Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Recovery of Quiet Standing Balance and Lower Limb Motor Impairment Early Poststroke: How Are They Related?

BACKGROUND: Recovery of quiet standing balance early poststroke has been poorly investigated using repeated measurements. OBJECTIVE: To investigate (1) the time course of steady-state balance in terms of postural stability and inter-limb symmetry, and (2) longitudinal associations with lower limb motor recovery in the first 3 months poststroke. METHODS: Forty-eight hemiparetic subjects (age: 58.9 ± 16.1 years) were evaluated at weeks 3, 5, 8, and 12 poststroke. Motor impairments concerned the Fugl-Meyer assessment (FM-LE) and Motricity Index total score (MI-LE) or ankle item separately (MI-ankle). Postural stability during quiet 2-legged stance was calculated as the net center-of-pressure area (COPArea) and direction-dependent velocities (COPVel-ML and COPVel-AP). Dynamic control asymmetry (DCA) and weight-bearing asymmetry (WBA) estimated inter-limb symmetries in balance control and loading. Linear mixed models determined (1) time-dependent change and (2) the between- and within-subject associations between motor impairments and postural stability or inter-limb symmetry. RESULTS: Time-dependent improvements were significant for FM-LE, MI-LE, MI-ankle, COPArea, COPVel-ML, and COPVel-AP, and tended to plateau by week 8. DCA and WBA did not exhibit significant change. Between-subject analyses yielded significant regression coefficients for FM-LE, MI-LE, and MI-ankle scores with COPArea, COPVel-ML, and COPVel-AP up until week 8, and with WBA until week 12. Within-subject regression coefficients of motor recovery with change in COPArea, COPVel-ML, COPVel-AP, DCA, or WBA were generally non-significant. CONCLUSIONS: Postural stability improved significantly in the first 8 weeks poststroke, independent of lower limb motor recovery at the most affected side within subjects. Our findings suggest that subjects preferred to compensate with their less affected side, making metrics reflecting inter-limb asymmetries in balance invariant for change early poststroke.Clinical Trial Registration: Clinicaltrials.gov. unique identifier NCT03728036.

A systematic review and synthesis of global stroke guidelines on behalf of the World Stroke Organization.

BACKGROUND: There are multiple stroke guidelines globally. To synthesize these and summarize what existing stroke guidelines recommend about the management of people with stroke, the World Stroke Organization (WSO) Guideline committee, under the auspices of the WSO, reviewed available guidelines. AIMS: To systematically review the literature to identify stroke guidelines (excluding primary stroke prevention and subarachnoid hemorrhage) since 1 January 2011, evaluate quality (The international Appraisal of Guidelines, Research and Evaluation (AGREE II)), tabulate strong recommendations, and judge applicability according to stroke care available (minimal, essential, advanced). SUMMARY OF REVIEW: Searches identified 15,400 titles; 911 texts were retrieved, 200 publications scrutinized by the three subgroups (acute, secondary prevention, rehabilitation), and recommendations extracted from most recent version of relevant guidelines. For acute treatment, there were more guidelines about ischemic stroke than intracerebral hemorrhage; recommendations addressed pre-hospital, emergency, and acute hospital care. Strong recommendations were made for reperfusion therapies for acute ischemic stroke. For secondary prevention, strong recommendations included establishing etiological diagnosis; management of hypertension, weight, diabetes, lipids, and lifestyle modification; and for ischemic stroke, management of atrial fibrillation, valvular heart disease, left ventricular and atrial thrombi, patent foramen ovale, atherosclerotic extracranial large vessel disease, intracranial atherosclerotic disease, and antithrombotics in non-cardioembolic stroke. For rehabilitation, there were strong recommendations for organized stroke unit care, multidisciplinary rehabilitation, task-specific training, fitness training, and specific interventions for post-stroke impairments. Most recommendations were from high-income countries, and most did not consider comorbidity, resource implications, and implementation. Patient and public involvement was limited. CONCLUSION: The review identified a number of areas of stroke care where there was strong consensus. However, there was extensive repetition and redundancy in guideline recommendations. Future guideline groups should consider closer collaboration to improve efficiency, include more people with lived experience in the development process, consider comorbidity, and advise on implementation.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

BACKGROUND: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. METHODS: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. RESULTS: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]). CONCLUSIONS: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Time Course and Mechanisms Underlying Standing Balance Recovery Early After Stroke: Design of a Prospective Cohort Study With Repeated Measurements.

