Propranolol or Beta-Blockers for Cerebral Cavernous Malformation: a Systematic Review and Meta-analysis of Literature in Both Preclinical and Clinical Studies.

Cerebral cavernous malformation (CCM), either sporadic or familial, is a devastating vascular malformation affecting the central nervous system that can present with intracerebral hemorrhage, seizure, and new focal neurologic deficits resulting in substantial morbidity and mortality. To date, there is no effective evidence-based preventive regimen. There have been several preclinical and clinical studies investigating the potential mechanisms and benefits of beta-blockers, especially on propranolol. We aimed to conduct a systematic review on the published literature investigating the use of beta-blockers in the treatment of CCM, including both preclinical and clinical studies between 2008 and 2023 using public databases. A total of 2 preclinical studies and 6 clinical studies met the inclusion/exclusion criteria and were included. Data was extracted and synthesized from 5 clinical studies for meta-analysis. The meta-analysis failed to demonstrate a statistically significant protective effect of beta-blockers in preventing intracerebral hemorrhage or developing focal neurologic deficits in subjects with CCM (overall effect = 0.78 (0.20, 3.11), p = 0.73). Overall, there was a paucity of high quality clinical trials, partially due to limited cases of CCM. Addressing this gap may require collaborative efforts at a national or international level. In this review, we summarized all barriers and opportunities on this topic. Additionally, we proposed establishing an evidence-based approach on the use of beta-blockers in preventing recurrent hemorrhage and focal neurological deficits in patients with CCM.

Revisiting Transcranial Light Stimulation as a Stroke Therapeutic-Hurdles and Opportunities.

Near-infrared laser therapy, a special form of transcranial light therapy, has been tested as an acute stroke therapy in three large clinical trials. While the NEST trials failed to show the efficacy of light therapy in human stroke patients, there are many lingering questions and lessons that can be learned. In this review, we summarize the putative mechanism of light stimulation in the setting of stroke, highlight barriers, and challenges during the translational process, and evaluate light stimulation parameters, dosages and safety issues, choice of outcomes, effect size, and patient selection criteria. In the end, we propose potential future opportunities with transcranial light stimulation as a cerebroprotective or restorative tool for future stroke treatment.

Numerical and experimental evaluation of low-intensity transcranial focused ultrasound wave propagation using human skulls for brain neuromodulation.

BACKGROUND: Low-intensity transcranial focused ultrasound (tFUS) has gained considerable attention as a promising noninvasive neuromodulatory technique for human brains. However, the complex morphology of the skull hinders scholars from precisely predicting the acoustic energy transmitted and the region of the brain impacted during the sonication. This is due to the fact that different ultrasound frequencies and skull morphology variations greatly affect wave propagation through the skull. PURPOSE: Although the acoustic properties of human skull have been studied for tFUS applications, such as tumor ablation using a multielement phased array, there is no consensus about how to choose a single-element focused ultrasound (FUS) transducer with a suitable frequency for neuromodulation. There are interests in exploring the magnitude and dimension of tFUS beam through human parietal bone for modulating specific brain lobes. Herein, we aim to investigate the wave propagation of tFUS on human skulls to understand and address the concerns above. METHODS: Both experimental measurements and numerical modeling were conducted to investigate the transmission efficiency and beam pattern of tFUS on five human skulls (C3 and C4 regions) using single-element FUS transducers with six different frequencies (150-1500 kHz). The degassed skull was placed in a water tank, and a calibrated hydrophone was utilized to measure acoustic pressure past it. The cranial computed tomography scan data of each skull were obtained to derive a high-resolution acoustic model (grid point spacing: 0.25 mm) in simulations. Meanwhile, we modified the power-law exponent of acoustic attenuation coefficient to validate numerical modeling and enabled it to be served as a prediction tool, based on the experimental measurements. RESULTS: The transmission efficiency and -6 dB beamwidth were evaluated and compared for various frequencies. An exponential decrease in transmission efficiency and a logarithmic decrease of -6 dB beamwidth with an increase in ultrasound frequency were observed. It is found that a >750 kHz ultrasound leads to a relatively lower tFUS transmission efficiency (<5%), whereas a <350 kHz ultrasound contributes to a relatively broader beamwidth (>5 mm). Based on these observations, we further analyzed the dependence of tFUS wave propagation on FUS transducer aperture size. CONCLUSIONS: We successfully studied tFUS wave propagation through human skulls at different frequencies experimentally and numerically. The findings have important implications to predict tFUS wave propagation for ultrasound neuromodulation in clinical applications, and guide researchers to develop advanced ultrasound transducers as neural interfaces.

