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Ischemic stroke is a leading cause of disability and there is a paucity of therapeutic strategies that promote functional recovery after stroke. Transcutaneous vagus nerve stimulation (tVNS) has shown promising evidence as a tool to reduce infarct size in animal models of hyperacute stroke. In chronic stroke, tVNS paired with limb movements has been shown to enhance neurological recovery. In this review, we summarize the current evidence for tVNS in preclinical models and clinical trials in humans. We highlight the mechanistic pathways involved in the beneficial effects of tVNS. We critically evaluate the current gaps in knowledge and recommend the key areas of research required to translate tVNS into clinical practice in acute and chronic stroke., Competing Interests: Disclosures Prof Dawson has received institutional funding for vagus nerve stimulation (VNS)-related research and reimbursement for conference expenses to present study data related to use of VNS, both from MicroTransponder Inc. All other authors report no conflicts of interest.

Stroke is one of the leading causes of death and disability globally. A significant proportion of stroke survivors are left with long term neurological deficits that have a detrimental effect on personal wellbeing and wider socioeconomic impacts. As such, there is an unmet need for novel therapies that improve neurological recovery after stroke. Invasive vagus nerve stimulation (VNS) paired with rehabilitation has been shown to improve upper limb motor function in chronic stroke. However, invasive VNS requires a surgical procedure and therefore may not be suitable for all stroke patients. Non-invasive, transcutaneous VNS (tVNS) via auricular vagus nerve stimulation in the ear (taVNS) and cervical vagus nerve stimulation in the neck (tcVNS) have been shown to activate similar vagal nerve projections in the central nervous system to invasive VNS. A number of pre-clinical studies indicate that tVNS delivered in acute middle cerebral artery occlusion reduces infarct size through anti-inflammatory effects, reduced excitotoxicity and increased blood-brain barrier integrity. Longer term effects of tVNS in stroke that may mediate neuroplasticity include microglial polarisation, angiogenesis and neurogenesis. Pilot clinical trials of taVNS indicate that taVNS paired with rehabilitation may improve upper limb motor and sensory function in patients with chronic stroke. In this review, we summarise and critically appraise the current pre-clinical and clinical evidence, outline the major ongoing clinical trials and detail the challenges and future directions regarding tVNS in acute and chronic stroke., (Copyright © 2021. Published by Elsevier B.V.)

Background: Sensory impairment is associated with reduced functional recovery in stroke survivors. Invasive vagus nerve stimulation (VNS) paired with rehabilitative interventions improves motor recovery in chronic stroke. Noninvasive approaches, for example, transcutaneous auricular VNS (taVNS) are safe, well-tolerated and may also improve motor function in those with residual weakness. We report the impact of taVNS paired with a motor intervention, repetitive task practice, on sensory recovery in a cohort of patients with chronic stroke., Methods: Twelve participants who were more than 3 months postischemic stroke with residual upper limb weakness received 18 × 1 hour sessions over 6 weeks with an average of at least 300 repetitions of functional arm movements per session concurrently with taVNS at maximum tolerated intensity. Light touch and proprioception were scored as part of the Upper Limb Fugl-Meyer (UFM) assessment at baseline and postintervention (score range for sensation 0-12)., Results: Eleven participants (92%) had sensory impairment at baseline of whom 7 (64%) regained some sensation (proprioception n = 6 participants, light touch n = 2, both modalities n = 1) postintervention. The maximal increase in UFM sensation score (3 points) was seen in the patient with the greatest improvement in motor function., Conclusions: taVNS paired with motor rehabilitation may improve sensory recovery in chronic stroke patients. The relative contribution of motor and sensory rehabilitation to overall functional recovery in chronic stroke needs further characterization in a larger, phase 2 study., (Copyright © 2019. Published by Elsevier Inc.)

