Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Diverging Trends in the Incidence of Spontaneous Intracerebral Hemorrhage in Sweden 2010-2019: An Observational Study from the Swedish Stroke Register (Riksstroke).

INTRODUCTION: Although ischemic stroke incidence has decreased in Sweden over the past decade, trends in spontaneous intracerebral hemorrhage (ICH) incidence are less well delineated. In this time period, there has been a dramatic increase in use of oral anticoagulants (OAC). The aim of our study was to investigate incidence trends in spontaneous first-ever ICH in Sweden between 2010 and 2019, with a focus on non-OAC-associated and OAC-associated ICH. METHODS: We included patients (≥18 years) with first-ever ICH registered in the hospital-based Swedish Stroke Register (Riksstroke) 2010-2019. Data were stratified by non-OAC and OAC ICH and analyzed for 2010-2012, 2013-2016, and 2017-2019. Incidence rates are shown as crude and age-specific per 100,000 person-years. RESULTS: Between 2010 and 2019, 22,289 patients with first-ever ICH were registered; 18,325 (82.2%) patients with non-OAC ICH and 3,964 (17.8%) patients with OAC ICH. Annual crude incidence (per 100,000) of all first-ever ICH decreased by 10% from 29.5 (95% CI 28.8-30.3) to 26.7 (95% CI 26.0-27.3) between 2010-2012 and 2017-2019. The crude incidence rate of non-OAC ICH decreased by 20% from 25.7 (95% CI 25.0-26.3) to 20.7 (95% CI 20.1-21.2), whereas OAC ICH increased by 56% from 3.86 (95% CI 3.61-4.12) to 6.01 (95% CI 5.70-6.32). The proportion of OAC ICH of all first-ever ICH increased between 2010-2012 and 2017-2019 from 13.1% to 22.5% (p < 0.001). Proportional changes were largest in the age group ≥85 years with a decrease in non-OAC ICH by 32% from 155 (95% CI 146-164) to 106 (95% CI 98.6-113) and an increase in OAC ICH by 155% from 25.7 (95% CI 22.1-29.4) to 65.5 (95% CI 59.9-71.2). CONCLUSION: Incidence of first-ever ICH in Sweden decreased by 10% between 2010 and 2019. We found diverging trends with a 20% decrease in non-OAC-associated ICH and a 56% increase in OAC-associated ICH. Further research on ICH epidemiology, analyzing non-OAC and OAC-associated ICH separately, is needed to follow up these diverging trends including underlying risk factors.

Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Current evidence supports the use of intravenous thrombolysis with alteplase in patients with wake-up stroke selected with MRI or perfusion imaging and is recommended in clinical guidelines. However, access to advanced imaging techniques is often scarce. We aimed to determine whether thrombolytic treatment with intravenous tenecteplase given within 4·5 h of awakening improves functional outcome in patients with ischaemic wake-up stroke selected using non-contrast CT. METHODS: TWIST was an investigator-initiated, multicentre, open-label, randomised controlled trial with blinded endpoint assessment, conducted at 77 hospitals in ten countries. We included patients aged 18 years or older with acute ischaemic stroke symptoms upon awakening, limb weakness, a National Institutes of Health Stroke Scale (NIHSS) score of 3 or higher or aphasia, a non-contrast CT examination of the head, and the ability to receive tenecteplase within 4·5 h of awakening. Patients were randomly assigned (1:1) to either a single intravenous bolus of tenecteplase 0·25 mg per kg of bodyweight (maximum 25 mg) or control (no thrombolysis) using a central, web-based, computer-generated randomisation schedule. Trained research personnel, who conducted telephone interviews at 90 days (follow-up), were masked to treatment allocation. Clinical assessments were performed on day 1 (at baseline) and day 7 of hospital admission (or at discharge, whichever occurred first). The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days and analysed using ordinal logistic regression in the intention-to-treat population. This trial is registered with EudraCT (2014-000096-80), ClinicalTrials.gov (NCT03181360), and ISRCTN (10601890). FINDINGS: From June 12, 2017, to Sept 30, 2021, 578 of the required 600 patients were enrolled (288 randomly assigned to the tenecteplase group and 290 to the control group [intention-to-treat population]). The median age of participants was 73·7 years (IQR 65·9-81·1). 332 (57%) of 578 participants were male and 246 (43%) were female. Treatment with tenecteplase was not associated with better functional outcome, according to mRS score at 90 days (adjusted OR 1·18, 95% CI 0·88-1·58; p=0·27). Mortality at 90 days did not significantly differ between treatment groups (28 [10%] patients in the tenecteplase group and 23 [8%] in the control group; adjusted HR 1·29, 95% CI 0·74-2·26; p=0·37). Symptomatic intracranial haemorrhage occurred in six (2%) patients in the tenecteplase group versus three (1%) in the control group (adjusted OR 2·17, 95% CI 0·53-8·87; p=0·28), whereas any intracranial haemorrhage occurred in 33 (11%) versus 30 (10%) patients (adjusted OR 1·14, 0·67-1·94; p=0·64). INTERPRETATION: In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging. Current evidence does not support treatment with tenecteplase in patients selected with non-contrast CT. FUNDING: Norwegian Clinical Research Therapy in the Specialist Health Services Programme, the Swiss Heart Foundation, the British Heart Foundation, and the Norwegian National Association for Public Health.

