Wake-Up Stroke: Current Understanding : Topics in Magnetic Resonance Imaging

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Wake-Up Stroke

Current Understanding

Tsai, Jenny P. MDCM, FRCPC; Albers, Gregory W. MD

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Topics in Magnetic Resonance Imaging 26(3):p 97-102, June 2017. | DOI: 10.1097/RMR.0000000000000126
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A wake-up stroke is clinically defined as an ischemic stroke that is associated with neurological symptoms on awakening. By definition, the patient's last-known-well time corresponds to the onset of sleep on the evening before presentation. Wake-up strokes are often compared and contrasted to daytime strokes of either witnessed or uncertain onset.

As patients with wake-up strokes usually have a lapse of several hours between bedtime and awakening, they are often excluded from acute stroke therapy options for being out of safe treatment windows. Yet, retrospective data estimate the prevalence of wake-up strokes as 14% to 28% of all ischemic cerebrovascular events.1–4 Therefore, the ability to deliver acute stroke therapy to patients with wake-up strokes would extend treatment eligibility to approximately 3 million additional patients per year worldwide, and potentially relieve a significant portion of the societal burden of stroke-related disability.5

There are 2 fundamental questions to address, to understand and manage wake-up strokes. The first is whether there truly is a distinct physiological process that differentiates them from daytime strokes of witnessed or unknown onset, or if they are simply a misleading artefact of a history-based diagnostic classification. The second question is how to select patients with wake-up strokes for clinical acute stroke treatment—an approach that requires the use of advanced diagnostic imaging. In the following sections, we aim to review of the currently proposed pathophysiology and recognized risk factors underlying wake-up strokes, their clinical features, and neuroimaging's role in identifying patients that may benefit from treatment.


We conducted a review of the literature pertaining to wake-up strokes, including all publications indexed in Medline from 1989 to 2016. We searched primary medical subject headings, including “wake-up stroke” and “stroke and circadian rhythm,” and limited our search to articles published in the English language. We reviewed article references for additional pertinent primary sources.


The primary search identified 685 articles published in peer-reviewed sources, including case reports and series, observational studies, and review articles. The following sections outline the current perspectives on the physiology and pathophysiology of wake-up stroke, its clinical and radiographic features.

Circadian Rhythm, Sleep, and Pathophysiology of Wake-Up Stroke

The close association between wake-up strokes and morning awakening has supported a long-suspected predisposition related to normal circadian fluctuations in autonomic and cardiovascular functions. Since the 1980s, several studies have explored the circadian distribution of ischemic strokes.6–9 By subdividing the day into periods spanning 3 to 6 hours, a morning peak in stroke incidence was consistently replicated.6,7,10 A meta-analysis of 11,816 stroke cases consolidated the data from 31 studies completed prior to 1998, and showed a 55% higher risk of ischemic strokes and 50% higher risk of transient ischemic attacks between 6 AM and noon.8

This morning risk excess is comparable to the early diurnal peak in risk by 40% for acute myocardial infarction. Moreover, it also correlates with the increase in sympathetic activity, renin-angiotensin-aldosterone axis activity, plasma cortisol level, blood pressure, and heart rate.8,11 Atrial fibrillation is another cardiovascular risk factor strongly associated with wake-up stroke.12,13 Riccio et al12 reported a 3-fold increase in odds of a new diagnosis of atrial fibrillation in patients presenting with wake-up strokes and transient ischemic attacks. Although the occurrence of atrial fibrillation shows a bimodal circadian peak, respectively, at midnight and 1 PM, its most frequent termination and conversion to sinus rhythm tends to occur at approximately 6 AM.11,14 Given the association between cardioembolism and cardioversion to normal sinus rhythm, the frequent termination of atrial fibrillation in morning hours may explain its time association with wake-up strokes.15 Meanwhile, pro-thrombotic hematological parameters, such as plasminogen activator inhibitor-1 and platelet aggregation function, also demonstrate early diurnal peaks in their activity, and may have some contribution to the incidence of wake-up strokes.16–18

However, circadian rhythm does not independently account for the risks of wake-up strokes. Normal phases of sleep have been shown to carry different cerebrovascular and cardiovascular risks: wake-up strokes are rare in the earlier and deeper stages of sleep, particularly in slow-wave sleep (SWS).8,19 The relatively protective effect of deep stages of sleep is also supported by the observation that reduction in SWS is linked with exacerbation in other modifiable cerebrovascular risk factors, such as hypertension.20 Laboratory data suggest that an increase in endothelial, myogenic, and neurogenic cerebral vasomotor tone in transitioning from SWS to rapid-eye movement sleep may be partly responsible for this observation.21

Meanwhile, sleep-disordered breathing has frequently been associated with stroke risk, and particularly with wake-up strokes.22 Obstructive sleep apnea is common in stroke patients and is an independent risk factors for stroke.23 The risk of stroke is estimated to be increased 2- to 4-fold in patients with obstructive sleep apnea.24,25 Conversely, obstructive sleep apnea is common in stroke patients: using simple pulse oximetry on a stroke unit, Kim et al26 demonstrated that patients admitted with wake-up strokes have a 3 times higher odds than other ischemic stroke patients to have nocturnal desaturation events.