Background: Invasive vagus nerve stimulation (VNS) has the potential to enhance the effects of physiotherapy for upper limb motor recovery after stroke. Noninvasive, transcutaneous auricular branch VNS (taVNS) may have similar benefits, but this has not been evaluated in stroke recovery. We sought to determine the feasibility of taVNS delivered alongside upper limb repetitive task-specific practice after stroke and its effects on a range of outcome measures evaluating limb function., Materials and Methods: Thirteen participants at more than 3 months postischemic stroke with residual upper limb dysfunction were recruited from the community of Sheffield, United Kingdom (October-December 2016). Participants underwent 18 × 1-hour sessions over 6 weeks in which they made 30-50 repetitions of 8-10 arm movements concurrently with taVNS (NEMOS; Cerbomed, Erlangen, Germany, 25 Hz, .1-millisecond pulse width) at maximum tolerated intensity (mA). An electrocardiogram and rehabilitation outcome scores were obtained at each visit. Qualitative interviews determined the acceptability of taVNS to participants., Results: Median time after stroke was 1.16 years, and baseline median/interquartile range upper limb Fugl-Meyer (UFM) score was 63 (54.5-99.5). Participants attended 92% of the planned treatment sessions. Three participants reported side effects, mainly fatigue, but all performed mean of more than 300 arm repetitions per session with no serious adverse events. There was a significant change in the UFM score with a mean increase per participant of 17.1 points (standard deviation 7.8)., Conclusion: taVNS is feasible and well-tolerated alongside upper limb repetitive movements in poststroke rehabilitation. The motor improvements observed justify a phase 2 trial in patients with residual arm weakness., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: For symptomatic patients with carotid artery stenosis, the risk benefit for surgical intervention may vary among patient groups. Various modalities of plaque imaging have been promoted as potential tools for additional risk stratification, particularly in patients with moderate stenosis. However, it remains uncertain to what extent carotid plaque components predict risk of future ipsilateral ischemic stroke., Methods: In 2 large atherosclerotic carotid plaque biobank studies, we related histological characteristics of 1640 carotid plaques with a validated risk model for the prediction of individual 1- and 5-year stroke risk., Results: No significant heterogeneity between the studies was found. Predicted 5-year stroke risk (top versus bottom quartile) was related to plaque thrombus (odds ratio, 1.42; 95% confidence interval, 1.11-1.89; P=0.02), fibrous content (0.65; 0.49-0.87; P=0.004), macrophage infiltration (1.41; 1.05-1.90; P=0.02), high microvessel density (1.49; 1.05-2.11; P=0.03), and overall plaque instability (1.40; 1.05-1.87; P=0.02). This association was not observed for cap thickness, calcification, intraplaque hemorrhage, or lymphocyte infiltration. Plaques removed within 30 days of most recent symptomatic event were most strongly correlated with predicted stroke risk., Conclusions: Features of the vulnerable carotid plaque, including plaque thrombus, low fibrous content, macrophage infiltration, and microvessel density, correlate with predicted stroke risk. This study provides a basis for plaque imaging studies focused on stroke risk stratification., (© 2014 American Heart Association, Inc.)

Aims: Diabetes accelerates progression of atherosclerotic disease, but data on associations between diabetes and advanced atherosclerotic plaque composition are scarce., Methods and Results: We used one of the largest biobanks, the Athero-Express study (n=1455) at carotid endarterectomy (CEA). All plaques were subjected to histological analysis to assess lipid core size, collagen, macrophages, smooth muscle cells, micro-vessel density and calcifications. In addition, within a subset of patients cytokines and chemokines were assessed. The 295 patients (20%) with type-2 diabetes showed a higher proportion of previous cardiovascular interventions and more stringent treatment for hypertension and hypercholesterolaemia compared with patients without type-2 diabetes. Surprisingly, no associations between diabetes and histological plaque characteristics were observed. In addition, no differences were observed in the expression of inflammatory chemokines, cytokines or advanced glycation end products in plaques of diabetic and non-diabetic patients., Conclusion: In patients suffering from significant carotid artery disease, diabetes does not appear to be associated with specific atherosclerotic plaque characteristics., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Patients with carotid artery stenosis and ocular ischemic events have a much lower risk of future ipsilateral ischemic stroke on medical treatment and lower procedural risks for endarterectomy and stenting than patients with cerebral ischemic events, and are closer in risk to patients with asymptomatic stenosis. The reasons for this difference in prognosis are not fully understood, but may reflect differences in carotid plaque pathology., Methods: In consecutive patients undergoing carotid endarterectomy for recently symptomatic stenosis (Oxford Plaque Study, Athero-Express Study), we compared carotid plaque histology (using validated semiquantitative scales) in those who had cerebral events within the last 6 months (n=1317) versus those with ocular events only (n=323)., Results: Compared with plaques from patients with ocular events only, those from patients with cerebral events had significantly more large lipid core (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.05-1.82; P=0.02), inflammation (OR, 1.32; 95% CI, 1.02-1.72; P=0.04) and overall plaque instability (OR, 1.37; 95% CI, 1.05-1.80; P=0.02), and less fibrous content (OR, 0.71; 95% CI, 0.54-0.92; P=0.01), and calcification (OR, 0.70; 95% CI, 0.54-0.91; P=0.008). The overall number of histological features known to be associated with vulnerable plaque was greater in patients with cerebral events than in those with ocular events (P=0.002)., Conclusions: Carotid plaques from patients undergoing endarterectomy for previous ocular ischemic events have fewer vulnerable plaque features than those from patients with recent cerebral ischemic events, possibly explaining some of the differences in risk of stroke between these groups.