Epidemiology of First and Recurrent Ischemic Stroke in Sweden 2010-2019: A Riksstroke Study.

INTRODUCTION: Ischemic stroke incidence appears to have decreased during the last decades, but most studies focus on the first-ever events and epidemiological data on recurrent stroke are scarce. The aim of our study was to investigate trends in incidence, risk factors, and medication in patients with first-ever and recurrent ischemic stroke between 2010 and 2019 in Sweden. METHODS: We included patients (≥18 years old) with ischemic stroke registered in the hospital-based Swedish Stroke Register (Riksstroke) 2010-2019. The coverage of Riksstroke was consistently high (about 90%) during this period. Data were stratified by first-ever and recurrent ischemic stroke in three different time periods (2010-2012, 2013-2016, and 2017-2019) and shown as crude and age-specific incidence rates per 100,000 person-years. Statistics Sweden provided census data on the Swedish population in different age groups. RESULTS: During the study period, 201,316 cases of ischemic stroke were registered in Riksstroke, including 153,865 (76.4%) cases of first-ever ischemic stroke and 46,248 (23.0%) cases of recurrent ischemic stroke (0.6% of cases unclassified). The crude incidence of first-ever ischemic stroke decreased by 17% from 216 (95% CI 214-218) to 179 (95% CI 177-181) between 2010-2012 and 2017-2019, whereas recurrent ischemic stroke decreased by 33% from 72 (95% CI 71-73) to 48 (95% CI 47-49). Between these time periods, diminishing ischemic stroke incidence was seen in all age groups with highest decline noted in those aged 75-84 years (928 [95% CI 914-943] to 698 [95% CI 686-709]; -25% in first-ever ischemic stroke and 361 [95% CI 351-370] to 219 [95% CI 213-226]; -39% in recurrent ischemic stroke) and ≥85 years (1,674 [95% CI 1,645-1,703] to 1,295 [95% CI 1,270-1,320]; -23% in first-ever ischemic stroke and 683 [95% CI 664-702] to 423 [95% CI 409-437]; -38% in recurrent ischemic stroke). Treatment with anticoagulants in patients with atrial fibrillation and lipid-lowering drugs increased considerably in patients with first-ever and recurrent ischemic stroke both at admission and discharge during the study period. CONCLUSION: Whereas both first-ever and recurrent ischemic stroke rates declined in Sweden between 2010 and 2019, the proportional decline was almost double for recurrent ischemic stroke than for first-ever ischemic stroke and most pronounced in the elderly. Increased use of secondary preventive drugs, in particular anticoagulants in atrial fibrillation, appears to have contributed, but further studies on precise causes for the decline in recurrent ischemic stroke are needed.

