Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults-A Worldwide Meta-analysis: The GOAL Initiative.

BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Effects of Spinal Cord Stimulation on Heart Rate Variability in Patients With Failed Back Surgery Syndrome: Comparison Between a 2-lead ECG and a Wearable Device.

OBJECTIVES: Heart rate variability recordings have the potential to examine the role of the autonomic nervous system. Several wearable devices are nowadays readily available. Up until now, no studies explored whether a wearable device is able to reliably measure a treatment response in chronic pain patients. Therefore, the aim of this study is to evaluate the reliability of a Polar V800 (Polar Electro Oy, Finland) wearable device to accurately measure RR intervals in patients with failed back surgery syndrome (FBSS) during spinal cord stimulation (SCS), as compared with an eMotion 2-lead ECG recording. MATERIALS AND METHODS: Twenty-two patients diagnosed with FBSS and treated with SCS participated in this study. HRV was measured with a 2-lead ECG registration tool and a Polar V800 during on and off state of SCS. Intraclass correlation coefficients, correlations, limits of agreement, Cronbach's α, and effect sizes were calculated. RESULTS: Analysis based on the recordings from the ECG and wearable device revealed the same HRV parameters (except for the time-frequency domain) to capture the treatment response of SCS. Parameters that are relevant for measuring the SCS treatment response have strong correlations (r ≥ .82), good ICC values (ICC ≥0.82), acceptable consistency (α ≥ .9), and limited bias. CONCLUSIONS: Similar pre- to posttreatment changes were revealed between a wearable device and 2-lead ECG with reliable HRV estimates for parameters that are able to capture the treatment changes. This suggests that a wearable heart rate monitor might be a reliable wearable tool for the detection of pre- to post treatment changes of SCS, in patients with FBSS.

The Long-Term Response to High-Dose Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome After Conversion From Standard Spinal Cord Stimulation: An Effectiveness and Prediction Study.

OBJECTIVES: Spinal cord stimulation (SCS) is nowadays available with several stimulation paradigms. New paradigms, such as high dose (HD-)SCS, have shown the possibility to salvage patients who lost their initial pain relief. The first aim of this study is to evaluate the effectiveness of HD-SCS after conversion from standard SCS. The second aim is to develop a model for prediction of long-term response of HD-SCS after unsatisfactory standard SCS. MATERIALS AND METHODS: Seventy-eight patients with failed back surgery syndrome (FBSS) who are treated with standard SCS were enrolled in the study. Self-reporting questionnaires and outcomes were assessed before conversion and at 1, 3, and 12 months of HD-SCS. Longitudinal mixed models were used to determine the effectiveness of HD-SCS. Logistic regression and classification and decision tree analyses were performed to predict responders (NRS decrease ≥2/10) after 12 months of HD-SCS. RESULTS: Significant time effects were found for both low back and leg pain responders, suggesting the effectiveness of HD-SCS after conversion. Logistic regression models revealed the importance of pain intensity scores, medication use, paresthesia coverage (for back pain) and EQ5D (for leg pain) as predictors for being a responder after 12 months of HD-SCS. CONCLUSIONS: Converting patients with unsatisfactory responses from standard SCS to HD-SCS may be an effective strategy to obtain and maintain pain relief in a challenging subgroup of patients with FBSS refractory to standard SCS. The prediction models may guide clinicians in their decision making when considering conversion to HD-SCS in patients with FBSS experiencing inadequate response to standard SCS.

The relationship between Home-time, quality of life and costs after ischemic stroke: the impact of the need for mobility aids, home and car modifications on Home-time.

Purpose: Home-time (the number of days spent at home during the first 3 months after stroke) shows a strong association with the modified Rankin scale (mRS). We studied whether Home-time was also a determinant of quality-of-life and medical care costs after ischemic stroke, and assessed factors delaying discharge home.Materials and methods: Five hundred and sixty nine patients participated in a retrospective study when returning for an in-person visit after an ischemic stroke. Home-time, mRS, EQ-5D-3L, inpatient and outpatient resource utilization, use of mobility aids, changes to home and car, comorbidities were recorded.Results: Each additional Home-time day was significantly associated with an increase in utility of 0.0056 (p < 0.0001) and an in- and outpatient cost saving of $99 (p = 0.0158). Requiring extra material support significantly decreased Home-time by 76 days (including: requiring home changes: -68 days, car alterations: -49 days, needing a wheelchair: -80 days or walker: -71 days, needing bed or bath rails: -79 days). This univariable effect was confirmed in multivariable analysis when comparing with patients having the same disability level without requiring material support.Conclusions: Home-time is a stroke outcome associated with disease severity, healthcare costs and patient wellbeing. Streamlining the discharge process for those requiring extra material support may lead to cost savings and higher quality-of-life.Implications for rehabilitationDelays in discharge from the acute hospital or rehabilitation facility are incurred when patients need extra material support in order to return home.Staff from the discharging facility should assist families by giving timely information on the availability and the cost of wheel chairs and walkers; and explaining and planning the need of a stair lift, bed and bath rails as well as car modifications.Planning the discharge process with the families will lead to a more rapid return home and will result in reduced overall health care costs and higher quality of life for the patients.