The hypereosinophilic syndrome - an unusual cause of myocarditis and cardioembolic strokes.

Hypereosinophilic syndrome is a rare disorder characterized by excessive peripheral eosinophilia and eosinophil associated end-organ damage. Clinical presentations are heterogenous and can involve skin, pulmonary, cardiac and neurologic dysfunction. Eosinophilic myocarditis is a life-threatening complication that increases the risk of cardiac microemboli, which can subsequently lead to embolic strokes. Secondary to changes in blood viscosity, impaired clearance of microemboli, impaired cerebral blood flow, and pro-thrombotic conditions in the setting of hypereosinophilia, infarcts often present in vascular border zone regions. Here we present two cases of cardioembolic strokes involving borderzone regions in the setting of hypereosinophilic syndrome.

Bridging thrombolysis in atrial fibrillation stroke is associated with increased hemorrhagic complications without improved outcomes.

BACKGROUND: Atrial fibrillation (AF) associated ischemic stroke is associated with worse functional outcomes, less effective recanalization, and increased rates of hemorrhagic complications after intravenous thrombolysis (IVT). Conversely, AF is not associated with hemorrhagic complications or functional outcomes in patients undergoing mechanical thrombectomy (MT). This differential effect of MT and IVT in AF associated stroke raises the question of whether bridging thrombolysis increases hemorrhagic complications in AF patients undergoing MT. METHODS: This international cohort study of 22 comprehensive stroke centers analyzed patients with large vessel occlusion (LVO) undergoing MT between June 1, 2015 and December 31, 2020. Patients were divided into four groups based on comorbid AF and IVT exposure. Baseline patient characteristics, complications, and outcomes were reported and compared. RESULTS: 6461 patients underwent MT for LVO. 2311 (35.8%) patients had comorbid AF. In non-AF patients, bridging therapy improved the odds of good 90 day functional outcomes (adjusted OR (aOR) 1.29, 95% CI 1.03 to 1.60, p=0.025) and did not increase hemorrhagic complications. In AF patients, bridging therapy led to significant increases in symptomatic intracranial hemorrhage and parenchymal hematoma type 2 (aOR 1.66, 1.07 to 2.57, p=0.024) without any benefit in 90 day functional outcomes. Similar findings were noted in a separate propensity score analysis. CONCLUSION: In this large thrombectomy registry, AF patients exposed to IVT before MT had increased hemorrhagic complications without improved functional outcomes, in contrast with non-AF patients. Prospective trials are warranted to assess whether AF patients represent a subgroup of LVO patients who may benefit from a direct to thrombectomy approach at thrombectomy capable centers.

Effects of Low-Frequency Repetitive Transcranial Magnetic Stimulation on Language Recovery in Poststroke Survivors With Aphasia: An Updated Meta-analysis.

The effects of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) on treating poststroke aphasia (PSA) remain inconclusive. We aimed to evaluate the efficacy and safety of LF-rTMS on language function poststroke and determine potential factors that may affect treatment effects. Electronic databases, including MEDLINE, EMBASE, and Cochrane Library were searched to identify relevant randomized controlled trials (RCTs) concerning the effects of LF-rTMS on language performance poststroke. We adopted fixed- and random-effects models to estimate intervention effects, which were represented by the Hedges' g and 95% CIs. Subgroup analyses regarding several factors potentially influencing the effects of LF-rTMS on language recovery were also conducted. A total of 14 RCTs involving 374 participants were included in the meta-analysis. The pooled analysis showed the positive and significant effects of LF-rTMS on language function, both short-term (Hedges' g = 0.65; P < .05) and long-term (Hedges' g = 0.46; P < .05). Subgroup analyses demonstrated that LF-rTMS for 20 minutes per day over 10 days yielded the largest effect size (Hedges' g = 1.02; P < .05) and that LF-rTMS significantly improved language performance in the chronic stage after stroke (Hedges' g = 0.55; P < .05). Patients with different native languages might have diverse responses to LF-rTMS treatment efficacy. Additionally, there were significant improvements in language subtests, including naming, repetition, comprehension, and writing. Overall, this updated meta-analysis demonstrated that LF-rTMS has significant positive effects on PSA, with moderate treatment effects. It provides additional evidence to support LF-rTMS as a promising complementary therapy to promote language recovery in PSA.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Mesenchymal Stem Cell Therapy in Stroke: A Systematic Review of Literature in Pre-Clinical and Clinical Research.

