Autonomic dysfunction after mild acute ischemic stroke and six months after: a prospective observational cohort study.

INTRODUCTION: Autonomic dysfunction is prevalent in ischemic stroke patients and associated with a worse clinical outcome. We aimed to evaluate autonomic dysfunction over time and the tolerability of the head-up tilt table test in an acute stroke setting to optimize patient care. PATIENTS AND METHOD: In a prospective observational cohort study, patients were consecutively recruited from an acute stroke unit. The patients underwent heart rate and blood pressure analysis during the Valsalva maneuver, deep breathing, active standing, and head-up tilt table test if active standing was tolerated. In addition, heart rate variability and catecholamines were measured. All tests were performed within seven days after index ischemic stroke and repeated at six months follow-up. RESULTS: The cohort was comprised of 91 acute stroke patients, mean (SD) age 66 (11) years, median (IQR) initial National Institute of Health Stroke Scale 2 (1-4) and modified Ranking Scale 2 (1-3). The head-up tilt table test revealed 7 patients (10%) with orthostatic hypotension. The examination was terminated before it was completed in 15%, but none developed neurological symptoms. In the acute state the prevalence of autonomic dysfunction varied between 10-100% depending on the test. No changes were found in presence and severity of autonomic dysfunction over time. CONCLUSION: In this cohort study of patients with mild stroke, autonomic dysfunction was highly prevalent and persisted six months after index stroke. Head-up tilt table test may be used in patients who tolerate active standing. Autonomic dysfunction should be recognized and handled in the early phase after stroke.

Cortical hemodynamic response during cognitive Stroop test in acute stroke patients assessed by fNIRS.

BACKGROUND: Following acute ischemic stroke (AIS) many patients experience cognitive impairment which interferes neurorehabilitation. Understanding and monitoring pathophysiologic processes behind cognitive symptoms requires accessible methods during testing and training. Functional near-infrared spectroscopy (fNIRS) can assess activational hemodynamic responses in the prefrontal cortex (PFC) and feasibly be used as a biomarker to support stroke rehabilitation. OBJECTIVE: Exploring the feasibility of fNIRS as a biomarker during the Stroop Color and Word Test (SCWT) assessing executive function in AIS patients. METHODS: Observational study of 21 patients with mild to moderate AIS and 22 healthy age- and sex-matched controls (HC) examined with fNIRS of PFC during the SCWT. Hemodynamic responses were analyzed with general linear modeling. RESULTS: The SCWT was performed worse by AIS patients than HC. Neither patients nor HC showed PFC activation, but an inverse activational pattern primarily in superolateral and superomedial PFC significantly lower in AIS. Hemodynamic responses were incoherent to test difficulty and performance. No other group differences or lateralization were found. CONCLUSIONS: AIS patients had impaired executive function assessed by the SCWT, while both groups showed an inverse hemodynamic response significantly larger in HC. Investigations assessing the physiology behind inverse hemodynamic responses are warranted before deeming clinical implementation reasonable.

A Systematic Review of the Circadian Rhythm of Bone Markers in Blood.

There exists a marked circadian variation for several bone markers (BM), which is influenced by endogenous as well as exogenous factors including hormones, physical activity, and fasting. Consequently, was the aim of this review to provide an overview of the knowledge of the circadian variation of BM and which factors influence this rhythmicity. A systematic search of PubMed was performed for studies evaluating the circadian variation of BM and which factors influence this rhythmicity. The studies were screened for eligibility by a set of predetermined criteria including a list of relevant BM and a minimum study duration of 24 h with at least 3 blood samples of which two should be at least 6 h apart. In total were 29 papers included. There exists a marked circadian variation for most BM including Carboxy-terminal Cross-Linked Telopeptide of Type I Collagen (CTX) and osteocalcin (OC) with nighttime or early morning peak. Pro-collagen Type I N-terminal Propeptide (PINP) and PTH also showed circadian rhythm but with less amplitude. The inter-osteoblast-osteoclast regulatory markers such as OPG, RANKL, FGF23, and sclerostin showed no circadian rhythm. The markers were differently affected by exogenous factors like fasting, which greatly reduced the circadian variation of CTX but did not affect PINP or OC. The marked circadian variation and the factors which influence the rhythmicity, e.g., fasting are of great consequence when measuring BM. To reduce variation and heighten validity should circadian variation and fasting be kept in mind when measuring BM.

Capillary transit time heterogeneity inhibits cerebral oxygen metabolism in patients with reduced cerebrovascular reserve capacity from steno-occlusive disease.

