Poststroke Intravenous Transplantation of Human Mesenchymal Stem Cells Improves Brain Repair Dynamics and Functional Outcomes in Aged Mice.

BACKGROUND: Stroke is the primary cause of chronic disability in the elderly, as there are no neurorestorative treatments for those who do not qualify for recanalization therapy. Experimental evidence in stroke animals suggests that transplantation of bone marrow-derived human mesenchymal stem cells (hMSCs) holds promise, but hMSC transplantation has not been systematically tested in aged animals. We tested the hypothesis that poststroke hMSC transplantation improves stroke recovery in aged mice by promoting brain repair. METHODS: Permanent focal cerebral ischemia was induced in 20-month-old C57BL/6 male mice by distal middle cerebral artery occlusion. Bone marrow-derived hMSCs were expanded in vitro and then administrated intravenously into mice (1×106 cells in PBS) 24 hours after distal middle cerebral artery occlusion. Sensorimotor and cognitive functions, brain atrophy, and brain repair processes (neurogenesis, angiogenesis, oligodendrogenesis) were assessed for up to 56 days after stroke. RESULTS: Poststroke hMSC transplantation did not mitigate brain atrophy or improve neuronal survival at 56 days after distal middle cerebral artery occlusion. However, hMSC-treated mice displayed superior neurobehavioral performances in the open field, rotarod, adhesive removal, novel object, and Morris water maze tests compared with PBS-treated controls. hMSCs promoted white matter integrity and enhanced angiogenesis and oligodendrogenesis-but not neurogenesis-in the stroke brain. Positive correlations between neurobehavioral performance and brain repair profiles or white matter integrity were observed in stroke mice. CONCLUSIONS: Poststroke hMSC transplantation improves long-term stroke recovery in aged mice, likely via mechanisms involving enhanced microvascular regeneration and white matter restoration.

Most Promising Approaches to Improve Stroke Outcomes: The Stroke Treatment Academic Industry Roundtable XII Workshop.

The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop brought together representatives from academia, industry, and government representatives. The discussion examined approaches in 4 epochs: pre-reperfusion, reperfusion, post-reperfusion, and access to acute stroke interventions. The participants identified areas of priority for developing new and existing treatments and approaches to improve stroke outcomes. Although many advances in acute stroke therapy have been achieved, more work is necessary for reperfusion therapies to benefit the most possible patients. Prioritization of promising approaches should help guide the use of resources and investigator efforts.

How to Establish the Outer Limits of Reperfusion Therapy.

Reperfusion therapy with intravenous alteplase and endovascular therapy are effective treatments for selected patients with acute ischemic stroke. Guidelines for treatment are based upon randomized trials demonstrating substantial treatment effects for highly selected patients based on time from stroke onset and imaging features. However, patients beyond the current established guidelines might benefit with lesser but still clinically significant treatment effects. The STAIR (Stroke Treatment Academic Industry Roundtable) XI meeting convened a workgroup to consider the "outer limits" of reperfusion therapy by defining the current boundaries, and exploring optimal parameters and methodology for determining the outer limits. In addition to statistical significance, the minimum clinically important difference should be considered in exploring the limits of reperfusion therapy. Societal factors and quality of life considerations should be incorporated into assessment of treatment efficacy. The threshold for perception of benefit in the medical community may differ from that necessary for the Food and Drug Administration approval. Data from alternative sources such as platform trials, registries and large pragmatic trials should supplement randomized controlled trials to improve generalizability to routine clinical practice. Further interactions between industry and academic centers should be encouraged.

Acute Stroke Trial Enrollment through a Telemedicine Network: A 12-Year Experience.