Unlabelled: Many patients with minor stroke are referred to outpatient clinics and are not scanned immediately. A clinical rule is needed to identify patients who are likely to have intracerebral haemorrhage (ICH) and require urgent brain imaging and patients who can safely start antiplatelet agents before scanning., Methods: Clinical factors associated with ICH were determined in 334 consecutive patients with minor stroke (National Institute of Health Stroke Scale score < or = 3), and a predictive model for ICH that was validated in a cohort of 280 patients presenting to a hospital-stroke clinic was derived. Prognostic value was quantified as the area under the ROC curve (c statistics)., Results: The proportion of ICH in minor stroke was 5.1% (95% CI 3.2% to 8.0%) in OXVASC, and 5.4% (3.3% to 8.7%) in the clinic cohort. Clinical factors predictive of ICH in OXVASC included blood pressure on initial assessment > or = 180/110 mm Hg (OR 14.5, 95% CI 1.8 to 114, p=0.001), vomiting (OR 15.7, 95% CI 5.4 to 46, p<0.001), confusion (OR 8.2, 95% CI 2.9 to 23, p<0.001) and anticoagulation use (OR 7.8, 95% CI 2.2 to 28, p=0.006), and at least one predictive factor was identified in all 17 patients with ICH and in 35% overall (c statistic 0.92, 95% CI 0.88 to 0.97). Therefore, we derived the SCAN rule to identify ICH if > or = 1 of the following were present: (S) severe hypertension, (C) confusion, (A) anticoagulation, (N) nausea and vomiting. In the clinic validation cohort, > or = 1 predictive factor was identified in 14/15 of patients with ICH and in 24% overall (c statistic 0.87, 95% CI 0.79 to 0.95)., Conclusion: The SCAN rule appears to be specific and sensitive at identifying ICH in an independent cohort of patients with minor stroke, although further independent validations are needed.

Background: A previous hospital clinic-based study estimated that 3.5% of minor strokes are due to primary intracerebral haemorrhage, but the confidence intervals were wide. Moreover this figure may be an underestimate in older patients, who are less likely to be referred to secondary care, and who may have higher rates of intracerebral haemorrhage. Further studies are required to validate and increase the precision of this estimate and to determine any association with age, in order to plan appropriate services for minor stroke., Method: We determined the frequency of intracerebral haemorrhage and haemorrhagic transformation of infarction in consecutive patients presenting with minor stroke (National Institute of Health Stroke Scaleor=85 years (0-3%). We identified only one previous study with a reliable estimate of the proportion of minor stroke due to intracerebral haemorrhage, and in a pooled analysis including 842 patients, the overall frequency of intracerebral haemorrhage was 4.8% (4.5-5.0%)., Conclusion: We have shown that the proportion of minor stroke due to intracerebral haemorrhage was very similar in a population-based cohort and a hospital clinic-based cohort using different imaging strategies, and that the frequency is independent of age. A frequency of between 4.5 and 5.0% appears to be a reliable estimate at all ages.