The healthy cerebral perfusion demonstrates a homogenous distribution of capillary transit times. A disruption of this homogeneity may inhibit the extraction of oxygen. A high degree of capillary transit time heterogeneity (CTH) describes that some capillaries have very low blood flows, while others have excessively high blood flows and consequently short transit times. Very short transit times could hinder the oxygen extraction due to insufficient time for diffusion of oxygen into the tissue. CTH could be a consequence of cerebral vessel disease. We examined whether patients with cerebral steno-occlusive vessel disease demonstrate high CTH and if elevation of cerebral blood flow (CBF) by administration of acetazolamide (ACZ) increases the cerebral metabolic rate of oxygen (CMRO2), or if some patients demonstrate reduced CMRO2 related to detrimental CTH. Thirty-four patients and thirty-one healthy controls participated. Global CBF and CMRO2 were acquired using phase-contrast MRI. Regional brain maps of CTH were acquired using dynamic contrast-enhanced MRI. Patients with impaired cerebrovascular reserve capacity demonstrated elevated CTH and a significant reduction of CMRO2 after administration of ACZ, which could be related to high CTH. Impaired oxygen extraction from CTH could be a contributing part of the declining brain health observed in patients with cerebral vessel disease.

Sleep-disordered breathing and cerebral small vessel disease-acute and 6 months after ischemic stroke.

PURPOSE: Sleep-disordered breathing (SDB) occurs frequently after stroke and is associated with poor functional outcome and increased mortality. The purpose of this study was to detect changes in SDB over time after acute ischemic stroke and investigate relationships between SDB and stroke etiologies with focus on cerebral small vessel disease. METHODS: From May 2015 to August 2016, we conducted an observational study of 99 patients with mild to moderate stroke (median age: 68 years, range 36-88; 56% men). Polysomnography was performed within 7 days of stroke onset (n = 91) and after 6 months (n = 52). The strokes were classified using the etiological TOAST classification. Total small vessel disease (SVD) scores were calculated based on MRIs. RESULTS: SDB, defined as an apnea-hypopnea index (AHI) ≥ 15, was found in 56% of patients in the acute state and in 44% at follow-up. AHI decreased over time (median change 4.7, 95% confidence interval [95% CI] 0.5-8.9; p = 0.03). Patients with AHI ≥ 15 in both the acute state and at follow-up had higher SVD score at follow-up (p = 0.003). AHI was not associated with ischemic stroke subgroups according to the TOAST classification. DISCUSSION: In conclusion, 6 months after stroke, AHI decreased, but 44% still had AHI ≥ 15. Persistent SDB in both the acute state and at follow-up was associated with a higher SVD score, but not to the TOAST subgroups. SDB evaluation should be offered to stroke patients, and the effect of SDB on cerebral small vessel disease needs to be further investigated using the well-defined SVD score. TRIAL REGISTRATION: clinicaltrials.gov NCT02111408, April 11, 2014.

An exploratory investigation of the effect of naturalistic light on fatigue and subjective sleep quality in stroke patients admitted for rehabilitation: A randomized controlled trial.

BACKGROUND: Daylight entrains the central circadian pacemaker to the 24-hour day and is crucial for optimal alertness and sleep-quality. Rehabilitation patients tend to lack exposure to sufficient natural light. OBJECTIVE: Installed diurnal naturalistic light may reduce the known disrupted sleep quality and fatigue seen in post stroke patients. METHODS: Stroke patients were randomized to either an intervention rehabilitation unit (IU) equipped with naturalistic lighting (artificial sunlight spectrum) or to a control rehabilitation unit (CU) with standard indoor lighting. At inclusion and discharge, fatigue and subjective sleep quality were measured. RESULTS: Ninety stroke patients were included between May 2014, and June 2015. At discharge, patients from the IU experienced less fatigue than the CU patients, based on the Multidimensional Fatigue Inventory questionnaire general (IU, n = 28; CU, n = 30; diff - 20.6%, 95% confidence interval (CI) [- 35.0%; - 3.0%]; P = 0.025) and the Rested Statement (IU, n = 28; CU, n = 30; diff + 41.6%, 95% CI [+4.6%; +91.8%]; P =  0.025). No differences were detected between groups in sleepiness or subjective sleep quality by the Pittsburgh Sleep Quality Index. CONCLUSIONS: Fatigue was significantly reduced in rehabilitation patients exposed to naturalistic lighting during admission.

An exploratory investigation of the effect of naturalistic light on depression, anxiety, and cognitive outcomes in stroke patients during admission for rehabilitation: A randomized controlled trial.

