Emerging Roles of Exosomes in Stroke Therapy.

Stroke is the number one cause of morbidity in the United States and number two cause of death worldwide. There is a critical unmet medical need for more effective treatments of ischemic stroke, and this need is increasing with the shift in demographics to an older population. Recently, several studies have reported the therapeutic potential of stem cell-derived exosomes as new candidates for cell-free treatment in stoke. This review focuses on the use of stem cell-derived exosomes as a potential treatment tool for stroke patients. Therapy using exosomes can have a clear clinical advantage over stem cell transplantation in terms of safety, cost, and convenience, as well as reducing bench-to-bed latency due to fewer regulatory milestones. In this review article, we focus on (1) the therapeutic potential of exosomes in stroke treatment, (2) the optimization process of upstream and downstream production, and (3) preclinical application in a stroke animal model. Finally, we discuss the limitations and challenges faced by exosome therapy in future clinical applications.

Probabilistic tractography of the extracranial branches of the trigeminal nerve using diffusion tensor imaging.

PURPOSE: The peripheral course of the trigeminal nerves is complex and spans multiple bony foramen and tissue compartments throughout the face. Diffusion tensor imaging of these nerves is difficult due to the complex tissue interfaces and relatively low MR signal. The purpose of this work is to develop a method for reliable diffusion tensor imaging-based fiber tracking of the peripheral branches of the trigeminal nerve. METHODS: We prospectively acquired imaging data from six healthy adult participants with a 3.0-Tesla system, including T2-weighted short tau inversion recovery with variable flip angle (T2-STIR-SPACE) and readout segmented echo planar diffusion weighted imaging sequences. Probabilistic tractography of the ophthalmic, infraorbital, lingual, and inferior alveolar nerves was performed manually and assessed by two observers who determined whether the fiber tracts reached defined anatomical landmarks using the T2-STIR-SPACE volume. RESULTS: All nerves in all subjects were tracked beyond the trigeminal ganglion. Tracts in the inferior alveolar and ophthalmic nerve exhibited the strongest signal and most consistently reached the most distal landmark (58% and 67%, respectively). All tracts of the inferior alveolar and ophthalmic nerve extended beyond their respective third benchmarks. Tracts of the infraorbital nerve and lingual nerve were comparably lower-signal and did not consistently reach the furthest benchmarks (9% and 17%, respectively). CONCLUSION: This work demonstrates a method for consistently identifying and tracking the major nerve branches of the trigeminal nerve with diffusion tensor imaging.

Characterizing Tissue Remodeling and Mechanical Heterogeneity in Cerebral Aneurysms.

Accurately assessing the complex tissue mechanics of cerebral aneurysms (CAs) is critical for elucidating how CAs grow and whether that growth will lead to rupture. The factors that have been implicated in CA progression - blood flow dynamics, immune infiltration, and extracellular matrix remodeling - all occur heterogeneously throughout the CA. Thus, it stands to reason that the mechanical properties of CAs are also spatially heterogeneous. Here, we present a new method for characterizing the mechanical heterogeneity of human CAs using generalized anisotropic inverse mechanics, which uses biaxial stretching experiments and inverse analyses to determine the local Kelvin moduli and principal alignments within the tissue. Using this approach, we find that there is significant mechanical heterogeneity within a single acquired human CA. These results were confirmed using second harmonic generation imaging of the CA's fiber architecture and a correlation was observed. This approach provides a single-step method for determining the complex heterogeneous mechanics of CAs, which has important implications for future identification of metrics that can improve accuracy in prediction risk of rupture.

Identifying symptomatic trigeminal nerves from MRI in a cohort of trigeminal neuralgia patients using radiomics.

