Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review.

BACKGROUND AND PURPOSE: Outcome prognostication in ischemic stroke patients remains challenging due to limited predictive properties of existing models. Blood-based biomarkers might provide additional information to established prognostic factors. We intended to identify the most promising prognostic biomarkers in ischemic stroke, their incremental prognostic value, and whether their predictive value differs among etiologies. METHODS: We searched MEDLINE (Ovid) and Institute for Scientific Information Web of Knowledge for articles reporting the predictive performance of blood-based biomarkers measured up to 7 days after ischemic stroke and reporting functional outcome or death at least 7 days after stroke. This work updates a previous systematic review (up to January 2007), follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was registered (International Prospective Register of Systematic Reviews PROSPERO 2018; https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018094671). RESULTS: Two hundred ninety-one articles published between January 2007 and August 2018 comprising 257 different biomarkers met inclusion criteria. Median sample size was 232 (interquartile range, 110-455); 260 (89%) articles reported regression analyses with 78% adjusting for stroke severity, 82% for age, 67% for both, and 9% for none of them; 37% investigated discrimination, 5% calibration, and 11% reclassification. Including publications from a previous systematic review (1960-January 2007), natriuretic peptides, copeptin, procalcitonin, mannose-binding lectin, adipocyte fatty acid-binding protein, and cortisol were the biomarkers most consistently associated with poor outcome in higher-quality studies showing an incremental value over established prognostic factors. Other biomarkers were less consistently associated with poor outcome or were reported in lower quality studies. High heterogeneity among studies precluded the performance of a meta-analysis. CONCLUSIONS: The number of reports on prognostic blood-based biomarkers in ischemic stroke increased 3.5-fold in the period January 2007 to August 2018. Although sample size increased, methodological flaws are still common. Natriuretic peptides and markers of inflammation, atherogenesis, and stress response are the most promising prognostic biomarkers among identified studies.

Clinical Importance of Temporal Bone Features for the Efficacy of Contrast-Enhanced Sonothrombolysis: a Retrospective Analysis of the NOR-SASS Trial.

Contrast-enhanced sonothrombolysis (CEST) seems to be a safe and promising treatment in acute ischemic stroke. It remains unknown if temporal bone features may influence the efficacy of CEST. We investigated the association between different temporal bone features on admission computed tomography (CT) scan and the outcome in acute ischemic stroke patients included in the randomized Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS). Patients diagnosed as stroke mimics and those with infratentorial stroke or with incorrect insonation were excluded. We retrospectively assessed temporal bone heterogeneity (presence of diploë), diploë ratio, thickness, and density on admission CT scans. National institute of Health Stroke Scale (NIHSS) at 24 h and modified Rankin Scale (mRS) at 3 months were correlated with CT findings both in CEST and sham CEST patients. A total of 99 patients were included of which 52 were assigned to CEST and 47 to sham CEST. Approximately 20% patients had a heterogeneous temporal bone in both the CEST and sham CEST group. All temporal bone CT features studied were associated with female sex. In the CEST group, temporal bone heterogeneity (p = 0.006) and higher temporal bone diploë ratio (p = 0.002) were associated with higher NIHSS at 24 h. There was no association between temporal bone features and mRS at 3 months. Approximately 20% of acute ischemic stroke patients have heterogeneous temporal bone and may be resistant to standard 2-MHz transcranial Doppler ultrasound treatment. Sonothrombolysis resistance may easily be predicted by admission CT for better selection.

NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): Randomized Controlled Contrast-Enhanced Sonothrombolysis in an Unselected Acute Ischemic Stroke Population.

BACKGROUND AND PURPOSE: The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. METHODS: Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. RESULTS: A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis. CONCLUSIONS: CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01949961.

U-curve relation between cholesterol and prior ischemic stroke.