Exogenous stem cell therapy (SCT) has been recognized recently as a promising neuroregenerative strategy to augment recovery in stroke survivors. Mesenchymal stem cells (MSCs) are the primary source of stem cells used in the majority of both pre-clinical and clinical studies in stroke. In the absence of evidence-based guidelines on the use of SCT in stroke patients, understanding the progress of MSC research across published studies will assist researchers and clinicians in better achieving success in translating research. We conducted a systematic review on published literature using MSCs in both pre-clinical studies and clinical trials between 2008 and 2017 using the public databases PubMed and Ovid Medline, and the clinical trial registry ( www.clinicaltrials.gov ). A total of 78 pre-clinical studies and eight clinical studies were identified. While majority of the pre-clinical and clinical studies demonstrated statistically significant effects, the clinical significance of these findings was still unclear. Effect sizes could not be measured mainly due to reporting issues in pre-clinical studies, thus limiting our ability to compare results across studies quantitatively. The overall quality of both pre-clinical and clinical studies was sub-optimal. By conducting a systematic review of both pre-clinical and clinical studies on MSCs therapy in stroke, we assessed the quality of current evidence and identified several issues and gaps in translating animal studies to human trials. Addressing these issues and incorporating changes into future animal studies and human trials may lead to better success of stem cells-based therapeutics in the near future.

Thrombectomy for acute ischemic stroke in the elderly: a 'real world' experience.

INTRODUCTION: Completed randomized trials on endovascular thrombectomy (ET) did not independently assess the efficacy of ET in the elderly (≥80 years old) who were often excluded or under-represented in trials. There were also inconsistent criteria for patient selection in this population across the different trials. This work evaluates outcomes after ET for acute ischemic stroke (AIS) in the elderly at a high volume stroke center. METHODS: We reviewed all cases of AIS that underwent a direct aspiration first pass technique (ADAPT) thrombectomy for large vessel occlusions between March 2013 and October 2017 while comparing outcomes in the elderly with younger counterparts. We also reviewed AIS cases in elderly patients undergoing medical management who were matched to the ET counterparts by demographics, comorbidities, baseline deficits, and stroke severity. RESULTS: Of 560 patients undergoing ET for AIS, 108 patients were in the elderly group (≥80 years of age), and had a significantly lower likelihood of functional independence (defined as a modified Rankin Scale score of 0-2) at 90 days compared with younger patients (20.5% vs 44.4%, P<0.001), and higher mortality rates (34.3% vs 20%, P<0.001). When compared with patients undergoing medical management, elderly patients did not have a significant improvement in rates of good outcomes (20.5% vs 19.5%, P>0.05), and had significantly higher rates of hemorrhage (40.7% vs 9.3%, P<0.001). We also identified baseline stroke severity and the incidence of hemorrhage as two independent predictors of outcome in the elderly patients. CONCLUSIONS: ET in the elderly did not show a similar benefit to younger patients when compared with medical management. These findings emphasize the need for more optimal selection criteria for the elderly population to improve the risk to benefit ratio of ET.

Ultrasonographical Features Associated with Progression of Atherosclerosis in Patients with Moderate Internal Carotid Artery Stenosis.

