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.

Vagus Nerve Stimulation in Ischemic Stroke.

PURPOSE OF REVIEW: Vagus nerve stimulation (VNS) has emerged as a potential therapeutic approach for neurological and psychiatric disorders. In recent years, there has been increasing interest in VNS for treating ischemic stroke. This review discusses the evidence supporting VNS as a treatment option for ischemic stroke and elucidates its underlying mechanisms. RECENT FINDINGS: Preclinical studies investigating VNS in stroke models have shown reduced infarct volumes and improved neurological deficits. Additionally, VNS has been found to reduce reperfusion injury. VNS may promote neuroprotection by reducing inflammation, enhancing cerebral blood flow, and modulating the release of neurotransmitters. Additionally, VNS may stimulate neuroplasticity, thereby facilitating post-stroke recovery. The Food and Drug Administration has approved invasive VNS (iVNS) combined with rehabilitation for ischemic stroke patients with moderate to severe upper limb deficits. However, iVNS is not feasible in acute stroke due to its time-sensitive nature. Non-invasive VNS (nVNS) may be an alternative approach for treating ischemic stroke. While the evidence from preclinical studies and clinical trials of nVNS is promising, the mechanisms through which VNS exerts its beneficial effects on ischemic stroke are still being elucidated. Therefore, further research is needed to better understand the efficacy and underlying mechanisms of nVNS in ischemic stroke. Moreover, large-scale randomized clinical trials are necessary to determine the optimal nVNS protocols, assess its long-term effects on stroke recovery and outcomes, and identify the potential benefits of combining nVNS with other rehabilitation strategies.

Antiplatelet Use in Ischemic Stroke.

OBJECTIVE: A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. DATA SOURCES: Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors. STUDY SELECTION AND DATA EXTRACTION: English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors. DATA SYNTHESIS: An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed. CONCLUSIONS: Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.

Effect of Exercise Interventions on Health-Related Quality of Life After Stroke and Transient Ischemic Attack: A Systematic Review and Meta-Analysis.

Exercise interventions have been shown to help physical fitness, walking, and balance after stroke, but data are lacking on whether such interventions lead to improvements in health-related quality of life (HRQoL). In this systematic review and meta-analysis, 30 randomized controlled trials (n=1836 patients) were found from PubMed, OVID MEDLINE, Web of Science, CINAHL, SCOPUS, The Cochrane Library, and TRIP databases when searched from 1966 to February 2020 that examine the effects of exercise interventions on HRQoL after stroke or transient ischemic attack. Exercise interventions resulted in small to moderate beneficial effects on HRQoL at intervention end (standardized mean difference, -0.23 [95% CI, -0.40 to -0.07]) that appeared to diminish at longer-term follow-up (standardized mean difference, -0.11 [95% CI, -0.26 to 0.04]). Exercise was associated with moderate improvements in physical health (standardized mean difference, -0.33 [95% CI, -0.61 to -0.04]) and mental health (standardized mean difference, -0.29 [95% CI, -0.49 to -0.09]) domains of HRQoL while effects on social or cognitive composites showed little difference. Interventions that were initiated within 6 months, lasted at least 12 weeks in duration, involved at least 150 minutes per week, and included resistance training appeared most effective. Exercise can lead to moderate beneficial effects on HRQoL and should be considered an integral part of stroke rehabilitation.

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.

The neurology of space flight; How does space flight effect the human nervous system?

RATIONALE AND HYPOTHESIS: Advancements in technology, human adaptability, and funding have increased space exploration and in turn commercial spaceflight. Corporations such as Space X and Blue Origin are exploring methods to make space tourism possible. This could lead to an increase in the number of patients presenting with neurological diseases associated with spaceflight. Therefore, a comprehensive understanding of spaceflight stressors is required to manage neurological disease in high-risk individuals. OBJECTIVES: This review aims to describe the neurological effects of spaceflight and to assess countermeasures such as pre-flight prophylaxis, training, and possible therapeutics to reduce long-term effects. METHODOLOGY: A literature search was performed for experimental studies conducted in astronauts and in animal models that simulated the space environment. Many studies, however, only discussed these with scientific reasoning and did not include any experimental methods. Relevant studies were identified through searching research databases such as PubMed and Google Scholar. No inclusion or exclusion criteria were used. FINDINGS: Analysis of these studies provided a holistic understanding of the acute and chronic neurological changes that occur during space flight. Astronauts are exposed to hazards that include microgravity, cosmic radiation, hypercapnia, isolation, confinement and disrupted circadian rhythms. Microgravity, the absence of a gravitational force, is linked to disturbances in the vestibular system, intracranial and intraocular pressures. Furthermore, microgravity affects near field vision as part of the spaceflight-associated neuro-ocular syndrome. Exposure to cosmic radiation can increase the risk of neurodegenerative conditions and malignancies. It is estimated that cosmic radiation has significantly higher ionising capabilities than the ionising radiation used in medicine. Space travel also has potential benefits to the nervous system, including psychological development and effects on learning and memory. Future work needs to focus on how we can compare a current astronaut to a future space tourist. Potentially the physiological and psychological stresses of space flight might lead to neurological complications in future space travellers that do not have the physiological reserve of current astronauts.

