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.

Vessel wall imaging features of Moyamoya disease in a North American population: patterns of negative remodelling, contrast enhancement, wall thickening, and stenosis.

BACKGROUND: This study characterized vessel wall imaging (VWI) features of Moyamoya disease (MMD) in a predominantly adult population at a North American center. METHODS: Consecutive patients with VWI were included. Twelve arterial segments were analyzed for wall thickening, degree and pattern of contrast enhancement, and remodeling. RESULTS: Overall, 286 segments were evaluated in 24 patients (mean age = 36.0 years [range = 1-58]). Of 172 affected segments, 163 (95%) demonstrated negative remodeling. Complete vessel wall obliteration was most frequent in the proximal M1 (17/48, 35%). Affected segments enhanced in 72/172 (42%) (n = 15 for grade II; n = 54 for concentric and n = 18 for eccentric); 20 of 24 (83%) patients had at least one enhancing segment. Both enhancing and non-enhancing segments were present in 19/20 (95%) patients. Vessel wall enhancement was most common in the proximal segments and correlated to the degree of stenosis (p < 0.001), and outer wall diameter (p < 0.001), but not disease duration (p = 0.922) or Suzuki score (p = 0.477). Wall thickening was present in 82/172 (48%) affected segments and was associated with contrast enhancement (p < 0.001), degree of stenosis (p < 0.001), and smaller outer wall diameter (p = 0.004). CONCLUSION: This study presents VWI findings in North American patients with MMD. Negative remodeling was the most common finding. Most patients had both enhancing and non-enhancing abnormal segments. Vessel wall enhancement was most common in proximal segments, variable in pattern or degree and was correlated to the degree of stenosis and smaller outer wall diameter.

Pipeline embolization for recurrent vertebral artery thromboembolic events secondary to a misplaced pedicle screw.

BACKGROUND: Cervical spine instrumentation carries a risk of vertebral artery injury which can cause devastating neurological events. Flow diversion using the Pipeline embolization device (PED) is a commonly used endovascular modality that can treat various vessel wall abnormalities including aneurysms and arterial dissections. CASE DESCRIPTION: We report the case of a 69-year-old female who presented with multiple cryptogenic strokes secondary to a vertebral artery irregularity from a misplaced pedicle screw. She continued having ischemic infarcts despite maximal medical therapy. The patient was successfully treated with the PED and has not had any further ischemic events at 1-year follow-up. CONCLUSIONS: To our knowledge, this is the first published case of a chronic vertebral artery abnormality secondary to a misplaced pedicle screw that was treated with flow diversion. This is likely a safe and effective treatment for this rare complication of pedicle screw placement.

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.

Cardiac manifestations in a western moyamoya disease population: a single-center descriptive study and review.

An embryological association between moyamoya disease (MMD) and cardiac manifestations has been proposed. Data up to this point remains anecdotal, and the prevalence of cardiac manifestations in a western MMD population is uncertain. The objective of this study was to determine the prevalence of cardiac manifestations including coronary artery disease (CAD) and congenital cardiac defects in a mostly Caucasian population of MMD patients and review prior reports of such cases. Medical records of MMD patients who presented to our institution between 1990 and 2019 were retrospectively reviewed for the presence of various congenital cardiac malformations and concomitant CAD. The prevalence of congenital cardiac defects and CAD was determined. A literature search for prior cases of MMD with concomitant cardiac manifestations was performed. A total of 181 MMD patients were included in our analysis, 139 (76.8%) of whom were Caucasian. Ten patients had cardiac manifestations (5.5%). There were six total MMD patients with congenital cardiac defects (3.3%). All patients with congenital defects were diagnosed in childhood. The prevalence of congenital defects in MMD was slightly higher than the general population as reported previously (0.8-1.2%). Four MMD patients had CAD (2.2%). The mean age of patients with CAD was 41.0 years (SD = 12.3, range = 33-59) in our series and 33.1 years (SD = 15.0) in a review of prior reports. These mean ages of CAD are in contrast to the 7th and 8th decades of lifein the general population as indicated by prior studies. Our findings support an association between MMD and cardiac manifestations. Further investigation is warranted in order to further characterize this potential relationship and shed light on a possible cardio-cephalic neural crest syndrome.

Location-based treatment of intracranial aneurysms in moyamoya disease: a systematic review and descriptive analysis.

