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1.  A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS) 
BMC Neurology  2015;15:110.
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.
Acute ischaemic stroke patients ≥18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4½ 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.
NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤4½ 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; NCT01949961.
PMCID: PMC4499181  PMID: 26162826
Randomised controlled trial; Acute ischemic stroke; Arterial occlusion; Contrast; Recanalisation; Outcome; Safety; Sonolysis; Sonothrombolysis; Thrombolysis; Transcranial ultrasound
2.  Stroke patients’ knowledge about cardiovascular family history - the Norwegian Stroke in the Young Study (NOR-SYS) 
BMC Neurology  2015;15:30.
Family history (FH) is a risk factor for cardiovascular disease, especially coronary artery disease (CAD). The impact on risk of stroke is less clear. This study investigated young and middle-aged ischemic stroke patients’ knowledge on FH of stroke, CAD, and peripheral artery disease (PAD) with a special regard to sex differences.
From September 2010 to February 2014, all ischemic stroke patients aged 15–60 years were prospectively included in the Norwegian Stroke in the Young Study (NOR-SYS). FH of stroke, CAD and PAD in offspring, siblings, parents, and grandparents was assessed using a standardized face-to-face interview. In addition to ‘yes’ and ‘no’, the optional reply ‘don’t know’ was included to improve accuracy. McNemar’s test was used to compare paired proportions, i.e. FH in male vs. female relatives. Multiple logistic regression analyses were used to test the influence of patient sex on FH reporting and to adjust for possible confounding factors.
Altogether 257 patients were included. Mean age was 49.5 years and 68.1% were males. FH of cardiovascular disease was reported by 59% of patients. When asked about FH of stroke, 48 (18.7%) and 46 (17.9%) patients reported yes, whereas 17 (6.6%) and 9 (3.5%) reported ‘don’t know’ regarding father and mother respectively, similarly patients reported ‘don’t know’ regarding 117 (45.5%) paternal vs. 83 (32.4%) maternal grandmothers (p < 0.001). Female patients reported less ‘don’t know’ and were more likely to report a positive cardiovascular FH than males (OR: 3.4; 95% CI: 1.5 to 7.7; p = 0.004). Patients had more detailed knowledge about CAD than stroke in fathers (p < 0.001), mothers (p < 0.001) and siblings (p = 0.01).
Young and middle-aged stroke patients reported a high FH burden of cardiovascular disease. Females are more likely to report a positive FH than males. Detailed knowledge on FH was best for CAD. Our results suggest sex has a big impact on FH knowledge. Females have more knowledge of FH than males and knowledge is better for relatives with a female than male linkage.
Clinical trial registration, unique identifier: NCT01597453.
PMCID: PMC4359475  PMID: 25884546
Young stroke; Family history; Ischemic stroke; Cardiovascular disease
3.  The Norwegian tenecteplase stroke trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke 
BMC Neurology  2014;14:106.
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.
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.
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 (NCT01949948).
PMCID: PMC4029902  PMID: 24886064
Acute ischaemic stroke; Alteplase; Intravenous thrombolysis; Tenecteplase
4.  The Norwegian Stroke in the Young Study (NOR-SYS): Rationale and design 
BMC Neurology  2013;13:89.
Ischemic stroke in young adults is a major health problem being associated with a higher vascular morbidity and mortality compared to controls, and a stroke recurrence rate of 25% during the first decade. The assumed cause of infarction and the detected risk factors determine the early- and long-term treatment. However, for many patients the cause of stroke remains unknown. Risk factor profile and etiology differ in young and elderly ischemic stroke patients, and atherosclerosis is the determined underlying condition in 10 to 15%. However, subclinical atherosclerosis is probably more prevalent and may go unrecognized.
Ultrasound imaging is a sensitive method for the detection of arterial disease and for measurement of adipose tissue. The relationship between intima-media thickness (IMT), plaques, cardiovascular risk factors including visceral adipose tissue (VAT) and ischemic events has repeatedly been shown.
We have established The Norwegian Stroke in the Young Study (NOR-SYS) as a three-generation research program with the goal to increase our knowledge on heredity and the development of arterial disease and ischemic stroke. Extended standardized ultrasound examinations are done in order to find subclinical vessel disease for early and better prophylaxis.
NOR-SYS is a prospective long-term research program. Standardized methods are used for anamnestic, clinical, laboratory, imaging, and ultrasound data collection in ischemic stroke patients aged ≤60 years, their partners and joint adult offspring. The ultrasound protocol includes the assessment of intracranial, carotid and femoral arteries, abdominal aorta, and the estimation of VAT. To date, the study is a single centre study with approximately 400 patients, 250 partners and 350 adult offspring expected to be recruited at our site.
NOR-SYS aims to increase our knowledge about heredity and the development of arterial vascular disease in young patients with ischemic stroke and their families. Moreover, optimization of diagnostics, prophylaxis and early intervention are major targets with the intention to reduce stroke recurrence and other clinical arterial events, physical disability, cognitive impairment and death.
NOR-SYS is reviewed and approved by the Regional Committee for Medical and Health Research Ethics, Western-Norway (REK-Vest 2010/74), and registered in NCT01597453.
PMCID: PMC3721997  PMID: 23865483
Ischemic stroke; Stroke in the young; Atherosclerosis; Arterial disease; Ultrasound; Heredity; Vascular risk; Long-term outcome; Mortality
5.  Serum uri acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study 
BMC Neurology  2011;11:114.