Introduction: Although most stroke survivors show some spontaneous neurological recovery from motor impairments of the most-affected leg, the contribution of this leg to standing balance control remains often poor. Consequently, it is unclear how spontaneous processes of neurological recovery contributes to early improvements in standing balance. Objective: We aim to investigate (1) the time course of recovery of quiet stance balance control in the first 12 weeks poststroke and (2) how clinically observed improvements of lower limb motor impairments longitudinally relate to this limb's relative contribution to balance control. Methods and Analysis: In this prospective longitudinal study, a cohort of 60 adults will be recruited within the first 3 weeks after a first-ever hemispheric stroke and mild-to-severe motor impairments. Individual recovery trajectories will be investigated by means of repeated measurements scheduled at 3, 5, 8, and 12 weeks poststroke. The Fugl-Meyer Motor Assessment and Motricity Index of the lower limb serve as clinical measures of motor impairments at the hemiplegic side. As soon as subjects are able to stand independently, bilateral posturography during quietly standing will be measured. First, the obtained center-of-pressure (COP) trajectories at each foot will be used for synchronization and contribution measures that establish (a-)symmetries between lower limbs. Second, the COP underneath both feet combined will be used to estimate overall stability. Random coefficient analyses will be used to model time-dependent changes in these measures and, subsequently, a hybrid model will be used to investigate longitudinal associations with improved motor impairments. Discussion: The current study aims to investigate how stroke survivors "re-learn" to maintain standing balance as an integral part of daily life activities. The knowledge gained through this study may contribute to recommending treatment strategies for early stroke rehabilitation targeting behavioral restitution of the most-affected leg or learning to compensate with the less-affected leg.

The impact of COVID-19 on acute stroke care in Belgium.

A worldwide decline in stroke hospitalizations during the COVID-19 pandemic has been reported. Information on stroke care during the pandemic in Belgium is lacking. This study aims to analyze the impact of COVID-19 on acute stroke care in eight Belgian stroke centers. This Belgian study is part of an international observational and retrospective study in 70 countries and 457 stroke centers. We compared volumes of COVID-19 and stroke hospitalizations, intravenous thrombolysis and endovascular treatment rates, acute treatment time intervals and functional outcome at 90 days during the first wave of the pandemic to two control intervals (March-May 2019 and December-February 2020). From March 2020 to May 2020, 860 stroke patients were hospitalized. In the same time period, 2850 COVID-19 patients were admitted, of which 37 (1.3%) were diagnosed with a stroke. Compared to the months prior to the pandemic and the same time epoch one year earlier, stroke hospitalizations were reduced (relative difference 15.9% [p = 0.03] and 14.5% [p = 0.05], respectively). Despite a reduction in absolute volumes, there was no difference in the monthly proportion of thrombolysis or endovascular treatment provided to the overall stroke hospitalizations. Acute treatment time metrics did not change between COVID-19 pandemic and control time epochs. We found no difference in 90-day functional outcomes nor in mortality after stroke between patients admitted during the pandemic versus control periods. We found a decline in the volume of stroke hospitalizations during the first wave of the COVID-19 pandemic in Belgium. Stroke care quality parameters remained unchanged.

Vessel territory mapping after cerebral revascularization surgery using selective angiographic flat detector perfusion imaging.

The technical feasibility and diagnostic potential of angiographic flat-detector perfusion imaging technique, combining digital subtraction angiography with a flat-detector computed tomography steady-state perfusion imaging, was explored in patients treated with direct or indirect revascularization surgery. This short communication is about an imaging modality with great potential for evaluation, comparison and grading of vascular perfusion territory areas and anatomical location selectively perfused by direct and indirect cerebral bypasses.

