Stroke With Unknown Time of Symptom Onset
Baseline Clinical and Magnetic Resonance Imaging Data of the First Thousand Patients in WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial)
Background and Purpose—We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort.
Methods—We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery.
Results—Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P<0.001), and more often aphasia (72.5% versus 34.0%; P<0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30).
Conclusions—Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age.
In a large proportion of stroke patients, information on the exact time of symptom onset is not available. This includes the large group of patients waking up with stroke symptoms, the so-called wake-up stroke, representing around 1 in 5 (14%–24%) of stroke patients in registries or epidemiological studies.1,2 Information on time of symptom onset may also be unavailable in unwitnessed stroke at daytime in patients not capable of providing this information themselves. All these patients are currently excluded from reperfusion treatment based on the available evidence.3
Magnetic resonance imaging (MRI) has been suggested to select patients with unknown time of symptom onset likely to benefit from acute reperfusion treatment using diffusion-weighted imaging (DWI)–fluid-attenuated inversion recovery (FLAIR) mismatch as surrogate marker of lesion age.4 However, the proportion of patients qualifying for intravenous thrombolysis based on imaging criteria within a population of unknown symptom onset stroke patients otherwise considered eligible is not known. Furthermore, there are findings indicating that patients with wake-up stroke might differ from those with daytime-unwitnessed stroke with regards to clinical and imaging characteristics that might affect acute treatment decisions.5
We aimed at studying clinical and imaging characteristics of stroke patients with unknown time of symptom onset otherwise considered eligible for treatment with intravenous thrombolysis.
We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), a trial enrolling acute stroke patients with unknown time of symptom onset.6 In this trial, patients are studied with MRI, including DWI and FLAIR, and the presence of a DWI–FLAIR mismatch4 represents the main imaging criterion for randomization to treatment with Alteplase or placebo. For the present analysis, only baseline information, including demographic, clinical, and imaging data, was considered. A database export was performed on April 1, 2016. The sample includes all patients enrolled in the trial, that is, patients with eligibility verified who gave informed consent and were then subjected to screening with MRI. All patients with at least information on date and time of enrollment, informed consent, symptom onset, age, and sex were included in the analysis.
MRI judgment was made by local investigators according to the image analysis standards provided together with the study protocol. Unwitnessed daytime stroke was compared with nighttime sleep wake-up stroke.
For group comparison, Fisher exact test or χ2 test were used for categorical variables, and Mann–Whitney U test for continuous variables. SAS software, version 9.3 (SAS Institute Inc, Cary, NC), was used for statistical analysis.
Overall, 1005 patients were included in the analysis. In the majority of patients, stroke symptoms were discovered in the morning hours between 06:00 and 10:00 (Figure). Clinical and imaging characteristics are presented in Table. Overall, 793 patients (81.3%) had a visible DWI lesion, whereas 72 (7.2%) had findings of intracranial hemorrhage. DWI–FLAIR mismatch was present in 479 patients (48.0%).
Patients with daytime-unwitnessed stroke had a shorter delay between symptom recognition and arrival at the hospital (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P<0.001), and more frequently aphasia (72.5% versus 34.0%; P<0.001). Medical history and presence of vascular risk factors were similar between groups. Groups were also comparable as to baseline imaging findings including the proportion of patients presenting with DWI–FLAIR mismatch (43.7% versus 48.7%; P=0.30).
In this large prospective sample consisting of the first 1005 patients enrolled in the multicentre multinational randomized controlled WAKE-UP trial, DWI–FLAIR mismatch was observed in virtually half of the patients (48.0%). This confirms the notion that a relevant proportion of patients with unknown time of symptom onset have an MRI signature indicative of stroke lesions within the first 4.5 hours of symptom onset. The number is comparable to the 43.7% DWI–FLAIR mismatch reported in a previous small case series of stroke with unknown time of symptom onset.7 In another recently published case series, DWI–FLAIR mismatch was present in only 35.1% of daytime-unwitnessed stroke and 21.9% of patients with wake-up stroke.5 Smaller numbers may result from a longer delay between symptom recognition to hospital arrival when compared with our sample.
Comparing patients waking up from nighttime sleep to those with daytime-unwitnessed stroke revealed some differences. Patients with unknown time of symptom onset at daytime had more severe neurological symptoms reflected by a higher National Institutes of Stroke Scale score on admission, a higher rate of aphasia, and a trend toward a higher rate of disturbed level of consciousness. These results are in line with a recently published retrospective analysis reporting higher mean National Institutes of Stroke Scale values for and higher rates of aphasia in patients with daytime onset unwitnessed stroke when compared with wake-up stroke.5 Because aphasia and disturbed level of consciousness represent common reasons for the inability of patients with daytime onset stroke to report the time of symptom onset, these findings might at least in part be considered as a bias resulting from the definition of unwitnessed stroke at daytime. On the other hand, there are hints toward pathophysiological differences between strokes occurring at night and those at daytime which may contribute to differences in risk profile, stroke cause, and symptom severity between groups. A higher risk of newly diagnosed atrial fibrillation was observed in wake-up stroke8 that might relate to the well-known circadian variation of occurrence of atrial fibrillation with most frequent occurrence in the early morning hours.9
To summarize, in this large prospective cohort of stroke patients with unknown time of symptom onset otherwise considered potential candidates for thrombolysis, almost half of the patients showed a DWI–FLAIR mismatch, rendering them likely to be within a time window for effective reperfusion treatment. We found no difference in the presence of DWI–FLAIR mismatch between patients with wake-up stroke and those with daytime-unwitnessed stroke, but the analysis was not adequately powered to detect whether the observed small absolute difference was statistically significant. When considering reperfusion treatment in patients with unknown time of symptom onset, these considerations should not be restricted to wake-up strokes but also include daytime onset unwitnessed stroke.
WAKE-UP Steering Committee: Christian Gerloff (Chair), Götz Thomalla (Coordinating Investigator), Martin Ebinger, Claus Z. Simonsen, Salva Pedraza, Robin Lemmens, Norbert Nighoghossian, Keith Muir, Ian Ford, and Matthias Endres.
Sources of Funding
WAKE-UP receives funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°278276 (WAKE-UP).
Dr Endres has received grant support from Deutsche Forschungsgemeinschaft (DFG), German Federal Ministry of Education and Research (BMBF), European Union (EU), Corona Foundation, Fondation Leducq, and Bayer and has received fees from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ever, Glaxo Smith Kline, MSD, Pfizer, Novartis, and Sanofi. Dr Fiebach has received consulting, lecture, and advisory board fees from Perceptive, BioClinica, Boehringer Ingelheim, Cerevast, Brainomix, and Lundbeck and a grant from the German Federal Ministry of Education and Research (BMBF). Dr Fiehler has received fees as a consultant or lecture fees from Codman, Covidien, Siemens, and Stryker. Dr Gerloff has received fees as a consultant or lecture fees from Bayer Vital, Boehringer Ingelheim, EBS technologies, Glaxo Smith Kline, Lundbeck, Pfizer, Sanofi Aventis, Silk Road Medical, and UCB. Dr Muir has received honoraria for speaking from Boehringer Ingelheim and Bayer and has received consultancy fees from ReNeuron Ltd. Dr Pedraza has received fees as a board member, consultant, or lecturer from Lundbeck and Synarc. Dr Lemmens is a senior clinical investigator of FWO Flanders. Dr Simonsen has received lecture fees from Boehringer Ingelheim. Dr Thijs has participated in advisory board meetings of Boehringer Ingelheim, Pfizer, and Bristol-Myers Squibb and has received honoraria from Astra Zeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Pfizer. Dr Thomalla has received fees as a consultant or lecture fees from Acandis, Bayer Vital, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daichii Sankyo, GlaxoSmithKline, and Stryker. The other authors report no conflicts.
Guest Editor for this article was Gregory W. Albers, MD.
- Received September 11, 2016.
- Revision received November 10, 2016.
- Accepted December 12, 2016.
- © 2017 American Heart Association, Inc.
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