Carotid artery stenosis (CAS) is a leading cause of ischemic stroke. Plaque stabilization is a major management approach. Information about the ultrasonographical and clinical features associated with the progression of moderate internal carotid artery (ICA) stenosis (50-69%) could assist with prognostication and risk factor modifications. We evaluated 287 patients with moderate ICA stenosis (50-69%) and subsequently evaluated them at follow-up points at 12, 24, and 36 months. Patients were divided into three groups according to the degree of ICA stenosis: progression (70-99%, n = 48), stable (50-69%, n = 210), and regression (< 50%, n = 29). Responsible plaque thickness (RPT) across groups during follow-up was compared using a repeated measure ANOVA test. An ordinal regression was subsequently applied to identify risk factors for atherosclerosis progression. Male (P = 0.04), hypoechoic plaque (P < 0.01), smoking (P = 0.02), plaque ulceration (P = 0.05), and contralateral severe CAS or occlusions (P = 0.04) on ultrasound was more frequent in the progression group vs. other two groups. The ordinal regression revealed that only hypoechoic plaque (OR, 7.03; 95% CI, 3.34-14.81; P < 0.01) and contralateral ICA severe stenosis or occlusion (OR, 2.86; 95% CI, 1.41-5.80; P < 0.01) were independently associated with stenosis progression, while statin use was inversely associated with stenosis progression (OR, 0.26; 95% CI, 0.13-0.54; P < 0.01). Of note, symptomatic vs. asymptomatic moderate CAS at baseline was not associated with progression. For patients with moderate CAS, hypoechoic plaque, contralateral severe stenosis or occlusion on ultrasonography, and statin use are independently related to stenosis progression. Statin use may delay the progression of carotid stenosis.

Mobile health as a viable strategy to enhance stroke risk factor control: A systematic review and meta-analysis.

BACKGROUND: With the rapid growth worldwide in cell-phone use, Internet connectivity, and digital health technology, mobile health (mHealth) technology may offer a promising approach to bridge evidence-treatment gaps in stroke prevention. We aimed to evaluate the effectiveness of mHealth for stroke risk factor control through a systematic review and meta-analysis. METHODS: We searched PubMed from January 1, 2000 to May 17, 2016 using the following keywords: mobile health, mHealth, short message, cellular phone, mobile phone, stroke prevention and control, diabetes mellitus, hypertension, hyperlipidemia and smoking cessation. We performed a meta-analysis of all eligible randomized control clinical trials that assessed a sustained (at least 6months) effect of mHealth. RESULTS: Of 78 articles identified, 13 met eligibility criteria (6 for glycemic control and 7 for smoking cessation) and were included for the final meta-analysis. There were no eligible studies for dyslipidemia or hypertension. mHealth resulted in greater Hemoglobin A1c reduction at 6months (6 studies; 663 subjects; SMD: -0.44; 95% CI: [-0.82, -0.06], P=0.02; Mean difference of decrease in HbA1c: -0.39%; 95% CI: [-0.74, -0.04], P=0.03). mHealth also lead to relatively higher smoking abstinence rates at 6months (7 studies; 9514 subjects; OR: 1.54; 95% CI: [1.24, 1.90], P<0.0001). CONCLUSIONS: Our meta-analysis supports that use of mHealth improves glycemic control and smoking abstinence rates.

Clopidogrel and ischemic stroke outcomes by smoking status: Smoker's paradox?

BACKGROUND AND PURPOSE: Active smokers with myocardial infarction were shown to have enhanced benefit with clopidogrel compared with aspirin. Whether this "paradox" exists in ischemic stroke patients is unknown. We aimed to investigate whether smoking status has a differential impact on the efficacy of clopidogrel vs. aspirin in patients with non-cardioembolic strokes. METHODS: This single-center study retrospectively assessed 1792 non-cardioembolic ischemic stroke patients discharged from January 2013 to October 2014, and followed for 12months. Patients were categorized as current-smokers and never-smokers. Primary outcome was a composite of secondary ischemic stroke, myocardial infarction and all-cause death. Secondary outcome was secondary ischemic stroke. RESULTS: 1066 patients were current-smokers and 726 were never-smokers. Compared with never-smokers, current-smokers had significantly higher rates of ischemic stroke (4.3% vs. 1.2%; adjusted OR: 3.60, 95%CI: 1.50-8.64, p=0.004). Regarding the primary outcome, among smokers, rates showed a lower trend in clopidogrel vs. aspirin groups (3.7% vs. 6.4%; adjusted OR 0.57, 95%CI: 0.31-1.07, p=0.08), but no difference among never-smokers (2.1% vs. 1.0%; adjusted OR: 1.67, 95%CI: 0.47-5.89, p=0.42). Similarly, among smokers, trending lower rates for recurrent ischemic stroke were observed in clopidogrel vs. aspirin group (3.1% vs. 5.0%; adjusted OR: 0.60, 95%CI: 0.31-1.18, p=0.14); but no difference between the two groups among never-smokers (1.7% vs. 1.0%; adjusted OR 1.36, 95%CI: 0.36-5.52, p=0.65). CONCLUSIONS: Smoking is a major risk factor for recurrent stroke in our retrospective non-cardioembolic ischemic stroke cohort. Active-smokers trend toward better cardiovascular outcomes when on clopidogrel. This finding needs to be confirmed in a prospective cohort.