Anesthetic Management of Emergency Insulinoma Resection: Case Report and Review of Literature.

Insulinoma, a neuroendocrine tumor originating from pancreatic islets, presents unique challenges in diagnosis and management. We present a case of a 73-year-old female with recurrent hypoglycemia leading to syncope, who underwent emergency pancreatectomy for a secreting insulinoma with multiple comorbidities. This case report aims to shed light on the complexities of insulinoma management and the importance of tailored perioperative strategies. The patient, presenting with severe hypoglycemia, was admitted for optimization. Preoperative assessment labeled her as ASA IVE and indicated a high risk of perioperative morbidity. General anesthesia, invasive monitoring, and epidural anesthesia were planned. Intraoperative glucose control was crucial, achieved with continuous blood glucose monitoring, octreotide administration, and insulin titration. The patient was extubated post-surgery, and pain was managed with epidural infusion. She was discharged on the 4th postoperative day with follow-up care. Insulinoma diagnosis relies on clinical, biochemical, and imaging tests, with 72-hour fasting as the gold standard. Localizing the tumor within the pancreas is essential for surgical success, often requiring invasive techniques. Surgical resection remains the definitive treatment, while medical management may be necessary in select cases. Anesthetic management should prioritize agents that minimize the cerebral metabolic rate for oxygen. Careful intraoperative glucose control and vigilant postoperative monitoring are essential. This case report highlights the intricate management of insulinoma, emphasizing tailored perioperative strategies that balance glucose regulation, anesthesia techniques, and postoperative care. However, the limited existing literature underscores the need for further research to refine anesthesia protocols, glucose control methods, and postoperative care, ultimately improving outcomes for patients with insulinoma.

Effect of Remote Ischemic Conditioning on Heart Rate Responses to Walking in People with Multiple Sclerosis.

Background: Remote ischemic conditioning (RIC), exposure of body parts to brief periods of circulatory occlusion and reperfusion, has been shown to improve cardiovascular responses to exercise in healthy individuals but its effects in people with MS are unknown. Objective: This study aimed to assess the effect of RIC on heart rate responses to walking in people with MS. Design: Double blind randomized controlled trial. Setting: Multiple sclerosis clinic of tertiary care center teaching hospital in the United Kingdom. Methods: Three cycles of RIC were delivered by occluding the upper arm with a blood pressure cuff inflated to a pressure of 30 mmHg above the systolic blood pressure. In the sham group, the blood pressure cuff was inflated to 30 mmHg below diastolic blood pressure. Heart rate responses to the 6-minute walk test (6MWT), the tolerability of RIC using a numerical rating scale for discomfort (0-10), and adverse events were studied. Results: Seventy-five participants (RIC -38 and Sham-37) completed the study. RIC was well tolerated. Compared to sham, RIC significantly decreased the rise in heart rate (P = 0.04) and percentage of predicted maximum heart rate (P = 0.016) after the 6MWT. Conclusion: RIC was well tolerated and improved the heart rate response to walking in people with MS. Further studies on RIC in the management of MS are needed.

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.

Remote ischaemic conditioning for stroke: unanswered questions and future directions.

Remote ischaemic conditioning (RIC) refers to a process whereby periods of intermittent ischaemia, typically via the cyclical application of a blood pressure cuff to a limb at above systolic pressure, confers systemic protection against ischaemia in spatially distinct vascular territories. The mechanisms underlying this have not been characterised fully but have been shown to involve neural, hormonal and systemic inflammatory signalling cascades. Preclinical and early clinical studies have been promising and suggest beneficial effects of RIC in acute ischaemic stroke, symptomatic intracranial stenosis and vascular cognitive impairment. Through systematic searches of several clinical trials databases we identified 48 active clinical trials of RIC in ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage. We summarise the different RIC protocols and outcome measures studied in ongoing clinical trials and highlight which studies are most likely to elucidate the underlying biological mechanisms of RIC and characterise its efficacy in the near future. We discuss the uncertainties of RIC including the optimal frequency and duration of therapy, target patient groups, cost-effectiveness, the confounding impact of medications and the absence of a clinically meaningful biomarker of the conditioning response. With several large clinical trials of RIC expected to report their outcomes within the next 2 years, this review aims to highlight the most important studies and unanswered questions that will need to be addressed before this potentially widely accessible and low-cost intervention can be used in clinical practice.

Exercise referral to promote cardiovascular health in stroke and TIA patients: a pilot feasibility study.