Background: Diabetes is associated with an increased risk of incident stroke and both early and late recurrent stroke after transient ischaemic attack. Some small studies have suggested that atherosclerotic plaques from diabetics have a higher prevalence of unstable features than plaques from non-diabetics but results have been inconsistent., Method: We made detailed histological assessments of 526 plaques from consecutive patients undergoing carotid endarterectomy for recently symptomatic stenosis and related these to the presence of diabetes and impaired glucose tolerance (IGT)., Results: 53 (10.1%) patients had diabetes, 26 (5%) had IGT and 447 (84.9%) had normal glucose tolerance (NGT). The overall prevalence of unstable plaque features was similar across these groups. However, whereas plaques removed >60 days after last symptoms in patients with NGT had less surface thrombus (OR = 0.61, 95% CI = 0.40-0.92, p = 0.02), fewer plaque macrophages (OR = 0.78, 95% CI = 0.51-1.19, p < 0.001) and less marked overall instability (OR = 0.57, 95% CI = 0.35-0.88, p = 0.009) than plaques removed more acutely, these features tended to be more persistent in patients with diabetes/IGT (OR = 1.08, 95% CI = 0.42-2.77, OR = 1.16, 95% CI = 0.46-2.96 and OR = 1.51, 95% CI = 0.60-3.77, respectively)., Conclusion: Overall, the prevalence of unstable histology features in recently symptomatic carotid plaques is similar in patients with diabetes, IGT and NGT. However, surface thrombus and plaque macrophages appear to persist for longer after ischaemic symptoms in plaques from patients with diabetes/IGT compared to plaques from patients with NGT. This may contribute to the increased risk of recurrent stroke that is associated with diabetes/IGT., ((c) 2008 S. Karger AG, Basel)

Background and Purpose: Early risk of stroke after a transient ischemic attack can be reliably predicted with risk scores based on clinical features of the patient and of the ischemic event, but it is unclear how these features correlate with findings on brain imaging., Methods: We performed a systematic review of the literature and identified all previous studies which reported patient characteristics and the nature of transient ischemic attack symptoms in relation to appearances on diffusion-weighted imaging (DWI). We then performed a meta-analysis of the associations between the components of the risk scores and positive DWI. Authors were contacted for additional unpublished data., Results: Nineteen studies were identified by the systematic review, and additional unpublished data were obtained from 11 of these studies. On meta-analysis, several components of the risk scores were associated with positive DWI, including symptom duration > or =60 minutes (13 studies, odds ratio [OR], 1.50; 95% CI, 1.16 to 1.96; P=0.004), dysphasia (9 studies, OR, 2.25; 95% CI, 1.57 to 3.22; P<0.001), dysarthria (8 studies, OR, 1.73; 95% CI, 1.11 to 2.68; P=0.03) and motor weakness (9 studies, OR, 2.20; 95% CI, 1.56 to 3.10; P<0.001). However patient age, sex, hypertension and diabetes were not associated with the presence of DWI lesions. From an etiologic perspective, atrial fibrillation (9 studies, OR, 2.75; 95% CI, 1.78 to 4.25; P<0.001) and ipsilateral > or =50% carotid stenosis (10 studies, OR, 1.93; 95% CI, 1.34 to 2.76; P=0.001) were associated with positive DWI., Conclusions: Presence of acute ischemic lesions on DWI correlates with several clinical features known to predict stroke risk after transient ischemic attack. Large studies (sample size >1000) will therefore be required to determine the independent prognostic value of DWI and its interactions with these clinical characteristics.

Introduction: Diffusion-weighted imaging (DWI) is mainly used in acute stroke, and signal evolution in the acute phase has been studied extensively. However, patients with a minor stroke frequently present late. Recent studies suggest that DWI may be helpful at this stage, but only very few published data exist on the evolution of the DW-signal in the weeks and months after a stroke. We performed a follow-up study of DWI in the late stages after a minor stroke., Methods: 28 patients who presented 48 hours to 14 days after a minor stroke underwent serial MRI at baseline, 4 weeks, 8 weeks, 12 weeks, 6 months and>or=9 months after their event. Signal intensity within the lesion was determined on T2-weighted images, DW-images and the Apparent Diffusion Coefficient (ADC) map at each time-point, and ratios were calculated with contralateral normal values (T2r, DWIr, ADCr)., Results: T2r was increased in all patients from the beginning, and showed no clear temporal evolution. ADCr normalized within 8 weeks in 83% of patients, but still continued to increase for up to 6 months after the event. The DW-signal decreased over time, but was still elevated in 6 patients after>or=6 months. The evolution of ADCr and DWIr showed statistically highly significant inter-individual variation (p<0.0001), which was not accounted for by age, sex, infarct size or infarct location., Conclusion: The ADC and the DW-signal may continue to evolve for several months after a minor ischaemic stroke. Signal evolution is highly variable between individuals. Further studies are required to determine which factors influence the evolution of the ADC and the DW-signal.