BACKGROUND: Patients admitted for rehabilitation often lack sufficient natural light to entrain their circadian rhythm. OBJECTIVE: Installed diurnal naturalistic light may positively influence the outcome of depressive mood, anxiety, and cognition in such patients. METHODS: A quasi-randomized controlled trial. Ninety stroke patients in need of rehabilitation were randomized between May 1, 2014, and June 1, 2015 to either a rehabilitation unit equipped entirely with always on naturalistic lighting (IU), or to a rehabilitation unit with standard indoor lighting (CU).Examinations were performed at inclusion and discharge. The following changes were investigated: depressive mood based on the Hamilton Depression scale (HAM-D6) and Major Depression Inventory scale (MDI), anxiety based on the Hospital Anxiety and Depression Scale (HADS), cognition based on the Montreal Cognitive Assessment (MoCA) and well-being based on the Well-being Index (WHO-5). RESULTS: Depressive mood (MDI p = 0.0005, HAM-D6 p = 0.011) and anxiety (HADS anxiety p = 0.045) was reduced, and well-being (WHO-5 p = 0.046) was increased, in the IU at discharge compared to the CU. No difference was found in cognition (MoCA p = 0.969). CONCLUSIONS: This study is the first to demonstrate that exposure to naturalistic light during admission may significantly improve mental health in rehabilitation patients. Further studies are needed to confirm these findings.

Neuroregeneration and Vascular Protection by Citalopram in Acute Ischemic Stroke (TALOS).

Background and Purpose- Recent studies indicate a possible beneficial effect on neuroregeneration and vascular protection of selective serotonin reuptake inhibitors after stroke. We conducted a national multicentre study to explore these effects. Methods- The TALOS study (The Efficacy of Citalopram Treatment in Acute Stroke) is a Danish placebo-controlled, randomized, double-blind study of citalopram started within 7 days after symptom onset to detect improvement in functional outcomes and cardiovascular protection in nondepressed, first-ever ischemic stroke. Study medication was given as add-on to standard medical care and treatment duration and follow-up was 6 months. There were 2 coprimary outcomes: changes in functional disability from 1 to 6 months on the modified Rankin Scale, and a composite vascular end point of transient ischemic attack/stroke, myocardial infarction, or vascular mortality during the first 6 months. Results- We enrolled 642 patients randomized to either citalopram (n=319) or placebo (n=323). Median National Institutes of Health Stroke Scale was 5.3 (range, 0-27) versus 4.8 (range, 0-28) at admission. Improvement in functional recovery from 1 to 6 months occurred in 160 (50%) patients on citalopram and 136 (42%) on placebo (odds ratio, 1.27; 95% CI, 0.92-1.74; P=0.057). When dropouts before 31 days were excluded (n=90), the analysis population showed an odds ratio of 1.37 (95% CI, 0.97-1.91; P=0.07). During a median follow-up of 150 days, 23 (7%) patients in the citalopram group and 26 (8%) patients in the placebo group had a primary, vascular end point (hazard ratio, 0.89; 95% CI, 0.50-1.60; P=0.24). A total of 28 patients (4%) died (16 versus 12; P=0.42) during the study. Conclusions- Early citalopram treatment did not improve functional recovery in nondepressed ischemic stroke patients within the first 6 months, although a borderline statistical significant effect was observed in the analysis population. The risk of cardiovascular events was similar between treatment groups, and citalopram treatment was well tolerated. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01937182. URL: https://www.clinicaltrialsregister.eu/ . EudraCT number: 2013-002253-30.

Assessing low-frequency oscillations in cerebrovascular diseases and related conditions with near-infrared spectroscopy: a plausible method for evaluating cerebral autoregulation?

BACKGROUND: Cerebral autoregulation (CA) is the brain's ability to always maintain an adequate and relatively constant blood supply, which is often impaired in cerebrovascular diseases. Near-infrared spectroscopy (NIRS) examines oxygenated hemoglobin (OxyHb) in the cerebral cortex. Low- and very low-frequency oscillations ( LFOs ≈ 0.1 Hz and VLFOs ≈ 0.05 to 0.01 Hz) in OxyHb have been proposed to reflect CA. AIM: To systematically review published results on OxyHb LFOs and VLFOs in cerebrovascular diseases and related conditions measured with NIRS. APPROACH: A systematic search was performed in the MEDLINE database, which generated 36 studies relevant for inclusion. RESULTS: Healthy people have relatively stable LFOs. LFO amplitude seems to reflect myogenic CA being decreased by vasomotor paralysis in stroke, by smooth muscle damage or as compensatory action in other conditions but can also be influenced by the sympathetic tone. VLFO amplitude is believed to reflect neurogenic and metabolic CA and is lower in stroke, atherosclerosis, and with aging. Both LFO and VLFO synchronizations appear disturbed in stroke, while the former is also altered in internal carotid stenosis and hypertension. CONCLUSION: We conclude that amplitudes of LFOs and VLFOs are relatively robust measures for evaluating mechanisms of CA and synchronization analyses can show temporal disruption of CA. Further research and more coherent methodologies are needed.