INTRODUCTION: Trigeminal neuralgia (TN) is a devastating neuropathic condition. This work tests whether radiomics features derived from MRI of the trigeminal nerve can distinguish between TN-afflicted and pain-free nerves. METHODS: 3D T1- and T2-weighted 1.5-Tesla MRI volumes were retrospectively acquired for patients undergoing stereotactic radiosurgery to treat TN. A convolutional U-net deep learning network was used to segment the trigeminal nerves from the pons to the ganglion. A total of 216 radiomics features consisting of image texture, shape, and intensity were extracted from each nerve. Within a cross-validation scheme, a random forest feature selection method was used, and a shallow neural network was trained using the selected variables to differentiate between TN-affected and non-affected nerves. Average performance over the validation sets was measured to estimate generalizability. RESULTS: A total of 134 patients (i.e., 268 nerves) were included. The top 16 performing features extracted from the masks were selected for the predictive model. The average validation accuracy was 78%. The validation AUC of the model was 0.83, and sensitivity and specificity were 0.82 and 0.76, respectively. CONCLUSION: Overall, this work suggests that radiomics features from MR imaging of the trigeminal nerves correlate with the presence of pain from TN.

Effect of Hispanic Status in Mechanical Thrombectomy Outcomes After Ischemic Stroke: Insights From STAR.

Background and Purpose: Epidemiological studies have shown racial and ethnic minorities to have higher stroke risk and worse outcomes than non-Hispanic Whites. In this cohort study, we analyzed the STAR (Stroke Thrombectomy and Aneurysm Registry) database, a multi-institutional database of patients who underwent mechanical thrombectomy for acute large vessel occlusion stroke to determine the relationship between mechanical thrombectomy outcomes and race. Methods: Patients who underwent mechanical thrombectomy between January 2017 and May 2020 were analyzed. Data included baseline characteristics, vascular risk factors, complications, and long-term outcomes. Functional outcomes were assessed with respect to Hispanic status delineated as non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic patients. Multivariate analysis was performed to identify variables associated with unfavorable outcome or modified Rankin Scale ≥3 at 90 days. Results: Records of 2115 patients from the registry were analyzed. Median age of Hispanic patients undergoing mechanical thrombectomy was 60 years (72­84), compared with 63 years (54­74) for NHB, and 71 years (60­80) for NHW patients (P<0.001). Hispanic patients had a higher incidence of diabetes (41%; P<0.001) and hypertension (82%; P<0.001) compared with NHW and NHB patients. Median procedure time was shorter in Hispanics (36 minutes) compared to NHB (39 minutes) and NHW (44 minutes) patients (P<0.001). In multivariate analysis, Hispanic patients were less likely to have favorable outcome (odds ratio, 0.502 [95% CI, 0.263­0.959]), controlling for other significant predictors (age, admission National Institutes Health Stroke Scale, onset to groin time, number of attempts, procedure time). Conclusions: Hispanic patients are less likely to have favorable outcome at 90 days following mechanical thrombectomy compared to NHW or NHB patients. Further prospective studies are required to validate our findings.

Neurosurgical management of aneurysms of the vertebrobasilar system: increasing indications for endovascular therapy with a continued role for open microneurosurgery.

Aneurysms of the vertebrobasilar system remain among the most challenging subsets of aneurysms to treat with an open surgical approach. Since Charles Drake's pioneering work in the 1960s, several advances in microsurgical techniques have improved outcomes and feasibility in the open surgical management of these aneurysms. In parallel, the field of endovascular neurosurgery has provided several safe and effective treatment options. Multiple trials have suggested that endovascular therapy for aneurysms of the vertebrobasilar system is superior to open surgical management in most cases. In some instances, however, open surgical management likely represents a more effective and durable option relative to endovascular therapy. Therefore, continued training of future cerebrovascular specialists in open surgery of vertebrobasilar aneurysms remains crucial. With widespread utilization of endovascular techniques, however, proper exposure of trainees to such aneurysms is growing increasingly difficult. In this review, we discuss the recent advances in the endovascular management of vertebrobasilar aneurysms while also emphasizing the continued importance of open microneurosurgery in such cases.

The foramen ovale "mirage" and how this impacts percutaneous cannulation for treatment of trigeminal neuralgia: a report of two cases.