Background: Early risk of stroke after a transient ischaemic attack (TIA) can be reliably predicted with risk scores based on clinical features of the patient and the event, but it is unclear how these features correlate with findings on brain imaging and few studies have investigated this in the subacute phase., Methods: Two hundred consecutive patients attending a specialist clinic underwent diffusion-weighted brain imaging (DWI) on the day of the clinic (> or =3 days after a TIA) and the presence of recent lesions (positive DWI) was related to the presence of clinical features associated with a high stroke risk and to 2 validated risk scores (ABCD and California)., Results: Thirty-one patients (16%) had positive DWI. Increasing ABCD and California scores were associated with positive DWI (p = 0.02 for both) independent of the delay from TIA to scan., Conclusion: Presence of recent ischaemic lesions on DWI correlates with validated clinical scores for risk of stroke after TIA in patients scanned subacutely. Future prognostic studies of DWI after TIA should adjust for the risk scores to determine the independent predictive value of DWI and hence the likely role of DWI in refinements of the scores.

Background: Atherosclerotic plaque at the carotid bifurcation is often associated with transient ischemic attack (TIA) and ischemic stroke, but the mechanisms are not completely understood. Previous histological studies have been too small or insufficiently detailed to reliably determine the temporal course of features of plaque instability or to stratify analyses by the nature of presenting symptoms., Methods and Results: We performed the largest-ever histological study of symptomatic carotid plaques from consecutive patients (n=526) undergoing endarterectomy and related detailed reproducible histological assessments to the nature and timing of presenting symptoms. There was a high prevalence of many features of coronary-type plaque instability. Dense plaque inflammation (especially infiltration with macrophages) was the feature most strongly associated with both cap rupture (odds ratio 3.39, 95% confidence interval 2.31 to 4.98, P<0.001) and time since stroke (P=0.001). Strong negative associations with time since stroke were also seen for cap rupture (P=0.02), overall plaque inflammation (P=0.003), and "unstable plaque" (P=0.001). Although plaques removed < or =60 days after the most recent event were more unstable after a stroke than after a TIA, the instability persisted after a TIA, and plaques removed >180 days after most recent event were less unstable after a stroke than after a TIA (plaque inflammation: < or =60 days, odds ratio 2.33 [95% confidence interval 0.76 to 7.19]; >180 days, 0.36 [0.16 to 0.84]; P=0.008; unstable plaque: odds ratio 3.27 [95% confidence interval 0.93 to 11.50] versus 0.74 [0.33 to 1.69], P=0.05)., Conclusions: Pathology of recently symptomatic carotid plaques is similar to that of culprit coronary plaques, with strong correlations between macrophage infiltration and plaque instability. The tendency for plaque inflammation and overall instability to persist with time after a TIA but to decrease with time after a stroke suggests that the nature of the underlying pathology may differ.

