(COR IIb; LOE B-NR) Wake-up and unknown time of onset IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 min with initial 10% of dose given as bolus over 1 min) administered within 4.5 h of stroke symptom recognition can be beneficial in patients with AIS who awake with stroke symptoms or have unclear time of onset >4.5 h from last known well or at baseline state and who have a DW-MRI lesion smaller than one- third of the MCA territory and no visible signal change on FLAIR. (COR IIa; LOE B-R) Preexisting disability Preexisting disability does not seem to independently increase the risk of sICH after IV alteplase, but it may be associated with less neurological improvement and higher mortality. Therapy with IV alteplase for acute stroke patients with preexisting disability (mRS score 2) may be reasonable, but decisions should take into account relevant factors, including quality of life, social support, place of residence, need for a caregiver, patients and families preferences, and goals of care. (COR IIb; LOE B-NR) Patients with preexisting dementia may benefit from IV alteplase. Individual considerations such as life expectancy and premorbid level of function are important to determine whether alteplase may offer a clinically meaningful benefit. (COR IIb; LOE B-NR) Early improvement IV alteplase treatment is reasonable for patients who present with moderate to severe ischemic stroke and demonstrate early improvement but remain moderately impaired and potentially disabled in the judgment of the examiner. (COR IIa; LOE A) Seizure at onset IV alteplase is reasonable in patients with a seizure at the time of onset of acute stroke if evidence suggests that residual impairments are secondary to stroke and not a postictal phenomenon. 