conditioning is critically dependent on the class of anesthetic agent.
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Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.
Assuntos
Linfocintigrafia , Biópsia de Linfonodo Sentinela , Humanos , Linfocintigrafia/métodos , Projetos Piloto , Biópsia de Linfonodo Sentinela/métodos , Compostos Radiofarmacêuticos , Metástase LinfáticaRESUMO
Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is pathologically associated with vasospasm. We previously showed that a brief exposure to isoflurane, an inhalational anesthetic, provided multifaceted protection against DCI after SAH. The aim of our current study is to investigate the role of NF-kB in isoflurane-conditioning-induced neurovascular protection against SAH-induced DCI. Twelve-week-old wild type male mice (C57BL/6) were divided into five groups: sham, SAH, SAH + Pyrrolidine dithiocarbamate (PDTC, a selective NF-kB inhibitor), SAH + isoflurane conditioning, and SAH + PDTC with isoflurane conditioning. Experimental SAH was performed via endovascular perforation. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. Three doses of PDTC (100 mg/kg) were injected intraperitoneally. NF-kB and microglial activation and the cellular source of NF-kB after SAH were assessed by immunofluorescence staining. Vasospasm, microvessel thrombosis, and neuroscore were assessed. NF-kB was activated after SAH; it was attenuated by isoflurane conditioning. Microglia was activated and found to be a major source of NF-kB expression after SAH. Isoflurane conditioning attenuated microglial activation and NF-kB expression in microglia after SAH. Isoflurane conditioning and PDTC individually attenuated large artery vasospasm and microvessel thrombosis, leading to improved neurological deficits after SAH. The addition of isoflurane to the PDTC group did not provide any additional DCI protection. These data indicate isoflurane-conditioning-induced DCI protection after SAH is mediated, at least in part, via downregulating the NF-kB pathway.