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ObjectivesNeurologic 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.MethodsWe described the clinical presentation, disease course, diagnostic workup, therapeutic measures, and pathologic findings of ANM associated with COVID-19 infection.ResultsA 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.DiscussionCOVID-19 infection can cause ANM. It adds to the spectrum of reported cases of COVID-19 –associated encephalitis and myelitis.

Purpose of the ReviewTo 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 FindingsRandomized 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.SummaryStroke 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.

Introduction: Cell-based therapies for stroke remain under development and there is a lack of pre-clinical large animal data defining optimal dosing and delivery methods. Whereas safety and efficacy of intra-arterial (IA) mesenchymal stem cells (MSC) have been demonstrated in rodent models, large animal model are lacking, hampering advancement of the field and limiting mechanistic insights. Methods: An endovascular canine reversible Middle Cerebral Artery Occlusion (MCAO) model using a retractable platinum coil for 60-120 min was established. At 48-hour post-MCAO, allogeneic male canine MSCs (10-80 million) were delivered using a microcatheter in the ipsilateral upper cervical internal carotid artery of female canine subjects. Serial MRIs and neurological deficit scoring (NDS) were performed over 30 days. Animals were euthanized at15-30 d post-MCAO and brains were harvested for histology and molecular analyses. Results: There was a dose-dependent reduction of infarct volume on MRI associated with improved neurological scoring and corticospinal tract caliber on Diffusion Tensor Imaging over the range of 10, 20 and 40 million MSCs vs. PBS control. This dose-range was safe and did not result in worsening of stroke volume or behavioral outcomes. In contrast, 80 million IA MSCs led to a worsened neurological score immediately following the injection and an increase in the infarct volume at 4 days post injection. Conclusion: Together these findings establish a successful preclinical canine model of stroke in which dose-dependent efficacy of IA MSC therapy is demonstrated to reduce stroke size and augment DTI. These findings have important clinical implications in designing early-stage trials of IA delivery in humans.

OBJECTIVEThyroid 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.METHODSThe 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.RESULTSTwo 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.CONCLUSIONSHypothyroidism 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.

Background: Despite the efficacy of thrombectomy for large vessel occlusion acute ischemic stroke (AIS) , ~50% of patients have significant residual deficits. Pre-clinical data on intra-arterially (IA) administered mesenchymal stem cells (MSCs) in stroke are promising and this approach is attractive for clinical application. While there is a concern for micro-occlusion with IA delivery due to the large size of MSCs, a dose of 1 x 10 5 MSCs given 24-48 hr in a rodent reperfusion middle cerebral artery occlusion (rMCAo) model has been shown to be safe and effective. As per STAIR recommendations, we performed a dose-escalation (DE) study of IA-MSCs in a large animal stroke model. Methods: An endovascular canine rMCAo model using retractable platinum coil for 60-120 min was established. At 48 hr post-rMCAo, allogeniec canine MSCs were delivered using a 0.0165” microcatheter in the ipsilateral upper cervical internal carotid artery in escalating doses (based on proportion of rodent to canine total cerebral blood volume). Serial MRIs and neurological deficit scoring (NDS) were performed over 30 days. Animals were euthanized at 15-30 d post-rMCAo and brains were harvested. Results: Female canines (n=13), age 12-36 months, weighing 22-26 kg received IA MSCs ranging from 5-80 x 10 6 (M). At doses of 5-40 M IA-MSCs no neurological worsening was observed. Serial NDS and stroke volume on MRI showed no increase post-IA-MSCs and actually showed progressive reduction. A higher numerical reduction was seen in the 10-40 M groups compared to 5 M. However, in the one canine receiving 80 M IA-MSCs, there was significant worsening of the MCA-area infarction and NDS due to microembolization at this higher dose. Gross examinations and histopathology of brain tissue were consistent with ischemia. The brain of a canine receiving 80 M cells showed differentially aged areas of necrosis supporting two ischemic events. Neuroblasts, doublecortin-positive cells, and neovascularization were observed in canine brains suggesting regenerative mechanisms. Conclusions: These data suggest that IA-MSCs are safe in a large animal model up to 40 M IA-MSCs and is the maximum tolerated dose in this DE study. Furthermore, our data suggests that up to 40 M IA-MSCs may be promising in exploring efficacy in AIS.