OBJECTIVES: Exercise programmes studied after stroke often involve specialist supervision. Determine the feasibility and safety for people with stroke (PwS) or transient ischaemic attack (TIA) participating in readily accessible, non-stroke specialised, community-based exercise programmes. METHODS: Participants were recruited into a structured, group-based, 12-week programme of aerobic and resistance exercise delivered two times per week at one of five local leisure centres. Completion rates, successful attainment of intended exercise intensity (Borg Rating of Perceived Exertion (RPE)) and safety outcomes were recorded. Measures of physical activity (International Physical Activity Questionnaire), health-related quality of life (EQ-5D) and blood pressure (BP) were recorded at baseline and day 1 post intervention. RESULTS: 79% of participants completed >75% of the intended sessions, with >90% attainment of intended RPE. Exercise was safe with no serious and very few minor adverse events related to exercise. Exercise led to significant increases in EQ-5D (Best of Health p<0.001), levels of weekly moderate physical activity (p<0.001) and decreases in systolic BP (mean change [95% CI]=-5.4 mmHg [-2.84 to -7.96]; p<0.001). CONCLUSION: Generalised exercise programmes delivered through existing local services, appears feasible, safe and may improve quality of life, physical activity and systolic BP, for PwS and TIA.

22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium.

This corrects the article DOI: 10.1038/ejhg.2016.36.

The global prevalence of Huntington's disease: a systematic review and discussion.

The ascertained prevalence of Huntington's disease (HD) increased significantly following the provision of diagnostic testing. A systematic review was conducted to estimate the prevalence of HD in the post-diagnostic testing era. 22 studies with original data pertaining to the prevalence of HD (1993-2015) were included and analyzed. A global meta-analysis was not performed due to heterogeneity in study methods and geographical variation. The prevalence of HD is significantly lower in Asian populations compared with western Europe, North America and Australia. The global variation in HD prevalence is partly explained by the average CAG repeat lengths and frequency of different HTT gene haplotypes in the general population. Understanding the prevalence of HD has significant implications for healthcare resource planning.

22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium.

Huntington's disease (HD) is a progressive neurodegenerative condition. At-risk individuals have accessed predictive testing via direct mutation testing since 1993. The UK Huntington's Prediction Consortium has collected anonymised data on UK predictive tests, annually, from 1993 to 2014: 9407 predictive tests were performed across 23 UK centres. Where gender was recorded, 4077 participants were male (44.3%) and 5122 were female (55.7%). The median age of participants was 37 years. The most common reason for predictive testing was to reduce uncertainty (70.5%). Of the 8441 predictive tests on individuals at 50% prior risk, 4629 (54.8%) were reported as mutation negative and 3790 (44.9%) were mutation positive, with 22 (0.3%) in the database being uninterpretable. Using a prevalence figure of 12.3 × 10(-5), the cumulative uptake of predictive testing in the 50% at-risk UK population from 1994 to 2014 was estimated at 17.4% (95% CI: 16.9-18.0%). We present the largest study conducted on predictive testing in HD. Our findings indicate that the vast majority of individuals at risk of HD (>80%) have not undergone predictive testing. Future therapies in HD will likely target presymptomatic individuals; therefore, identifying the at-risk population whose gene status is unknown is of significant public health value.

Major geographical variations in elective coronary revascularization by stents or surgery in England.

OBJECTIVES: Revascularization in stable coronary artery disease (CAD) can be achieved through percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) depending on the anatomical pattern of CAD, comorbidities and patient preference. Recent studies in the USA, Canada and Australia show marked local variation in the PCI/CABG ratio that is unexplained by patient-related factors. This current study assesses the geographical variation in elective coronary revascularization interventions across England and discusses its appropriateness. METHODS: The rates and actual procedure numbers of total CABG, total PCIs and elective PCIs were collated for each of 151 primary care trusts (PCTs). The 'elective PCI/total CABG ratio' was taken as an indicator of elective coronary revascularization practices. The Index of Multiple Deprivation (IMD) for PCTs was taken as a marker of deprivation. RESULTS: In 2010/2011, the degree of variation in elective PCI/total CABG ratios across 151 PCTs in England was >13-fold (min = 0.36, max = 4.74, median = 1.19, interquartile range = 0.98, 1.73). The ratio was not correlated to the IMD 2010 rank of the PCTs (Spearman's ρ = 0.08, P = 0.36) and was not explained by the volume of interventions performed. CONCLUSIONS: Despite clear evidence-based guidelines for intervention, marked geographical variation in elective coronary revascularization practices also exists in England. This variation is unexplained by procedure volume or deprivation, suggesting the contribution of unwarranted influences which may include practitioner preference. To reduce this level of unwarranted variation, we suggest that all interventions should be underpinned by internationally recognized guidelines or approved by a multidisciplinary team approach (The Heart Team).