UCL Throwing Injuries in Nonprofessional Baseball Players: A 14-Year Retrospective Study.

BACKGROUND: This study evaluated treatment modality (surgical vs nonoperative) of medial ulnar collateral ligament (UCL) injuries in nonprofessional throwing baseball athletes by comparing type, severity, and location of UCL injury. HYPOTHESIS: Baseball players with closed medial epicondyle physes and concomitant throwing-related UCL injury will be more likely to undergo surgical intervention than players with open medial epicondyle physes. STUDY DESIGN: Retrospective. LEVEL OF EVIDENCE: Level 5. METHODS: A total of 119 baseball players with a mean age of 16.9 ± 2.5 years (range, 11-25 years) were included in the study. Datapoints included sex, age at time of injury, severity, and location of UCL injury, growth plate status, operative versus conservative management, and concomitant flexor forearm injury. RESULTS: A total of 75 players were treated conservatively; 43 underwent UCL reconstruction (UCL-R), and 1 had an unknown treatment outcome. No significant difference was found for age related to treatment type, UCL-R (17.2 ± 2.2) versus conservative treatment (16.8 ± 2.6). Athletes with closed medial epicondylar growth plates were more likely to undergo UCL-R than athletes with open medial epicondylar growth plates (P = 0.02). There were no significant differences between UCL injury location (42 distal, 37 proximal, 18 combined tear locations, 11 complete tears, and 11 intact UCLs with inflammation) by treatment type (P = 0.09). There was a significant difference for UCL severity (11 complete tears, 96 partial tears) by treatment type (P = 0.03). CONCLUSION: Nonprofessional athletes with closed medial epicondylar growth plates and throwing-related UCL injuries were more likely to be treated surgically. Baseball athletes with partial tears, if skeletally immature, require further long-term evaluation. CLINICAL RELEVANCE: Continued knowledge gains in this area of throwing medicine will further improve our treatment algorithms in nonprofessional baseball players.

Neutrophils: Novel Contributors to Estrogen-Dependent Intracranial Aneurysm Rupture Via Neutrophil Extracellular Traps.

Background Intracranial aneurysms (IAs) are more prevalent in women than men, and aneurysmal subarachnoid hemorrhage disproportionately affects postmenopausal women. These sex differences suggest estrogen protects against IA progression that can lead to rupture, but the underlying mechanisms are not fully understood. Although studies have demonstrated estrogen regulates inflammatory processes that contribute to IA pathogenesis, the role of neutrophils remains to be characterized. Using a murine model, we tested our hypothesis that neutrophils contribute to IA pathophysiology in an estrogen-dependent manner. Methods and Results We compared neutrophil infiltration in C57BL/6 female mice that develop IAs to those with a normal circle of Willis. Next, we investigated the estrogen-dependent role of neutrophils in IA formation, rupture, and symptom-free survival using a neutrophil depletion antibody. Finally, we studied the role of neutrophil extracellular trap formation (NETosis) as an underlying mechanism of aneurysm progression. Mice that developed aneurysms had increased neutrophil infiltration compared with those with a normal circle of Willis. In estrogen-deficient female mice, both neutrophil depletion and NETosis inhibition decreased aneurysm rupture. In estrogen-deficient female mice treated with estrogen rescue and estrogen-intact female mice, neither neutrophil depletion nor NETosis inhibition affected IA formation, rupture, or symptom-free survival. Conclusions Neutrophils contribute to aneurysm rupture in an estrogen-dependent manner. NETosis appears to be an underlying mechanism for neutrophil-mediated IA rupture in estrogen deficiency. Targeting NETosis may lead to the development of novel therapeutics to protect against IA rupture in the setting of estrogen deficiency.

Clopidogrel Is Associated with Reduced Likelihood of Aneurysmal Subarachnoid Hemorrhage: a Multi-Center Matched Retrospective Analysis.