OBJECTIVES: Previous prospective studies on ischemic stroke patients have shown conflicting results concerning the association between cholesterol level and patient outcome. We aimed to investigate the relation between cholesterol level and prior ischemic stroke. We hypothesized that acute ischemic stroke patients with increased cholesterol on admission more frequently had experienced prior ischemic stroke. METHODS: All consecutive patients with acute ischemic stroke (the index stroke) admitted to the Stroke Unit, Department of Neurology, Haukeland University Hospital between February 2006 and October 2013 were prospectively registered in The Bergen NORSTROKE Registry. On admission, cholesterol, low-density lipoprotein, and high-density lipoprotein levels were measured and prior ischemic stroke, risk factors, and medication were registered. Patients with prior versus no prior ischemic stroke were compared regarding risk factors, cholesterol levels, and use of statins on admission for the index stroke. Only patients with available cholesterol values measured on admission were included in the analyses. RESULTS: Of the 2,514 included patients admitted with acute ischemic stroke, 429 (17%) patients had prior ischemic stroke. We found a U-curve relationship between the relative frequency of prior ischemic stroke and cholesterol level. Lower frequency of prior ischemic stroke was associated with high cholesterol level on admission up to 5.5 mmol/L. For cholesterol levels higher than this, the opposite was true. These associations included all patients and statin-naive patients. For patients using statin there was a declining relative frequency of prior ischemic stroke from low to high cholesterol levels. CONCLUSION: Our hypothesis was falsified. The association between lower cholesterol levels and higher frequency of prior ischemic stroke in patients with cholesterol <5.5 mmol/L cannot be solely an effect of aggressive statin treatment in patients with prior ischemic stroke, as the association pertained also to patients who did not use statin.

Novel Thrombolytics for Acute Ischemic Stroke: Challenges and Opportunities.

Progress in finding a better alternative to alteplase has been slow. Tenecteplase and desmoteplase have better pharmacological profiles compared with alteplase, but definite clinical evidence of their superiority is lacking. The two major phase III studies that have tested the efficacy and safety of desmoteplase in ischemic stroke patients have shown neutral results and a promising safety profile, but the trials compared desmoteplase with placebo only in late admitted patients. Future trials should focus on testing novel thrombolytics in the early time window either as the sole acute recanalizing treatment or combined with thrombectomy.

A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS).

BACKGROUND: Ultrasound accelerates thrombolysis with tPA (sonothrombolysis). Ultrasound in the absence of tPA also accelerates clot break-up (sonolysis). Adding intravenous gaseous microbubbles may potentiate the effect of ultrasound in both sonothrombolysis and sonolysis. The Norwegian Sonothrombolysis in Acute Stroke Study aims in a pragmatic approach to assess the effect and safety of contrast enhanced ultrasound treatment in unselected acute ischaemic stroke patients. METHODS/DESIGN: Acute ischaemic stroke patients ≥ 18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4(½) hours after symptom onset, are included in NOR-SASS. NOR-SASS is superimposed on a separate trial randomising patients with acute ischemic stroke to either tenecteplase or alteplase (The Norwegian Tenecteplase Stroke Trial NOR-TEST). The NOR-SASS trial has two arms: 1) the thrombolysis-arms (NOR-SASS A and B) includes patients given intravenous thrombolysis (tenecteplase or alteplase), and 2) the no-thrombolysis-arm (NOR-SASS C) includes patients with contraindications to thrombolysis. First step randomisation of NOR-SASS A is embedded in NOR-TEST as a 1:1 randomisation to either tenecteplase or alteplase. Second step NOR-SASS randomisation is 1:1 to either contrast enhanced sonothrombolysis (CEST) or sham CEST. Randomisation in NOR-SASS B (routine alteplase group) is 1:1 to either CEST or sham CEST. Randomisation of NOR-SASS C is 1:1 to either contrast enhanced sonolysis (CES) or sham CES. Ultrasound is given for one hour using a 2-MHz pulsed-wave diagnostic ultrasound probe. Microbubble contrast (SonoVue®) is given as a continuous infusion for ~30 min. Recanalisation is assessed at 60 min after start of CEST/CES. Magnetic resonance imaging and angiography is performed after 24 h of stroke onset. Primary study endpoints are 1) major neurological improvement measured with NIHSS score at 24 h and 2) favourable functional outcome defined as mRS 0-1 at 90 days. DISCUSSION: NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤ 4(½) hours after stroke onset in an unselected acute ischaemic stroke population eligible or not eligible for intravenous thrombolysis, with or without a defined arterial occlusion on CTA. If a positive effect and safety can be proven, contrast enhanced ultrasound treatment will be an option for all acute ischaemic stroke patients. EudraCT No 201200032341; www.clinicaltrials.gov NCT01949961.

Complicating autoimmune diseases in myasthenia gravis: a review.