Patient factors associated with receiving reversal therapy in oral anticoagulant-related intracerebral hemorrhage.

BACKGROUND: We aimed to describe baseline characteristics of patients with oral anticoagulant-related intracerebral hemorrhage (OAC-ICH) in Sweden and to identify predictive variables associated with receiving hemostatic treatment in the event of OAC-ICH. METHODS: We performed an observational study based on data from Riksstroke and the Swedish Causes of Death Register to define baseline characteristics of patients with OAC-ICH who received reversal treatment compared with patients who did not receive reversal treatment during 2017-2019. Predictive analysis was performed using multivariable logistic regression to identify odds ratios for factors associated with receiving OAC reversal treatment. RESULTS: We included 1902 patients ((n = 1146; OAC reversal treatment) (n = 756; no OAC reversal treatment)). The proportion of non-Vitamin K oral anticoagulant associated ICH (NOAC-ICH) patients who received reversal treatment was 48.4% and the proportion of Vitamin K antagonist-associated ICH (VKA-ICH) patients was 72.9%. Factors associated with a lower odds of receiving reversal treatment were increased age (OR = 0.98; 95% CI: 0.96-0.99), previous stroke (OR = 0.78; 95% CI: 0.62-0.98), comatose LOC (OR = 0.36;95%CI: 0.27-0.48; ref. = alert), pre-stroke dependency (OR = 0.72; 95% CI: 0.58-0.91), and NOAC treatment (OR = 0.34; 95% CI: 0.28-0.42). Care at a university hospital was not associated with higher odds of receiving reversal treatment compared to treatment at a county hospital. CONCLUSION: Treatment with a reversal agent following OAC-ICH was related to several patient factors including type of OAC drug. We identified that only 48% of patients with NOAC-ICH received hemostatic treatment despite an increase in these cases. Further studies are required to guide the use of reversal therapies more precisely, particularly in NOAC-ICH.

Statistical analysis plan for the randomized controlled trial Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST).

BACKGROUND: Patients with wake-up ischemic stroke are frequently excluded from thrombolytic treatment due to unknown symptom onset time and limited availability of advanced imaging modalities. The Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) is a randomized controlled trial of intravenous tenecteplase 0.25 mg/kg and standard care versus standard care alone (no thrombolysis) in patients who wake up with acute ischemic stroke and can be treated within 4.5 h of wakening based on non-contrast CT findings. OBJECTIVE: To publish the detailed statistical analysis plan for TWIST prior to unblinding. METHODS: The TWIST statistical analysis plan is consistent with the Consolidating Standard of Reporting Trials (CONSORT) statement and provides clear and open reporting. DISCUSSION: Publication of the statistical analysis plan serves to reduce potential trial reporting bias and clearly outlines the pre-specified analyses. TRIAL REGISTRATION: ClinicalTrials.gov NCT03181360 . EudraCT Number 2014-000096-80 . WHO ICRTP registry number ISRCTN10601890 .

Fetal posterior cerebral artery configurations in an ischemic stroke versus an unselected hospital population.

BACKGROUND: Few MRA-based studies have systematically evaluated the prevalence and laterality of a fetal configuration of the posterior cerebral artery (FTP) in ischemic stroke populations versus other populations. This common variant is important in the setting of acute stroke and secondary prevention decisions. OBJECTIVE: To determine the prevalence and laterality of FTP configurations in MRI-DWI verified acute ischemic stroke patients investigated with MRA, and compare the findings with an unselected hospital population investigated with computed tomography angiography (CTA). We also evaluated the association of FTP with posterior cerebral artery (PCA) territory infarctions. METHODS: We reviewed the MRAs of 1407 ischemic stroke patients with acute lesions on MRI-DWI sequences and 546 consecutive CTAs of patients investigated on any indication in a tertiary hospital. The MRA and CTA assessments were made by neuroradiologists blinded to original reports on stroke location and vessel anatomy. RESULTS: The prevalence of any FTP was similar in ischemic stroke patients (31%) and unselected patients (32%). Unilateral FTP was significantly more frequent on the right than on the left side in both groups (15% right vs. 8% left). The presence of FTP ipsilateral to stroke side was not associated with involvement of the PCA territory versus no FTP on the stroke side. CONCLUSIONS: FTP is present in approximately 30% of ischemic stroke patients and unselected hospital populations and was detected significantly more frequently on the right versus left side in both groups. PCA territory infarction was not associated with the presence of ipsilateral FTP.