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and The Netherlands: insights from the ETNA-AF-Europe study.

BACKGROUND: Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. METHODS: With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50 mL/min, weight ≤60 kg, and/or use of strong p-glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). RESULTS: Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. CONCLUSION: There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. TRIAL REGISTRATION: NCT02944019; Date of registration: October 24, 2016.

Predictors of 30-day and 90-day mortality among hemorrhagic and ischemic stroke patients in urban Uganda: a prospective hospital-based cohort study.

BACKGROUND: We report here on a prospective hospital-based cohort study that investigates predictors of 30-day and 90-day mortality and functional disability among Ugandan stroke patients. METHODS: Between December 2016 and March 2019, we enrolled consecutive hemorrhagic stroke and ischemic stroke patients at St Francis Hospital Nsambya, Kampala, Uganda. The primary outcome measure was mortality at 30 and 90 days. The modified Ranking Scale wasused to assess the level of disability and mortality after stroke. Stroke severity at admission was assessed using the National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS). Examination included clinical neurological evaluation, laboratory tests and brain computed tomography (CT) scan. Kaplan-Meier curves and multivariate Cox proportional hazard model were used for unadjusted and adjusted analysis to predict mortality. RESULTS: We enrolled 141 patients; 48 (34%) were male, mean age was 63.2 (+ 15.4) years old; 90 (64%) had ischemic and 51 (36%) had hemorrhagic stroke; 81 (57%) were elderly (≥ 60 years) patients. Overall mortality was 44 (31%); 31 (23%) patients died within the first 30 days post-stroke and, an additional 13 (14%) died within 90 days post-stroke. Mortality for hemorrhagic stroke was 19 (37.3%) and 25 (27.8%) for ischemic stroke. After adjusting for age and sex, a GCS score below < 9 (adjusted hazard ratio [aHR] =3.49, 95% CI: 1.39-8.75) was a significant predictor of 30-day mortality. GCS score < 9 (aHR =4.34 (95% CI: 1.85-10.2), stroke severity (NIHSS ≥21) (aHR = 2.63, 95% CI: (1.68-10.5) and haemorrhagic stroke type (aHR = 2.30, 95% CI: 1.13-4.66) were significant predictors of 90-day mortality. Shorter hospital stay of 7-13 days (aHR = 0.31, 95% CI: 0.11-0.93) and being married (aHR = 0.22 (95% CI: 0.06-0.84) had protective effects for 30 and 90-day mortality respectively. CONCLUSION: Mortality is high in the acute and sub-acute phase of stroke. Low levels of consciousness at admission, stroke severity, and hemorrhagic stroke were associated with increased higher mortality in this cohort of Ugandan stroke patients. Being married provided a protective effect for 90-day mortality. Given the high mortality during the acute phase, critically ill stroke patients would benefit from early interventions established as the post-stroke- standard of care in the country.

Multicenter, retrospective analysis of endovascular treatment for acute ischemic stroke in nonagenarians.

BACKGROUND: With the increasing age of acute stroke patients being admitted to hospitals, more data are needed on indications, complications and outcome of endovascular treatment (EVT) in the very elderly. METHODS: Retrospective observational study with data collection from Belgian, Swiss, Canadian comprehensive stroke centers and Swedish EVT National database. All patients with acute ischemic stroke were eligible if aged older than or ≥90 years and treated with EVT ± pretreatment with intravenous thrombolysis (IVT). Safety assessment comprised presence of periprocedural complications, hemorrhagic transformation or other adverse events (<7days). Efficacy and outcome measures were successful recanalization (modified Treatment In Cerebral Infarction (mTICI) score ≥2b), favorable clinical outcome (modified Rankin Score (mRS) 0-2) and 3-months mortality. RESULTS: Inclusion of 112 nonagenarians (mean age 93.3 ± 2.5 years; 76.8% women; pre-mRS ≤2 in 69.4%). Pretreatment with IVT was performed in 54.7%. In 74.6% successful recanalization (mTICI ≥2b) was achieved. Favorable outcome (mRS ≤2) was seen in 16.4% and 3-months mortality was 62.3%. Multivariate logistic regression analysis showed younger age (odds ratio [OR] 2.99; 1.29-6.95; P = .011) and lower prestroke mRS (OR 13.46; 2.32-78.30; P = .004) as significant predictors for good clinical outcome at 90 days. CONCLUSIONS: Our observational study on EVT in nonagenarians demonstrates the need for careful patient selection. A substantial proportion of nonagenarians shows an unfavorable clinical outcome and high mortality, despite acceptable recanalization rates. A high prestroke disability (mRS) and advancing age predict an unfavorable outcome. Treatment decisions should be made on case-by-case evaluation, keeping in mind limited chances of favorable outcome and high risk of mortality.