Global Outcome Assessment Life-long after stroke in young adults initiative-the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis.

INTRODUCTION: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients. METHODS AND ANALYSIS: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence. ETHICS AND DISSEMINATION: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.

Interventions to promote work participation after ischaemic stroke: A systematic review.

Only a disappointingly low proportion of patients successfully engage in professional activities after ischaemic stroke. This systematic review maps all contemporary evidence regarding interventions aiming to promote return-to-work in survivors of ischaemic stroke. We performed a search according to Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines and searched five reference databases. Prospective trial registers and grey literature were also assessed, and we executed backwards and forward reference searching. The study protocol was registered in PROSPERO (CRD42017077796). The search yielded 444 records of which 174 were duplicates. Backward and forward reference searching resulted in 808 unique records. Eleven articles were retained for full-text analysis and two met the selection criteria. A controlled before-after study showed beneficial effects of intravenous thrombolytic treatment in patients with moderate to severe acute ischaemic stroke. A retrospective study with low methodological quality reported improved vocational outcome of an outpatient rehabilitation program in patients with mild to moderate ischaemic stroke. We conclude that there currently is insufficient evidence regarding the effectiveness of interventions to promote return-to-work in patients with ischaemic stroke, though intravenous thrombolytic therapy has shown beneficial effects and there are indications that rehabilitation programs may also be advantageous.

Effects of spinal cord stimulation on heart rate variability in patients with Failed Back Surgery Syndrome.

BACKGROUND: Building on the recent finding that chronic pain patients with impaired functioning of the descending nociceptive inhibitory system (DNIS) present lower resting heart rate variability (HRV), this study aims to investigate the impact of Spinal Cord Stimulation (SCS) on HRV in patients with Failed Back Surgery Syndrome (FBSS). More precisely, we hypothesize that SCS influences the DNIS, with increased parasympathetic tone as a consequence, as measurable by HRV analysis. METHODS: Twenty-two patients diagnosed with FBSS and treated with SCS participated in this study. HRV was measured with a 2-lead ECG registration tool during on and off states of SCS. HRV analysis for time, frequency, time-frequency and nonlinear domain parameters was based on a 5-minute recording segment. RESULTS: The mean heart rate and low frequency power were significantly lower when SCS was activated. HRV, absolute and normalized high frequency power significantly increased during SCS compared to without SCS. The ratio of low frequency/high frequency ratios, as parameter for global sympathetic-parasympathetic equilibrium, significantly decreased when SCS was activated. CONCLUSIONS: When SCS is switched off, patients with FBSS present relatively stronger sympathetic tone and weaker parasympathetic activity. Activation of the SCS, possibly via stimulation of the DNIS, restores this disbalance of autonomic activity.

Association Between Spinal Cord Stimulation and Top-Down Nociceptive Inhibition in People With Failed Back Surgery Syndrome: A Cohort Study.

BACKGROUND: Descending nociceptive inhibitory pathways often malfunction in people with chronic pain. Conditioned pain modulation (CPM) is an experimental evaluation tool for assessing the functioning of these pathways. Spinal cord stimulation (SCS), a well-known treatment option for people with failed back surgery syndrome (FBSS), probably exerts its pain-relieving effect through a complex interplay of segmental and higher-order structures. OBJECTIVE: To the best of our knowledge, no clinical studies have thoroughly investigated the associations between SCS and CPM. DESIGN: This was a prospective cohort study in people with FBSS. METHODS: Seventeen people who had FBSS and were scheduled for SCS were enrolled in this study. The CPM model was evaluated at both sural nerves and was induced by electrical stimulation as the test stimulus and the cold pressor test as the conditioning stimulus. RESULTS: Before SCS, less than 30% of the participants with FBSS showed a CPM effect. Significant increases in the electrical detection threshold on the symptomatic side and the nonsymptomatic side were found. On the symptomatic side, no differences in the numbers of CPM responders before and after SCS could be found. On the nonsymptomatic side, more participants showed a CPM effect during SCS. Additionally, there were significant differences for CPM activation and SCS treatment. LIMITATIONS: Limitations were the small sample size and the subjective outcome parameters in the CPM model. CONCLUSIONS: This study revealed a bilateral effect of SCS that suggests the involvement of higher-order structures, such as the periaqueductal gray matter and rostroventromedial medulla (key regions in the descending pathways), as previously suggested by animal research.