We conducted a systematic review of the literature to evaluate the efficacy of various treatment modalities for intracranial aneurysms (IA) in patients with moyamoya disease (MMD) based on anatomical location of IA. A comprehensive review of studies documenting single cases or series of MMD patients with concomitant IA was conducted. Aneurysms were classified into two primary anatomical categories: those of the Circle of Willis (CoW) and those of peripheral "moyamoya" collateral vessels. Conservative, endovascular, and open surgical treatment modalities and their outcomes between each anatomical subgroup were descriptively compared. A total of 124 studies consisting of 275 patients with 313 IA were included. Of all IA, 59.6% were located on CoW vessels, 33.7% on peripheral vessels, and 6.7% in "other" locations. Of all CoW IA, 87.2% treated with endovascular techniques had no or minimal deficit at follow-up as compared with 56.7% of those treated with open surgery. Ninety-five percent of patients with peripheral aneurysms treated with endovascular therapy had no or minimal deficit, in contrast to open surgery (69.6%). Of peripheral IA treated conservatively with or without revascularization, 65.7% had spontaneous resolution as compared with 12.0% IA of the CoW. Our results support the use of endovascular techniques for direct treatment of both CoW and peripheral IA. Aneurysms of peripheral vessels respond well to indirect treatment through surgical revascularization as opposed to CoW aneurysms. The quality of evidence is limited due to heterogeneity of included studies and IA management in MMD patients should be considered in a case-specific manne.

The Frequency of Carotid Intraplaque Hemorrhage on Vessel Wall Imaging in Patients With Retinal Artery Occlusion: A Cross-Sectional Prevalence Study.

BACKGROUND: Intraplaque hemorrhage (IPH) in a carotid artery plaque viewed on vessel wall imaging has been shown to be associated with ischemic stroke. Whether such an association between carotid IPH and retinal artery occlusion (RAO) exists remains unknown. METHODS: This was a cross-sectional prevalence study. Medical and imaging records of all patients who underwent neck MRA with plaque imaging sequences at our institution from 2015 to 2020 were retrospectively reviewed. Fourteen patients with confirmed RAO and plaque imaging performed within 6 weeks of presentation were included. A group of 211 patients without a prior ischemic event (RAO, stroke, etc.) with plaque imaging were used as controls. A single artery from control patients was randomly selected. The prevalence of IPH and degree of ipsilateral carotid stenosis were compared between RAO and control patients. Multiple regression analysis was performed to determine independent associations between variables and RAO. RESULTS: Five patients (35.7%) with RAO had imaging evidence of ipsilateral IPH in contrast to 7 of 211 (3.3%) patients in the control group (odds ratio [OR]: 16.2, 95% confidence interval [95% CI]: 4.3-61.1, P = 0.0002). Of the 5 patients with RAO and ipsilateral IPH, only one (20.0%) was found to ipsilateral carotid stenosis greater than 70%. Carotid IPH was the only variable that was independently associated with RAO (OR: 12.6, 95% CI = 2.2-73.6, P = 0.005). CONCLUSIONS: Carotid IPH is independently associated with RAO. The use of plaque imaging in the evaluation of patients with acute RAO is therefore supported.

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.

Carotid Intraplaque Hemorrhage Is Associated with Cardiovascular Risk Factors.

INTRODUCTION: Intraplaque hemorrhage (IPH) is a known predictor of symptomatic cervical carotid artery disease. However, the association between IPH and modifiable cardiovascular risk factors, patient demographics, and pertinent laboratory values has not been extensively studied. METHODS: A retrospective review was performed of consecutive patients who have undergone dedicated carotid plaque imaging over a 3-year period. Patients were excluded if the MR examination did not include high-resolution carotid plaque imaging. Intraplaque hyperintense signal on carotid plaque images was presumed to represent IPH. The presence or absence of IPH was compared to various demographic and clinical variables. Multivariable regression analysis was performed in order to determine an independent association between variables and IPH. RESULTS: Of 643 included patients, 114 patients (17.7%) had IPH in one or both carotids, 529 patients (82.3%) did not; 39.5% of patients with IPH had coronary artery disease compared to 23.1% of patients without (p = 0.0003). Patients with IPH also had higher proportions of hypertension (77.2 vs. 60.7%, p = 0.009), hyperlipidemia (HLD; 89.5 vs. 62.4%, p < 0.0001), diabetes mellitus (29.0 vs. 18.7%, p = 0.01), and a history of tobacco smoking (63.2 vs. 52.6%, p = 0.003). Patients without IPH had, on average, higher high-density lipoprotein levels (46.1 vs. 56.7%, p = 0.003). Factors independently associated with IPH were advanced age (odds ratio [OR]: 1.1, 95% CI: [1.0-1.05], p <0.0001), male sex (OR: 2.5, 95% CI: [1.4-4.4], p = 0.0001), presence of carotid stenosis (OR: 8.4, 95% CI: [4.6-15.3], p < 0.0001), and HLD (OR: 2.6, 95% CI: [1.3-5.2], p = 0.009). CONCLUSIONS: IPH is associated with multiple cardiovascular risk factors, in particular advanced age, male sex, presence of carotid stenosis, and HLD. Such risk factors likely play a role in the development of IPH and may provide insight into the pathophysiology of unstable carotid plaques.