Although hypoxia and carbon dioxide retention associated with sleep apnea adversely impacts cerebrovascular function via exacerbation of systemic vascular risk factors, obstructive sleep apnea also demonstrates direct impact on cerebral perfusion.27–29 Regional cerebral blood flow appears abnormally decreased in individuals with obstructive sleep apnea based on single positron emission computed tomography (SPECT), computed tomography perfusion (CTP), arterial spin labeling perfusion imaging, and positron emission tomography (PET) studies.27,30–32 Co-localization of regional hypoperfusion, gray matter atrophy, and impaired diffusivity on diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) primarily occurs in the basal forebrain, insular cortices and pontomedullary nuclei, providing additional physiological basis of the dysregulated sympathetic, respiratory, and cardiovascular functions in further contributing to the disordered sleep-related stroke risk in patients with obstructive sleep apnea.28,30,31,33

Do these associations between circadian variations of physiological parameters, normal, and disordered sleep reconcile to define wake-up strokes as a distinct entity? Wake-up strokes are more accurately defined as the result of high cerebrovascular risk, which is in turn due to a convergence of pre-existing vascular comorbidities under the physiological effect of a normal circadian cycle. In other words, wake-up strokes likely have a distinct risk profile, with otherwise no significant difference in pathophysiology from witnessed or unwitnessed daytime strokes.

Clinical Features of Wake-Up Strokes

Numerous retrospective and cross-sectional studies have compared clinical characteristics between wake-up and awake-onset strokes. No conclusive difference has been identified between the characteristics of wake-up and awake-onset strokes.3,34–36 Observational studies attempting to define wake-up strokes proposed numerous demographic and clinical features that appear to distinguish the affected patient population, though most fail to be replicated between studies. Inconsistently reported features of wake-up strokes include older age, female predominance, higher incidence in winter, more severe syndromes (as reflected by initial National Institute of Health Stroke Scale (NIHSS) score), and higher blood pressure on presentation.2,3,7,37,38 The one characteristic that demonstrated greater consistency is the stroke subtype, per the Trial of ORG 10172 in Acute Stroke (TOAST) classification. Several studies, including a subanalysis of 17,398 patients from the International Stroke Trial, showed a slightly higher prevalence of lacunar subtype in wake-up stroke, with lower incidence of severe anterior circulation stroke syndromes.7,9,35

Although clinical features of wake-up strokes are inconsistently reported, outcome analysis across multiple studies agree that clinical outcome in patients with wake-up strokes are comparable to those with awake-onset strokes. In a Canadian single-center stroke registry, 3890 patients with wake-up strokes had similar stroke severity and 6-month functional outcome as awake-onset strokes.34 In the International Stroke Trial, 14-day mortality and 6-month rates of poor outcome (death or functional dependence) are similar in wake-up and awake-onset strokes.35 Despite apparently similar rates of good outcomes, these results in fact suggest that patients with wake-up strokes have the potential to do better, as significantly fewer of them actually received acute stroke treatment. Approximately 13% of awake-onset strokes were treated with intravenous thrombolysis, versus only 0.3% to 2.1% of wake-up strokes.34,35 The number of wake-up stroke patients treated is well below what it could potentially be: A population-based analysis showed that at least 35.9% of wake-up stroke patients would have met eligibility for thrombolysis, if it were not for an unclear last-known-well time.3 Therefore, a greater proportion of wake-up stroke patients could conceivably achieve good outcomes, if their eligibility for acute stroke treatment could be confirmed using alternative, imaging-based criteria.

Neuroimaging Findings in Wake-Up Strokes

To select a patient for acute stroke treatment, neuroimaging in acute ischemic stroke should accurately establish that there is salvageable brain tissue. This can be achieved by estimating the core and penumbra lesion sizes, which is commonly considered in patients with awake-onset stroke being evaluated for acute treatment. In considering infarct core and ischemic penumbra, are there truly differences in imaging characteristics between wake-up and awake-onset strokes? No studies have yet identified any clinically significant differences between imaging features of wake-up and awake-onset strokes.39 Therefore, it is justified to assume that neuroimaging can play similar roles in the evaluation of wake-up and awake-onset strokes: to estimate actual lesion age, and assess for the presence of salvageable brain tissue in consideration for acute stroke treatment.

