tVNS in Stroke: A Narrative Review on the Current State and the Future.

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.

Transcutaneous vagus nerve stimulation (tVNS) in stroke: the evidence, challenges and future directions.

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.

Transcutaneous Auricular Vagus Nerve Stimulation with Upper Limb Repetitive Task Practice May Improve Sensory Recovery in Chronic Stroke.

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.

Transcutaneous Auricular Vagus Nerve Stimulation with Concurrent Upper Limb Repetitive Task Practice for Poststroke Motor Recovery: A Pilot Study.

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.

Symptomatic carotid atherosclerotic disease: correlations between plaque composition and ipsilateral stroke risk.

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.

Type 2 diabetes is not associated with an altered plaque phenotype among patients undergoing carotid revascularization. A histological analysis of 1455 carotid plaques.

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.

Histological features of carotid plaque in patients with ocular ischemia versus cerebral events.

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.

Histological features of symptomatic carotid plaques in relation to age and smoking: the oxford plaque study.

BACKGROUND AND PURPOSE: Rates of incident and recurrent cardiovascular events rise steadily with age, due partly to more extensive atherosclerotic burden. However, in patients with similarly severe symptomatic carotid stenosis, increasing age is associated with a greater risk of ipsilateral ischemic stroke. This effect may be due to age-related differences in the pathology of symptomatic carotid plaques. However, previous studies of plaque pathology in relation to age have not accounted for potential confounders, particularly smoking, which is often less prevalent in the elderly population undergoing endarterectomy. Method-We related patient age (<55, 55 to 64, 65 to 74, 75+ years) and smoking habit (never, exsmoker, recent smoker, and current smoker; and number of cigarettes smoked per day) to detailed histological assessments of 526 carotid plaques from consecutive patients undergoing carotid endarterectomy for symptomatic carotid stenosis. RESULTS: Three hundred seventy-nine (72.1%) patients were male (mean/SD age 66.6/8.7). Current/recent smokers were on average 7 years younger at carotid endarterectomy than ex-/never smokers (P<0.001), and age at carotid endarterectomy decreased with increasing number of cigarettes smoked per day (P trend=0.005). Plaques from current/recent smokers had a lower prevalence of intraplaque hemorrhage (P -trend=0.01), but histology was otherwise similar to that in ex-/never smokers, and both groups showed similar changes with age. With increasing age, plaque calcification and large lipid core increased (P<0.001 and P=0.01, respectively) and fibrous tissue (P=0.01) decreased, but lymphocyte infiltration of the plaque (P=0.03) and cap (P=0.002) and overall plaque inflammation (P=0.03) also decreased such that overall plaque instability was unrelated to age. CONCLUSIONS: Smoking is associated with a lower age at carotid endarterectomy suggesting that it may accelerate the development and/or progression of atherosclerosis. However, the mechanisms of plaque instability seem largely unrelated to smoking. Plaques from younger patients had greater inflammatory cell infiltration, whereas those from older patients had a larger lipid core, but there were no age trends in overall plaque instability suggesting the increased risk of stroke in the elderly with symptomatic carotid stenosis is due to other factors.

Reliability of clinical diagnosis of the symptomatic vascular territory in patients with recent transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Knowledge of the vascular territory of a recent transient ischemic attack or minor stroke determines appropriate investigations and the need for territory-specific interventions such as endarterectomy and stenting. However, there are few published data on the accuracy of clinical assessment of the vascular territory. METHODS: We studied agreement of clinical diagnosis of vascular territory in consecutive patients with transient ischemic attack or minor stroke with diffusion-weighted MRI who had an acute ischemic lesion(s) in a single vascular territory (determined by a neuroradiologist). Three independent neurologists (one had seen the patients, the others had a clinical summary) diagnosed the most likely vascular territory (carotid or vertebrobasilar) for each patient blind to brain imaging. RESULTS: One hundred thirty-three (28.0%) of 476 patients had a high signal lesion on diffusion-weighted imaging of whom 115 (86.5%) had a minor stroke and 18 (13.5%) a transient ischemic attack. Interobserver agreement (kappa statistic) on the territory ranged from 0.46 to 0.60. The agreement with diffusion-weighted imaging was only moderate (observer 1: kappa=0.54, 95% CI=0.36 to 0.72; observer 2: 0.48, 0.31 to 0.64; observer 3: 0.48, 0.28 to 0.67). Only the presence of visual symptoms improved the accuracy of the vascular territory diagnosis (range of kappa: 0.63 to 0.77) but not the presence of motor, speech, or sensory symptoms. Sensitivity and specificity for the diagnosis of vertebrobasilar territory ranged between 54.2% and 70.8% and 84.4% to 91.7%, respectively. CONCLUSIONS: The reliability of clinical diagnosis of the vascular territory is only moderate, highlighting the importance of sensitive brain imaging after transient ischemic attack or minor stroke. Further imaging-based research is required to determine the optimal clinical diagnostic criteria for classification of the vascular territory.