Cerebral venous thrombosis in women of childbearing age: diagnosis, treatment, and prophylaxis during a future pregnancy.

Sex-specific risk factors for cerebral venous thrombosis (CVT) in women include oral contraceptives, pregnancy, puerperium, and hormone replacement therapy. The acute treatment of CVT is anticoagulation using therapeutic doses of low molecular weight heparin, which is also the preferred treatment in the post-acute phase in pregnancy and during breastfeeding. In patients with imminent brain herniation decompressive surgery is probably life-saving. A medical history of CVT alone is not a contraindication for future pregnancies. The optimal dosage of low molecular weight heparin as thrombosis prophylaxis during future pregnancies after a history of venous thrombosis including CVT is the topic of an ongoing trial.

Caring for a stroke patient: The burden and experiences of primary caregivers in Uganda - A qualitative study.

AIM: We assessed the burden and experiences of caregivers looking after stroke patients in Kampala, Uganda. DESIGN: We conducted a qualitative cross-sectional study between May 2018-July 2018 among primary caregivers of stroke patients. METHODS: The primary caregiver was defined as the person spending most of the time providing daily care for the stroke patient for at least four months. Purposive sampling was used to consecutively recruit the primary caregivers. In-depth interviews were conducted, and audiotape recorded, and observations were also made. Data were managed using NVIVO 12.0 following thematic approach. RESULTS: Twenty-five caregivers were included in the analysis with a mean age of 39.3, SD 10.7. Four themes were identified from the qualitative analysis on caregivers' experiences of looking after stroke patients: taking on new responsibilities, factors that protected caregivers from breaking down, limited resources and experiences with patient outcomes. Our findings highlight the need for interventions to support stroke patients and their caregivers.

Complete Transection of Optic Nerve After Endovascular Coiling of a Large Ophthalmic Artery Aneurysm.

BACKGROUND: We describe a patient who developed delayed blindness of the left eye at 5 weeks after endovascular coiling of a large ophthalmic aneurysm. CASE DESCRIPTION: A 44-year-old male was admitted with visual decline due to compression of the optic nerve by a large ophthalmic aneurysm. The aneurysm was treated by endovascular coiling, but visual function was unchanged. One month and 7 days later, the patient developed sudden blindness of the affected eye, despite complete angiographical occlusion of the aneurysm. Surgical exploration in an attempt to restore vision showed a fully thrombosed aneurysm but, surprisingly, complete transection of the optic nerve just proximal to its entry into the optic canal. CONCLUSIONS: This report describes a rare complication of a sudden increase in size of a large ophthalmic aneurysm despite successful endovascular occlusion.

Current concepts in imaging and endovascular treatment of acute ischemic stroke: implications for the clinician.

During the last decade, the management of acute ischemic stroke has changed dramatically, from an expectant bedside "wait and see" attitude towards active treatment, thanks to the continuous improvement of new therapeutic options. In addition to the use of intravenous (IV) thrombolysis in emergent large vessel occlusion (ELVO), endovascular therapy (EVT) has proven to be very efficient in selected acute stroke patients. The indications for EVT have progressed from the era of thrombolysis to individual patient profiling. Recently, several indication parameters, e.g., "treatment time window" or "more distal vessel occlusion," are under debate for adjustment. In this article, we review the imaging strategies in acute stroke and discuss several EVT indication dogmas, which are subject to change.

