Utilizing RNA sequencing to identify gene expression markers of stroke-causing thrombi origin: A pilot study.

INTRODUCTION: Stroke embolic source have an unknown origin in 30-40% of cases. Mechanical thrombectomy for acute large vessel occlusion stroke has provided us with a method to directly retrieve the thrombi from patients for analysis. By collecting stroke-causing thrombi from known sources, we can then use high-throughput RNA sequencing (RNAseq) technology to directly measure the gene expression signatures of these clots. This may allow us to identify genetic markers to predict the cause of cryptogenic embolism. METHODS: This is a prospective study in which RNAseq was used to analyze cerebral thrombi retrieved by mechanical thrombectomy devices in acute ischemic stroke patients. Samples were separated into two groups based on known stroke thrombus etiology, including Carotid group (patients with ipsilateral >70% carotid stenosis) and Atrial fibrillation (AF) group (patients with atrial fibrillation). Gene expression was compared by RNAseq analysis between the groups. RESULTS: From October 2016 to September 2017, 8 thrombi (4 in Carotid group, 4 in Afib group) were included in this study. There were 131 genes that were significantly up- or down-regulated between the two groups defined as a false discovery rate ≤ 0.05 and a fold change ≥ 2. Twenty-six genes were selected as candidate gene biomarkers based on the criteria in the methods section. Candidate genes HSPA1B, which encodes a heatshock protein, and GPRC5B, which encodes a G-protein, showed the greatest fold differences in expression between the two groups. CONCLUSION: This study has shown that RNA sequencing of acute ischemic stroke thrombi is feasible and indentified potential novel biomarkers for identifying stroke-causing thrombi origin, especially in cryptogenic stroke.

Acute Ascending Necrotizing Myelitis After COVID-19 Infection: A Clinicopathologic Report.

Objectives: Neurologic manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, COVID-19) infection are common and varied. The objective of this report was to describe clinicopathologic findings of rare acute ascending necrotizing myelitis (ANM) and briefly summarize similar COVID-19-associated longitudinally extended transverse myelitis cases. Methods: We described the clinical presentation, disease course, diagnostic workup, therapeutic measures, and pathologic findings of ANM associated with COVID-19 infection. Results: A 31-year-old previously healthy woman developed a longitudinally extensive lower thoracic myelopathy 3 weeks after COVID-19 infection. The thoracic spinal cord lesion extended to cervical level in 1 week and to the lower medullary level in 2 more weeks. Thoracic laminectomy at T5-T6 level and cord biopsy revealed necrobiotic changes without viral particles or microglial nodules. The clinical deficit stabilized after immunomodulatory and eculizumab therapies. Discussion: COVID-19 infection can cause ANM. It adds to the spectrum of reported cases of COVID-19 -associated encephalitis and myelitis.

Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions.

PURPOSE OF THE REVIEW: To provide an up-to-date review of the incidence of stroke and large vessel occlusion (LVO) around the globe, as well as the eligibility and access to IV thrombolysis (IVT) and mechanical thrombectomy (MT) worldwide. RECENT FINDINGS: Randomized clinical trials have established MT with or without IVT as the usual care for patients with LVO stroke for up to 24 hours from symptom onset. Eligibility for IVT has extended beyond 4.5 hours based on permissible imaging criteria. With these advances in the last 5 years, there has been a notable increase in the population of patients eligible for acute stroke interventions. However, access to acute stroke care and utilization of MT or IVT is lagging in these patients. SUMMARY: Stroke is the second leading cause of both disability and death worldwide, with the highest burden of the disease shared by low- and middle-income countries. In 2016, there were 13.7 million new incident strokes globally; ≈87% of these were ischemic strokes and by conservative estimation about 10%-20% of these account for LVO. Fewer than 5% of patients with acute ischemic stroke received IVT globally in the eligible therapeutic time window and fewer than 100,000 MTs were performed worldwide in 2016. This highlights the large gap among eligible patients and the low utilization rates of these advances across the globe. Multiple global initiatives are underway to investigate interventions to improve systems of care and bridge this gap.

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs.

