Patients who awaken with stroke symptoms that weren’t present prior to falling asleep is a phenomenon known as wake-up stroke. Photo courtesy Raf Vittone

Patients who awaken with stroke symptoms that weren’t present prior to falling asleep is a phenomenon known as wake-up stroke. Photo courtesy Raf Vittone


EMS was dispatched at 6:43 a.m. for a 47-year-old man who was experiencing right-sided paralysis.

On arrival, the medics noticed that he couldn’t seem to understand them and thus wasn’t able to follow commands. The patient’s wife stated that her husband was perfectly normal when they went to bed at about 11 p.m. the previous night.

Upon arrival at a primary stroke center, the time last known normal was acknowledged as 11 p.m., which meant the patient wasn’t eligible for tissue plasminogen activator (tPA).

The patient was admitted to the floor for secondary stroke prevention. Could anything else have been done for this man who was the sole breadwinner for his household of five with three school-aged children?

Stoke Management Dilemma

Patients who go to sleep normally and awaken with stroke symptoms that weren’t present prior to falling asleep is a phenomenon known as wake-up stroke.

Wake-up stroke occurs in roughly one in five acute ischemic strokes, and remains a therapeutic dilemma.

Patients with wake-up stroke are excluded from most ischemic stroke treatment trials, and they are often not eligible for acute reperfusion therapy in clinical practice, leading to poor outcomes.

Studies of neuroimaging with standard non-contrast computed tomography (CT), magnetic resonance imaging (MRI), and multimodal perfusion-based CT and MRI, suggest that wake-up stroke may occur shortly before awakening from sleep, and may assist in selecting patients for acute reperfusion therapies.

Acute stroke evaluation and management is fundamentally predicated on time from symptom onset. IV tissue plasminogen activator (tPA) remains the only Food and Drug Administration (FDA)-approved nonsurgical reperfusion therapy for acute stroke with evidence-based efficacy.

Well-designed, adequately powered studies have consistently shown that efficacy is extremely time sensitive. That being the case, knowledge of the exact time of symptom onset, or at least the time at which the patient was last known to be normal, is paramount.

Knowledge of the exact time of symptom onset, or at least the time at which the patient was last known to be normal, is paramount.

Patients likely to have experienced a wake-up stroke present a management dilemma for acute stroke providers. Sometimes the period of sleep is short and the patient can still be eligible for tPA, based on standard time-based criteria.

However, when the time at which the patient was last known to be normal is the night prior to a morning presentation, which is often the case, the acute stroke provider is left without the key time-based data typically needed to make a safe therapeutic decision for tPA candidacy. This makes for a diagnostic and therapeutic gray area in acute stroke practice.

Research Revelations

The best estimate of wake-up stroke prevalence comes from a retrospective population-based study of 1,854 acute ischemic strokes in the Greater Cincinnati/Northern Kentucky region. In this representative bi-racial sample, 273 (14.3%) of acute strokes were wake-up strokes, resulting in an adjusted event rate of 26.0/100,000.1

There have been several non-contrast CT-based studies that have compared early ischemic changes between wake-up stroke and stroke of known onset. Overall, there was no significant difference in early CT changes between wake-up stroke and stroke of known onset within 3 hours or 6 hours, suggesting that the ischemic insult may occur shortly before or at the time of awakening in the absence of early ischemic change.2,3

Perfusion and volume-based imaging with magnetic resonance or advanced CT-based studies provide more granular physiologic data than non-contrast CT for acute stroke.

These advanced neuroimaging techniques estimate the volume of brain tissue potentially at risk for progression to infarction or ischemic penumbra if recanalization doesn’t occur.

The volumetric difference between a surrogate for established infarction and penumbra, if present, is referred to as a “mismatch” and represents a rational biomarker for treatment selection.

Studies of advanced neuroimaging techniques have been conducted in patients with wake-up stroke. An MRI-based study of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI), imaging surrogates of ischemic, and “at-risk” tissue, respectively, found that patients with wake-up stroke and stroke of known onset had similar DWI and PWI lesion volumes as well as a similarly high proportion of DWI-PWI mismatch.4

A similarly designed CT-based study of mismatch between cerebral blood volume DWI, the estimate of infarcted tissue and cerebral blood flow PWI, the at-risk tissue found no difference between the percentage of mismatch between patients with wake-up stroke and stroke of known onset within a therapeutic window.5

Another interesting mismatch approach utilizes DWI and fluid attenuated inversion recovery (FLAIR) sequences of magnetic resonance imaging to identify infarcted vs. at-risk tissue.