Galactosidase Alpha p.A143T Variant Fabry Disease May Result in a Phenotype With Multifocal Microvascular Cerebral Involvement at a Young Age.

INTRODUCTION: A 16-year-old male presented with episodic headaches and a brain magnetic resonance imaging (MRI) that showed multifocal punctate to patchy white matter lesions. The diagnosis of Fabry disease (FD) was suggested upon the finding of significantly reduced plasma alpha-galactosidase A activity (0.62 µmol/L or 13% of normal; normal range ≥ 1.65 µmol/L) and genetic investigation confirmed the presence of a hemizygous missense variant in the galactosidase alpha (GLA) gene (p.A143T). Baseline assessment of other systemic involvement showed only a discrete proteinuria. BACKGROUND: FD is a rare lysosomal storage disorder. Genetic screening studies have revealed over 600 variants in the GLA gene. The p.A143T variant is a genetic variant of unknown significance, with its associated phenotype ranging from classical FD to healthy unaffected patients. Some authors, however, deem this variant non-pathogenic. We describe the case of a 16-year-old male with multifocal white matter lesions on brain MRI, who was diagnosed with FD and carried this genetic variant. DISCUSSION: The causative p.A143T mutation can be associated with a more severe subclinical phenotype than has been reported to date. Furthermore, a diagnosis of FD should be considered when finding asymptomatic cerebral white matter lesions in a young patient.

Risk Factors for Hemorrhagic and Ischemic Stroke in Sub-Saharan Africa.

INTRODUCTION: In sub-Saharan Africa (SSA), there is a significant burden of ischemic stroke (IS) and hemorrhagic stroke (HS), although data on risk factors for each type are sparse. In this systematic review we attempt to characterize the risk factors. METHODS: We systematically reviewed (PubMed, EMBASE, WHOLIS, Google Scholar, Wiley online, and the Cochrane Central Register of Controlled Trials (CENTRAL)) case-control studies and case series from 1980 to 2016 that reported risk factors for IS and/or HS in SSA. For each risk factor we calculated random-effects pooled odds ratios (ORs) for case-control studies and pooled prevalence estimates for case series. Results. We identified 12 studies, including 4,387 stroke patients. Pooled analysis showed that patients who had diabetes (OR = 2.39; 95% CI: 1.14-5.03) and HIV (OR = 2.46 (95% CI: 1.59-3.81) were at a significantly greater risk of suffering from all stroke types. There were insufficient data to examine these factors by stroke type. Among case series, the pooled prevalence of hypertension was higher for HS than for IS (73.5% versus 62.8%), while diabetes mellitus (DM) and atrial fibrillation (AF) were more prevalent among IS compared to HS (15.9% versus 10.6% and 9.6% versus 2.3%, respectively). CONCLUSIONS: There remain too few data from SSA to reliably estimate the effect of various factors on the risk of IS and HS. Furthermore, the vast majority of cases were identified in hospital and so are unlikely to be representative of the totality of stroke cases in the community.

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia.

Classical or M1 activity of microglia/macrophages has been described in several neurodegenerative and brain inflammatory conditions and has also been linked to expansion of ischemic injury in post-stroke brain. While different pathways of M1 polarization have been suggested to occur in the post-stroke brain, the precise underlying mechanisms remain undefined. Using a transient middle cerebral artery occlusion (MCAO) rat model, we showed a progressive M2 to M1 polarization in the perilesional brain region with M1 cells becoming one of the dominant subsets by day 4 post-stroke. Comparing key receptors involved in M1 polarization (CD8, IFNγR, Clec4, FcγR, TLR3 and TLR4) and their signal transducers (Syk, Stat1, Irf3, and Traf6) at the day 4 time point, we showed a strong upregulation of CD8 along with SYK transducer in dissected perilesional brain tissue. We further showed that CD8 expression in the post-stroke brain was associated with activated (CD68+) macrophages and that progressive accumulation of CD8+CD68+ cells in the post-stroke brain coincided with increased iNOS (M1 marker) and reduced Arg1 (M2 marker) expression on these cells. In vitro ligand-based stimulation of the CD8 receptor caused increased iNOS expression and an enhanced capacity to phagocytose E. coli particles; and interestingly, CD8 stimulation was also able to repolarize IL4-treated M2 cells to an M1 phenotype. Our data suggest that increased CD8 signaling in the post-stroke brain is primarily associated with microglia/macrophages and can independently drive M1 polarization, and that modulation of CD8 signaling could be a potential target to limit secondary post-stroke brain damage.