BACKGROUND: A major barrier to acute stroke trial enrollment is timely access to participating centers. Establishing referral relationships via telemedicine may broaden trial access. We sought to understand the utilization of telemedicine in trial enrollment at a large academic center. METHODS: This is a single center, retrospective review of subjects consecutively enrolled into cerebrovascular trials requiring urgent consent between January 2005 and December 2016. Subjects were classified to either direct presentation to hub hospital, or transfer from spoke hospitals. We used Pearson linear correlation and a simple linear regression model to describe the relationship between annual trial enrollment rate and the number of spoke sites capable of audio-video evaluation (AVR) as a proxy for the size of the telemedicine network. We correlated the annual increase in enrollment with that of each group using parametric and nonparametric analysis. RESULTS: Sixteen trials met our criteria, enrolling 299 subjects: 117 in the hub group and 182 in the spoke group. There was a direct relationship between the number of AVR-capable sites and annual trial enrollment rate (P = <.05). Annual increase in spoke enrollment was higher compared to hub enrollment (15.55 ± 11.30 versus 0.68 ± 1.03, P <.0005) and better correlated with total increase in enrollments (0.98 versus 0.94, P <.0001). CONCLUSIONS: Telemedicine networks are a major resource for trial enrollment. Expanding the use of remote enrollment could expedite the completion of acute cerebrovascular trials.

Impact of Stroke Call on the Stroke Neurology Workforce in the United States: Possible Challenges and Opportunities.

BACKGROUND: The Stroke & Vascular Neurology Section of the American Academy of Neurology was charged to identify challenges to the recruitment and retention of stroke neurologists and to make recommendations to address any identified problems. The Section initiated this effort by determining the impact of stroke on-call requirements as a barrier to the recruitment and retention of vascular neurologists. METHODS: This is a cross-sectional survey of a sample of US Neurologists providing acute stroke care. RESULTS: Of the 900 neurologists who were sent surveys, 313 (35%) responded. Of respondents from institutions providing stroke coverage, 71% indicated that general neurologists and 45% indicated that vascular neurologists provided that service. Of those taking stroke call, 36% agreed with the statement, "I spent too much time on stroke call," a perception that was less common among those who took less than 12-hour shifts (P < .0001); 21% who participated in stroke call were dissatisfied with their current job. Forty-six percent indicated that their stroke call duties contributed to their personal feeling of "burnout." CONCLUSIONS: Although the reasons are likely multifactorial, our survey of neurologists providing stroke care suggests that over-burdensome on-call responsibilities may be contributing to the vascular neurology workforce burnout and could be affecting recruitment and retention of vascular neurologists. Strategies to reduce the lifestyle impact of stroke call may help address this problem.

Interfacility Transfer Directly to the Neuroangiography Suite in Acute Ischemic Stroke Patients Undergoing Thrombectomy.

BACKGROUND AND PURPOSE: In patients identified at referring facilities with acute ischemic stroke caused by a large vessel occlusion, bypassing the emergency department (ED) with direct transport to the neuroangiography suite may safely shorten reperfusion times. METHODS: We conducted a single-center retrospective review of consecutive patients transferred to our facility for consideration of endovascular therapy. Patients were identified as admitted directly to the neuroangiography suite (DAN), transferred to the ED before intra-arterial therapy (ED-IA), and transferred to the ED but did not receive IA therapy (ED-IV). RESULTS: A retrospective review of a prospectively maintained database of transfer patients between January 2013 and October 2016 with large vessel occlusions identified 108 ED-IV patients and 261 patients who underwent mechanical thrombectomy (DAN=111 patients and ED-IA=150 patients). There were no differences in baseline characteristics among the 3 groups. The median computed tomography ASPECTS (Alberta Stroke Program Early CT Score) was lower in the ED-IV group versus the ED-IA and DAN groups (8 versus 9; P=0.001). In the DAN versus ED-IA cohort, there were comparable rates of TICI2b/3 recanalization and access to recanalization time. There was significantly faster hospital arrival to groin access time in the DAN cohort (81 minutes versus 22 minutes; P=0.001). Functional independence at 90 days was comparable in the DAN versus ED-IA cohorts but worse in the ED-IV group (43% versus 44% versus 22%; P=0.001). CONCLUSIONS: DAN is safe, feasible, and associated with faster times of hospital arrival to recanalization. The clinical benefit of this approach should be assessed in a prospective randomized trial.

