Current Recommendations for the Management of Stroke Patients in the Middle East in the Era of COVID-19 Pandemic; Statement from the MENA SINO.

COVID-19 pandemic has led to a change in the way we manage acute medical illnesses. This pandemic had a negative impact on stroke care worldwide. The World Stroke Organization (WSO) has raised concerns due to the lack of available care and compromised acute stroke services globally. The numbers of thrombolysis and thrombectomy therapies are declining. As well as, the rates and door-to treatment times for thrombolysis and thrombectomy therapies are increasing. The stroke units are being reallocated to serve COVID-19 patients, and stroke teams are being redeployed to COVID-19 centers. Covid 19 confirmed cases and deaths are rising day by day. This pandemic clearly threatened and threatening all stroke care achievements regionally. Managing stroke patients during this pandemic is even more challenging at our region. The Middle East and North Africa Stroke and Interventional Neurotherapies Organization (MENA-SINO) is the main stroke organization regionally. MENA-SINO urges the need to developing new strategies and recommendations for stroke care during this pandemic. This will require multiple channels of interventions and create a protective code stroke with fast triaging path. Developing and expanding the tele-stroke programs are urgently required. There is an urgent need for enhancing collaboration and cooperation between stroke expertise regionally and internationally. Integrating such measures will inevitably lead to an improvement and upgrading of the services to a satisfactory level.

Intra-cortical brain-machine interfaces for controlling upper-limb powered muscle and robotic systems in spinal cord injury.

OBJECTIVE: Intracortical brain-machine interface (iBMI) is an assistive strategy to restore lost sensorimotor function by bridging the disrupted neural pathways to reanimate paralyzed limbs. However, to date, none of the studies explored the trade-offs between the performance criteria of different iBMI systems that decode discrete upper limb movements from intracortical neural recordings. METHODS: A systematic review of electronic databases using different MeSH terms from January 1990 to December 2019 was conducted. IBM® SPSS statistics version 25 (Released 2017, Armonk, NY: IBM) was used to evaluate for differences between groups using independent sample t-tests. RESULTS: A total of 18 patients from 15 studies were included in our analysis. The included studies involved iBMI controlled 5-robotic and 10-neuromuscular stimulated orthotics to perform skillful and coordinated movements that resulted in a clinically significant gain in tests of upper-limb functions. Pooled analysis revealed that the mean response time to execute 3-D reach and grasp task by the robotic-assisted limb was relatively longer (46.8 +/-101.5 s) compared to the neuro-muscular stimulated orthotics (15.8 +/-15.2 s); however, statistically insignificant [Mean difference (MD): 30.9, 95 % Confidence Interval (CI): -40.4-102.3, p = 0.35]. Furthermore, the accuracy in performing 3-D reach and grasp tasks after repetitive trials were better among patients with neuro-muscular stimulated orthotics (83.5 +/-12.7 %) compared to those with robotic-assisted prosthetic limb (69.1 +/- 23.6 %) with statistically significant difference (MD: 15.9, 95 % CI: 1.65-32.5, p = 0.05). CONCLUSION: Our study demonstrates that iBMI-assisted prosthetic limbs showed better accuracy and shorter response time among patients with neuro-muscular stimulated orthotics compared to robotic neuro-prosthetics.

Characteristics of Recurrent Ischemic Stroke After Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial.

Importance: The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS. Objective: To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke. Design, Setting, and Participants: The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019. Interventions: Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d. Main Outcomes and Measures: Association of recurrent ESUS with stroke characteristics. Results: A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively). Conclusions and Relevance: In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.

Predictors of Recurrent Ischemic Stroke in Patients with Embolic Strokes of Undetermined Source and Effects of Rivaroxaban Versus Aspirin According to Risk Status: The NAVIGATE ESUS Trial.