Patient-accessible online health records: Reconfigurations of clinical rhythms and doctors' front- and backstage spaces.

With patients' increasing online access to medical information traditionally contained within healthcare institutions, researchers have argued that the spaces of medicine are increasingly becoming blurred, allowing patients to sidestep their doctors and challenge their prior information dominance. In this context, Sweden has recently been spotlighted as it allows its inhabitants to continually access medical record content online. Based on an interview study on Swedish doctors' clinical experiences of the patient-accessible online health record, this paper expands on the theme of emergent medical information spaces accessible to laypersons online by arguing that this not only may challenge the traditional spaces of medicine but can impose on its temporal orders too. We detail doctors' attitudes toward the patient-accessible online health record, patients as continually updated record readers, and how this may transform clinical work rhythms and affect doctors' perceptions of the boundary between front- and backstage spaces. We moreover show how doctors can avoid "inappropriate intrusion" into the record by delaying patient access, but also that doctors can experience patients opposing to adapt to doctors' preferred pace and instead attempting to control the clinical rhythm. By intertwining clinical rhythms with doctors' front- and backstage, this paper contributes with an extended analysis of the emergent spaces of online medical information, adding a temporal layer. The paper furthermore enlarges the existing sociological body on historical developments of medical records and adds a piece to the so-far piecemeal social science literature on how online records may affect the medical profession.

Off the record: The invisibility work of doctors in a patient-accessible electronic health record information service.

In this article, we draw on Michael Lipsky's work on street-level bureaucrats and discretion to analyse a real case setting comprising an interview study of 30 Swedish doctors regarding their experiences of changes in clinical work following patients being given access to medical records information online. We introduce the notion of invisibility work to capture how doctors exercise discretion to preserve the invisibility of their work, in contrast to the well-established notion of invisible work, which denotes work made invisible by parties other than those performing it. We discuss three main forms of invisibility work in relation to records: omitting information, cryptic writing and parallel note writing. We argue that invisibility work is a way for doctors to resolve professional tensions arising from the political decision to provide patients with online access to record information. Although invisibility work is understood by doctors as a solution to government-initiated visibility, we highlight how it can create difficulties for doctors concerning accountability towards patients, peers and authorities.

Prognosis of Intracerebral Hemorrhage Related to Antithrombotic Use: An Observational Study From the Swedish Stroke Register (Riksstroke).