A possible synergic role of serum uric acid (SUA) with thrombolytic therapies is controversial and needs further investigations. We therefore evaluated association of admission SUA with clinical improvement and clinical outcome in patients receiving rt-PA, early admitted patients not receiving rt-PA, and patients admitted after time window for rt-PA.
SUA levels were obtained at admission and categorized as low, middle and high, based on 33° and 66° percentile values. Patients were categorized as patients admitted within 3 hours of symptom onset receiving rt-PA (rt-PA group), patients admitted within 3 hours of symptom onset not receiving rt-PA (non-rt-PA group), and patients admitted after time window for rt-PA (late group). Short-term clinical improvement was defined as the difference between NIHSS on admission minus NIHSS day 7. Favorable outcome was defined as mRS 0 - 3 and unfavorable outcome as mRS 4 - 6.
SUA measurements were available in 1136 patients. Clinical improvement was significantly higher in patients with high SUA levels at admission. After adjustment for possible confounders, SUA level showed a positive correlation with clinical improvement (r = 0.012, 95% CI 0.002-0.022, p = 0.02) and was an independent predictor for favorable stroke outcome (OR 1.004; 95% CI 1.0002-1.009; p = 0.04) only in the rt-PA group.
SUA may not be neuroprotective alone, but may provide a beneficial effect in patients receiving thrombolysis.
PMCID: PMC3188473  PMID: 21943291
6.  Microemboli-monitoring during the acute phase of ischemic stroke: Is it worth the time? 
BMC Neurology  2010;10:79.
The prevalence of microembolic signals (MES) during the acute phase of ischemic stroke and its influence on outcome is not well studied. The aim of our study was to determine the prevalence of MES, the different factors that are associated with the presence of MES and the association between MES and outcomes in stroke patients investigated within 6 hours after the onset of ischemic stroke.
We included unselected ischemic stroke patients who underwent microemboli-monitoring within six hours after stroke onset. Microemboli-monitoring of both middle cerebral arteries (MCA) was done for a period of 1 hour using 2-MHz probes applied over the trans-temporal window. Prevalence of MES, predictors for the presence of MES and the association between MES and various outcome factors were analyzed.
Forty patients were included. The mean age of the patients was 70 years. The prevalence of either ipsilateral or contralateral MES were 25% (n = 10). The predictors for the presence of MES were older age (OR 9; p = 0.03), higher NIHSS (OR 28; p = 0.02), intracranial stenosis (OR 10; p = 0.04) and embolic stroke (large-artery atherosclerosis and cardioembolism on TOAST classification) (OR 7; p = 0.06). MES were not independently associated with short-term functional outcome, long-term mortality or future vascular events.
MES are moderately frequent following acute ischemic stroke. Microemboli-monitoring helps to better classify the stroke etiology. However, the presence MES did not have any prognostic significance in this study.
PMCID: PMC2944121  PMID: 20831778
7.  Clinical presentation and diffusion weighted MRI of acute cerebral infarction. The Bergen Stroke Study 
BMC Neurology  2009;9:44.
No large study has compared the yield of diffusion-weighted imaging (DWI) with clinical examination in order to differentiate lacunar stroke from other stroke subtypes. This differentiation is important for guiding further investigations and treatment.
Consecutive patients admitted with cerebral infarction were classified according to the Oxfordshire Community Stroke Project scale. Based on DWI and CT stroke was classified as lacunar (LI) and non-lacunar (NLI). Acute ischemic lesion <1.5 cm and located in subcortex or in brainstem were classified as LI. All other infarctions were classified as NLI.
DWI was performed in 419 (69%) patients. Among patients with lacunar syndrome (LACS) 45 (40.5%) had NLI on DWI. All patients with total anterior syndrome (TACS) and 144 (88.3%) with partial anterior syndrome (PACS) had NLI on DWI.
DWI is important among patients presenting with clinical symptoms suggestive of lacunar syndrome to differentiate between LI and NLI. On the other hand, there is good correspondence between TACS or PACS and NLI on DWI.
PMCID: PMC2734341  PMID: 19689814
8.  Admission C – reactive protein after acute ischemic stroke is associated with stroke severity and mortality: The 'Bergen stroke study' 
BMC Neurology  2009;9:18.
There is growing evidence that inflammation plays an important role in atherogenesis. Previous studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. It is not clear whether this is due a direct dose-response effect or rather an epiphenomenon. We studied the effect of CRP measured within 24 hours after stroke onset on functional outcome, mortality and future vascular events.
We prospectively studied 498 patients with ischemic stroke who were admitted within 24 hours after the onset of symptoms. CRP and NIH stroke scale (NIHSS) were measured at the time of admission. Short-term functional outcome was measured by modified Rankin scale (mRS) and Barthel ADL index (BI) 7 days after admission. Patients were followed for up to 2.5 years for long-term mortality and future vascular events data.
The median CRP at admission was 3 mg/L. High CRP was associated with high NIHSS (p = 0.01) and high long-term mortality (p < 0.0001). After adjusting for confounding variables, high CRP remained to be associated with high NIHSS (p = 0.02) and high long-term mortality (p = 0.002). High CRP was associated with poor short-term functional outcomes (mRS > 3; BI < 95) (p = 0.01; p = 0.03). However, the association was not significant after adjusting for confounding variables including stroke severity (p = 0.98; p = 0.88). High CRP was not associated with future vascular events (p = 0.98).
Admission CRP is associated with stroke severity and long-term mortality when measured at least 24 hours after onset. There is a crude association between high CRP and short-term functional outcome which is likely secondary to stroke severity. CRP is an independent predictor of long-term mortality after ischemic stroke.
PMCID: PMC2680802  PMID: 19400931

Results 1-8 (8)