The combined impact of dependency on caregivers, disability, and coping strategy on quality of life after ischemic stroke.

BACKGROUND: To estimate the additional impact of coping and of being dependent on caregivers, over and above the large effects of disability on utility after ischemic stroke. METHODS: A total of 539 patients were recruited into an observational, retrospective study when returning for a check-up between 3 and 36 months after an ischemic stroke. Patients' modified Rankin Scale (mRS), dependency on caregivers, the Brandtstädter and Renner Coping questionnaire (with summary scores: Tenacity of Goal Pursuit (TGP) and Flexible Goal Adjustment (FGA) coping styles), EQ-5D-3 L and co-morbidities were evaluated. RESULTS: In multivariable regression, greater disability (mRS) resulted in large utility losses, between 0.06 for mRS 1 to 0.65 for mRS 5 (p < 0.0001). Dependency on caregivers caused an additional dis-utility of 0.104 (p = 0.0006) which varied by mRS (0.044, 0.060, 0.083, 0.115, 0.150 and 0.173 for mRS 0-5). The effect of coping on utility varied by coping style, by the disability level of the patient and by his or her dependency on caregivers. FGA coping was associated with additional increases in utility (p < 0.0001) over and above the effect of disability and dependency, whereas TGA had no significant impact. FGA coping was associated with larger utility changes among more disabled patients (0.018 to 0.105 additional utility, for mRS 0 to mRS 5 respectively). Dependent patients had more to gain from FGA coping than patients who function independently of caregivers: utility gains were between 0.049 and 0.072 for moderate to high levels of FGA coping. In contrast, the same positive evolution in FGA coping resulted in 0.039 and 0.057 utility gain among independent patients. Finally, we found that important stroke risk factors and co-morbidities, such as diabetes and atrial fibrillation, were not predictors of EQ-5D utility in a multivariable setting. CONCLUSIONS: This study suggests that treatment strategies targeting flexible coping styles and decreasing dependency on caregivers may lead to significant gains in quality of life above and beyond treatment strategies that solely target disability.

Health Economic Evaluations of Digital Health Interventions for Secondary Prevention in Stroke Patients: A Systematic Review.

BACKGROUND: In the first 5 years after their stroke, about a quarter of patients will suffer from a recurrent stroke. Digital health interventions facilitating interactions between a caregiver and a patient from a distance are a promising approach to improve patient adherence to lifestyle changes proposed by secondary prevention guidelines. Many of these interventions are not implemented in daily practice, even though efficacy has been shown. One of the reasons can be the lack of clear economic incentives for implementation. We propose to map all health economic evidence regarding digital health interventions for secondary stroke prevention. SUMMARY: We performed a systematic search according to PRISMA-P guidelines and searched on PubMed, Web of Science, Cochrane, and National Institute for Health Research Economic Evaluation Database. Only digital health interventions for secondary prevention in stroke patients were included and all study designs and health economic outcomes were accepted. We combined the terms "Stroke OR Cardiovascular," "Secondary prevention," "Digital health interventions," and "Cost" in one search string using the AND operator. The search performed on April 20, 2017 yielded 163 records of which 26 duplicates were removed. After abstract screening, 20 articles were retained for full-text analysis, of which none reported any health economic evidence that could be included for analysis or discussion. Key Messages: There is a lack of evidence on health economic outcomes on digital health interventions for secondary stroke prevention. Future research in this area should take health economics into consideration when designing a trial and there is a clear need for health economic evidence and models.