BACKGROUND AND PURPOSE: To date, large studies comparing mortality and functional outcome of intracerebral hemorrhage (ICH) during oral anticoagulant (OAC), antiplatelet, and nonantithrombotic use are few and show discrepant results. METHODS: We used data on 13 291 patients with ICH registered in Riksstroke between 2012 and 2016 to compare 90-day mortality and functional outcome following OAC-related ICH (n=2300), antiplatelet-related ICH (n=3637), and nonantithrombotic ICH (n=7354). Univariable and multivariable Cox regression analyses, with adjustment for relevant confounders, were used to compare 90-day mortality. Early (≤24 hours and 1-7 days) and late (8-90 days) mortality was also studied in subgroup analyses. Univariable and multivariable 90-day functional outcome, based on self-reported modified Rankin Scale, was determined using logistic regression. RESULTS: Patients with antithrombotic treatment were more often prestroke dependent, older, and had a larger comorbidity burden compared with patients without antithrombotic treatment. At 90 days, antiplatelet and OAC were associated with an increased death rate in multivariable analysis (antiplatelet ICH: hazard ratio, 1.23 [95% CI, 1.14-1.33]; OAC ICH: hazard ratio, 1.40 [95% CI, 1.26-1.57]) compared with nonantithrombotic ICH (reference). OAC ICH and antiplatelet ICH were associated with higher risk of early mortality (≤24 hours: OAC ICH: hazard ratio, 1.93 [95% CI, 1.57-2.38]; antiplatelet ICH: hazard ratio, 1.32 [95% CI, 1.13-1.54]). In multivariable analysis, the odds ratios for the association of antiplatelet and OAC treatment on functional dependency (modified Rankin Scale score, 3-5) at 90 days were nonsignificant (antiplatelet: odds ratio, 1.07 [95% CI, 0.92-1.24]; OAC: odds ratio, 0.96 [95% CI, 0.76-1.22]). CONCLUSIONS: In this large observational study, we found that 90-day mortality outcome was worse not only in OAC ICH but also in antiplatelet ICH, compared with patients with nonantithrombotic ICH. Antiplatelet ICH is common and is a serious condition with poor clinical outcome. Further studies are, therefore, warranted in determining the appropriate clinical management of these patients.

Tenecteplase in wake-up ischemic stroke trial: Protocol for a randomized-controlled trial.

BACKGROUND: Patients with wake-up ischemic stroke who have evidence of salvageable tissue on advanced imaging can benefit from intravenous thrombolysis. It is not known whether patients who do not fulfil such imaging criteria might benefit from treatment, but studies indicate that treatment based on non-contrast CT criteria may be safe. Tenecteplase has shown promising results in patients with acute ischemic stroke. The aim of the Tenecteplase in Wake-up Ischemic Stroke Trial (TWIST) is to compare the effect of thrombolytic treatment with tenecteplase and standard care versus standard care alone in patients with wake-up ischemic stroke selected by non-contrast CT. METHODS/DESIGN: TWIST is an international, investigator-initiated, multi-centre, prospective, randomized-controlled, open-label, blinded end-point trial of tenecteplase (n = 300) versus standard care (n = 300) in patients who wake up with an acute ischemic stroke and can be treated within 4.5 h upon awakening. Seventy-seven centres in 10 countries (Denmark, Estonia, Finland, Latvia, Lithuania, New Zealand, Norway, Sweden, Switzerland, and the United Kingdom) participate. The primary outcome is the modified Rankin Scale on the ordinal scale (0-6) at three months. DISCUSSION: TWIST aims to determine the effect and safety of thrombolytic treatment with tenecteplase in patients with wake-up ischemic stroke selected by non-contrast CT. TRIAL REGISTRATION: ClinicalTrials.gov NCT03181360. EudraCT Number 2014-000096-80.

Ischemic stroke patients with prestroke dependency: Characteristics and long-term prognosis.

OBJECTIVE: This paper aims at examining the clinical characteristics of ischemic stroke patients with different levels of prestroke functional dependency, their long-term outcome, and determinants of five-year mortality. MATERIALS AND METHODS: We describe demographics, comorbidity, treatment, as well as long-term mortality, and functional status of 5899 prestroke-dependent ischemic stroke patients stratified by dependency level and compared to a concurrent cohort of 14 148 prestroke-independent patients. The study was based on 2016 survey data from Riksstroke, the Swedish national stroke register, and patients were followed up at three months, 12 months, and either at three or five years. We used Cox regression for mortality predictor analysis and multiple imputation was performed to minimize bias from loss to follow-up. RESULTS: With increasing level of prestroke dependency, comorbidity burden was higher, drug prescription lower, and prognosis less favorable. At three years, the proportion that had died or deteriorated were 82.6%, 87.5%, and 86.3% in moderate, moderately severe, and severe dependency, respectively. In moderate dependency, prognosis was relatively favorable: Three-month mortality was half of that seen in severe dependency (25.3% versus 49.6%). Differences in overall outcome between groups of varying prestroke functional dependency level were statistically significant (P < .05) at all follow-up time points. CONCLUSIONS: There was great heterogeneity between groups of different level of prestroke dependency; those of moderate dependency had a relatively favorable prognosis. Patients of different prestroke level of dependency need to be addressed separately, and further research is needed characterizing this group and exploring management strategies.