Background: Acute coronary, cerebrovascular, and peripheral vascular events have common underlying arterial pathology, risk factors, and preventive treatments, but they are rarely studied concurrently. In the Oxford Vascular Study, we determined the comparative epidemiology of different acute vascular syndromes, their current burdens, and the potential effect of the ageing population on future rates., Methods: We prospectively assessed all individuals presenting with an acute vascular event of any type in any arterial territory irrespective of age in a population of 91 106 in Oxfordshire, UK, in 2002-05., Findings: 2024 acute vascular events occurred in 1657 individuals: 918 (45%) cerebrovascular (618 stroke, 300 transient ischaemic attacks [TIA]); 856 (42%) coronary vascular (159 ST-elevation myocardial infarction, 316 non-ST-elevation myocardial infarction, 218 unstable angina, 163 sudden cardiac death); 188 (9%) peripheral vascular (43 aortic, 53 embolic visceral or limb ischaemia, 92 critical limb ischaemia); and 62 unclassifiable deaths. Relative incidence of cerebrovascular events compared with coronary events was 1.19 (95% CI 1.06-1.33) overall; 1.40 (1.23-1.59) for non-fatal events; and 1.21 (1.04-1.41) if TIA and unstable angina were further excluded. Event and incidence rates rose steeply with age in all arterial territories, with 735 (80%) cerebrovascular, 623 (73%) coronary, and 147 (78%) peripheral vascular events in 12 886 (14%) individuals aged 65 years or older; and 503 (54%), 402 (47%), and 105 (56%), respectively, in the 5919 (6%) aged 75 years or older. Although case-fatality rates increased with age, 736 (47%) of 1561 non-fatal events occurred at age 75 years or older., Interpretation: The high rates of acute vascular events outside the coronary arterial territory and the steep rise in event rates with age in all territories have implications for prevention strategies, clinical trial design, and the targeting of funds for service provision and research.

Background: Effective early management of patients with transient ischaemic attacks (TIA) is undermined by an inability to predict who is at highest early risk of stroke., Methods: We derived a score for 7-day risk of stroke in a population-based cohort of patients (n=209) with a probable or definite TIA (Oxfordshire Community Stroke Project; OCSP), and validated the score in a similar population-based cohort (Oxford Vascular Study; OXVASC, n=190). We assessed likely clinical usefulness to front-line health services by using the score to stratify all patients with suspected TIA referred to OXVASC (n=378, outcome: 7-day risk of stroke) and to a hospital-based weekly TIA clinic (n=210; outcome: risk of stroke before appointment)., Results: A six-point score derived in the OCSP (age [> or =60 years=1], blood pressure [systolic >140 mm Hg and/or diastolic > or =90 mm Hg=1], clinical features [unilateral weakness=2, speech disturbance without weakness=1, other=0], and duration of symptoms in min [> or =60=2, 10-59=1, <10=0]; ABCD) was highly predictive of 7-day risk of stroke in OXVASC patients with probable or definite TIA (p<0.0001), in the OXVASC population-based cohort of all referrals with suspected TIA (p<0.0001), and in the hospital-based weekly TIA clinic-referred cohort (p=0.006). In the OXVASC suspected TIA cohort, 19 of 20 (95%) strokes occurred in 101 (27%) patients with a score of 5 or greater: 7-day risk was 0.4% (95% CI 0-1.1) in 274 (73%) patients with a score less than 5, 12.1% (4.2-20.0) in 66 (18%) with a score of 5, and 31.4% (16.0-46.8) in 35 (9%) with a score of 6. In the hospital-referred clinic cohort, 14 (7.5%) patients had a stroke before their scheduled appointment, all with a score of 4 or greater., Conclusions: Risk of stroke during the 7 days after TIA seems to be highly predictable. Although further validations and refinements are needed, the ABCD score can be used in routine clinical practice to identify high-risk individuals who need emergency investigation and treatment.

Background and Purpose: Carotid plaque instability is an important determinant of stroke risk. There are now a number of different imaging techniques that provide information on carotid plaque morphology. However, it is unclear how they compare with one another or whether they can reliably assess plaque instability. Studies comparing imaging with pathology have shown highly variable results, even for similar imaging techniques. This may be because of variable pathology techniques rather than differences in imaging., Methods: We performed a systematic review of studies that compared carotid imaging with histology of the excised plaque published between January 1995 and September 2004. We assessed the quality and comparability of these studies. In particular, we determined which histology methods were used and whether observer reproducibility of the histology assessment was reported., Results: Among 73 eligible studies, histological methods were poorly reported and highly variable; 23% reported reproducibility data for imaging and only 12% reported reproducibility data for histology. Of 29 studies that reported quantitative results of blinded comparisons, there were methodological deficiencies and the results were highly variable. No study considered the extent to which the lack of reproducibility influenced the imaging-pathological correlations reported., Conclusions: Pathological correlation in studies of carotid plaque imaging cannot be reliably interpreted or compared because of incomparable and poorly reported histology methods. We make recommendations for the performance, reporting, and interpretation of imaging-pathological correlation studies and highlight the need for consensus guidelines.