Percutaneous stereotactic radiofrequency rhizotomy (PSR) for trigeminal neuralgia most commonly utilizes 2D fluoroscopy for intraoperative needle guidance into the foramen ovale (FO). We describe two cases in which needle advancement into FO was unachievable despite appropriate needle placement on biplane fluoroscopy. Intraoperative multiplanar reconstruction was helpful in more accurately depicting foraminal anatomy which allowed the manipulation of the tip of the needle, which was followed by successful FO cannulation. We propose that this "mirage" is likely created by the inherent nature of X-ray-based fluoroscopy in which the FO appears to be readily penetrable, when in fact the 3D anatomy actually prevents cannulation.

Microsurgical Management of the Middle Cerebral Artery Bifurcation Aneurysms: An Anatomic Feasibility Study.

BACKGROUND: The proper head positioning decreases the surgical complications by enabling a better surgical maneuverability. Middle cerebral artery (MCA) bifurcation aneurysms have been classified by Dashti et al. [Surg Neurol. 2007 May;67(5):441-56] as the intertruncal, inferior, lateral, insular, and complex types based on dome projection. Our aim was to identify the optimum head positions and to explain the anatomic variables, which may affect the surgical strategy of MCA bifurcation aneurysms. METHODS: The lateral supraorbital approach bilaterally was performed in the 4 cadaveric heads. All steps of the dissection were recorded using digital camera. RESULTS: The distal Sylvian fissure (SF) dissection may be preferred for insular type and the proximal SF dissection may be preferred for all other types. Fifteen degrees head rotation was found as the most suitable position for the intertruncal, lateral type and subtype of complex aneurysms related with superior trunk. Thirty degrees head rotation was found the most suitable position for the inferior type, insular type, and subtype of complex aneurysms related with inferior trunk. CONCLUSIONS: The head positioning in middle cerebral bifurcation aneurysms surgery is a critical step. It should be tailored according to the projection and its relationship with the parent vessels of the middle cerebral bifurcation.

Gsx2 controls region-specific activation of neural stem cells and injury-induced neurogenesis in the adult subventricular zone.

Neural stem cells (NSCs) reside in widespread regions along the lateral ventricle and generate diverse olfactory bulb (OB) interneuron subtypes in the adult mouse brain. Molecular mechanisms underlying their regional diversity, however, are not well understood. Here we show that the homeodomain transcription factor Gsx2 plays a crucial role in the region-specific control of adult NSCs in both persistent and injury-induced neurogenesis. In the intact brain, Gsx2 is expressed in a regionally restricted subset of NSCs and promotes the activation and lineage progression of stem cells, thereby controlling the production of selective OB neuron subtypes. Moreover, Gsx2 is ectopically induced in damaged brains outside its normal expression domains and is required for injury-induced neurogenesis in the subventricular zone (SVZ). These results demonstrate that mobilization of adult NSCs is controlled in a region-specific manner and that distinct mechanisms operate in continuous and injury-induced neurogenesis in the adult brain.

A Case Report of Thoracic Endovascular Aneurysm Repair under Local Anesthesia with Resolution of Acute Onset Lower Extremity Paraplegia from an Acute Complicated Type B Aortic Dissection.

Spinal cord ischemia (SCI) is a rare presenting symptom of acute complicated type B aortic dissection, occurring in approximately 3% of patients . We present a case report of a patient with this presentation who had observed resolution of his paraplegia symptoms immediately after placement of a thoracic stent graft under local anesthesia. The temporal association between true lumen flow restoration and paraplegia resolution intraoperatively is a novel finding. We feel that this case report may provide support for recognized cord perfusion theory , as well as contribute to the understanding of the time frame associated with SCI and reversibility of paraplegia.

Prospective Trial of Cerebrospinal Fluid Filtration After Aneurysmal Subarachnoid Hemorrhage via Lumbar Catheter (PILLAR).

