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.

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).

Serum uri acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: SUA may not be neuroprotective alone, but may provide a beneficial effect in patients receiving thrombolysis.

Microemboli-monitoring during the acute phase of ischemic stroke: is it worth the time?

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Preadmission use of warfarin improves short-term outcome in patients with acute cerebral infarction. The Bergen Stroke Study.

BACKGROUND: We hypothesized that patients with cerebral infarction on preadmission warfarin have less severe neurological deficits on admittance, less severe neurological deficits 1 week after the onset of cerebral infarction and a larger improvement as to neurological deficits within 1 week of acute cerebral infarction. METHODS: All patients with cerebral infarction who did not receive thrombolytic treatment were included. Preadmission use of warfarin was registered. The National Institute of Health Stroke Scale (NIHSS) score was obtained on admittance and 7 days after stroke onset. RESULTS: In total, 42 patients (8.1%) used warfarin at the time of stroke onset. The mean NIHSS score on admittance was 6.9 among the patients on warfarin and 5.2 among those without warfarin (p = 0.10). The 1-week improvement in the NIHSS score was 3.5 among the patients on warfarin and 0.8 among the participants without warfarin (p < 0.001). Linear regression showed that a low NIHSS score on day 7 was independently associated with a low NIHSS score on admittance (p < 0.001), low age (p = 0.002) and preadmission use of warfarin (p < 0.001). CONCLUSION: Preadmission warfarin was not associated with less severe neurological deficits on admittance. However, it was related to both less severe neurological deficits 1 week after the onset of cerebral infarction and larger improvement as to neurological deficits within 1 week of acute cerebral infarction.

Serum albumin in ischemic stroke patients: the higher the better. The Bergen Stroke Study.

BACKGROUND: Animal studies show a neuroprotective effect of serum albumin in ischemic stroke. The neuroprotective effect of albumin in ischemic stroke in humans is not well studied. This study was aimed to determine the association of serum albumin with outcome and mortality after ischemic stroke. METHODS: In a prospective study, we included 444 patients with ischemic stroke. Serum albumin was measured at the time of admission. Stroke severity was measured at the time of admission with the National Institutes of Health Stroke Scale (NIHSS). Functional outcome was measured with the modified Rankin scale (mRS) on day 7. Multiple logistic regression analysis was used to assess the independent association between variables and outcome. Survival was analyzed by Cox regression analysis after adjusting for age, sex and NIHSS score on admission. RESULTS: The mean age (SD) of the patients was 70.4 (14.4) years. The median NIHSS score (interquartile range) on admission was 4 (1-8) and the median mRS score (interquartile range) on day 7 was 2 (1-3). Sixty patients (13%) died during a median follow-up period of 2 years. High serum albumin was independently associated with a better outcome (OR = 1.12, 95% CI = 1.05-1.20, p = 0.001). After adjusting for age, sex and NIHSS score on admission, high serum albumin was associated with lower mortality (OR = 0.88, 95% CI = 0.83-0.93, p < 0.0001). CONCLUSIONS: The current study indicates that high serum albumin is associated with better outcome and lower mortality in ischemic stroke patients. High serum albumin may be neuroprotective in ischemic stroke in humans.

Admission C-reactive protein after acute ischemic stroke is associated with stroke severity and mortality: the 'Bergen stroke study'.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The effect of physiologic derangement in patients with stroke treated with thrombolysis.