Return to Work of Patients Treated With Spinal Cord Stimulation for Chronic Pain: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic pain has a substantial negative impact on work-related outcomes, which underscores the importance of interventions to reduce the burden. Spinal cord stimulation (SCS) efficiently causes pain relief in specific chronic pain syndromes. The aim of this review was to identify and summarize evidence on returning to work in patients with chronic pain treated with SCS. MATERIALS AND METHODS: A systematic literature review was performed including studies from PubMed, EMBASE, SCOPUS, and Web of Science (up till October 2017). Risk of bias was assessed using a modified version of the Downs & Black checklist. Where possible, we pooled data using random effects meta-analysis. The study protocol was registered prior to initiation of the review process (PROSPERO CRD42017077803). RESULTS: Fifteen full-text articles (total articles screened: 2835) were included. Risk of bias for these articles was scored low. Seven trials provided sufficient data and were judged similar enough to be pooled for meta-analysis on binary outcomes. SCS intervention results in a higher prevalence of patients at work compared with before treatment (odds ratio [OR] 2.15; 95% confidence interval [CI], 1.44-3.21; I2 = 42%; p < 0.001). SCS treatment also results in high odds to return to work (OR 29.06; 95% CI, 9.73-86.75; I2 = 0%; p < 0.001). CONCLUSIONS: Based on available literature, SCS proved to be an effective approach to stimulate return to work in patients with specific chronic pain syndromes.

Cerebral Biochemical Effect of Pregabalin in Patients with Painful Diabetic Neuropathy: A Randomized Controlled Trial.

INTRODUCTION: With the development of new neuroimaging tools it has become possible to assess neurochemical alterations in patients experiencing chronic pain and to determine how these factors change during pharmacological treatment. The goal of this study was to examine the exact neurochemical mechanism underlying pregabalin treatment, utilizing magnetic resonance spectroscopy (1H-MRS), in a population of patients with painful diabetic polyneuropathy (PDN), with the overall aim to ultimately objectify the clinical effect of pregabalin. METHODS: A double blind, randomized, placebo-controlled study was conducted. A total of 27 patients with PDN were enrolled in the study, of whom 13 received placebo treatment (control group) and 14 received pregabalin (intervention group). Pregabalin treatment consisted of stepwise dose escalation over the study period from 75 mg daily ultimately to 600 mg daily. 1H-MRS was performed at 3T on four regions of interest in the brain: the rostral anterior cingulate cortex (rACC), left and right thalamus and prefrontal cortex. The absolute concentrations of N-acetyl aspartate, glutamate, glutamine, gamma-amino-butyric-acid (GABA), glucose (Glc) and myo-inositol (mINS) were determined using LCModel. RESULTS: The concentration of most neurometabolites in the placebo and pregabalin group did not significantly differ over time, with only a small significant difference in Glc level in the left thalamus (p = 0.049). Comparison of the effects of the different doses revealed significant differences for mINS in the rACC (baseline 2.42 ± 1.21 vs. 450 mg 1.58 ± 0.94; p = 0.022) and dorsolateral prefrontal cortex (75 mg 2.38 ± 0.89 vs. 450 mg 1.59 ± 0.85; p = 0.042) and also for GABA in the rACC (75 mg 0.53 ± 0.51 vs. 225 mg 0.28 ± 0.19; p = 0.014). CONCLUSION: No differences were found in metabolite concentrations between the placebo (control) and intervention groups, but some differences, although small, were found between the different doses. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT01180608). FUNDING: Lyrica Independent Investigator Research Award (LIIRA) 2010 (Pfizer) funded the study.

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

BACKGROUND: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. RESULTS: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. CONCLUSIONS: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.

Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study.

BACKGROUND: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients. OBJECTIVES: We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated. STUDY DESIGN: A controlled, randomized cross-over trial. SETTING: University Hospital Brussels. METHODS: Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties. RESULTS: There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01). LIMITATIONS: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises. CONCLUSION: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise. KEY WORDS: Chronic pain, physical exercise, emotional stress, pain modulation, cardiovascular systems, temporal summation, pain pressure thresholds, transcranial Doppler, plethysmography.

Time Gain Needed for In-Ambulance Telemedicine: Cost-Utility Model.