Maladaptive inflammation underlies the formation and rupture of human intracranial aneurysms. There is a growing body of evidence that anti-inflammatory pharmaceuticals may beneficially modulate this process. Clopidogrel (Plavix) is a commonly used irreversible P2Y12 receptor antagonist with anti-inflammatory activity. In this paper, we investigate whether clopidogrel is associated with the likelihood of aneurysm rupture in a multi-institutional propensity-matched cohort analysis. Patients presenting for endovascular treatment of their unruptured intracranial aneurysms and those presenting with aneurysm rupture between 2015 and 2019 were prospectively identified at two quaternary referral centers. Patient demographics, comorbidities, and medication usage at the time of presentation were collected. Patients taking clopidogrel or not taking clopidogrel were matched in a 1:1 fashion with respect to location, age, smoking status, aneurysm size, aspirin usage, and hypertension. A total of 1048 patients with electively treated aneurysms or subarachnoid hemorrhages were prospectively identified. Nine hundred twenty-one patients were confirmed to harbor aneurysms during catheter-based diagnostic angiography. A total of 172/921 (19%) patients were actively taking clopidogrel at the time of presentation. Three hundred thirty-two patients were matched in a 1:1 fashion. A smaller proportion of patients taking clopidogrel at presentation had ruptured aneurysms than those who were not taking clopidogrel (6.6% vs 23.5%, p < .0001). Estimated treatment effect analysis demonstrated that clopidogrel usage decreased aneurysm rupture risk by 15%. We present, to the best of our knowledge, the first large-scale multi-institutional analysis suggesting clopidogrel use is protective against intracranial aneurysm rupture. It is our hope that these data will guide future investigation, revealing the pathophysiologic underpinning of this association.

Cost Comparison: Evaluating Transfemoral and Transradial Access for Diagnostic Cerebral Angiography.

BACKGROUND: Modern medicine necessitates the delivery of increasingly complex health care while minimizing cost. Transradial access (TRA) for neuroendovascular procedures is becoming more common as accumulating data demonstrate fewer complications, improved patient satisfaction, and high rates of treatment success compared with the transfemoral access (TFA) approach; however, disparities in cost between these approaches remain unclear. We compared supply and equipment costs between TRA and TFA for diagnostic cerebral angiography and evaluate the specific items that account for these differences. METHODS: We reviewed all adult patients who underwent diagnostic cerebral angiography from July 1, 2019 to December 31, 2019. Data related to patient demographics, vascular access site, catheters used, cost of catheters, arterial access sheath use, cost of sheaths, closure devices used, and cost of closure devices were collected. RESULTS: The transradial approach resulted in higher price of radial access sheath; however, the overall cost of closure devices was much lower in TRA group than in the TFA cohort. There was no significant difference in the cost of catheters. Overall, the total supply costs for TRA cerebral angiography were significantly lower than those of TFA cerebral angiography. The relative materials cost difference of using TRA was 20.9%. CONCLUSION: This study is the first itemized materials cost analysis of TRA versus TFA cerebral angiography. TRA necessitates the use of a more expensive access sheath device; however, this cost is offset by the increased cost of devices used for femoral arteriotomy closure. Overall, the supply and equipment costs were significantly lower for TRA than TFA.

Decrease in cortical vein opacification predicts outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND: The pathophysiology of brain injury after aneurysmal subarachnoid hemorrhage (aSAH) remains incompletely understood. Cerebral venous flow patterns may be a marker of hemodynamic disruptions after aneurysm rupture. We hypothesized that a decrease in venous filling after aSAH would predict cerebral ischemia and poor outcome. OBJECTIVE: To examine the hypotheses that venous filling as measured by the cortical venous opacification score (COVES) would (1) decrease after aSAH and (2) that decreased COVES would be associated with higher rates of hydrocephalus, vasospasm, delayed cerebral iscemia (DCI), and poor functional evaluation at outcome. METHODS: In this retrospective observational cohort study of consecutive patients with aSAH admitted to our tertiary care center between 2016 and 2018, we measured the COVES at admission and at subsequent CT angiography (CTA). We collected clinical variables and compared hydrocephalus, vasospasm, DCI, and outcome at discharge in patients with decrease in COVES with patients with stable COVES. RESULTS: A total of 22 patients were included in the analysis. COVES decreased from first CTA to second CTA in 11 (50%) patients, by an average of 1.1 points (P=0.01). Patients whose COVES decreased between admission and follow-up imaging were more likely to develop DCI (58% vs 0%, P=0.03) and have a poor outcome at discharge (100% vs 55%, P=0.03) than patients who had no change in COVES. aSAH severity was not associated with initial COVES, and there was no association between change in COVES and development of hydrocephalus or vasospasm. CONCLUSIONS: Development of decreased venous filling on CTA is associated with poor outcome after aSAH. This association suggests that venous hemodynamics may be reflective of, or contribute to, the pathophysiological mechanisms of brain injury after aSAH. Larger prospective studies are necessary to substantiate our findings.