Background and Purpose- The PILLAR (Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter) study is a first-in-human trial of cerebrospinal fluid (CSF) filtration in aneurysmal subarachnoid hemorrhage. The study evaluates the safety and feasibility of a novel filtration system to rapidly remove blood and blood breakdown products from CSF after securement of a ruptured aneurysm. Methods- Patients with aneurysmal subarachnoid hemorrhage had a dual-lumen lumbar, intrathecal catheter placed after aneurysm securement and received up to 24 hours of CSF filtration (neurapheresis therapy). The catheter aspirated blood-contaminated CSF from the lumbar cistern and returned filtered CSF to the thoracic subarachnoid space. Neuro checks were performed q2 hours, and CSF samples were collected for cell counts, total protein, and gram stain. Computed tomography scans were acquired at baseline and post-filtration. Clinical follow-up occurred at 2 weeks and 30 days. Results- Thirteen patients had a catheter placed (mean time 24:13 hours after ictus). The system processed 632.0 mL (180.6-1447.6 mL) CSF in 15:07 hours (5:32-24:00 hours) of filtration. The mean initial CSF red blood cell count, 2.78×105 cells/µL, reduced to 1.17×105 cells/µL after filtration (52.9% reduction), and total protein reduced 71%. Independent analysis of baseline and postfiltration computed tomographies found notable cisternal blood decrease, with 46.5% mean Hijdra Score reduction. Three mild, anticipated adverse events were reported. Conclusions- The initial safety and feasibility of Neurapheresis therapy in aneurysmal subarachnoid hemorrhage demonstrated the potential to safely filter CSF and remove blood and blood byproducts. Future studies are warranted. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT0287263.

Ex vivo method for rapid quantification of post traumatic brain injury lesion volumes using ultrasound.

BACKGROUND: Studies of traumatic brain injury often involve the quantification of the lesion volume as a major outcome measure. The determination of lesion volume typically employs the cutting and mounting of brain tissue, and the calculation of the cross-sectional area of the lesion within each section of brain after histological staining. This is a time consuming and laborious task often requiring many weeks to determine the lesion volume for an individual brain. METHODS: In this report we present a method for determining the lesion volume within the brain following traumatic brain injury that involves the use of ultrasound imaging. With this process the lesion volume can be determined within a time period of 90 min per brain rather than weeks and months. Moreover, we have developed a pipeline that will combine the cross-sectional ultrasound images of the brain with the Allen Mouse Brain Atlas to provide the precise anatomical structures that are affected by traumatic injury to the brain. The anatomical detail was lastly paired with behavioral data showing neurological deficits correlated with specific areas of brain injury. RESULTS: The accuracy and precision of this method was shown to be highly consistent with the traditional histological approach. Additionally, the mapping process and behavioral data show that neurological recovery from 1 to 3 weeks post injury is not correlated with gross anatomical recovery of the TBI lesion in our TBI model. CONCLUSION: Together these approaches will enhance the pipeline for processing brain tissue in experimental conditions where the lesion volume is an important outcome parameter and provide more high resolution information about the identity of the damaged regions of the brain.

Effect of lesion temperature on the durability of percutaneous radiofrequency rhizotomies to treat trigeminal neuralgia.

OBJECTIVE: Percutaneous radiofrequency rhizotomy is a common procedure for trigeminal neuralgia (TN) that creates thermocoagulative lesions in the trigeminal ganglion. Lesioning parameters for the procedure are left to the individual surgeon's discretion, and published guidance is primarily anecdotal. The purpose of this work was to assess the role of lesioning temperature on long-term surgical outcomes. METHODS: This was a retrospective analysis of patients who underwent percutaneous radiofrequency rhizotomy from 2009 to 2020. Patient data, including demographics, disease presentation, surgical treatment, and outcomes, were collected from medical records. The primary endpoint was the recurrence of TN pain. Univariate and multivariate Cox proportional hazards regressions were used to assess the impact of chosen covariates on pain-free survival. RESULTS: A total of 280 patients who had undergone 464 procedures were included in the analysis. Overall, roughly 80% of patients who underwent rhizotomy would have a recurrence within 10 years. Lower lesion temperature was predictive of longer periods without pain recurrence (HR 1.05, p < 0.001). The inclusion of lesion time, postoperative numbness, prior history of radiofrequency rhizotomy, surgeon, and multiple sclerosis as confounding variables did not affect the hazard ratio or the statistical significance of this finding. Postoperative numbness and the absence of multiple sclerosis were significant protective factors in the model. CONCLUSIONS: The study findings suggest that lower lesion temperatures and, separately, postoperative numbness result in improved long-term outcomes for patients with TN who undergo percutaneous radiofrequency rhizotomies. Given the limitations of retrospective analysis, the authors suggest that a prospective multisite clinical trial testing lesion temperatures would provide definitive guidance on this issue with specific recommendations about the number needed to treat and trial design.