espanolUn marteloscopioes una herramienta didactica de gran utilidad para el entrenamiento en selvicultura. La disponibilidad de datos reales sobre la masa forestal en dispositivos moviles (tablets) en combinacion con un software adecuado permite la retroalimentacion directa entre las decisiones selvicolas y los resultados, tanto economicos como ecologicos de las mismas. A traves de este Proyecto de Innovacion Docente, se ha avanzado en esta linea formativa disenando e implementando, por primera vez, un marteloscopio en monte alcornocal orientado a la produccion de corcho. Como resultado, se ha establecido una parcela permanente de entrenamiento en un alcornocal, que se ha monitorizado de forma exhaustiva, y se ha desarrollado un software nuevo para pc o tablet que simula en tiempo real los efectos de ejercicios de claras selvicolas y de descorches, que el usuario introduce, y que genera salidas instantaneas sobre la produccion de corcho obtenida y sus caracteristicas y sus efectos sobre la masa forestal. Esta simulacion facilita el aprendizaje realista de la gestion de alcornocales y la comprension de los efectos que las decisiones de gestion tomadas tienen sobre los aspectos productivos y ecologicos de la masa forestal. EnglishA Marteloscopeis an educational tool for silvicultural and forest management training. The availability of actual stand data on mobile devices (tablets) in combination with the appropriate software allows direct feedback among silvicultural decisions and the resulting economic and ecological outcomes. Through this Teaching Innovation Project, we have gone further on this approach by designing and implementing, for the first time, a Marteloscopein a cork oak stand managed for cork production. As a result, we have set up a permanent training plot in the forest, where all trees have been geolocated, measured, both in size and cork production features, marked and also assessed for their ecological value through microhabitat identification approach. We have developed new software for pc or tablets to simulate in real-time silvicultural and cork stripping exercises made by the user, producing instantaneous outputs showing the effects on cork production and forest stand, both currently and after 9 years period (duration of debarking rotation). This simulation facilitates realistic learning of cork oak stands management practices and the understanding of the effects of management decisions on productive and ecological dynamics of forest stand.

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.

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.

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 (

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.

Background: Imaging biomarkers of stroke recovery are critical for translational studies. Diffusion tensor imaging (DTI) to assess white matter microstructure in the brain using fractional anisotropy (FA) to dertermine the structural integrity of the corticospinal tract (CST). Our prior data suggest a possible correlation between neurological recovery and the improvement in FA. The purpose of this study was to compare DTI analysis of the CST at 30 days after an ipsilateral intra-arterial (IA) Mesenchymal Stem Cell (MSCs) versus control, in canines with a reversible Middle Cerebral Artery occlusion (rMCAo). Methods: Mongrel Hounds (n=7), aged 12-36 months, were included in this study. rMCAo was induced via endovascular approach using a detachable helical ultra-coil over 35-80 min. MSCs (1-20 millions) or saline (240 cc) were infused intra-arterially 48hrs post stroke in the ipsilesional cervical internal carotid. Brain MRIs were performed at 48h post rMCAo pre-IA cell delivery, 15 & 30 days. FA values of the right and left CST were determined. DTT was also generated for a visual analysis of the CST fibers. Weekly neuro evaluations were performed using blinded canine stroke-score. Results: We observed a higher average change in the FA values from at 30 days post stroke in the MSCs treated group versus control (0.085 ± 0.025, n=5 versus 0.068 ± 0.058, n=2: p=0.82). A visual increase in the caliber of CST ipsilateral to stroke from IA injection to day 30 post-stroke was observed on the DTT in two of the treated canines. Figure-1 from left to right, a. FA changes, b. DTT treated group, C. DTT control. Conclusions: Serial DTI-DTT imaging after IA MSCs therapy in large animal stroke model appears to have a trend towards higher change in FA. These findings could support further development of DTI-DTT biomarkers to measure neurologic recovery in experimental models as well as early clinical trials of novel stroke therapies.