Patterns in hospital readmissions after ischaemic stroke - An observational study from the Swedish stroke register (Riksstroke).

INTRODUCTION: While acute treatment and secondary prevention in stroke have undergone major improvements, hospital readmission after index stroke remains high. However, there are few reports on long-term readmission patterns. PATIENTS AND METHODS: For this prospective observational study, data on demographics, functional status and living conditions were obtained from the Swedish Stroke Register (Riksstroke). Data on comorbidity and hospital readmissions up to five years post-index stroke were obtained from the Swedish National Patient Register. Patients were grouped based on number of readmissions: low (0-1) intermediate (2-4), high (5-9) or very high (≥10). RESULTS: Of the 10,092 patients included, 43.7% had been readmitted within 12 months and 74.0% within 5 years. There was an average of three readmissions per individual during the five-year interval. A small group of patients with a high-comorbidity burden accounted for the majority of readmissions: approximately 20% of patients accounted for 60% of readmissions, and 5% of patients accounted for 25%. Circulatory conditions were the most common cause followed by infectious disease, stroke, trauma and diseases of the nervous system other than stroke. The proportion of readmissions due to stroke decreased sharply in the first six months. CONCLUSION: A small number of patients with a high degree of comorbidity accounted for the majority of hospital readmissions after index stroke. Our results highlight the need for further development of strategies to support high-risk comorbid stroke patients in the community setting. Further research describing characteristics and healthcare utilisation patterns in this group is warranted.

Reversal Treatment in Oral Anticoagulant-Related Intracerebral Hemorrhage-An Observational Study Based on the Swedish Stroke Register.

Introduction: Intracerebral hemorrhage (ICH) is the most serious adverse effect of oral anticoagulant (OAC) treatment. The effect of OAC reversal therapy on outcome is uncertain. We compared 90-day survival and functional outcome in patients with OAC-ICH who received OAC reversal therapy with those who did not. Methods: Data from The Swedish Stroke Register (Riksstroke) for all registered cases of OAC-ICH during 2017 (572 patients) were used to obtain information on reversal (n = 369) and non-reversal (n = 203) treatment receiving patients. Univariate and multivariate Cox regression analysis stratified for level of consciousness (LOC) on admission, and adjustment for relevant baseline variables, was used to compare 90-day Hazard Ratios (HR) for mortality. Results: Sixty-five percent of patients received reversal treatment. These patients were younger, more often pre-stroke independent and alert at presentation. Withholding reversal treatment was associated with an increased death rate (HR = 1.47; 95% CI: 1.08-2.01) in a Cox regression model stratified for LOC and adjusted for baseline imbalances. Additional factors associated with an increased 90-day death rate were male sex (HR = 1.42; 95% CI: 1.06-1.92), age (HR = 1.05; 95% CI: 1.02-1.07), and intraventricular hemorrhage (HR = 2.41; CI: 1.77-3.29). Conclusion: In this large observational study 35% of patients with OAC-ICH did not receive reversal treatment. Patients receiving OAC-reversal treatment had an improved 90-day mortality outcome compared to those not receiving treatment. Mortality was strongly related to LOC. Further, and larger, studies are required to determine which patient groups may benefit from reversal therapy and in whom non-reversal is adequate.

Alcohol Consumption and Risk of Parkinson's Disease: Data From a Large Prospective European Cohort.