Myasthenia gravis (MG) is a rare autoimmune disease of skeletal muscle endplates. MG subgroup is relevant for comorbidity, but usually not accounted for. MG patients have an increased risk for complicating autoimmune diseases, most commonly autoimmune thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. In this review, we present concomitant autoimmune disorders associated with the different MG subgroups, and show how this influences treatment and prognosis. Concomitant MG should always be considered in patients with an autoimmune disorder and developing new neuromuscular weakness, fatigue or respiratory failure. When a second autoimmune disorder is suspected, MG should be included as a differential diagnosis.

The Norwegian tenecteplase stroke trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke.

BACKGROUND: Alteplase is the only approved thrombolytic agent for acute ischaemic stroke. The overall benefit from alteplase is substantial, but some evidence indicates that alteplase also has negative effects on the ischaemic brain. Tenecteplase may be more effective and less harmfull than alteplase, but large randomised controlled phase 3 trials are lacking. The Norwegian Tenecteplase Stroke Trial (NOR-TEST) aims to compare efficacy and safety of tenecteplase vs. alteplase. METHODS/DESIGN: NOR-TEST is a multi-centre PROBE (prospective randomised, open-label, blinded endpoint) trial designed to establish superiority of tenecteplase 0.4 mg/kg (single bolus) as compared with alteplase 0.9 mg/kg (10% bolus + 90% infusion/60 minutes) for consecutively admitted patients with acute ischaemic stroke eligible for thrombolytic therapy, i.e. patients a) admitted <4½ hours after symptoms onset; b) admitted <4½ hours after awakening with stroke symptoms c) receiving bridging therapy before embolectomy.Randomisation tenecteplase:alteplase is 1:1. The primary study endpoint is favourable functional outcome defined as modified Rankin Scale 0-1 at 90 days. Secondary study endpoints are: 1) haemorrhagic transformation (haemorrhagic infarct/haematoma); 2) symptomatic cerebral haemorrhage on CT 24-48 hours; 3) major neurological improvement at 24 hours; 4) recanalisation at 24-36 hours; 5) death. DISCUSSION: NOR-TEST may establish a novel approach to acute ischaemic stroke treatment. A positive result will lead to a more effective, safer and easier treatment for all acute ischaemic stroke pasients.NOR-TEST is reviewed and approved by the Regional Committee for Medical and Health Research Ethics (2011/2435), and The Norwegian Medicines Agency (12/01402). NOR-TEST is registered with EudraCT No 2011-005793-33 and in ClinicalTrials.gov (NCT01949948).

Is higher body temperature beneficial in ischemic stroke patients with normal admission CT angiography of the cerebral arteries?

BACKGROUND: Low body temperature is considered beneficial in ischemic stroke due to neuroprotective mechanisms, yet some studies suggest that higher temperatures may improve clot lysis and outcomes in stroke patients treated with tissue plasminogen activator (tPA). The effect of increased body temperature in stroke patients treated with tPA and with normal computed tomography angiography (CTA) on admission is unknown. We hypothesized a beneficial effect of higher body temperature in the absence of visible clots on CTA, possibly due to enhanced lysis of small, peripheral clots. METHODS: Patients with ischemic stroke admitted to our Stroke Unit between February 2006 and April 2013 were prospectively registered in a database (Bergen NORSTROKE Registry). Ischemic stroke patients treated with tPA with normal CTA of the cerebral arteries were included. Outcomes were assessed by the modified Rankin Scale (mRS) after 1 week. An excellent outcome was defined as mRS=0, and a favorable outcome as mRS=0-1. RESULTS: A total of 172 patients were included, of which 48 (27.9%) had an admission body temperature ≥37.0°C, and 124 (72.1%) had a body temperature <37.0°C. Body temperature ≥37.0°C was independently associated with excellent outcomes (odds ratio [OR]: 2.8; 95% confidence interval [CI]: 1.24-6.46; P=0.014) and favorable outcomes (OR: 2.8; 95% CI: 1.13-4.98; P=0.015) when adjusted for confounders. CONCLUSION: We found an association between higher admission body temperature and improved outcome in tPA-treated stroke patients with normal admission CTA of the cerebral arteries. This may suggest a beneficial effect of higher body temperature on clot lysis in the absence of visible clots on CTA.