Brain capillary telangiectasias: from normal variants to disease.

BACKGROUND: Brain capillary telangiectasias (BCTs) are small, dilated capillary networks in the brain that are most commonly asymptomatic. Though rare, symptomatic cases of BCTs have been reported, and it is therefore important to understand the nature of these lesions in order to facilitate proper recognition. Relative to other intracranial vascular malformations, updated information on the various epidemiologic, radiographic, and pathologic features of BCTs within the published literature may be inadequate. METHODS: We searched the PubMed database for prior reports of symptomatically-manifested BCTs. Moreover, Google Scholar and PubMed were searched in order to review current epidemiologic, radiographic, pathologic, and pathogenetic features of BCTs. RESULTS: Forty-eight published studies were included for a total of 99 individual cases of BCTs with symptomatic manifestations. Thirty-three symptomatic BCTs were hemorrhagic in nature, while 66 were non-hemorrhagic. The mean age at presentation of hemorrhagic lesions was 25.5 years, and the most common location was the supratentorial CNS (54.5%) with motor disturbance representing the most commonly encountered presenting symptom (26.1%). 15.2% of hemorrhagic lesions were treated with surgical removal. In non-hemorrhagic lesions, the mean age at presentation was 39.8 years with the pons being the most common lesion location (78.5%) and headache being the most common presenting symptom (22.2%). 12.1% of patients with non-hemorrhagic lesions were treated with surgical removal. CONCLUSIONS: Despite their rarity, symptomatic BCTs, both hemorrhagic and non-hemorrhagic, can cause devastating neurological sequelae, potentially through multiple mechanisms. The large majority of these lesions do not require intervention, though surgical removal has been achieved with good outcome in select cases. Further documentation of symptomatic manifestations with or without surgical intervention is vital in order to further understand the clinical, surgical, and pathogenic implications of these less-appreciated vascular malformations.

High prevalence of pro-thrombotic conditions in adult patients with moyamoya disease and moyamoya syndrome: a single center study.

BACKGROUND: Moyamoya Disease (MMD) and moyamoya Syndrome (MMS) have been reported to be associated with pro-thrombotic states in some patients. To date, however, such reports have been limited to case reports or small case series. We sought to determine the prevalence of pro-thrombotic states among a large cohort of both MMD and MMS patients. METHODS: We retrospectively reviewed the medical records of all adult patients who were diagnosed with MMD or MMS from our institution. In addition to basic demographic and clinical data, the presence of certain pro-thrombotic conditions was noted. The presence of such conditions was determined based on review of clinical diagnoses and laboratory reports. The length of follow-up and the presence of interval ischemic events were obtained. RESULTS: Out of a total of 180 patients diagnosed with MMD or MMS, 33 were found to have a concomitant pro-thrombotic condition (18.3%). Of 147 patients with MMD, 23 were found to have a pro-thrombotic condition (15.6%). There were 10 out of 33 total patients (30.3%) in the MMS cohort that had a concomitant pro-thrombotic condition. There were no differences in specific pro-thrombotic conditions between MMD and MMS cohorts. There were no differences in future ischemic events between moyamoya patients with pro-thrombotic tendencies compared to those without (13.3% versus 23.7%, respectively, P = 0.32), and this was also true for patients who underwent revascularization procedures (22.6% versus 29.4%, P = 0.76). There was also no difference in prevalence of revascularization graft occlusion between moyamoya patients with pro-thrombotic tendencies and those without at follow-up (1.2% versus 5.9%, P = 0.31). CONCLUSIONS: It is likely that both MMD and MMS are associated with or predispose to pro-thrombotic conditions in adult patients, although the clinical and surgical significance is uncertain. Further study is needed in order to further elucidate and characterize this potential association.