BACKGROUND: Parkinson's disease (PD) etiology is not well understood. Reported inverse associations with smoking and coffee consumption prompted the investigation of alcohol consumption as a risk factor, for which evidence is inconclusive. OBJECTIVE: To assess the associations between alcohol consumption and PD risk. METHODS: Within NeuroEPIC4PD, a prospective European population-based cohort, 694 incident PD cases were ascertained from 209,998 PD-free participants. Average alcohol consumption at different time points was self-reported at recruitment. Cox regression hazard ratios were estimated for alcohol consumption and PD occurrence. RESULTS: No associations between baseline or lifetime total alcohol consumption and PD risk were observed. Men with moderate lifetime consumption (5-29.9 g/day) were at ~50% higher risk compared with light consumption (0.1-4.9 g/day), but no linear exposure-response trend was observed. Analyses by beverage type also revealed no associations with PD. CONCLUSION: Our data reinforce previous findings from prospective studies showing no association between alcohol consumption and PD risk. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Long-term outcome after ischemic stroke in relation to comorbidity - An observational study from the Swedish Stroke Register (Riksstroke).

PURPOSE: Comorbidity in stroke is common, but comprehensive reports are sparse. We describe prevalence of comorbidity and the prognostic impact on mortality and functional outcome in a large national ischemic stroke cohort. METHODS: We used outcome data from a long-term follow-up survey conducted in 2016 by the Swedish Stroke Register (Riksstroke). Those included in the study were 11 775 pre-stroke functionally independent patients with first-ever ischemic stroke followed up at three months and 12 months (all patients), and three years (2013 cohort) or five years (2011 cohort). Pre-stroke comorbidity data for 16 chronic conditions were obtained from the Swedish National Patient Register, the Swedish Prescribed Drugs Register and the Riksstroke register. Individuals were grouped according to number of conditions: none (0), low (1), moderate (2-3) or high (≥4). Co-occurrence was analysed using hierarchical clustering, and multivariable analyses were used to estimate the prognostic significance of individual conditions. RESULTS: The proportion of patients without comorbidity was 24.8%; 31.8% had low comorbidity; 33.5% had moderate comorbidity and 9.9% had high comorbidity. At 12 months, the proportion of poor outcome (dead or dependent: mRS ≥3) was 24.8% (no comorbidity), 34.7% (low), 45.2% (moderate) and 59.4% (high). At five years, these proportions were 37.7%, 50.3%, 64.3%, and 81.7%, respectively. There was clustering of cardiovascular conditions and substantial negative effects of dementia, kidney, and heart failure. CONCLUSION: Comorbidity is common and has a strong impact on mortality and functional outcome. Our results highlight the need for health systems to shift focus to a comprehensive approach in stroke care that includes multimorbidity as a key component.

Evaluation of small nerve fiber dysfunction in type 2 diabetes.

OBJECTIVES: To assess potential correlations between intraepidermal nerve fiber densities (IENFD), graded with light microscopy, and clinical measures of peripheral neuropathy in elderly male subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM), respectively. MATERIALS AND METHODS: IENFD was assessed in thin sections of skin biopsies from distal leg in 86 men (71-77 years); 24 NGT, 15 IGT, and 47 T2DM. Biopsies were immunohistochemically stained for protein gene product (PGP) 9.5, and intraepidermal nerve fibers (IENF) were quantified manually by light microscopy. IENFD was compared between groups with different glucose tolerance and related to neurophysiological tests, including nerve conduction study (NCS; sural and peroneal nerve), quantitative sensory testing (QST), and clinical examination (Total Neuropathy Score; Neuropathy Symptom Score and Neuropathy Disability Score). RESULTS: Absent IENF was seen in subjects with T2DM (n = 10; 21%) and IGT (n = 1; 7%) but not in NGT. IENFD correlated weakly negatively with HbA1c (r = -.268, P = .013) and Total Neuropathy Score (r = -.219, P = .042). Positive correlations were found between IENFD and sural nerve amplitude (r = .371, P = .001) as well as conduction velocity of both the sural (r = .241, P = .029) and peroneal nerve (r = .258, P = .018). Proportions of abnormal sural nerve amplitude became significantly higher with decreasing IENFD. No correlation was found with QST. Inter-rater reliability of IENFD assessment was good (ICC = 0.887). CONCLUSIONS: Signs of neuropathy are becoming more prevalent with decreasing IENFD. IENFD can be meaningfully evaluated in thin histopathological sections using the presented technique to detect neuropathy.