Neuroimaging facilitates the translation of animal pre-clinical research to human application. The large porcine spinal cord is useful for testing invasive interventions. Ideally, the safety and efficacy of a delayed intervention is tested in pigs that have recovered sufficiently after spinal cord injury (SCI) to allow either deterioration or improvement of function to be detected. We set out to create moderate severity T9 injuries in Yucatan minipigs by conducting a bridging study adapting methods previously developed in infant piglets. The injury severity was varied according to two pneumatic impactor parameters: the piston compression depth into tissue or the velocity. To stratify locomotor recovery, a 10-point scale used in prior piglet studies was redefined through longitudinal observations of spontaneous recovery. Using hindlimb body weight support to discriminate injury severity, we found that end-point recovery was strongly bimodal to either non-weight-bearing plegia with reciprocating leg movements (<5/10) or recovery of weight bearing that improved toward a ceiling effect (≥ 8/10). No intermediate recovery animals were observed at 2 months post-injury. The ability of intra-operative ultrasound and acute magnetic resonance imaging (MRI) to provide immediate predictive feedback regarding tissue and vascular changes following SCI was assessed. There was an inverse association between locomotor outcome and early gray matter hemorrhage on MRI and ultrasound. Epicenter blood flow following contusion predicted recovery or non-recovery of weight-bearing. The depth of the dorsal cerebrospinal fluid space, which varied between animals, influenced injury severity and confounded the results in this fixed-stroke paradigm.

Association of hypothyroidism with unruptured cerebral aneurysms: a case-control study.

OBJECTIVE Thyroid disorder has been known to affect vascular function and has been associated with aortic aneurysm formation in some cases; however, the connection has not been well studied. The authors hypothesized that hypothyroidism is associated with the formation of cerebral aneurysms. METHODS The authors performed a retrospective case-control study of consecutive patients who had undergone cerebral angiography at an academic, tertiary care medical center in the period from April 2004 through April 2014. Patients with unruptured aneurysms were identified from among those who had undergone 3-vessel catheter angiography. Age-matched controls without cerebral aneurysms on angiography were also identified from the same database. Patients with previous subarachnoid hemorrhage or intracranial hemorrhage were excluded. History of hypothyroidism and other risk factors were recorded. RESULTS Two hundred forty-three patients with unruptured cerebral aneurysms were identified and age matched with 243 controls. Mean aneurysm size was 9.6 ± 0.8 mm. Hypothyroidism was present in 40 patients (16.5%) and 9 matched controls (3.7%; adjusted OR 3.2, 95% CI 1.3-7.8, p = 0.01). Subgroup analysis showed that men with hypothyroidism had higher odds of an unruptured cerebral aneurysm diagnosis than the women with hypothyroidism, with an adjusted OR of 12.7 (95% CI 1.3-121.9) versus an OR of 2.5 (95% CI 1.0-6.4) on multivariate analysis. CONCLUSIONS Hypothyroidism appears to be independently associated with unruptured cerebral aneurysms, with a higher effect seen in men. Given the known pathophysiological associations between hypothyroidism and vascular dysfunction, this finding warrants further exploration.

Characterization of Motor and Somatosensory Evoked Potentials in the Yucatan Micropig Using Transcranial and Epidural Stimulation.

Yucatan micropigs have brain and spinal cord dimensions similar to humans and are useful for certain spinal cord injury (SCI) translational studies. Micropigs are readily trained in behavioral tasks, allowing consistent testing of locomotor loss and recovery. However, there has been little description of their motor and sensory pathway neurophysiology. We established methods to assess motor and sensory cortical evoked potentials in the anesthetized, uninjured state. We also evaluated epidurally evoked motor and sensory stimuli from the T6 and T9 levels, spanning the intended contusion injury epicenter. Response detection frequency, mean latency and amplitude values, and variability of evoked potentials were determined. Somatosensory evoked potentials were reliable and best detected during stimulation of peripheral nerve and epidural stimulation by referencing the lateral cortex to midline Fz. The most reliable hindlimb motor evoked potential (MEP) occurred in tibialis anterior. We found MEPs in forelimb muscles in response to thoracic epidural stimulation likely generated from propriospinal pathways. Cranially stimulated MEPs were easier to evoke in the upper limbs than in the hindlimbs. Autopsy studies revealed substantial variations in cortical morphology between animals. This electrophysiological study establishes that neurophysiological measures can be reliably obtained in micropigs in a time frame compatible with other experimental procedures, such as SCI and transplantation. It underscores the need to better understand the motor control pathways, including the corticospinal tract, to determine which therapeutics are suitable for testing in the pig model.

Utilizing CT with Maximum Intensity Projection Reconstruction Bypassing CTA Improves Time to Groin Puncture in Large Vessel Occlusion Stroke Thrombectomy.