Impact of naturalistic lighting on hospitalized stroke patients in a rehabilitation unit: Design and measurement.

INTRODUCTION AND RATIONALE: Stroke is a major cause of acquired cerebral disability among adults, frequently accompanied by depression, anxiety, cognitive impairment, disrupted sleep and fatigue. New ways of intervention to prevent these complications are therefore needed. The major circadian regulator, the suprachiasmatic nucleus, is mainly controlled by natural daylight, and the blue spectrum is considered the most powerful. During stroke rehabilitation, patients typically are mostly indoors and therefore not exposed to the natural daytime variation in light intensity. Furthermore, several rehabilitation hospitals may be exposed to powerful light in the blue spectrum, but at a time that is adversely related to their endogenous circadian phase, for example in the late evening instead of the daytime. HYPOTHESIS: Naturalistic light that mimics the natural daytime spectrum variation will have a positive impact on the health of poststroke patients admitted to rehabilitation. We test specifically for improved sleep and less fatigue (questionnaires, polysomnography, Actiwatch), improved well-being (questionnaires), lessen anxiety and depression (questionnaires), improved cognition (tests), stabilizing of the autonomous nervous system (ECG/HR, blood pressure, temperature) and stabilizing of the diurnal biochemistry (blood markers). STUDY DESIGN: The study is a prospective parallel longitudinal randomized controlled study (quasi randomization). Stroke patients in need of rehabilitation will be included at the acute stroke unit and randomized to either the intervention unit (naturalistic lighting) or the control unit (CU) (standard lighting). The naturalistic light is installed in the entire IU (Cromaviso, Denmark). CONCLUSION: This study aims to elucidate the influence of naturalistic light on patients during long-term hospitalization in a real hospital setting. The hypotheses are based on preclinical research, as studies using naturalistic light have never been performed before. Investigating the effects of naturalistic light in a clinical setting is therefore much needed.

Evaluation of pre-hospital transport time of stroke patients to thrombolytic treatment.

BACKGROUND: Effective treatment of stroke is time dependent. Pre-hospital management is an important link in reducing the time from occurrence of stroke symptoms to effective treatment. The aim of this study was to evaluate time used by emergency medical services (EMS) for stroke patients during a five-year period in order to identify potential delays and evaluate the reorganization of EMS in Copenhagen in 2009. METHODS: We performed a retrospective analysis of ambulance records from stroke patients suitable for thrombolysis from 1 January 2006 to 7 July 2011. We noted response time from dispatch of the ambulance to arrival at the scene, on-scene time and transport time to the hospital-in total, alarm-to-door time. In addition, we noted baseline characteristics. RESULTS: We reviewed 481 records (58% male, median age 66 years). The median (IQR) alarm-to-door time in minutes was 41 (33-52), of which 18 (12-24) minutes were spent on scene. Response time was reduced from the period before to the period after reorganization (7 vs. 5 minutes, p <0.001). In a linear multiple regression model, higher patient age and longer distance to the hospital correlated with significantly longer transportation time (p <0.001). CONCLUSIONS: This study shows an unchanged alarm-to-door time of 41 minutes over a five-year period. Response time, but not total alarm-to-door time, was reduced during the five years. On-scene time constituted nearly half of the total alarm-to-door time and is thus a point of focus for improvement.

[Santa Claus is perceived as reliable and friendly: results of the Danish Christmas 2013 survey]. / Julemanden er lige så troværdig som lægen, men venligere

INTRODUCTION: Several studies have indicated that the population in general perceives doctors as reliable. In the present study perceptions of reliability and kindness attributed to another socially significant archetype, Santa Claus, have been comparatively examined in relation to the doctor. MATERIALS AND METHODS: In all, 52 randomly chosen participants were shown a film, where a narrator dressed either as Santa Claus or as a doctor tells an identical story. Structured interviews were then used to assess the subjects' perceptions of reliability and kindness in relation to the narrator's appearance. RESULTS: We found a strong inclination for Santa Claus being perceived as friendlier than the doctor (p = 0.053). However, there was no significant difference in the perception of reliability between Santa Claus and the doctor (p = 0.524). CONCLUSION: The positive associations attributed to Santa Claus probably cause that he is perceived friendlier than the doctor who may be associated with more serious and unpleasant memories of illness and suffering. Surprisingly, and despite him being an imaginary person, Santa Claus was assessed as being as reliable as the doctor.