BOBBY balloon guide catheter thrombectomy in large-vessel occlusion stroke: Initial experience.

BACKGROUND AND PURPOSE: Nonrandomized studies have found Balloon Guide Catheter (BGC) use to improve technical and functional outcomes in patients undergoing mechanical thrombectomy (MT). MATERIALS AND METHODS: We performed a retrospective analysis on prospectively collected data of consecutive ischemic stroke patients undergoing MT at our institution (December 2020-October 2021). Interventions where BOBBY BGC (BBGC, MicroVentionTM, Aliso Viejo, CA) was used were identified. Baseline demographics and clinico-radiographic characteristics were retrospectively collected and analysed using descriptive statistics. RESULTS: A total of 43 patients received BBGC-MT (male: female = 26:17, median age 72 years [IQR 62-82]). The most common occlusion site was the middle cerebral artery (MCA) (60.4%). Over half (51.2%) received intravenous thrombolytics. The BBGC tracked well over tortuous aortic arches (type II 34.8%, type III 16.3%), with median arteriotomy-to-perfusion time of 29 min (IQR 20-46). Thromboaspiration was used as first-line MT technique in 69.7% cases, with 1 (IQR 1-2) median MT pass achieving modified TICI (thrombolysis in cerebral ischemia) scores of 3 and 2b/3 in 74.4% and 95.3% respectively. Our overall first pass effect (FPE, defined as mTICI 3 after firs-pass) and modified FPE (defined as, mTICI 2b/3 after first-pass) rates were 51.1% and 79.1% respectively, with rates of 92.3% and 100% respectively when stentretriever and thromboaspiration were combined. The median reduction in National Institutes of Health Stroke Scale (NIHSS) was 9 (IQR 4-15, p < 0.0001), with a median 90-day modified Rankin Score (mRS) of 1.5 (IQR 0-2). CONCLUSIONS: BOBBY BGC use resulted in a high first-pass effect rate and may contribute towards improved functional outcomes.

Trans-radial spinal angiography: A single-center experience.

INTRODUCTION: Spinal angiography (SpAn) is the gold standard for diagnosis of spinal dural fistulas and arteriovenous malformations. A complete spinal angiogram necessitates the interrogation of the segmental arteries arising from the aorta at every level as well, the internal iliac; and median sacral arteries at the caudal end; and the cervical vasculature at the cranial end. SpAn has traditionally been performed with transfemoral arterial access and could be challenging. Of late, transradial arterial access has emerged as a popular alternative for endovascular surgical Neuroradiology (ESN) procedures including SpAn. However, there is paucity of the literature regarding transradial access for spinal angiography. METHODS: After IRB approval, records and imaging were reviewed in a series of patients who underwent SpAn at our institution. RESULTS: A total of nine spinal angiograms were performed via transradial access in a consecutive series of eight patients between July 2019 and December 2020 at our institution. Eight of these were diagnostic SpAn's, and one patient underwent SpAn with transradial approach for the treatment of a type I spinal dural arteriovenous fistula. No complications occurred during or subsequent to the procedures. CONCLUSION: SpAn can be successfully and safely accomplished via transradial access. This approach appears to provide a stable method for interventions, as well.

Flow residence time in intracranial aneurysms evaluated by in vitro 4D flow MRI.

The process of an intracranial aneurysm development, growth, and rupture is multifaceted and complex. In addition, clinical observations have identified the potential of thrombus formation within such aneurysms. While the underlying mechanism is not fully understood, the thrombi represent a potential risk factor for ischemic stroke. Emerging studies indicate that blood residence time (RT) is a promising hemodynamic metric associated with the aneurysm rupture and formation of intra-aneurysmal thrombi. Here, we present a methodology to experimentally evaluate both trajectory-wise and local RT based on magnetic resonance imaging (MRI) velocimetry, and apply it to in vitro flow measurements in scaled-up replicas of 9 patient-specific intracranial aneurysms. Lagrangian tracks of massless tracers are integrated from the velocity fields and averaged to return the mean RT in the aneurysm sac. This is found to be closely approximated by a simple time scale based on the sac diameter and space-time average of the aneurysmal fluid velocity. The mean RT is also correlated with the inflow time scale at the parent artery. These results also provide a basis for the estimation of RT when high-resolution hemodynamic maps are not available. With the continuous increase in accuracy and resolution enabled by progress in MRI technology, the methodology described here may in the future be applicable to in vivo data.