Feasibility, Reliability and Predictive Value Of In-Ambulance Heart Rate Variability Registration.

BACKGROUND: Heart rate variability (HRV) is a parameter of autonomic nervous system function. A decrease of HRV has been associated with disease severity, risk of complications and prognosis in several conditions. OBJECTIVE: We aim to investigate the feasibility and the reliability of in-ambulance HRV registration during emergency interventions, and to evaluate the association between prehospital HRV parameters, patient characteristics, vital parameters and short-term outcome. METHODS: We conducted a prospective study using a non-invasive 2-lead ECG registration device in 55 patients transported by the paramedic intervention team of the Universitair Ziekenhuis Brussel. HRV assessment included time domain parameters, frequency domain parameters, nonlinear analysis, and time-frequency analysis. The correlation between HRV parameters and patient and outcome characteristics was analyzed and compared to controls. RESULTS: Artifact and ectopic detection rates were higher in patients during ambulance transportation compared to controls in resting conditions, yet technical reasons precluding in-ambulance HRV analysis occurred in only 9.6% of cases. HRV acquisition was possible without safety issues or interference with routine emergency care. Reliability of the results was considered sufficient for Sample entropy (SampEn), good for the ratio of low frequency and high frequency components (LF/HF ratio) in the frequency and the time frequency domain, and excellent for the triangular interpolation of the NN interval histogram (TINN), and for the short-term scaling exponent of the detrended fluctuation analysis (DFA α1). HRV indices were significantly reduced inpatients with unfavorable outcome compared to patients with favorable outcome and controls. Multivariate analysis identified lower DFA α1 as an independent predictor of unfavorable outcome (OR, 0.155; 95% CI 0.024-0.966; p = 0.049). CONCLUSION: In-ambulance HRV registration is technically and operationally feasible and produces reliable results for parameters in the time, frequency, nonlinear and time frequency domain. Especially non-linear HRV analysis during emergency ambulance transportation may be a promising approach to predict patient outcome.

Development and Pilot Testing of 24/7 In-Ambulance Telemedicine for Acute Stroke: Prehospital Stroke Study at the Universitair Ziekenhuis Brussel-Project.

BACKGROUND: In-ambulance telemedicine is a recently developed and a promising approach to improve emergency care. We implemented the first ever 24/7 in-ambulance telemedicine service for acute stroke. We report on our experiences with the development and pilot testing of the Prehospital Stroke Study at the Universitair Ziekenhuis Brussel (PreSSUB) to facilitate a wider spread of the knowledge regarding this technique. METHODS: Successful execution of the project involved the development and validation of a novel stroke scale, design and creation of specific hardware and software solutions, execution of field tests for mobile internet connectivity, design of new care processes and information flows, recurrent training of all professional caregivers involved in acute stroke management, extensive testing on healthy volunteers, organisation of a 24/7 teleconsultation service by trained stroke experts and 24/7 technical support, and resolution of several legal issues. RESULTS: In all, it took 41 months of research and development to confirm the safety, technical feasibility, reliability, and user acceptance of the PreSSUB approach. Stroke-specific key information can be collected safely and reliably before and during ambulance transportation and can adequately be communicated with the inhospital team awaiting the patient. CONCLUSION: This paper portrays the key steps required and the lessons learned for successful implementation of a 24/7 expert telemedicine service supporting patients with acute stroke during ambulance transportation to the hospital.