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.

Background: Endocrine dysfunction, including thyroid function, has been known to affect cerebral vascular dysfunction. Hypothyroidism has been shown to cause mucopolysaccharide deposition which has been associated with the weakening of blood vessel walls and aneurysm formation in some case reports. However, the connection between hypothyroidism and cerebral aneurysm has not been well studied. We hypothesized that hypothyroidism maybe associated with occurrence of cerebral aneurysms. Methods: We performed a retrospective case-control study of consecutive patients receiving cerebral angiography at our tertiary-care academic medical center. Inclusion criteria included undergoing 3-vessel angiography. Exclusion criteria included any ruptured aneurysm or previous intracranial hemorrhage. Medical history of hypothyroidism was noted along with all other risk factors. The control group of patients did not have any intra-cranial abnormality on angiography. Patients with cerebral aneurysm were matched with controls for known risk factors of cerebral aneurysm, including: age, hypertension, and smoking history. Cases were further subdivided base on gender given females are known to have higher incidence of hypothyroidism. Results: From 2008 through 2013, 82 female and 59 male patients with aneurysms were identified for this study and were matched with equal numbers of controls. Among women, hypothyroidism was present in 20.7% (17/82) among patients with cerebral aneurysms vs. in only 6.1% (5/82) among matched controls: odds ratio (OR) 4.03 (95% CI 1.41-11.51, p=0.01). Among men, 8.5% (5/59) cases and 0/59 controls had hypothyroidism, showing no significant association, with an odds ratio of 12.01 (95% CI 0.65-222.3, p=0.095). Conclusion: We found a significant association of history of hypothyroidism with cerebral aneurysm in women in our patient cohort. Given the potential pathophysiologic connection between hypothyroidism and vascular wall dysfunction, this should be explored further.

Background: Cell therapy is promising in rodent pre-clinical studies. Confirmation of efficacy of this novel approach in large animals is recommended. Diffusion Tensor Imaging (DTI) assesses white matter microstructure in the CNS using Fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Diffusion Tensor Tractography (DTT) DTT produces a 3D representation of the white matter tracts (WMT) in which data are displayed on a colored map that helps to identify the integrity of the tracts selected under the region of Interest (ROI). The purpose of this study was to use DTI-DTT analysis, and correlate it with the neuro-assessment of dogs over one month after ipsilateral intra-arterial (IA) Mesenchymal Stem Cell (MSCs) 48 hours after a brain-stroke was reversible middle cerebral artery occlusion (rMCAo) Methods: Mongrel Hounds (n=5), aged 12-36 months, were included in this pilot study. rMCAo was induced via endovascular approach using a detachable helical ultra-coil over 35-80 min. MSCs (1-20 millions) were infused intra-arterially 48hrs post stroke in the ipsilesional cervical internal carotid. DTI-T images were obtained at 48h post rMCAo pre-IA cell delivery, 15 & 30 days. DTT was also generated. FA-ADC values of the right & left hemisphere and CST were determined. Weekly neuro-evaluations were performed using our canine neuro-scale Results: Our data suggest a correlation between the neurological recovery and improvement in the FA-ADC values (see figure). An increase in the caliber of corticospinal tracts ipsilateral to the stroke by day 30 compared to pre-injection was observed on the DTT reconstruction for two canines that showed neurological improvement ( see figure) Conclusions: Serial DTI-DTT imaging after IA cell therapy shows improvement in white matter tracts correlating with neurologic recovery. This supports further development of DTI-DTT biomarkers to measure neurologic recovery in experimental models as well as early clinical trials.