Biology and Hemodynamics of Aneurysm Rupture.

Predicting rupture risk in intracranial aneurysms is among one of the most critical questions in vascular surgery. The processes that govern an aneurysm growth are multifaceted and complex, but may be summarized into three components: hemodynamics, biology, and mechanics. We review and connect the literature in the three disciplines, identifying considerable strides in recent history and current gaps in research. Taken together, the findings from each field elucidate how and why certain aneurysms rupture, whereas others remain stable. These parameters could eventually inform a translatable predictive model that optimizes risk evaluation and physician's decision-making in treatment options for aneurysms.

The practical limits of high-quality magnetic resonance imaging for the diagnosis and classification of trigeminal neuralgia.

BACKGROUND: Neurovascular compression (NVC) has been the primary hypothesis for the underlying mechanism of classical trigeminal neuralgia (TN). However, a substantial body of literature has emerged highlighting notable exceptions to this hypothesis. The purpose of this study is to assess the reliability and diagnostic accuracy of high resolution, high contrast MRI-determined neurovascular contact for TN. METHODS: We performed a retrospective, randomized, and blinded parallel characterization of neurovascular interaction and diagnosis in a population of TN patients and controls using four expert reviewers. Performance statistics were calculated, as well as assessments for generalizability using shuffled bootstraps. RESULTS: Fair to moderate agreement (ICC: 0.32-0.68) about diagnosis between reviewers was observed using MRIs from 47 TN patients and 47 controls. On average reviewers performed no better than chance when diagnosing participants, with an accuracy of 0.57 (95% CI 0.40, 0.59) per patient. CONCLUSION: While MRI is useful in determining structural causes in secondary TN, expert reviewers do no better to only slightly better than chance with distinguishing TN with MRI, despite moderate agreement. Further, the causal role of NVC for TN is not clear, limiting the applicability of MRI to diagnose or prognosticate treatment of TN.

Use of reverse angle guide catheter with trans-radial approach in patients undergoing middle meningeal artery embolization.

Background: Trans-radial access (TRA) for MMA embolization has grown due to lower access site complications and greater patient satisfaction. Here, we describe the feasibility of utilizing a 6F Envoy Simmons 2 (6F-SIM2) as a guide catheter with TRA and compare outcomes with trans-femoral approach (TFA) in a single center case series. Methods: We performed a retrospective review of patients who underwent MMA embolization for management of chronic subdural hematoma (cSDH). TRA was performed by utilizing a combination of 6F 90cm Envoy (Codman & Shurtleff, Inc., Rayham, MA) Simmons 2 guide catheter and 5F 125cm Sofia (Microvention, Aliso Viejo, CA) intermediate catheter. Outcomes measured are Modified Rankin Score (mRS) at 90 days, inpatient mortality, post-embolization recurrence, fluoroscopy time and radiation exposure. Results: A total of 71 patients underwent 97 MMA embolization overall with 65 (67%) in trans-femoral access group, 11 (11.3%) in trans-radial access without use of Simmons 2 Guide catheter group and 21 (21.6%) in trans-radial access with use of Simmons 2 Guide catheter group. There were no direct access-related complications in either group. One patient had thromboembolic stroke in trans-femoral group. There was no difference in average procedure-related total fluro time or radiation dose among all three groups. Conclusion: Trans-radial approach using 6F-SIM2 guide catheter coupled with 5F Sofia intermediate catheter is safe and effective. It provides an alternative approach to access distal branches of bilateral anterior circulation in elderly patients with difficult anatomy undergoing MMA embolization.