Combination release of chemokines from coated coils to target aneurysm healing.

BACKGROUND: Monocyte chemoattractant protein 1 (MCP-1) and osteopontin (OPN) have been identified separately as key mediators of the aneurysm healing process following coil embolization in the rodent model. The ability of protein coated coils to accelerate this process is currently unknown. OBJECTIVE: To create coils coated with both MCP-1 and OPN to target aneurysm healing. METHODS: We used a polymer (poly(glycolide-co-caprolactone)) (Rao pharmaceuticals) (CG910) to test whether coils could be dual coated with active proteins with sequential reliable release. Coils were coated with poly-DL-lactic glycolic acid (PLGA), CG910, and subsequently dipped with protein OPN (inner layer for delayed release) and MCP-1 (outer layer for initial release). Release assays were used to measure protein elution from coils over time. To test in vivo feasibility, coated coils were implanted into carotid aneurysms to determine the effect on aneurysm healing. RESULTS: The in vitro protein release assay demonstrated a significant amount of OPN and MCP-1 release within 2 days. Using a 200 µg/µL solution of MCP-1 in phosphate-buffered saline, we showed that CG910 coated coils provide effective release of MCP over time. In the carotid aneurysm model, MCP-1 and OPN coated coils significantly increased tissue ingrowth (74% and 80%) compared with PLGA and CG910 coated coils alone (58% and 53%). To determine synergistic impact of dual coating, we measured ingrowth for MCP-1/OPN coils (63%) as well as overlap coefficients for NOX4 and NFκB with CD31. CONCLUSIONS: This study demonstrates that MCP-1 and OPN coated coils are viable and may promote early aneurysm healing. Dual coated coils may have synergistic benefit given different location of protein interaction measured in vivo. Further work is warranted.

Traumatic Brain Injury and Secondary Neurodegenerative Disease.

Traumatic brain injury (TBI) is a devastating event with severe long-term complications. TBI and its sequelae are one of the leading causes of death and disability in those under 50 years old. The full extent of secondary brain injury is still being intensely investigated; however, it is now clear that neurotrauma can incite chronic neurodegenerative processes. Chronic traumatic encephalopathy, Parkinson's disease, and many other neurodegenerative syndromes have all been associated with a history of traumatic brain injury. The complex nature of these pathologies can make clinical assessment, diagnosis, and treatment challenging. The goal of this review is to provide a concise appraisal of the literature with focus on emerging strategies to improve clinical outcomes. First, we review the pathways involved in the pathogenesis of neurotrauma-related neurodegeneration and discuss the clinical implications of this rapidly evolving field. Next, because clinical evaluation and neuroimaging are essential to the diagnosis and management of neurodegenerative diseases, we analyze the clinical investigations that are transforming these areas of research. Finally, we briefly review some of the preclinical therapies that have shown the most promise in improving outcomes after neurotrauma.

Sensorineural hearing loss due to delayed cerebral ischemia in bilateral auditory cortices following aneurysmal subarachnoid hemorrhage: illustrative case.

BACKGROUND: Recognizing rare signs of delayed cerebral ischemia (DCI) is crucial to caring for patients with subarachnoid hemorrhage. The authors presented a case of central hearing loss that occurred during the clinical course of a patient treated for aneurysmal subarachnoid hemorrhage. OBSERVATIONS: The patient had a ruptured right posterior communicating artery aneurysm successfully treated with coil embolization but later developed severe vasospasm and DCI. She developed bilateral hearing loss, and imaging revealed DCI to the left temporal lobe and the right auditory cortex. Computed tomography angiography and digital subtraction angiography demonstrated severe vasospasm of bilateral internal carotid arteries, bilateral middle cerebral arteries, and bilateral anterior cerebral arteries. One month after hospitalization, the patient had recovered fully neurologically intact except for persistent hearing loss. LESSONS: This case serves to teach important neuroanatomical features and discuss the unique pathophysiology of DCI affecting the auditory cortex.