Telemedicine Quality and Outcomes in Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association.

PURPOSE: Telestroke is one of the most frequently used and rapidly expanding applications of telemedicine, delivering much-needed stroke expertise to hospitals and patients. This document reviews the current status of telestroke and suggests measures for ongoing quality and outcome monitoring to improve performance and to enhance delivery of care. METHODS: A literature search was undertaken to examine the current status of telestroke and relevant quality indicators. The members of the writing committee contributed to the review of specific quality and outcome measures with specific suggestions for metrics in telestroke networks. The drafts were circulated and revised by all committee members, and suggestions were discussed for consensus. RESULTS: Models of telestroke and the role of telestroke in stroke systems of care are reviewed. A brief description of the science of quality monitoring and prior experience in quality measures for stroke is provided. Process measures, outcomes, tissue-type plasminogen activator use, patient and provider satisfaction, and telestroke technology are reviewed, and suggestions are provided for quality metrics. Additional topics include licensing, credentialing, training, and documentation.

Transcranial Doppler Monitoring in Carotid Endarterectomy: A Systematic Review and Meta-analysis.

OBJECTIVES: To evaluate the efficacy of intraoperative transcranial Doppler monitoring in predicting perioperative strokes after carotid endarterectomy (CEA). METHODS: An electronic search of PubMed, Embase, and Web of Science databases was conducted for studies on transcranial Doppler monitoring in CEA published from January 1970 through September 2015. All titles and abstracts were independently screened on the basis of predetermined inclusion criteria, which included randomized clinical trials and prospective or retrospective cohort reviews, patients who underwent CEA with intraoperative transcranial Doppler monitoring (either middle cerebral artery velocity [MCAV] or cerebral microembolic signals [MES]) and postoperative neurologic assessments up to 30 days after the surgery, and studies including an abstract, published in English on adult humans 18 years and older with a sample size of 50 or greater. RESULTS: A total of 25articles with a sample population of 4705 patients were analyzed. Among the study patients, 189 developed perioperative strokes. Transcranial Doppler monitoring (either MCAV or MES) showed specificity of 72.7% (95% confidence interval [CI], 61.2%-81.8%) and sensitivity of 56.1% (95% CI, 46.8%-65.0%) for predicting perioperative strokes. Intraoperative MCAV changes during CEA showed strong specificity of 84.1% (95% CI, 74.4%-90.6) and sensitivity of 49.7% (95% CI, 40.6%-58.8) for predicting perioperative strokes. CONCLUSIONS: Patients with perioperative strokes are 4 times more likely to have had transcranial Doppler changes (either MCAV or MES) during CEA compared to patients without strokes. Simultaneous MCAV and MES monitoring by transcranial Doppler sonography and combined intraoperative monitoring of transcranial Doppler sonography with somatosensory evoked potentials and electroencephalography during CEA to predict perioperative stroke could not be evaluated because of a lack of clinical studies combining these measures.

Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study.

BACKGROUND AND PURPOSE: Preclinical data suggest that cell-based therapies have the potential to improve stroke outcomes. METHODS: Eighteen patients with stable, chronic stroke were enrolled in a 2-year, open-label, single-arm study to evaluate the safety and clinical outcomes of surgical transplantation of modified bone marrow-derived mesenchymal stem cells (SB623). RESULTS: All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event. Six patients experienced 6 serious treatment-emergent adverse events; 2 were probably or definitely related to surgical procedure; none were related to cell treatment. All serious treatment-emergent adverse events resolved without sequelae. There were no dose-limiting toxicities or deaths. Sixteen patients completed 12 months of follow-up at the time of this analysis. Significant improvement from baseline (mean) was reported for: (1) European Stroke Scale: mean increase 6.88 (95% confidence interval, 3.5-10.3; P<0.001), (2) National Institutes of Health Stroke Scale: mean decrease 2.00 (95% confidence interval, -2.7 to -1.3; P<0.001), (3) Fugl-Meyer total score: mean increase 19.20 (95% confidence interval, 11.4-27.0; P<0.001), and (4) Fugl-Meyer motor function total score: mean increase 11.40 (95% confidence interval, 4.6-18.2; P<0.001). No changes were observed in modified Rankin Scale. The area of magnetic resonance T2 fluid-attenuated inversion recovery signal change in the ipsilateral cortex 1 week after implantation significantly correlated with clinical improvement at 12 months (P<0.001 for European Stroke Scale). CONCLUSIONS: In this interim report, SB623 cells were safe and associated with improvement in clinical outcome end points at 12 months. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01287936.

Time From Symptoms to Carotid Endarterectomy or Stenting and Perioperative Risk.

BACKGROUND AND PURPOSE: Prior meta-analysis showed that carotid endarterectomy benefits decline with increasing surgical delay following symptoms. For symptomatic patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), we assessed if differences in time between symptoms and carotid endarterectomy or carotid artery stenting are associated with differences in risk of periprocedural stroke or death. METHODS: We analyzed the 1180 symptomatic patients in CREST who received their assigned procedure and had clearly defined timing of symptoms. Patients were classified into 3 groups based on time from symptoms to procedure: <15, 15 to 60, and >60 days. RESULTS: For carotid endarterectomy, risk of periprocedural stroke or death was not significantly different for the 2 later time periods relative to the earliest time period (hazard ratio, 0.74; 95% confidence interval, 0.22-2.49 for 15-60 days and hazard ratio, 0.91; 95% confidence interval, 0.25-3.33 for >60 days; P=0.89). For carotid artery stenting, risk of periprocedural stroke or death was also not significantly different for later time periods relative to the earliest time period (hazard ratio, 1.12; 95% confidence interval, 0.53-2.40 for 15-60 days and hazard ratio, 1.15; 95% confidence interval, 0.48-2.75 for >60 days; P=0.93). CONCLUSIONS: Time from symptoms to carotid endarterectomy or carotid artery stenting did not alter periprocedural safety, supporting early revascularization regardless of modality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.

Provider Impressions of Inpatient Teleneurology Consultation.

Background and Objectives: Teleneurology usage has increased during the severe acute respiratory syndrome coronavirus 2 pandemic. However, studies evaluating physician impressions of inpatient teleneurology are limited. We implemented a quality improvement initiative to evaluate neurologists' impression following individual inpatient teleneurology consultation at a satellite hospital of a large academic center with no in-person neurology coverage. Methods: A REDCap survey link was embedded within templates used by neurologists for documentation of inpatient consultations to be completed immediately after encounters. All teleneurology encounters with completed surveys at a single satellite hospital of the University of Pennsylvania Health System Neurology Department between May 10, 2021, and August 14, 2022, were included. Individual patient-level and encounter-level data were extracted from the medical record. Results: A total of 374 surveys (response rate of 54.05%) were completed by 19 neurologists; 341 questionnaires were included in the analysis. Seven neurologists who specialized as neurohospitalists completed 231 surveys (67.74% of total surveys completed), while 12 non-neurohospitalists completed 110 (32.36%). The history obtained was rated as worse (14%) or the same (86%) as an in-person consult; none reported the history as better than nonteleneurology encounters. The physician-patient relationship was poor or fair in 25% of the encounters and good or excellent in 75% of visits. The overall experience was judged to be worse than in-person consultation in 32% of encounters, the same in 66%, and better in 2%. Fifty-one percent of providers responded that there were elements of the neurologic examination that might have changed their assessment and plan of care if performed in-person. Encounters with peripheral or neuromuscular-related chief complaints had the most inadequate examinations and worse overall experiences, while the most positive impressions of these clinical experiences were observed among seizure-related chief complaints. Discussion: Determining best practices for inpatient teleneurology should consider the patient chief complaint to use teleneurology in scenarios with the highest likelihood of a positive experience. Further efforts should be made to the patient experience and to improve the remote examination to enhance the applicability of teleneurology to the full spectrum of inpatient neurologic consultations.