BACKGROUND AND PURPOSE: Prior to thrombectomy for proximal anterior circulation large vessel occlusion (LVO) stroke, recent trials have utilized CT angiography (CTA) for vascular imaging immediately following noncontrast CT (NCCT) for decision-making, but thin-section NCCT with automated maximum intensity projection (MIP) reconstruction also has high accuracy in demonstrating the site of an occluding thrombus. We hypothesized that performing thin-section NCCT with MIP alone prior to thrombectomy improves the time to groin puncture (GP) compared to performing CTA after NCCT. MATERIALS AND METHODS: We performed a retrospective cohort study of anterior circulation LVO thrombectomy at our tertiary care academic medical center. All stroke patients evaluated with thin-section NCCT (0.625 mm) with automated MIP reconstructions alone and those who had additional CTA were included. We excluded transfer patients, in-hospital strokes, posterior circulation strokes, and patients that were evaluated with stroke imaging other than NCCT or CTA prior to thrombectomy. The study groups were compared for duration from NCCT to GP and total stroke imaging duration. RESULTS: From March 2008 through August 2015, 34 thrombectomy patients met the inclusion/exclusion criteria - 13 in the NCCT and 20 in the NCCT+CTA group. The total stroke imaging duration was shorter in the NCCT group than in the NCCT+CTA group (2 min [1-6] vs. 28 min [23-65]; p < 0.001). The NCCT-only group had a shorter time from NCCT to GP (68 min [32-99] vs. 104 min [79-128]; p = 0.030). CONCLUSION: Avoiding advanced imaging for patients with anterior circulation LVO in whom thin-section NCCT with MIPs reveals a hyperdense sign significantly shortens the imaging-to-GP time.

Safety Outcomes Using a Proximal Protection Device in Carotid Stenting of Long Carotid Stenoses.

BACKGROUND: Embolic protection devices can prevent atherosclerotic emboli during carotid stenting. Newer proximal protection devices reverse flow in the internal carotid artery (ICA), leading to reduction in perioperative microemboli. The risk of stroke is high for carotid stenting of ICA lesions with a length >10 mm and/or angiographic string sign. OBJECTIVE: We aimed to evaluate the safety outcomes of proximal embolic protection device usage in this high-risk group. METHODS: This is a retrospective analysis of patients who underwent carotid stenting procedures with proximal embolic protection devices at a tertiary care center. High-risk features for adverse events with carotid stenting were identified. Peri- and postprocedural outcomes were recorded. We further compared outcomes in patients with a carotid stenosis length >10 mm to those with shorter stenosis. RESULTS: From January 2011 to December 2014, we included 27 patients; 96.3% were symptomatic and 3.7% were asymptomatic. There was a stent placement technical success rate of 100%. No major stroke or coronary events were recorded. One minor stroke event developed in one patient. A carotid lesion length >10 mm and/or angiographic string sign was noted in 21/27 patients, with an average lesion length of 14.4 mm. One patient (4.8%) in this group developed a minor stroke event. Neither a coronary nor a major stroke event was recorded in this group. There was no significant difference in the complication rate between the long lesion and the control group. CONCLUSION: In our patient cohort, it was found that a proximal embolic protection device is safe for patients with carotid stenosis, including those with a carotid lesion length >10 mm and/or angiographic string sign.

Large animal canine endovascular ischemic stroke models: A review.

BACKGROUND: Stroke is one of the leading causes of death and long-term disability worldwide. Recent exciting developments in the field with endovascular treatments have shown excellent outcomes in acute ischemic stroke. Prior to translating these treatments to human populations, a large-animal ischemic stroke model is needed. With the advent of new technologies in digital subtraction angiography, less invasive endovascular stroke models have been developed. Canines have gyrencephalic brain similar to human brain and accessible neurovascular anatomy for stroke model creation. Canine stroke model can be widely utilized to understand the disease process of stroke and to develop novel treatment. Less invasive endovascular internal carotid emboli injection and coil embolization methods can be used to simulate transient or permanent middle cerebral artery occlusion. Major restriction includes the extensive collateral circulation of canine cerebral arteries that can limit the stroke size. Transient internal carotid artery occlusion can decrease collateral circulation and increase stroke size to some degree. Additional method of manipulating the extent of collateral circulation needs to be studied. Other types of canine stroke models, including vertebral artery occlusion and basilar artery occlusion, can also be accomplished by endovascular thrombi injection. CONCLUSIONS: We extensively review the literature on endovascular technique of creating canine ischemic stroke models and their application in finding new therapies for ischemic stroke.