General and abdominal adiposity and the risk of Parkinson's disease: A prospective cohort study.

INTRODUCTION: Due to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD. METHODS: In 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking. RESULTS: We found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD. CONCLUSION: Our data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.

Prognosis for intracerebral hemorrhage during ongoing oral anticoagulant treatment.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most serious adverse effect of treatment with oral anticoagulants. Prognostic data after ICH associated with non-vitamin K antagonist oral anticoagulants (NOAC) compared to vitamin K antagonists (VKA) are sparse. We compared 90-day survival and functional outcome following NOAC-ICH versus VKA-ICH using data from the Swedish Stroke Register (Riksstroke). METHODS: Using data from Riksstroke and the Swedish Causes of Death Register between 2012 and 2016, we compared all-cause 90-day mortality for patients with NOAC-ICH versus VKA-ICH using Kaplan-Meier survival analysis and Log-rank test. Cox regression, with adjustment for age, sex, previous stroke, and level of consciousness (LOC) on admission, was used to estimate hazard ratios (HR) for 90-day mortality. Estimated functional outcome at 90 days, based on the modified Rankin Scale (mRS), was compared between VKA- and NOAC-associated ICH using chi-squared test. RESULTS: We included 2483 patients; 300 with NOAC-ICH and 2183 with VKA-ICH. In both groups, mean age was 79 years, and 58% were male. No significant difference between NOAC-ICH and VKA-ICH was found for all-cause 90-day mortality (44.3% NOAC-ICH versus 42.6% VKA-ICH; P = 0.54, HR = 0.93; 95% confidence interval (CI): 0.78-1.12) or 90-day estimated functional outcome (mRS 0-2:13.7% and 15.3%; mRS 3-5:27.3% and 28.9%, respectively (P = 0.52)). Factors predicting death were increased age (HR = 1.03; 95%CI: 1.02-1.04) and reduced LOC (drowsy: HR = 3.48; 95%CI: 2.86-4.23; comatose: HR = 12.27; 95%CI: 10.13-14.87). CONCLUSION: In this large study on anticoagulant-associated ICH, we found no significant difference in mortality and functional outcome at 90 days between NOAC-ICH versus VKA-ICH.

Long-Term Survival and Function After Stroke: A Longitudinal Observational Study From the Swedish Stroke Register.

Background and Purpose- Longitudinal long-term prognostic data after stroke based on large cohorts are sparse. We report recent survival and functional outcome data on ischemic stroke (IS) and intracerebral hemorrhage (ICH) for up to 5 years poststroke from the Swedish Stroke Register (Riksstroke). Methods- Beyond Riksstroke's regular follow-up surveys at 3 and 12 months, additional surveys were conducted in 2016 on 2 one-year cohorts with stroke 3 and 5 years earlier. Functional dependency was defined as modified Rankin Scale ≥3. Mortality data of the original cohorts were obtained from the Swedish Causes of Death Register. Multiple imputation was used to estimate functional status in nonresponders. Results- The study included 22 929 patients, 87.5% with IS and 12.5% with ICH. Loss to follow-up in the 4 surveys was 12.8% to 21.2%. Thirty-day mortality was higher for ICH than for IS (30.7% versus 11.1%; P<0.01), whereas for 30-day survivors, 5-year mortality did not differ significantly (P=0.858). Functional outcome was less favorable for ICH at all follow-up points. At 5 years, poor outcome (death or dependency) was 79% in ICH and 70.6% in IS (including imputed data; P<0.01). Favorable outcome was less common with increasing age and in patients with prestroke functional dependency. Conclusions- Despite advances in stroke care, long-term prognosis remains a cause for concern. At 5 years after stroke over 2 in 3 patients with IS, and over 3 in 4 patients with ICH, were dead or dependent. We present robust long-term prognostic data to serve as a reference for further development of healthcare and research in stroke.