In a patient with an acute ischemic stroke of unknown onset, what diagnostic imaging and acute management—including intravenous alteplase (tissue plasminogen activator) and endovascular thrombectomy—should be performed?

Acute Ischemic Stroke of Unknown Onset: Diagnostic Imaging and Management

In a patient with acute ischemic stroke of unknown onset, immediate non-contrast CT (NCCT) or MRI should be performed to exclude hemorrhage, followed by CT angiography (CTA) to identify large vessel occlusion (LVO), and if presenting beyond 4.5 hours from last known well, advanced imaging with MRI showing DWI-FLAIR mismatch or CT/MRI perfusion imaging should guide eligibility for IV alteplase and/or endovascular thrombectomy (EVT). 1, 2

Initial Diagnostic Approach

Immediate Brain Imaging (Within Minutes of Arrival)

All patients with suspected acute stroke must undergo brain imaging without delay before any specific treatment 1. The choice depends on availability and time constraints:

• NCCT (preferred for speed): Excludes intracranial hemorrhage (absolute contraindication to thrombolysis) and assesses early ischemic changes 1, 3

  • Frank hypodensity involving >1/3 MCA territory is a strong contraindication to alteplase 3, 4
  • Early ischemic changes of mild-moderate extent are NOT contraindications 4

• MRI with DWI (if available without delay): Superior for detecting acute ischemia, especially small lesions and posterior circulation strokes 3

  • More effective than CT for excluding stroke mimics 3

Vascular Imaging - Essential for Treatment Planning

CTA should be performed immediately in all patients being considered for reperfusion therapy 1, 2:

• Identifies LVO location (ICA, M1, M2, basilar artery) 5
• High accuracy with excellent interrater reliability 5
• Minimal contrast nephropathy risk 5
• Can be completed in single acquisition covering arch-to-vertex 5

Advanced Imaging for Unknown Onset Strokes

For Patients Last Known Well >4.5 Hours

MRI with DWI-FLAIR mismatch is the validated approach for unknown onset strokes 1, 2:

• DWI-FLAIR mismatch = DWI hyperintensity with corresponding FLAIR hypointensity
• Indicates stroke occurred <4.5 hours ago 2
• Enables IV alteplase administration in wake-up strokes 1, 6, 7

CT or MRI perfusion imaging for extended window (6-24 hours) 1:

• Identifies core-perfusion mismatch or clinical-core mismatch
• Required for EVT eligibility beyond 6 hours 1, 2
• ASPECTS ≥6 on baseline imaging for EVT candidates 1

Acute Management Protocol

Pre-Treatment Essentials (Do NOT Delay Reperfusion)

Only blood glucose assessment must precede IV alteplase 1:

• Check capillary glucose immediately - treat if <60 mg/dL (3.3 mmol/L) 1
• Blood pressure must be <185/110 mmHg before alteplase 1, 4
• Obtain ECG, CBC, electrolytes, creatinine, INR/PTT, troponin - but do NOT wait for results 1
• Oxygen supplementation to maintain saturation ≥94% 1

IV Alteplase Administration

For unknown onset with DWI-FLAIR mismatch within 4.5 hours of symptom recognition 1, 2:

• Dose: 0.9 mg/kg (maximum 90 mg) 1, 4
  • 10% as IV bolus over 1 minute
  • Remaining 90% as infusion over 60 minutes 2
• Initiate as rapidly as possible - every minute counts 2
• Target door-to-needle time ≤30 minutes 2

Extended window alteplase (4.5-24 hours) with perfusion imaging showing salvageable tissue 1, 8:

• Recent HOPE trial (2025) demonstrated functional benefit in patients with perfusion mismatch treated 4.5-24 hours after onset 8
• Same dosing regimen: 0.9 mg/kg 8
• Increased symptomatic ICH risk (3.8% vs 0.5%) but no mortality difference 8

Endovascular Thrombectomy

EVT eligibility criteria for 0-6 hour window 1:

• Age ≥18 years
• Pre-stroke mRS 0-1
• ICA or MCA-M1 occlusion on CTA
• NIHSS ≥6
• ASPECTS ≥6
• Treatment initiated (groin puncture) within 6 hours 1

EVT in extended window (6-24 hours) 1:

• Requires advanced imaging (CTP or MRI-DWI/PWI)
• Must demonstrate sizable mismatch between:
  • Small ischemic core AND large perfusion deficit, OR
  • Small core AND severe clinical deficit 1

Critical management principle: Administer IV alteplase even if EVT is planned 1, 2:

• Do NOT wait to assess alteplase response before proceeding to angiography 1
• Combined therapy remains standard of care despite recent non-inferiority data from Asian populations 9

Common Pitfalls to Avoid

1. Delaying imaging for laboratory results: Only glucose must precede alteplase 1

2. Withholding alteplase due to "minor" symptoms: Disabling deficits warrant treatment regardless of NIHSS score 10

3. Assuming "too late" for treatment: Unknown onset strokes can be treated with appropriate imaging selection 1, 2, 6

4. Skipping vascular imaging: CTA is essential for identifying LVO and planning EVT 1, 2

5. Waiting for MRI when CT is faster: NCCT + CTA is acceptable if MRI causes delay 3, 5

6. Delaying EVT to assess alteplase response: Proceed directly to thrombectomy without waiting 1

Safety Monitoring

Symptomatic intracranial hemorrhage is the primary risk 4, 8:

• Risk increases with time from onset, extent of early ischemic changes, stroke severity 5
• Monitor neurologically for 24 hours post-treatment
• Repeat brain imaging if neurological deterioration occurs 4

Absolute contraindications to alteplase 4:

• Intracranial hemorrhage on imaging
• Recent intracranial/spinal surgery (<3 months)
• History of intracranial hemorrhage
• Active internal bleeding
• Suspected subarachnoid hemorrhage