BACKGROUND: Body temperature, blood glucose, and blood pressure (BP) may interfere with outcome in patients with acute ischemic stroke treated with thrombolysis. METHODS: We prospectively studied 127 patients who received thrombolysis with tissue plasminogen activator for acute stroke in Bergen, Norway. Body temperature, blood glucose, and BP were measured before thrombolysis. Maximum body temperature and maximum blood glucose within the first 5 days after thrombolysis and maximum BP within the first 24 hours after thrombolysis were measured. The outcome was measured with modified Rankin scale score obtained at 3 months after stroke onset. Variables were tested using multiple logistic regression analysis after adjusting for National Institute of Health Stroke Scale score before thrombolysis and potential confounders. RESULTS: The average age of the patients was 63 years and the median National Institute of Health Stroke Scale score was 13. On admission, diabetes mellitus was present in 6% of patients and hypertension in 51% of patients. High body temperature and high blood glucose after thrombolysis were associated with poor prognosis (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.29-6.25, P = .01; OR 1.33, 95% CI 1.02-1.74, P = .03). High body temperature and high blood glucose before thrombolysis were not associated with outcome (OR 0.79, 95% CI 0.39-1.58, P = .5; OR 1.04, 95% CI 0.75-1.20, P = .08). High systolic BP both before and after thrombolysis was associated with poor outcome (OR 1.27, 95% CI 1.03-1.52, P = .025; OR 1.22, 95% CI 1.00-1.44, P = .045). High diastolic BP both before and after thrombolysis was not associated with outcome (OR 1.03, 95% CI 0.97-1.36, P =.85; OR 1.16, 95% CI 0.99-1.46, P = .29). CONCLUSIONS: The current study indicates that in patients with ischemic stroke, high body temperature and high blood glucose after thrombolysis are associated with poor prognosis. Frequent monitoring of these parameters and the appropriate treatment of it, if elevated, are important during the first few days after thrombolysis. High systolic BP both before and after thrombolysis was associated with poor outcome. This finding may support the practice of reducing systolic BP below 185 mm Hg both before and after thrombolysis.

Neurological complications and aspects of basilar artery occlusive disease.

A recent case of basilar artery occlusion (BAO) in a 62-year-old woman is presented, along with a review of the literature on the clinical aspects of the disorder and treatment options. Therapeutic modalities such as intravenous and intra-arterial thrombolysis may significantly improve outcomes for patients with this disease.

Early Thrombectomy of a Proximal Middle Cerebral Artery Occlusion Leading to Complete Recovery with No Infarct.

Many recent trials show the benefit of mechanical thrombectomy in acute ischemic stroke caused by thrombi lodged in large arteries. We report the case of a 55-year-old patient who developed sudden-onset right-sided hemiplegia and aphasia. Computed tomography angiography showed a thrombus in the M1 segment of the left middle cerebral artery. The thrombus was removed by mechanical thrombectomy 85 min after the onset of symptoms. A magnetic resonance imaging (MRI) scan showed no infarct, and the patient was discharged symptom free. To the best of our knowledge, this is the first report of thrombectomy of a symptomatic proximal middle cerebral artery occlusion leading to complete rescue, both clinically and radiologically assessed by MRI. Our case report shows that an early thrombectomy can provide an excellent outcome.

Case report of a patient who underwent thrombolysis of a "silent" thrombus in the middle cerebral artery.

INTRODUCTION: Some stroke patients present with mild or absent measurable neurologic deficits in spite of a significant thromboembolic event. A thrombus in the distal region of the middle cerebral artery may have such a presentation. CT angiography in the acute phase helps to identify the culprit thrombus. Thrombolysis might be beneficial in these patients in spite of the lack of measurable neurologic deficits. We present a patient with a 'silent' thrombus in the middle cerebral artery. CASE REPORT: A 70-year-old man presented with a history of fluctuating neurologic symptoms for 2 days. Neurologic examination at the time of presentation revealed no measurable deficits. CT angiography showed a thrombus in the M2 segment of the middle cerebral artery which was treated with intravenous thrombolysis. Patient did not have recurrence of symptoms after thrombolysis. MR angiogram a day after thrombolysis showed partial recanalization of the artery. CONCLUSION: Some stroke patients with an intracranial thrombus may present with minimal or absent measurable neurologic deficits. CT angiography is a useful tool in identifying the thrombus. Intravenous thrombolysis may be beneficial in stroke patients presenting with a "silent" thrombus.