BACKGROUND: Embolic stroke of undetermined source (ESUS) identifies patients with cryptogenic ischemic stroke presumed due to embolism from several unidentified sources. Among patients with recent ESUS, we sought to determine independent predictors of recurrent ischemic stroke during treatment with aspirin or rivaroxaban and to assess the relative effects of these treatments according to risk. METHODS: Exploratory analyses of 7213 participants in the NAVIGATE ESUS international trial who were randomized to aspirin 100 mg/day or rivaroxaban 15 mg/day and followed for a median of 11 months, during which time there were 309 first recurrent ischemic strokes (4.6% per year). Baseline features were correlated with recurrent stroke by multivariate analysis. RESULTS: The 7 independent predictors of recurrent stroke were stroke or transient ischemic attack (TIA) prior to the qualifying stroke (hazard ratio [HR] 2.03 95% confidence internal [CI] 1.58-2.60), current tobacco user (HR 1.62, 95% CI 1.24-2.12), age (HR 1.02 per year increase, 95%CI 1.01-1.03), diabetes (HR 1.28, 95% CI 1.01-1.64), multiple acute infarcts on neuroimaging (HR 1.49, 95% CI 1.09-2.02), aspirin use prior to qualifying stroke (HR 1.34, 95% CI 1.02-1.70), and time from qualifying stroke to randomization (HR .98, 95% CI .97-.99). The rate of recurrent stroke rate was 2.6% per year for participants without any of these risk factors, and increased by an average of 45% for each independent predictor (P < .001). There were no significant interactions between treatment effects and independent stroke predictors or stroke risk status. CONCLUSIONS: In this large cohort of ESUS patients, several features including prior stroke or TIA, advanced age, current tobacco user, multiple acute infarcts on neuroimaging, and diabetes independently identified those with an increased risk of ischemic stroke recurrence. The relative effects of rivaroxaban and aspirin were similar across the spectrum of independent stroke predictors and recurrent stroke risk status.

An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial.

BACKGROUND: Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood-brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8-24 h after acute ischaemic stroke improved functional outcome. METHODS: ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40-80 years and women aged 40-85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8-24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059. FINDINGS: Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89-1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05-2·10; p=0·0258). There was an inverse U-shaped dose-response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low-midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population. INTERPRETATION: Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8-24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial's results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome. FUNDING: BrainsGate Ltd.

Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Importance: The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF). Objective: To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. Design, Setting, and Participants: Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. Intervention: Rivaroxaban treatment vs aspirin. Main Outcomes and Measures: Risk of ischemic stroke. Results: Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). Conclusions and Relevance: The HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

Secondary Stroke Prevention: Improving Diagnosis and Management with Newer Technologies.

Treatment of hypertension, diabetes, high cholesterol, smoking cessation, and healthy lifestyle have all contributed to the decline in the incidence of vascular disease over the last several decades. Patients who suffer an acute stroke are at a high risk for recurrence. Introduction of newer technologies and their wider use allows for better identification of patients in whom the risk of recurrence following an acute stroke may be very high. Traditionally, the major focus for diagnosis and management has focused on patient history, examination, imaging for carotid stenosis/occlusion, and detection of AF and paroxysmal AF (PAF) with 24-48 h cardiac monitoring. This review focuses on the usefulness of three newer investigative tools that are becoming widely available and lead to better prevention. Continuous ambulatory blood pressure measurements for 24 h or longer and 3D Doppler measures of the carotid arteries provide key useful information on the state of vascular health and enhance our ability to monitor the response to preventive therapies. Furthermore, the detection of PAF can be significantly improved with prolonged cardiac monitoring for 3 weeks or longer, enabling the initiation of appropriate prevention therapy. This review will focus on the potential impact and importance of these emerging technologies on the prevention of recurrent stroke in high-risk patients.

Early Rivaroxaban Use After Cardioembolic Stroke May Not Result in Hemorrhagic Transformation: A Prospective Magnetic Resonance Imaging Study.

BACKGROUND AND PURPOSE: Early anticoagulation after cardioembolic stroke remains controversial because of the potential for hemorrhagic transformation (HT). We tested the safety and feasibility of initiating rivaroxaban ≤14 days after cardioembolic stroke/transient ischemic attack. METHODS: A prospective, open-label study of patients with atrial fibrillation treated with rivaroxaban ≤14 days of transient ischemic attack or ischemic stroke (National Institute of Health Stroke Scale <9). All patients underwent magnetic resonance imaging <24 hours of rivaroxaban initiation and day 7. The primary end point was symptomatic HT at day 7. RESULTS: Sixty patients (mean±SD age 71±19 years, 82% stroke/18% transient ischemic attack) were enrolled. Median (interquartile range) time from onset to rivaroxaban was 3 (5) days. At treatment initiation, median National Institute of Health Stroke Scale was 2 (4), and median diffusion-weighted imaging volume was 7.9 (13.7) mL. At baseline, HT was present in 25 (42%) patients (hemorrhagic infarct [HI]1=19, HI2=6). On follow-up magnetic resonance imaging, no patients developed symptomatic HT. New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from HI1 to HI2 occurred in 5 patients; otherwise, HT remained unchanged at day 7. CONCLUSIONS: These data support the safety of rivaroxaban initiation ≤14 days of mild-moderate cardioembolic stroke/transient ischemic attack. Magnetic resonance imaging evidence of petechial HT, which is common, does not appear to increase the risk of symptomatic HT.