Critical cap thickness and rupture in symptomatic carotid plaques: the oxford plaque study.

BACKGROUND AND PURPOSE: Advances in carotid plaque imaging could allow quantification of fibrous cap thickness in vivo. While a cap thickness <65 microm is the accepted definition of rupture-prone plaque in the coronary circulation, the threshold value for carotid plaques is unknown. METHODS: We made detailed histological assessments of 526 carotid plaques from consecutive patients undergoing endarterectomy for symptomatic carotid stenosis. The thickness of the fibrous cap at the thinnest and most representative part was measured. RESULTS: Cap thickness could be measured reliably in 428 (81%) plaques. In the ruptured plaques (n=257), the median representative cap thickness was 300 microm (IQR 200 to 500 microm) and the median minimum cap thickness was 150 microm (80 to 210 microm; mean=181 microm), which is much greater than the mean cap thickness of 23 microm at the point of rupture that has been reported for coronary plaques. For nonruptured plaques, the median cap thickness values were 500 microm (300 to 700 microm) and 250 microm (180 to 400 microm), respectively. The optimum cut-offs for discriminating between ruptured and nonruptured plaques were a minimum cap thickness <200 microm (OR 5.00, 3.26 to 7.65, P<0.001), a representative cap thickness <500 microm (OR 3.38, 2.25 to 5.08, P<0.001), or a combination of both (OR 5.11, 3.19 to 8.19, P<0.001). Minimum and representative cap thickness were only modestly correlated (r(2)=0.30) and were both independently associated with cap rupture. CONCLUSIONS: Critical cap thickness is greater in carotid plaques than coronary plaques. Minimum and representative cap thicknesses were both independently associated with cap rupture. A combination of minimum cap thickness <200 microm and a representative cap thickness <500 microm identified ruptured plaques most reliably. Prospective imaging studies are required to establish whether these cut points predict clinical events in patients with asymptomatic carotid stenosis.

Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.

BACKGROUND: The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80-90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital. METHODS: We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical attention, with independent blinded (to study period) audit of all events. FINDINGS: Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2-5) days in phase 1 to less than 1 (0-3) day in phase 2 (p<0.0001), and median delay to first prescription of treatment fell from 20 (8-53) days to 1 (0-3) day (p<0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08-0.49; p=0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding. INTERPRETATION: Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.

Systematic review of associations between the presence of acute ischemic lesions on diffusion-weighted imaging and clinical predictors of early stroke risk after transient ischemic attack.

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.

Asymptomatic carotid stenosis: what to do.

PURPOSE OF REVIEW: Patients with asymptomatic carotid stenosis are at increased vascular risk but optimal treatment is controversial. We reviewed the current evidence for medical and surgical intervention in these patients. RECENT FINDINGS: Optimal medical treatment is the most important aspect of management of patients with asymptomatic carotid stenosis. On the basis of previous trials, endarterectomy is only of overall benefit in men, and this benefit may now be obviated by improved medical treatment. There is insufficient evidence to advocate the routine use of carotid angioplasty or stenting in patients with asymptomatic stenosis. Inaccuracy in the measurement of carotid stenosis may contribute to conflicting estimates of stroke risk in relation to the degree of asymptomatic stenosis. Advances in noninvasive imaging of plaque morphology and inflammation and the detection of microembolic signals may help to risk stratify patients but data on clinical usefulness are lacking. SUMMARY: Absolute benefit from endarterectomy for asymptomatic carotid stenosis is small, but can sometimes be justified in men. Further research is required to determine long-term benefit in women and to risk stratify patients, particularly in the light of advances in medical treatment.