Wake-up stroke (WUS)

David Goldemund M.D.
Updated on 15/10/2024, published on 15/10/2024

a Wake-Up Stroke (WUS) refers to a scenario in which a patient wakes up with stroke symptoms, making it difficult to determine the exact time of onset
this situation is particularly relevant in the management of ischemic stroke, as treatment options depend on the time elapsed since the symptom onset
original criteria excluded this quite large group of patients from thrombolysis, but this has changed in recent years

growing evidence suggests that many wake-up strokes occur close to awakening and that patients may still be within the approved time window
several imaging techniques show similar findings in WUS patients and those with stroke within 3 or 4.5 h (mismatch on CTP, DWI/FLAIR mismatch, similar early ischemic changes burden, etc.)
imaging techniques used with the concept of the midpoint of sleep improve thrombolysis availability in WUS patients

a meta-analysis of the WAKE-UP, EXTEND, THAWS, and ECASS-4 trials found that thrombolysis indicated by advanced imaging is safe and effective [Thomalla, 2020]
- IV alteplase resulted in a better functional outcome at 90 days than placebo or standard therapy
- a net benefit was observed for all functional outcomes despite an increased risk of sICH
- although there were more deaths with alteplase than with placebo, there were fewer cases of severe disability or death
if the patient is a candidate for both IVT and MT, IVT is more likely to be performed before MT (expert consensus) (ESO guidelines 2021)

a positive DWI with negative findings on FLAIR indicates that the stroke probably occurred within the previous 4.5 hours [Aoki, 2010] [Thomalla, 2009]
may be useful to guide intravenous thrombolysis (IVT) in patients with stroke of unknown onset or wake-up stroke (WUS)

WAKE-UP
- DWI/FLAIR mismatch is present (DWI positive in <1/3 of the MCA territory, FLAIR negative)
- n=503 ( 254 tPA vs. 249 placebo), median NIHSS 6
- good outcome 53.3 vs. 41.8 (placebo), median mRS/3m 1 vs. 2
- mortality 4.1% vs. 1.2% (placebo)
- sICH 2% vs. 0.4% (placebo)
MR WITNESS
- unwitnessed onset
- DWI/FLAIR mismatch (DWI positive in <1/3 of the MCA territory, FLAIR either negative or showing only minimal lesion)
- n = 80, sICH 1.25% (as defined by ECASS III)

EXTEND trial (2018)

time window:
- 4.5 – 9 hours after the onset of stroke
- on awakening with stroke (if within 9 hours from the midpoint of sleep)
≥ 18 years, premorbid mRS < 2, NIHSS 4-26
- median NIHSS was 12 (tPA) and 10 (placebo)
CTP system RAPID or MR DWI/PWI mismatch → inclusion criteria
- mismatch > 1.2, absolute difference > 10 ml (Tmax > 6 s on perfusion)
- core < 70 ml (CT-CBF) – rCBF<30% on CTP or ADC<620mm2/s (DWI
n=113 (tPA) vs. 112 (placebo) at 4.5-9h
primary outcome (mRS 0-1 /3m): 35.4% vs 29.5%, RR 44%
NNT 17 – efficacy similar to IVT at 3-4.5h
sICH 6% (tPA) vs 1% (placebo)
mortality 12% (tPA) vs. 9% (placebo)

trial investigated the efficacy of mechanical thrombectomy in patients with large vessel occlusion (LVO) who had an unclear time of stroke onset, including wake-up strokes
patients were selected based on imaging criteria (diffusion-perfusion mismatch on MRI or CT perfusion) to identify salvageable brain tissue despite unknown stroke onset
patients treated with thrombectomy showed significantly improved functional outcomes (modified Rankin Scale scores of 0-2 at 90 days) compared to those who did not undergo thrombectomy (Bücke, 2018)
no significant increase in symptomatic intracranial hemorrhage (sICH) was reported in the thrombectomy group compared to standard care

IVT can be performed in WUS patients who meet the following imaging criteria (derived from guidelines):
- DWI/FLAIR mismatch – DWI lesion < 1/3 of MCA territory + negative FLAIR – meets WAKE-UP trial criteria (AHA/ASA 2019 IIa/B-R) (ESO guidelines 2021)
  - FLAIR is usually negative in the first 2-3 hours (Levy, 1983)
- evidence of penumbra on CT perfusion (EXTEND trial criteria) (ESO guidelines 2021)
  - the trial used a 9-hour time window, which fits most WUS patients (especially if we use the midpoint of sleep rule)
some authors advocate thrombolysis in WUS based on normal NCCT alone; the ESO 2021 guidelines do not recommend IVT in the 4.5-9 hour window or in WUS without penumbral imaging
- it appears safe to thrombolyse patients with wake-up stroke and a normal NCCT (Armon, 2019)
- the non-randomized TRUST-CT trial showed benefit in patients with ASPECTS ≥ 7 (OR 1.94 )
- RCTs are needed

the estimated midpoint can guide treatment decisions
to calculate it, determine the interval between:
- the last time the patient was normal (bedtime or last interaction with others or, for example, visiting the toilet without difficulty) AND
- the time the symptoms were noticed upon awakening
midpoint = divide this interval by two and add it to the last time normal
examples
- last time seen 10:00 PM, symptoms noticed 6:00 AM, the estimated midpoint is 2:00 AM; if the patient arrives at the hospital at 7:00 AM, the estimated window is 5 hours ⇒ advanced imaging is required
- last time seen 11:00 PM, symptoms noticed 5:00 AM, the estimated midpoint is 2:00 AM; if the patient arrives at the hospital at 6:00 AM, the estimated window is 4 hours ⇒ NCCT is sufficient to indicate IVT

patients can be thrombolyzed if:
- brain NCCT shows no advanced early ischemia + interval from the midpoint of sleep to initiation of IVT is ≤ 4.5 hours
- advanced imaging criteria mentioned above are met + interval from the midpoint of sleep to initiation of IVT is < 9 hours

thrombectomy is effective for medium- and large vessel occlusions (MeVo and LVO) and can be performed:
- within 7 hours 18 minutes based on NCCT alone (using the estimated midpoint of sleep)
- within 24 hours after the midpoint in patients selected by advanced penumbral imaging (DAWN, DEFUSE3 trials) → Mechanical recanalization

standard secondary prevention with antiplatelets or anticoagulation, depending on stroke etiology + management of vascular risk factors