Computed Tomography-Based Imaging

Huisa et al39 compared the Alberta Stroke Programme Early Computed Tomography Score (ASPECTS) on non-contrast computed tomography (CT), in patients with wake-up strokes and those who presented within 4 hours of awake, known-onset strokes. The study identified only a <1-point difference in the absolute score between groups (9.0 ± 1.9 vs 9.8 ± 1.8, P = 0.0019). When analyzed using a clinically pragmatic, dichotomized ASPECTS classification, this difference became statistically insignificant (P = 0.35). However, non-contrast CT likely lacks in specificity in predicting good outcomes. Using non-contrast CT alone to determine patient eligibility, the AbESTT-II trial showed an elevated rate of hemorrhagic transformation in wake-up stroke patients treated with abciximab when compared with other subgroups.40 The disproportionate rate of hemorrhage led investigators to halt enrollment of wake-up stroke patients mid-trial.40 Because non-contrast CT may be insufficient for safe patient selection for acute treatment, multimodal CT and magnetic resonance imaging (MRI) are preferred imaging modalities in wake-up strokes.3,41

Contrast-enhanced CT provides some advantage over non-contrast CT for its additional insight into acute stroke physiology. Silva et al4 prospectively compared CT perfusion patterns and CT angiography source images between wake-up strokes, awake “known-onset” strokes within 3 hours of last-known-well time, and awake “indefinite-onset” strokes within 24 hours of last-known-well time. Using a qualitative cerebral blood flow to cerebral blood volume (CBF:CBV) mismatch definition, the study showed no difference in the prevalence of perfusion mismatch or ischemic lesion sizes between wake-up and awake-onset strokes. The prevalence of proximal large-vessel intracranial occlusions amenable to endovascular therapy, in either the anterior or posterior circulation, was identical across groups. Although patients with known-onset strokes were more commonly treated with intravenous or intra-arterial thrombolysis, follow-up CT showed no difference in the incidence of hemorrhagic transformation between wake-up strokes and awake, known-onset strokes.42 Although it provides little information on approximate timing of the infarct, CT perfusion likely allows for selection of wake-up stroke patients that are potentially safe to be considered for acute treatment (Fig. 1).

Mismatch on CTP and MRI. A, The automated CTP mismatch evaluation uses a relative CBF threshold of <0.3 to determine the infarct core, and time-to-maximum of the residue function (Tmax) >6 s to delineate the hypoperfused territory. B, On MRI, PWI-DWI mismatch is demonstrated by a small infarct core, based on ADC <620, and a larger hypoperfused region marked by Tmax >6 s.

MR-Based Imaging

Thanks to diffusion-weighted imaging (DWI)'s superior sensitivity and specificity in detecting infarct cores within minutes of stroke onset, MRI is the optimal modality for evaluating patients with wake-up strokes.43 By contrasting DWI with another imaging sequence, MRI is able to estimate time from of stroke onset, delineate the infarct core and penumbra, and reliably identify patients with potential for good functional outcome after reperfusion.44–47

The mismatch between DWI and fluid-attenuate inverse recovery (FLAIR) sequences is a reliable approach to estimate the infarct age. DWI-FLAIR mismatch is defined by the presence of a diffusion-restricting infarct core and the complete absence of FLAIR hyperintensity (Fig. 2). Petkova et al44 used DWI-FLAIR mismatch to distinguish patients as presenting within or after 3 hours from stroke onset, and reported sensitivity and specificity as high as, respectively, 94% and 97% by visual inspection alone. The interobserver agreement was also high with a kappa of 0.97. Meanwhile, Thomalla et al45 showed that DWI-FLAIR had a 62% sensitivity, 78% specificity, and a kappa of 56.9% in identifying patients imaged within 4.5 hours from stroke onset. In fact, DWI-FLAIR mismatch's performance has shown dependence on time from stroke onset, lesion volume, patient age, and the variability in magnetic susceptibility effect.44,45,48 The latter is based on different magnet field strength or MRI sequence parameters, which can significantly diminish the sensitivity of DWI-FLAIR mismatch when FLAIR images are acquired on 3.0-T scanners. Despite these variabilities, DWI-FLAIR mismatch's ability to narrow stroke onset to the first 3- to 4.5-hour window allows a subset of wake-up strokes to be considered for thrombolysis. DWI-FLAIR mismatch was used to select patients in the recently completed MR WITNESS trial on thrombolysis in wake-up stroke patients, and the ongoing phase 3 European trial on thrombolysis in wake-up strokes, the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke (WAKE-UP) trial.