Intracardiac Myxoma, Cerebral Aneurysms and Elevated Interleukin-6.

Cerebral aneurysms are well known to be associated with cardiac myxomas. The mechanism of cerebral aneurysm formation remains to be elucidated. Embolization of tumor particles in the vessel wall has been proposed as the likely mechanism for aneurysm formation. Recent reports suggest interleukin-6 (IL-6) may play a role as well. We describe a patient who presented with subarachnoid hemorrhage secondary to ruptured right middle cerebral artery (MCA) aneurysm and unruptured left MCA aneurysm. Subsequently, the patient was found to have an atrial myxoma and persistently elevated serum IL-6 levels. Transcranial Doppler monitoring showed multiple emboli in the right MCA vascular territory on day 1 after surgery but no recurrent embolization during the next 2 weeks on repeated tests. Elevated IL-6 levels were noted both on day 1 and on day 30. Our findings provide evidence that IL-6 elevation and not tumor embolization is likely the culprit for aneurysm formation in some patients with atrial myxoma.

Stroke assessment with diffusional kurtosis imaging.

BACKGROUND AND PURPOSE: Despite being the gold standard technique for stroke assessment, conventional diffusion MRI provides only partial information about tissue microstructure. Diffusional kurtosis imaging is an advanced diffusion MRI method that yields, in addition to conventional diffusion information, the diffusional kurtosis, which may help improve characterization of tissue microstructure. In particular, this additional information permits the description of white matter (WM) in terms of WM-specific diffusion metrics. The goal of this study is to elucidate possible biophysical mechanisms underlying ischemia using these new WM metrics. METHODS: We performed a retrospective review of clinical and diffusional kurtosis imaging data of 44 patients with acute/subacute ischemic stroke. Patients with a history of brain neoplasm or intracranial hemorrhages were excluded from this study. Region of interest analysis was performed to measure percent change of diffusion metrics in ischemic WM lesions compared with the contralateral hemisphere. RESULTS: Kurtosis maps exhibit distinct ischemic lesion heterogeneity that is not apparent on apparent diffusion coefficient maps. Kurtosis metrics also have significantly higher absolute percent change than complementary conventional diffusion metrics. Our WM metrics reveal an increase in axonal density and a larger decrease in the intra-axonal (Da) compared with extra-axonal diffusion microenvironment of the ischemic WM lesion. CONCLUSIONS: The well-known decrease in the apparent diffusion coefficient of WM after ischemia is found to be mainly driven by a significant drop in the intra-axonal diffusion microenvironment. Our results suggest that ischemia preferentially alters intra-axonal environment, consistent with a proposed mechanism of focal enlargement of axons known as axonal swelling or beading.

Recurrent lobar intracerebral hemorrhage in Tangier disease.

We report a patient with familial α-lipoprotein deficiency (Tangier disease) who presented with recurrent lobar intracerebral hemorrhages and accumulating microbleeds on T*2-weighted magnetic resonance imaging, suggestive of probable cerebral amyloid angiopathy. This case provides new insight into the links between the adenotriphosphate-binding cassette A1 (ABCA1) transporter gene mutation in Tangier disease and apolipoprotein-E expression in the brain and supports further investigation of the potential role of ABCA1 transporter in cerebral amyloid angiopathy.