BACKGROUND: Stroke is a very time-sensitive pathology, and many new solutions target the optimization of prehospital stroke care to improve the stroke management process. In-ambulance telemedicine, defined by live bidirectional audio-video between a patient and a neurologist in a moving ambulance and the automated transfer of vital parameters, is a promising new approach to speed up and improve the quality of acute stroke care. Currently, no evidence exists on the cost effectiveness of in-ambulance telemedicine. OBJECTIVE: We aim to develop a first cost effectiveness model for in-ambulance telemedicine and use this model to estimate the time savings needed before in-ambulance telemedicine becomes cost effective. METHODS: Current standard stroke care is compared with current standard stroke care supplemented with in-ambulance telemedicine using a cost-utility model measuring costs and quality-adjusted life-years (QALYs) from a health care perspective. We combine a decision tree with a Markov model. Data from the UZ Brussel Stroke Registry (2282 stroke patients) and linked hospital claims data at individual level are combined with literature data to populate the model. A 2-way sensitivity analysis varying both implementation costs and time gain is performed to map the different cost-effective combinations and identify the time gain needed for cost effectiveness and dominance. For several modeled time gains, the cost-effectiveness acceptability curve is calculated and mapped in 1 figure. RESULTS: Under the base-case scenario (implementation cost of US $159,425) and taking a lifetime horizon into account, in-ambulance telemedicine is a cost-effective strategy compared to standard stroke care alone starting from a time gain of 6 minutes. After 12 minutes, in-ambulance telemedicine becomes dominant, and this results in a mean decrease of costs by US -$30 (95% CI -$32 to -$29) per patient with 0.00456 (95% CI 0.00448 to 0.00463) QALYs on average gained per patient. In over 82% of all probabilistic simulations, in-ambulance telemedicine remains under the cost-effectiveness threshold of US $47,747. CONCLUSIONS: Our model suggests that in-ambulance telemedicine can be cost effective starting from a time gain of 6 minutes and becomes a dominant strategy after approximately 15 minutes. This indicates that in-ambulance telemedicine has the potential to become a cost-effective intervention assuming time gains in clinical implementations are realized in the future.

Cortical mapping of painful electrical stimulation by quantitative electroencephalography: unraveling the time-frequency-channel domain.

The goal of this study was to capture the electroencephalographic signature of experimentally induced pain and pain-modulating mechanisms after painful peripheral electrical stimulation to determine one or a selected group of electrodes at a specific time point with a specific frequency range. In the first experiment, ten healthy participants were exposed to stimulation of the right median nerve while registering brain activity using 32-channel electroencephalography. Electrical stimulations were organized in four blocks of 20 stimuli with four intensities - 100%, 120%, 140%, and 160% - of the electrical pain threshold. In the second experiment, 15 healthy participants received electrical stimulation on the dominant median nerve before and during the application of a second painful stimulus. Raw data were converted into the time-frequency domain by applying a continuous wavelet transform. Separated domain information was extracted by calculating Parafac models. The results demonstrated that it is possible to capture a reproducible cortical neural response after painful electrical stimulation, more specifically at 250 milliseconds poststimulus, at the midline electrodes Cz and FCz with predominant δ-oscillations. The signature of the top-down nociceptive inhibitory mechanisms is δ-activity at 235 ms poststimulus at the prefrontal electrodes. This study presents a methodology to overcome the a priori determination of the regions of interest to analyze the brain response after painful electrical stimulation.

Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke.

BACKGROUND: While neurogranin has no value as plasma biomarker for Alzheimer's disease, it may be a potential blood biomarker for traumatic brain injury. This evokes the question whether there are changes in neurogranin levels in blood in other conditions of brain injury, such as acute ischemic stroke (AIS). METHODS: We therefore explored neurogranin in paired cerebrospinal fluid (CSF)/plasma samples of AIS patients (n = 50) from a well-described prospective study. In parallel, we investigated another neuronal protein, i.e. tau, which has already been suggested as potential AIS biomarker in CSF and blood. ELISA as well as Single Molecule Array (Simoa) technology were used for the biochemical analyses. Statistical analyses included Shapiro-Wilk testing, Mann-Whitney analyses and Pearson's correlation analysis. RESULTS: In contrast to tau, of which high levels in both CSF and plasma were related to stroke characteristics like severity and long-term outcome, plasma neurogranin levels were only correlated with infarct volume. Likewise, CSF neurogranin levels were significantly higher in patients with an infarct volume > 5 mL than in patients with smaller infarct volumes. Finally, neurogranin and tau were significantly correlated in CSF, whereas a weaker relationship was observed in plasma. CONCLUSIONS: These findings indicate that although plasma and CSF neurogranin may reflect the volume of acute cerebral ischemia, this synaptic protein is less likely to be a potential AIS biomarker. Levels of tau correlated with severity and outcome of stroke in both plasma and CSF, in the present study as well as previous reports, confirming the potential of tau as an AIS biomarker.

Consensus guidelines for lumbar puncture in patients with neurological diseases.

INTRODUCTION: Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. METHODS: We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). RESULTS: Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. DISCUSSION: When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.