Examples of DWI-FLAIR mismatch and FLAIR-positive infarcts from the PRE-FLAIR study. The PRE-FLAIR study evaluated DWI and FLAIR images to identify the time window associated with DWI-FLAIR mismatch. A, Poor-quality images and patients with infarcts of multiple ages were excluded from the analysis. B, Paired images demonstrating DWI-FLAIR mismatch, associated with an infarct age of less than 4.5 hours. C, DWI-positive, FLAIR-positive infarcts are likely older than 4.5 hours.

Using susceptibility contrast imaging, perfusion- and diffusion-weighted imaging (PWI-DWI) mismatch directly establishes the patient's likelihood of achieving favorable clinical response upon successful reperfusion (Fig. 1). The Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) and DEFUSE 2 studies, and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) provide evidence that PWI-DWI mismatch can accurately estimate the ischemic penumbra that corresponds to salvageable tissue with reperfusion, when successfully treated with thrombolysis or endovascular therapy.49–52 A currently favored definition of ischemic penumbra uses a time-to-maximum of the residue function >6 seconds (Tmax > 6), which reliably identifies critically hypoperfused tissue that will likely be irreversibly injured without timely reperfusion.52–56 PWI-DWI offers several advantages over other advanced imaging techniques. In patients with a known stroke onset time, PWI-DWI mismatch can be present well beyond 3 hours. Its association with probability of favorable clinical outcome upon reperfusion persists beyond 12, and even up to 48, hours.46,50,52,57,58 Across these time windows, PWI-DWI mismatch is an independent predictor of both the final infarct size and functional outcome at 90 days.46,47,55,59 This effect can be accounted for by a widely variable infarct growth rate between individuals and suggests that a known or recent time of stroke onset may not be necessary for acute stroke treatment, in presence of a PWI-DWI mismatch (Fig. 3).46,47 Therefore, in patients with wake-up or awake, unknown-onset strokes, PWI-DWI mismatch is likely a reliable biomarker to guide treatment decision even when a precise clinical history is unavailable. Ongoing clinical trials on thrombolysis and endovascular therapy (Extending the Time for Thrombolysis in Emergency Neurological Deficits [EXTEND] and DEFUSE 3) use PWI-DWI mismatch to select patients with potential benefit from acute stroke treatment.60

Variable infarct growth rates estimated by DWI lesion volume and time from symptom onset to baseline MRI. By plotting a direct line between known time of symptom onset and DWI lesion volume at time of presentation and imaging, differential infarct growth rates can be demonstrated as patients may take a variable amount of time after stroke onset to reach similar infarct volumes.

Clinical- and MRA-DWI mismatch are alternative approaches to PWI-DWI mismatch to identify presence of an ischemic penumbra, when the time criterion for acute stroke treatment cannot be fulfilled based on history. These criteria often use a similar definition of small infarct core to PWI-DWI mismatch, with a maximum DWI lesion size of 50 to 70 mL. The mismatch is established by the discordance between the expected vascular territory at risk and the size of the DWI lesion. The clinical-DWI mismatch uses a high NIHSS score as a reflection of a large penumbra in presence of a small DWI lesion.61–63 Although a positive predictive value of up to 88.8% and a negative predictive value of 65% have been reported, the clinical applicability of clinical-DWI mismatch has not been consistently replicated.61,63–65 MRA-DWI mismatch relies on the demonstration of a proximal occlusion in the intracranial ICA or M1-MCA segment, with a limited infarct core defined as DWI lesion volume <50 mL.64,66,67 Although neither alternative mismatch criterion has been specifically validated in wake-up and unknown-onset stroke patients, MRA-DWI mismatch has shown good agreement with PWI-DWI mismatch in patient selection, with a kappa of 68%, up to 12 hours from estimated symptom onset.64,67 Therefore, MRA-DWI may be able to identify salvageable ischemic penumbra, in patients with wake-up strokes who were last known well within this timeframe.


Wake-up strokes are physiologically and clinically similar with awake-onset strokes. Because wake-up strokes account for up to one-fifth of stroke patients, and are often considered ineligible for acute stroke therapy, routine use of advanced CT and MRI may help extend treatment options to a significant number of patients. Several recently completed and ongoing clinical trials, on the efficacy and safety of acute stroke treatments, use these methods to selectively include patients with wake-up strokes. If positive, the results of MR WITNESS, WAKE-UP, EXTEND, DAWN, and DEFUSE 3 will support acute stroke treatments in eligible patients with wake-up strokes.5,68


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circadian rhythm; CT perfusion; diffusion-weighted imaging; DWI-fluid-attenuate inverse recovery mismatch; ischemic stroke; MR perfusion; obstructive sleep apnea; perfusion-weighted imaging; perfusion- and diffusion-weighted imaging mismatch; wake-up stroke

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