Hyperthermia worsens ischaemic brain injury through destruction of microvessels in an embolic model in rats.

PURPOSE: Basal lamina is a major part of the microvascular wall and plays a critical role in the integrity of microvasculature. The aim of this study is to determine whether hyperthermia worsens the destruction of microvascular integrity in the ischaemic injured brain. MATERIALS AND METHODS: Focal cerebral ischaemia was induced by embolising a pre-formed clot into the middle cerebral artery (MCA). Rats received either normothermic or hyperthermic treatment. Neurological score and infarct size were evaluated at 24 h after the MCA occlusion. Microvascular collagen type IV and laminin were measured with fluorescence microscopy. The activities of matrix metalloproteinases (MMP-2 and MMP-9) and plasminogen activators (tPA and uPA) were determined by zymography. RESULTS: Treatment with hyperthermia significantly increased infarct volume (p<0.01), cortex swelling (p<0.01), striatum swelling (p<0.05) and neurologic score (p<0.01) at 24 h after the MCA occlusion. Compared to the normothermic groups, hyperthermia significantly worsened the losses of microvascular basal lamina structure proteins, collagen type IV and laminin, at 6 h (p<0.001) and 24 h (p<0.01) after MCA occlusion. Hyperthermia increased the MMP-9 activity at 6 and 24 h after MCA occlusion compared with normothermia (p<0.05), whereas increased the MMP-2 activity at 6 h only (p<0.05). Hyperthermia also elevated uPA activity significantly at 6 and 24 h after MCA occlusion compared to normothermia (p<0.05). CONCLUSIONS: These results demonstrate that hyperthermia exacerbates the destruction of microvascular integrity possibly by increasing the activities of MMP-2, MMP-9 and uPA in the ischaemic cerebral tissues.

Reduction of ischemic brain injury in rats with normothermic and hyperthermic conditions.

OBJECT: Statins have been used for induction of ischemic tolerance after cerebral ischemia. The authors have previously shown that simvastatin is protective after ischemic cerebral injury in normothermic conditions. In this study they further examined whether treatment with simvastatin can reduce ischemic brain injury in a hyperthermic condition. METHODS: Focal ischemic brain injury was induced by embolizing a preformed clot into the middle cerebral artery in rats. The authors initially examined whether treatment with simvastatin could reduce ischemic brain injury without or with hyperthermia. The infarct volume, edema, and neurological deficits were examined. They then studied whether simvastatin could reduce the perfusion deficits, damage to the blood-brain barrier (BBB), and degeneration of neurons in the ischemic injured brain. RESULTS: Simvastatin significantly reduced the infarct volume in both normothermic and hyperthermic conditions, compared with appropriate controls. Concomitantly, this treatment also significantly reduced neurological deficits and brain edema. Administration of simvastatin significantly decreased perfusion deficits, BBB permeability, and degenerated neurons. CONCLUSIONS: These studies suggest that simvastatin is an effective agent for ischemic brain injury not only in normothermic but also in hyperthermic conditions, which may be through the decrease of BBB permeability, degenerated neurons, and perfusion deficits.

Effects of hyperthermia on infarct volume in focal embolic model of cerebral ischemia in rats.

Hyperthermia worsens outcome of stroke in patients and also in animal models. In the present study, we tested the effects of hyperthermia in a focal embolic model of cerebral ischemia in rats. Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery. Hyperthermia significantly increased the brain infarct volume as compared to the normothermic controls measured at 48 h following the ischemic insult. Neurological deficits were also significantly elevated in the animals undergoing hyperthermic treatment. In addition, hyperthermia also significantly increased mortality. Our data thus show that hyperthermia exacerbates neuronal injury in the focal embolic model of cerebral ischemia in rats.