Delayed cerebral ischemia: A look at the role of endothelial dysfunction, emerging endovascular management, and glymphatic clearance.

Delayed cerebral ischemia (DCI) contributes to extensive morbidity and mortality for patients with aneurysmal subarachnoid hemorrhage (SAH). Recent contributions to the basic and translational investigation of DCI have shed light on emerging concepts that may aid in the development of novel therapeutics. A clear association between cerebral vasospasm (CV) and DCI exists, but it is also known that DCI can affect brain parenchyma remote from sites of vasospasm. In this review, we highlight the most recent contributions to the understanding of the underlying pathophysiology of DCI including the emerging role of the glymphatic system. Furthermore, we discuss treatments for DCI, including both pharmacologic therapies and endovascular treatment of vasospasm. There continues to be a disconnect between interventions and targeted treatment against pathophysiology. This review is intended to serve as a catalyst for further research and discovery that can aid in improved treatment options for DCI.

Ticagrelor resistance: a case series and algorithm for management of non-responders.

The placement of cervical and intracranial stents requires the administration of antiplatelet drugs to prevent thromboembolic complications. Ticagrelor has emerged as the most widely used alternative in clopidogrel non-responders owing to its potent antiplatelet effects. Because ticagrelor does not require hepatic activation, many neurointerventionalists choose to forgo laboratory testing of platelet inhibition. In rare instances, patients may not achieve adequate platelet inhibition following ticagrelor administration. In this paper we review the mechanism of action of ticagrelor and its use in cerebrovascular procedures. We present two cases of ticagrelor non-responsiveness from two high-volume cerebrovascular centers, discuss their management, and propose an algorithm for managing ticagrelor non-responsiveness.

Understanding the genetics of intracranial aneurysms: A primer.

The genetics of intracranial aneurysms is complex. Much work has been done looking at the extracellular matrix surrounding cerebral vasculature as well as the role of matrix metalloproteinases. This comprehensive review summarizes what is known to date about the important genetic components that predispose to aneurysm formation and critically discusses the published findings. We discuss promising pre-clinical models of aneurysm formation and subarachnoid hemorrhage, and highlight avenues for future discovery, while considering limitations in the research to date. This review will further serve as a comprehensive reference guide to understand the genetic underpinnings for aneurysm pathophysiology and act as a primer for further investigation.

Adropin decreases endothelial monolayer permeability after cell-free hemoglobin exposure and reduces MCP-1-induced macrophage transmigration.

BACKGROUND: Cell-free heme-containing proteins mediate endothelial injury in a variety of disease states including subarachnoid hemorrhage and sepsis by increasing endothelial permeability. Inflammatory cells are also attracted to sites of vascular injury by monocyte chemotactic protein 1 (MCP-1) and other chemokines. We have identified a novel peptide hormone, adropin, that protects against hemoglobin-induced endothelial permeability and MCP-1-induced macrophage migration. METHODS: Human microvascular endothelial cells were exposed to cell-free hemoglobin (CFH) with and without adropin treatment before measuring monolayer permeability using a FITC-dextran tracer assay. mRNA and culture media were collected for molecular studies. We also assessed the effect of adropin on macrophage movement across the endothelial monolayer using an MCP-1-induced migration assay. RESULTS: CFH exposure decreases adropin expression and increases paracellular permeability of human endothelial cells. Treating cells with synthetic adropin protects against the increased permeability observed during the natural injury progression. Cell viability was similar in all groups and Hmox1 expression was not affected by adropin treatment. MCP-1 potently induced macrophage migration across the endothelial monolayer and adropin treatment effectively reduced this phenomenon. CONCLUSIONS: Endothelial injury is a hallmark of many disease states. Our results suggest that adropin treatment could be a valuable strategy in preventing heme-mediated endothelial injury and macrophage infiltration. Further investigation of adropin therapy in animal models and human tissue specimens is needed.

A Modification to a Murine Model for Intracranial Aneurysm Formation and Rupture.

