Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke

Inclusion Criteria: Clinical Inclusion Criteria * Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on awakening) * Last known well (without neurological symptoms) \> 4.5 hours of treatment initiation * Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor function, cognition, gaze, vision, neglect) * Age 18-80 years * Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening) * Written informed consent by patient or proxy Imaging Inclusion Criteria: * Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed * MRI showing a pattern of "DWI-FLAIR-mismatch", i.e. acute ischemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischemic lesion ≤4.5 hours of age Exclusion Criteria: Clinical Exclusion Criteria * Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis, mechanical recanalization techniques) * Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability corresponding to an MRS score \> 1) * Participation in any investigational study in the previous 30 days * Severe stroke by clinical assessment (e.g. NIHSS \> 25) * Hypersensitivity to Alteplase or any of the excipients * Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed in women up to 55 years of age) * Significant bleeding disorder at present or within past 6 months * Known haemorrhagic diathesis * Manifest or recent severe or dangerous bleeding * Known history of or suspected intracranial haemorrhage * Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from aneurysm * History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery) * Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel * Current use of anticoagulants (e.g. Phenprocoumon, Warfarin, new anticoagulants such as Dabigatran) or current use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed) * Platelet count \< 100.000/mm3 (\<100G/l) * Blood glucose \< 50 or \> 400 mg/dl (\< 2.8 or 22.2 mmol/l) * Severe uncontrolled hypertension, i.e. systolic blood pressure \> 185 mmHg or diastolic blood pressure \>110 mmHg or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits) * Manifest or recent bacterial endocarditis, pericarditis * Manifest or recent acute pancreatitis * Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations * Neoplasm with increased bleeding risk * Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis * Major surgery or significant trauma in past 3 months * Stroke within 30 days * Life expectancy 6 months or less by judgement of the investigator * Any condition associated with a significantly increased risk of severe bleeding not mentioned above * Any contraindication to MRI (e.g. cardiac pacemaker) Imaging Exclusion Criteria: * Poor MRI quality precluding interpretation according to the study protocol * Any sign of intracranial haemorrhage on baseline MRI * FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion indicative of an acute ischemic lesion with a high likelihood of being \> 4.5 hours old * Large DWI lesion volume \> 1/3 of the MCA or \> 50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or \> 100 ml * Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator