Introduction

About 20–25 % of stroke patients realize stroke symptoms after waking up from sleep [1, 2∙, 3, 4]. This subgroup of stroke patients differs from stroke patients who suffer from stroke while being awake and pose a specific challenge to stroke physicians. The most relevant difference between both groups is the fact that in wake-up stroke patients the exact time point of symptom onset is unknown. This excludes wake-up stroke patients from treatment with intravenous thrombolysis based on licensing criteria and international guidelines [5, 6], thus excluding patients from the only approved specific treatment of acute stroke with proven safety and efficacy. Within the past years, however, new approaches to guide treatment in wake-up stroke patients have been suggested and are currently being tested in clinical trials. In this article, we give an overview of the clinical problem of wake-up stroke and recent developments that are likely to improve the treatment of these patients in the near future.

The Challenge of Wake-Up Stroke

Stroke is a devastating disease leading to death and disability in large numbers of patients, with massive social and economic impact. Based on WHO estimates about 15 million people suffer from stroke each year, of whom 5 million are left permanently disabled [7]. Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA, alteplase) represents the only effective and approved specific treatment for acute ischemic stroke and is recommended by international and national guidelines [5, 6]. Following its approval by the FDA in 1996, treatment with intravenous rtPA (IV-tPA) has become the standard of care in acute stroke. Based on inclusion and exclusion criteria of two positive clinical trials of thrombolysis in ischemic stroke, treatment with alteplase is licensed for patients treated within 4.5 h of symptom onset [8, 9].

According to licensing criteria of alteplase, information on the time point of symptom onset is a prerequisite for treatment with intravenous thrombolysis. This information, however, is not available for patients who realize stroke symptoms only when waking up from sleep. From observational studies and registries as well as clinical trials of acute stroke, it can be estimated that about 20–25 % of strokes occur during sleep [1, 2∙, 3, 4], thus representing a large and clinically relevant patient population. There are even observations that point toward strokes occurring during sleep being more severe [10] and having a worse clinical outcome, with patients being less likely to return home [11].

However, clinical and imaging observations suggest that in a large number of patients waking up with stroke symptoms, strokes may have occurred in the early morning hours so that these patients might still be eligible for thrombolysis. Early ischemic signs on CT were reported to be comparably frequent in patients who woke up with stroke symptoms and patients studied by CT within 3 h [12] or 6 h of symptom recognition [4]. The proportion of patients showing a perfusion–diffusion mismatch pattern on MRI was also similar for wake-up strokes and patients within 3 h of symptom onset [1]. Similar findings were reported for the detection of ‘tissue at risk’ by perfusion CT in wake-up stroke patients [13∙]. Together these data suggest that a large number of patients with wake-up stroke might still be within a time window for thrombolysis when reaching the hospital.

Imaging Approaches to Guide Treatment in Wake-Up Stroke

Mainly two imaging approaches have been suggested to identify wake-up stroke patients likely to benefit from thrombolysis: the identification of tissue at risk by penumbral imaging (e.g., perfusion–diffusion mismatch) and the identification of patients within 4.5 h of symptom onset based on tissue characteristics depicted by stroke MRI (i.e., the DWI-FLAIR mismatch).

Penumbral Imaging in Wake-Up Stroke

Multiparametric MRI including diffusion-weighted imaging (DWI) and perfusion MRI (perfusion imaging, PI) allows for the characterization of different compartments of brain tissue in acute cerebral ischemia according to tissue status (i.e., already irreversibly damaged tissue, critically hyperperfused but potentially salvageable tissue). As a result of this, penumbral imaging with an operational definition of the penumbra by a mismatch between perfusion and diffusion MRI multiparametric MRI has been suggested as a tool for the selection of potential tPA-responsive patients beyond the approved time window or even completely independent from time [14–16]. Observational studies have demonstrated the potential of penumbral MRI to identify tissue at risk of infarction that may be saved by timely reperfusion within an extended time window of up to 6 h of symptom onset [17]. Moreover, while recent randomized controlled trials of stroke thrombolysis used penumbral imaging as the primary endpoints to select patients [18, 19], secondary analyses pointed toward reduced final infarct volumes [20] and a clinical benefit of treatment in patients with large volumes of perfusion–diffusion mismatch [21]. The experience from re-analyses of EPITHET and DEFUSE data has led to refined definitions of mismatch with more restrictive definitions of the perfusion lesion [22, 23]. These adapted definitions are used in the ongoing Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial [24]. It has already been proposed to extend the concept of perfusion-diffusion mismatch to the identification of wake-up stroke patients that are likely to benefit from thrombolysis [25–27]. In line with these considerations, the EXTEND trial will allow the randomization of patients with wake-up stroke based on penumbral imaging.

DWI–FLAIR Mismatch in Wake-Up Stroke

There is ample evidence of the benefit of intravenous thrombolysis in patients treated within 4.5 h of stroke onset [8, 9, 28∙]. This has raised the question of whether the age of ischemic stroke lesion onset can reliably be estimated by other means, e.g., surrogate markers provided by stroke imaging, thus providing the lacking information on the time window from symptoms in patients with wake-up stroke.

MRI findings change during the time course of acute cerebral ischemia, and tissue water changes after ischemic stroke follow a characteristic course: a drop in the cerebral blood flow below a critical threshold leads to a disruption of the energy metabolism, resulting in cytotoxic edema, which can be depicted by a reduced apparent diffusion coefficient (ADC) on DWI within minutes of stroke [29, 30]. During the following 1–4 h, tissue osmolality increases, accompanied by a net increase of water [31, 32]. This absolute increase in water content can be detected by T2-weighted MRI [29, 33]. Thus, DWI allows for the detection of acute ischemic lesions within minutes with a high contrast, but does not allow drawing any further conclusions on lesion age during the first hours of stroke, while T2 signal changes might allow further timely allocation of ischemic lesions. The identification of ischemic lesions on T2-weighted imaging (T2wI) is hampered by the high signal intensity of cerebrospinal fluid (CSF), with partial volume effects of CSF in particular limiting the detection of cortical lesions. Thus, in clinical practice, fluid attenuated inversion recovery (FLAIR) imaging with suppression of the CSF signal and strong T2 weighting is widely used as it was found to be superior to T2WI in the detection of ischemic lesions [34, 35]. The pattern of a visible ischemic lesion on DWI together with normal T2WI or FLAIR is a typical finding in human stroke if imaging is performed within the first hours of the stroke [36–38]. These results are also well in line with data from experimental stroke, where T2WI failed to detect acute ischemia until about 2–3 h of stroke [30, 39, 40].

These observations have led to a new concept, introduced in 2009, to identify patients likely to benefit from thrombolysis based on the assumed lesion age and the DWI–FLAIR mismatch [41]. In contrast to the previously suggested concept of perfusion-diffusion mismatch, which labels a mismatch between lesion volumes on two parameter maps, DWI–FLAIR mismatch refers to the mismatch between visibility of an ischemic lesion in one sequence (DWI), indicating the presence of acute ischemia, while it is not visible in the other sequence (FLAIR), indicating that the ischemic lesion is <4.5 h old (Fig. 1). Moreover, in contrast to perfusion–diffusion mismatch, which indicates tissue viability, DWI–FLAIR mismatch indicates lesion age, which is the essential piece of information missing in wake-up stroke.

Fig. 1
figure 1

The concept of DWI–FLAIR mismatch. Left Two examples of patients fulfilling the criterion of DWI–FLAIR mismatch: acute ischemic lesion clearly visible on DWI, but no clear parenchymal hyperintensity visible on FLAIR in regions corresponding to the DWI lesion; right two examples of patients not fulfilling the criterion of DWI–FLAIR mismatch: acute ischemic lesion clearly visible on DWI and clear parenchymal hyperintensity on FLAIR corresponding to the acute DWI lesion

Full size image

Following the first report, a series of single-center studies from different groups consistently reported a clear time dependency of the visibility of acute ischemic lesions on FLAIR, increasing to almost 100 % visibility after 3–6 h [42∙, 43, 44]. The pattern of DWI–FLAIR mismatch was reported to identify patients within a time window of 3 or 4.5 h with a high specificity and positive predictive value (PPV) [41–44]. Recently, these findings from retrospective single-center studies were confirmed in a large multicenter study including 643 patients (PRE-FLAIR: PREdictive value of FLAIR and DWI for the identification of acute ischemic stroke patients ≤3 and ≤4.5 h of symptom onset—a multicenter study) [45∙∙]. In this study, the DWI–FLAIR mismatch identified patients within 4.5 h with a specificity of 0.81 and a PPV of 0.87 from an assumed target population for thrombolysis, i.e., patients with stroke in the territory of the middle cerebral artery (MCA) and a relevant neurological deficit [45∙∙]. Together these studies provide compelling evidence that the DWI–FLAIR mismatch allows identification of patients with stroke of unknown onset with a sufficiently high likelihood of being in a time window in which thrombolysis is proven effective and safe (i.e., within 4.5 h). Several studies also reported predictive values to identify patients within 6 h of symptom onset that were even higher, with a PPV of 0.95 in PRE-FLAIR [45∙∙] and 0.98 in a Japanese sample [42∙]. This finding is important as both the pooled analysis of the clinical trials of rtPA in stroke and a Cochrane analysis indicate a possible beneficial effect of thrombolysis together with the absence of an increase in symptomatic intracranial hemorrhage (SICH) up to 6 h of symptom onset [28, 46]. Just recently, an observational study reported the first findings on the frequency of DWI–FLAIR mismatch in patients with wake-up stroke [47∙]. In this study, a high rate (44 %) of wake-up stroke patients showed a DWI–FLAIR mismatch pattern, thus providing further evidence for the assumption that a large proportion of wake-up stroke patients might still present within a time window for thrombolysis. Based on this evidence, the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke: a randomised, double-blind, placebo-controlled trial (WAKE-UP), will randomize wake-up stroke patients using the DWI–FLAIR mismatch as the imaging criterion to identify patients likely to benefit from thrombolysis [48].

Thrombolysis in Wake-Up Stroke: Case Reports and Observational Studies

Resulting from the dissatisfaction because of the lack of any evidence-based treatment recommendations for patients with wake-up stroke, there is a growing number of case reports and small case series that report on thrombolysis in patients with wake-up stroke based on imaging findings. These studies used plain CT [49], perfusion CT [49, 50] or multiparametric stroke MRI [25–27]. There is also a recent case series of thrombolysis in wake-up stroke patients based on the DWI–FLAIR mismatch concept [51]. In summary, these case reports and observational studies demonstrated the feasibility of imaging-guided thrombolysis in wake-up stroke patients with no excess of symptomatic intracranial hemorrhage and in large part similar outcomes as thrombolysis in patients treated within 4.5 h of symptom onset. However, given the lack of control groups and small patient numbers, no reliable conclusions can be drawn from these studies concerning the safety and efficacy of thrombolysis in wake-up stroke.

Clinical Trials of Thrombolysis in Wake-Up Stroke

There are two randomized controlled trials of intravenous thrombolysis that either focus on or at least allow the enrollment of patients with wake-up stroke: WAKE-UP and EXTEND.

The EXTEND study is a randomized, multicenter, double-blind, placebo-controlled phase III trial of intravenous thrombolysis with rt-PA in ischemic stroke patients [24]. Patients can be enrolled if treatment can be initiated within 3 h (or 4.5 h depending on local practice) up to 9 h of symptom onset or in case of wake-up stroke if the midpoint between sleep onset (or last known to be normal) and time of waking up is at maximum 9 h. Further clinical inclusion criteria include a National Institutes of Health Stroke Scale (NIHSS) score of 4–26. Patients will undergo MRI including diffusion and perfusion MRI or CT including CT perfusion. Patients will be randomized to either treatment with placebo or alteplase (0.6 or 0.9 mg/kg bodyweight based on local practice) if they show a penumbral pattern on MRI or CT, i.e., infarct core volume <70 ml, perfusion lesion/infarct core mismatch ratio >1.2 and absolute mismatch >10 ml. The perfusion lesion is defined as T max > 6 s for MRI and CT; the infarct core is defined using MRI diffusion imaging or CT-CBF imaging. The primary outcome measure is a favorable outcome defined by a score of 0–1 on the modified ranking scale (MRS) at day 90. EXTEND plans to enroll 400 patients in Australia and in an accompanying study in international study sites (EXTEND international). A European companion study is also planned (ECASS 4-EXTEND-Europe), which will only use MRI and the European dose of alteplase (0.9 mg/kg body weight).

WAKE-UP will be the first clinical trial to use the novel approach of DWI–FLAIR mismatch to prospectively identify patients for thrombolysis. WAKE-UP is an investigator-initiated, interventional, randomized, double-blind, placebo-controlled, parallel-assignment, international, multicenter efficacy and safety study [48]. The objective of WAKE-UP is to test the efficacy and safety of MRI-based intravenous thrombolysis with rtPA (Alteplase) in patients with unknown symptom onset, e.g., patients waking up with stroke symptoms who otherwise fulfill the approval criteria for intravenous thrombolysis in acute stroke. Patients complying with clinical inclusion and exclusion criteria will undergo MRI including DWI and FLAIR. Patients will be randomized 1:1 to either treatment or placebo if MRI is indicative of lesion age of less than 4.5 h, i.e., shows a DWI-FLAIR mismatch. Clinical inclusion criteria include age between 18 and 80 years and a disabling neurological deficit. The primary efficacy endpoint is favorable outcome defined by a score of 0–1 on the (MRS) 90 days after stroke. Primary safety endpoints are mortality and death or dependency 90 days after stroke. WAKE-UP plans to enroll 800 patients in 40–60 study sites in six European countries and started recruitment in October 2012.

In addition to these randomized controlled trials, there is a single-armed observational US study of thrombolysis with alteplase in patients with unknown symptom onset, MR WITNESS, a study of intravenous thrombolysis with alteplase in MRI-selected patients. MR WITNESS will also use the concept of DWI–FLAIR mismatch to identify patients likely to respond to thrombolysis and plans to enroll 80 patients.

Conclusion

Wake-up strokes represent a large group of patients who are currently excluded from intravenous thrombolysis based on licensing criteria. Evidence from imaging studies, however, suggests that a relevant proportion of patients with wake-up stroke might benefit from reperfusion treatment. New imaging approaches have been suggested to select wake-up stroke patients for thrombolysis based on the identification of tissue at risk of infarction independent of time by penumbral imaging or based on the identification of patients within the approved time window for thrombolysis by the concept of DWI–FLAIR mismatch. Both approaches are currently tested in large randomized controlled trials. If positive, these trials will change clinical practice and make available effective and safe treatment for a large group of acute stroke patients currently excluded from specific acute treatment.