Background: Stroke is a leading cause of major long-term disability worldwide. Despite availability of IV tPA and mechanical thrombectomy, over half of treated patients have significant disability. Cell based therapy is a promising in pre-clinical studies in improving stroke recovery. Brain infarct volume is a major predictor of stroke outcome and may decrease with this treatment. We hypothesized that patients treated with intra-arterial stem cell therapy will have a significant reduction in stroke volume compared to non-treated patients. Methods: The RECOVER-Stroke trial is a randomized, sham-controlled study to determine the safety and efficacy of processed autologous bone marrow cells (ALD-401) injection via intracarotid infusion in ischemic stroke patients. Ischemic stroke patients were double-blind randomized into 2 groups, receiving ALD-401 injection or sham procedure between 9-19 days post anterior circulation ischemic stroke. All enrolled patients at 1 of 8 sites in the trial were included in this analysis. Two blinded physicians used OSIRIX software to analyze stroke volume on DWI/ 24h CT brain and MRI at 90, 180, 365 days post intervention. Volumes were compared between the 2 groups at these timepoints. Results: A total of 11 patients at our center (out of 48 multicenter patients) were included in this study, 6 patients receiving sham procedure and 5 patients receiving ALD-401. The two groups did not show any significant difference in their baseline variables including age, Mean baseline stroke volumes were not significantly different between ALD-401 (103.9±96.2ml) and sham groups (70.2±46ml), p=0.53. The stroke volume reduction in the ALD-401 was 22.9±15.5ml vs. 4.04±12.5ml in the sham group (p=0.046). On day 180 and 365, both groups did not show any further significant stroke volume reduction from day 90. Conclusion: In this exploratory analysis from one center in the multi-center RECOVER-Stroke trial, intra-arterial stem cell injection with ALD-401 was associated with significant reduction in stroke volume at 90 days post therapy compared to sham procedure in subacute ischemic stroke patients.

Background: Cell therapy is promising in pre-clinical studies of global ischemia. The aim of this pilot study is to describe the first intra-arterial (IA) delivery of bone marrow derived ALD-401 cells in a persistent vegetative state (PVS) patient in the U.S. & findings on MRI Diffusion Tensor Imaging (DTI) and Diffusion Tensor Tractography (DTT). Material: A 51-yr. woman developed PVS due to cardiac arrest. At 2 years post PVS state, experimental cell therapy was requested by the family. The FDA approved a one-time compassionate use IA delivery of ALD-401 cells. Bone marrow harvest from the patient, followed by processing with flow cytometry was completed to separate ALD-401 cells. Intra-arterial infusion of cells was done bilaterally into each supra-clinoid carotid. Post-infusion neurological assessments- National Institute of Health Stroke Scale (NIHSS), JFKr coma recovery scale, brainstem reflexes, modified Rankin Scores (mRS) and MRI DTI imaging were collected at 1-, 3-, 6-, 9-mo & 1 year Result: The patient had no adverse events peri-operatively. Over 1-year follow-up the patient had 1 hospitalization for UTI and postmenopausal bleeding. No other adverse events occurred. Minor clinical improvement was shown on assessment scales above. However, DTI-DTT analysis of Fractional Anisotropy (FA) showed improvement in the FA and ADC of white matter tracts starting 7 months post injection for the Cortical Spinal Tract (CST) and starting 4 months post injection for the Corpus Callosum (CC) months (see figure). Diffusion Tensor Tractography also showed qualitative improvement in organization and caliber of CC & CST over follow-up post intervention (see figure) Conclusion: Assessing minor neurological improvements in this severe PVS patient remains challenging; DTI-DTT MRI imaging detects changes in white mater tracts that could serve as biomarkers for recovery. Further follow-up clinical assessments and imaging will continue in this patient to define further recovery.