Between 3.6% and 6.0% of the population has an intracranial aneurysm. The mechanisms underlying intracranial aneurysm formation and rupture are not fully known. Several rodent models have been developed to better understand intracranial aneurysm pathophysiology. Hypertension, hemodynamic changes, and vessel injury are all necessary for aneurysm induction; however, multiple invasive procedures may disrupt an animal's physiology. Therefore, we hypothesized that our method for inducing hypertension could be modified to create a simpler model. We previously developed a highly reproducible murine model of intracranial aneurysm formation and rupture that involves hemodynamic changes through ligation of the left common carotid artery, vessel wall degradation using elastase and a lysyl oxidase inhibitor, and hypertension through a high-salt diet, continuous angiotensin II infusion, and right renal artery ligation. In order to create a simpler model, we sought to eliminate renal artery ligation. We assessed aneurysm formation, aneurysm rupture, and blood pressure in two separate cohorts of C57BL/6 mice: one cohort underwent our model as above, while another cohort did not receive right renal artery ligation. Our results demonstrate that intracranial aneurysm formation and rupture rates did not differ between each group. Further, the blood pressures between cohorts did not differ at various timepoints in the model. Both cohorts, however, did have a significant increase in blood pressure from baseline, suggesting that renal artery ligation is not needed for inducing hypertension. These findings demonstrate that our murine model can be modified to eliminate right renal artery ligation. Thus, we propose this modification to our murine model for studying intracranial aneurysm pathophysiology.

Aneurysmal Subarachnoid Hemorrhage in Patients with Coronavirus Disease 2019 (COVID-19): A Case Series.

OBJECTIVE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a pressing public health issue. Although most cases do not result in severe illness requiring hospitalization, there is increasing evidence that SARS-CoV-2-induced inflammation can exacerbate pre-existing diseases. We sought to describe the characteristics of patients with aneurysmal subarachnoid hemorrhage who were actively or very recently infected with SARS-CoV-2. METHODS: We reviewed subarachnoid hemorrhage cases of patients who also were positive for SARS-CoV-2 at 5 high-volume cerebrovascular centers in the United States from March 2020 to January 2021. Cases of aneurysmal subarachnoid hemorrhage were analyzed. RESULTS: A total of 10 patients were identified, consisting of 5 women (50%) and 5 men (50%). Median age was 38.5 years. Four of the 10 patients (40%) were asymptomatic with respect to SARS-CoV-2-related symptoms, 3 patients (30%) had mild-to-moderate symptoms, and 3 patients (30%) had severe coronavirus disease 2019 (COVID-19), with pneumonia and sepsis. Of the 10 cases, 4 had dissecting pseudoaneurysms (40%), 3 in the posterior circulation and 1 in the anterior circulation. Among 6 saccular/blister aneurysms, 4 (67%) were ≤4 mm in largest diameter. CONCLUSIONS: Our experience with aneurysmal subarachnoid hemorrhage in patients positive for COVID-19 reveals a possibly distinct pattern compared with traditional aneurysmal subarachnoid hemorrhage, namely a high frequency of small aneurysms, dissecting pseudoaneurysms, and young patients.

Pathophysiology of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Review.

Delayed cerebral ischemia is a major predictor of poor outcomes in patients who suffer subarachnoid hemorrhage. Treatment options are limited and often ineffective despite many years of investigation and clinical trials. Modern advances in basic science have produced a much more complex, multifactorial framework in which delayed cerebral ischemia is better understood and novel treatments can be developed. Leveraging this knowledge to improve outcomes, however, depends on a holistic understanding of the disease process. We conducted a review of the literature to analyze the current state of investigation into delayed cerebral ischemia with emphasis on the major themes that have emerged over the past decades. Specifically, we discuss microcirculatory dysfunction, glymphatic impairment, inflammation, and neuroelectric disruption as pathological factors in addition to the canonical focus on cerebral vasospasm. This review intends to give clinicians and researchers a summary of the foundations of delayed cerebral ischemia pathophysiology while also underscoring the interactions and interdependencies between pathological factors. Through this overview, we also highlight the advances in translational studies and potential future therapeutic opportunities.

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND: The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1ß production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. METHODS: We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. RESULTS: NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. CONCLUSIONS: We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.