Experience with a hybrid recruitment approach of patient-facing web portal screening and subsequent phone and medical record review for a neurosurgical intervention trial for chronic ischemic stroke disability (PISCES III).

BACKGROUND: Recruitment of participants is the greatest risk to completion of most clinical trials, with 20-40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent. METHODS: Two tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted. RESULTS: The approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19. CONCLUSIONS: A tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03629275.

Formation and function of acute stroke-ready hospitals within a stroke system of care recommendations from the brain attack coalition.

BACKGROUND AND PURPOSE: Many patients with an acute stroke live in areas without ready access to a Primary or Comprehensive Stroke Center. The formation of care facilities that meet the needs of these patients might improve their care and outcomes and guide them and emergency responders to such centers within a stroke system of care. METHODS: The Brain Attack Coalition conducted an electronic search of the English medical literature from January 2000 to December 2012 to identify care elements and processes shown to be beneficial for acute stroke care. We used evidence grading and consensus paradigms to synthesize recommendations for Acute Stroke-Ready Hospitals (ASRHs). RESULTS: Several key elements for an ASRH were identified, including acute stroke teams, written care protocols, involvement of emergency medical services and emergency department, and rapid laboratory and neuroimaging testing. Unique aspects include the use of telemedicine, hospital transfer protocols, and drip and ship therapies. Emergent therapies include the use of intravenous tissue-type plasminogen activator and the reversal of coagulopathies. Although many of the care elements are similar to those of a Primary Stroke Center, compliance rates of ≥67% are suggested in recognition of the staffing, logistical, and financial challenges faced by rural facilities. CONCLUSIONS: ASRHs will form the foundation for acute stroke care in many settings. Recommended elements of an ASRH build on those proven to improve care and outcomes at Primary Stroke Centers. The ASRH will be a key component for patient care within an evolving stroke system of care.

Stroke treatment academic industry roundtable: research priorities in the assessment of neurothrombectomy devices.

BACKGROUND AND PURPOSE: The goal of the Stroke Treatment Academic Industry Roundtable (STAIR) meetings is to advance the development of stroke therapies. At STAIR VIII, consensus recommendations were developed for clinical trial strategies to demonstrate the benefit of endovascular reperfusion therapies for acute ischemic stroke. SUMMARY OF REVIEW: Prospects for success with forthcoming endovascular trials are robust, because new neurothrombectomy devices have superior reperfusion efficacy compared with earlier-generation interventions. Specific recommendations are provided for trial designs in 3 populations: (1) patients undergoing intravenous fibrinolysis, (2) early patients ineligible for or having failed intravenous fibrinolysis, and (3) wake-up and other late-presenting patients. Among intravenous fibrinolysis-eligible patients, key principles are that CT or MRI confirmation of target arterial occlusions should precede randomization; endovascular intervention should be pursued with the greatest rapidity possible; and combined intravenous and neurothrombectomy therapy is more promising than neurothrombectomy alone. Among patients ineligible for or having failed intravenous fibrinolysis, scientific equipoise was affirmed and the need to randomize all eligible patients emphasized. Vessel imaging to confirm occlusion is mandatory, and infarct core and penumbral imaging is desirable in later time windows. Additional STAIR VIII recommendations include approaches to test multiple devices in a single trial, utility weighting of disability end points, and adaptive designs to delineate time and tissue injury thresholds at which benefits from intervention no longer accrue. CONCLUSIONS: Endovascular research priorities in acute ischemic stroke are to perform trials testing new, highly effective neuro thrombectomy devices rapidly deployed in patients confirmed to have target vessel occlusions.