A review of histopathologic and radiologic features of non-atherosclerotic pathologies of the extracranial carotid arteries.

Diseases of the carotid arteries can be classified into different categories based on their origin. Atherosclerotic carotid disease remains the most encountered arterial wall pathology. However, other less-common non-atherosclerotic diseases can have detrimental clinical consequences if not appropriately recognized. The underlying histological features of each disease process may result in imaging findings that possess features that are obvious of the disease. However, some carotid disease processes may have histological characteristics that manifest as non-specific radiologic findings. The purpose of this manuscript is to review various non-atherosclerotic causes of carotid artery disease as well as their histologic-radiologic characteristics to aid in the appropriate recognition of these less-commonly encountered pathologies.

Radiculomedullary arterial contributions to the thoracolumbar spinal cord: an angiographic study.

BACKGROUND: Anterior (ASA) and posterior spinal arteries (PSA) receive vital collateral flow from radiculomedullary (RM) arteries. The purpose of this study was to review a series of spinal angiograms in order to characterize normal RM arterial anatomy. METHODS: The reports of digital subtraction spinal angiograms from consecutive patients from our institution from 2002-2019 were retrospectively reviewed. The RM contributions to both the ASA and PSA were characterized by noting laterality, spinal level and multiplicity. RESULTS: Overall, 336 spinal angiograms from 336 patients were included. Regarding RM input to the ASA, 328 patients (97.6%) had at least one RM contribution to the ASA. Forty-six patients (46/328, 14.1%) had multiple RM ASA contributions. Three hundred and eighty-one total RM with input to the ASA were visualized. Ninety-five RM of the ASA (95/381, 24.9%) were located on the right, 286 (75.1%) on the left. Three hundred and twenty-four RM arteries (85.0%) arose between T8 and L2: 246 (64.5% overall) were located on the left, and 78 (20.5%) on the right. Sixty-one patients (18.2%) had at least one visualized RM contribution to the PSA: 16 patients (16/61, 26.2%) had more than one RM contribution to the PSA. Eighty-seven total RM contributions to the PSA were visualized. Eighty-one (93.1%) RM arose between T6 and L1, 52 of which (59.8% overall) were from the left, and 29 (33.3%) from the right. CONCLUSIONS: RM anastomoses with both the ASA and PSA most-commonly originate from the left-sided T6-L2 spinal levels. Multiple RM contributions to the ASA or PSA are less common.

Carotid Artery Tortuosity and Internal Carotid Artery Plaque Composition.

BACKGROUND: Little is known about the association between carotid artery tortuosity and internal carotid artery atherosclerosis. This study sought to evaluate the associations between various types of arterial tortuosity and vulnerable plaque components on magnetic resonance angiography (MRA). MATERIAL AND METHODS: A retrospective review was completed of 102 patients who had undergone MRA neck imaging, with intraplaque hemorrhage (IPH) present in one or both cervical internal carotid arteries (ICA). Each ICA was assessed for two categories of tortuosity: variant arterial pathway(s) (retrojugular and/or retropharyngeal) and abnormal curvature (kinks, loops, and/or coils). All ICA plaques were assessed for the presence or absence of intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), ulceration, and enhancement, as well as the volume of IPH and degree of luminal stenosis. RESULTS: The mean age of included patients was 73.5 years (SD = 9.0 years) and 88 (86.3%) subjects were male. The left carotid plaque was significantly more likely to have IPH (68.6% vs. 47.1%; p = 0.02). The left ICA was more likely to have a retrojugular course (22% vs. 9.9%; p = 0.002) and any variant arterial course (26.5% versus 14.67%, p = 0.01). On the right there was an association between the presence of a LRNC and retropharyngeal and/or retrojugular arterial pathway (p = 0.03). On the left there was an association between the presence of any abnormal arterial curvature and IPH volume (p = 0.03). Neither association met the adjusted statistical threshold after Bonferroni correction, with alpha set at 0.0028. CONCLUSION: ICA tortuosity is not associated with carotid artery plaque composition, and likely does not play a role in the development of high-risk plaques.

Intraplaque hemorrhage on magnetic resonance angiography: How often do signal abnormalities persist on follow-up imaging?

BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH) in carotid atherosclerosis demonstrates increased signal on magnetic resonance angiography images. Little remains known about how this signal changes on subsequent examinations. MATERIALS AND METHODS: A retrospective observational study was completed of patients that had IPH on a neck MRA between 1/1/2016 and 3/25/2021, defined as ≥ 200 % signal intensity of the sternocleidomastoid muscle on MPRAGE images. Examinations were excluded if the patients had undergone carotid endarterectomy between examinations or had poor quality imaging. IPH volumes were calculated by manually outlining IPH components. Up to 2 subsequent MRAs, if available, were assessed for both the presence and volume of IPH. RESULTS: 102 patients were included, of which 90 (86.5 %) were male. IPH was on the right in 48 patients (average volume = 174.0 mm3), and on the left in 70 patients (average volume 186.9 mm3). 22 had at least one follow-up (average 444.7 days between exams), and 6 had two follow-up MRAs (average 489.5 days between exams). On the first follow-up, 19 (86.4 %) plaques had persistent hyperintense signal in the region of IPH. The second follow-up showed persistent signal in 5/6 plaques (88.3 %). Combined volume of IPH from right and left carotid arteries did not significantly decrease on the first follow-up exam (p = 0.08). CONCLUSIONS: IPH usually retains hyperintense signal on follow-up MRAs, possibly representing recurrent hemorrhage or degraded blood products.

The cerebrofacial metameric syndromes: An embryological review and proposal of a novel classification scheme.

The cerebrofacial metameric syndromes are a group of congenital syndromes that result in vascular malformations throughout specific anatomical distributions of the brain, cranium and face. Multiple reports of patients with high-flow or low-flow vascular malformations following a metameric distribution have supported this idea. There has been much advancement in understanding of segmental organization and cell migration since the concept of metameric vascular syndromes was first proposed. We aim to give an updated review of these embryological considerations and then propose a more detailed classification system for these syndromes, predominately incorporating the contribution of neural crest cells and somitomeres to the pharyngeal arches.

Normalized intraplaque hemorrhage signal on MP-RAGE as a marker for acute ischemic neurological events.

PURPOSE: This study sought to validate whether the signal intensity ratio (SIR) of carotid intraplaque hemorrhage (IPH) was associated with acute ischemic neurologic events. METHODS: A retrospective review was completed of consecutive patients that underwent neck magnetic resonance angiography using magnetization prepared-rapid gradient echo (MP-RAGE) and T1-CUBE sequences between 2017 and 2020. Patients with magnetic resonance evidence of IPH were included. SIRs were measured by comparing the maximum IPH signal with the mean intramuscular signal from the adjacent sternocleidomastoid. Patients were stratified into ischemic or non-ischemic groups based on the presence of acute ipsilateral ischemic events (stroke, retinal artery occlusion). Logistic regression analysis was performed to determine if increasing IPH SIR was associated with an increased risk of ipsilateral ischemic events. RESULTS: Of 85 included patients (85 arteries), 66 were male (77.6%). Mean age was 71.0 (SD ± 11.1). There were 70 arteries with IPH that were ipsilateral to an ischemic event, and 15 that belonged to patients without an ischemic event. No association was found between increasing IPH SIR seen on MP-RAGE (odds ratio (OR): 0.82; 95% confidence interval (CI): 0.58-1.4; P = 0.43) or T1-CUBE sequences (OR: 0.85; 95% CI: 0.53-1.5; P = 0.56). CONCLUSIONS: There was no association between the SIR of IPH and acute ischemia on either MP-RAGE or T1-CUBE sequences. Further investigation is required prior to widespread acceptance of SIR as a predictive imaging marker of symptomatic carotid plaque.

Imaging of benign cervicofacial vascular anomalies and associated syndromes.

Cervicofacial vascular anomalies can result in morbidity, pain, and cosmetic concerns in affected individuals. Each anomaly has its own unique natural history, treatment, and associations with underlying genetic syndromes. For optimal patient care, it is important for the neuroradiologist to accurately recognize and characterize these entities to ensure appropriate treatment and management. In this review, we discuss the general characteristics, classifications, and imaging features associated with the most common vascular anomalies such as hemangiomas, arteriovenous malformations and fistulas, capillary malformations, venous malformations, and lymphatic malformations in the context of associated syndromes. Additionally, we discuss novel imaging techniques that aid in identifying these vascular anomalies.