The T2-based FLAIR sequence measures the accumulation of cerebral edema as the infarction process proceeds.6 Thus, in principle, the presence of a DWI lesion and absence of a matched FLAIR abnormality should represent a relatively early infarct.

DWI-FLAIR mismatch was found to accurately identify ischemic tissue beyond three to six hours, and it can identify ischemia within the 3–4.5-hour window with excellent specificity.6

WAKE-UP is a European multicenter investigator-initiated randomized placebo-controlled clinical trial of MRI-based thrombolysis in acute stroke patients with unknown time of symptom onset.7

These patients are currently excluded from treatment with tPA only due to the missing information on the time of symptom onset, and the results from WAKE-UP show that half of the patients studied showed a DWI–FLAIR mismatch, rendering them likely to be within a time window for effective reperfusion treatment.7

Research Revelations

Patients are eligible for mechanical intervention up to 24 hours, based on the recent DAWN study.

DAWN was an international multicenter, blinded endpoint assessment, 1:1 randomized study, with the objective to demonstrate superior clinical outcomes at 90 days following mechanical thrombectomy with Stryker’s Trevo Retriever and medical management vs. medical management alone in selected patients treated 6–24 hours after last seen well.8

The study included 50 sites worldwide, and 65% of the cohort were wake-up strokes. The seminal findings from this trial established the therapeutic window for mechanical thrombectomy for large vessel occlusion out to 24 hours.8

This is a significant advance in stroke care, as occlusion of the large vessels of the brain—the internal carotid and M1 and M2 branches of the middle cerebral artery— produce significant long-term disability and mortality. Furthermore, it provides a therapeutic option for wake-up stroke patients.

Figure 1: Polk County Fire Rescue stroke alert protocol

Wake-Up Stroke Protocol

Polk County Fire Rescue has developed a wake-up stroke protocol for its citizens. (See Figure 1.)

The initial triage of a wake-up stroke patient involves using an expanded Cincinnati Prehospital Stoke Scale to verify whether the patient is having a stroke.9 Providers assess the patient’s balance and clarity of vision in addition to looking for facial droop, arm weakness and slurred speech.

If it’s determined that the patient is indeed having an acute stroke, a score is calcuated based on the Los Angeles Motor Scale (LAMS)11 and the time frame of the event is established.

Then, a modified Rankin score (mRS) based on the patient’s disabilities prior to the stroke is calcuated.10 (See Table 1.)

Table 1: Modified Rankin scale used in Polk County Fire Rescue stroke alert protocol




No symptoms at all


No signficant disability despite symptoms; able to carry out all usual duties and activities


Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance


Moderate disability; requiring some help, but able to walk without assistance


Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance


Severe disability; bedridden, incontinent and requiring constant nursing care and attention



Any patient with an mRS > 3, prior to the stroke event will only be taken to a primary stroke center.

Patients with an mRS < 4, may be eligible to be transported to a comprehensive stroke center with mechanical capabilities or a comprehensive stroke center.

This decision is based on the level of motor disability using the LAMS score, and the time frame of the event.


1. Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study of wake-up strokes. Neurology. 2011;76(19):1662–1667.

2. Todo K, Moriwaki H, Saito K, et al. Early CT findings in unknown-onset and wake-up strokes. Cerebrovasc Dis. 2006;21(5–6):367–371.

3. Roveri L, La Gioia S, Ghidinelli C, et al. Wake-up stroke within 3 hours of symptom awareness: Imaging and clinical features compared to standard recombinant tissue plasminogen activator treated stroke. J Stroke Cerebrovasc Dis. 2013; 22(6):703–708.

4. Schellinger PD, Bryan RN, Caplan LR, et al. Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke. Neurology. 2010;75(2):177–185.

5. Silva GS, Lima FO, Camargo EC, et al. Wake-up stroke: Clinical and neuroimaging characteristics. Cerebrovasc Dis. 2010;29(4):336–342.

6. Thomalla G, Cheng B, Ebinger M, et al. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): A multicentre observational study. Lancet Neurol. 2011;10(11):978–986.

7. Thomalla G, Boutitie F, Fiebach JB, et al. 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). Stroke. 2017;48(3):770–773.

8. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11–21.

9. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: Reproducibility and validity. Ann Emerg Med. 1999;33(4):373–378.

10. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957;2(5):200–215.

11 Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): A new measure to characterize stroke severity in the field. Prehosp Emerg Care. 2004;8(1):46–50.


Stroke Specialists Get Surprises, Too

Polk County Fire Rescue responded to a 26-year-old woman with sudden onset of difficulty speaking and a facial droop. Her right side was weak. Fortunately, her boyfriend was there to witness the event and called 9-1-1.

EMS personnel were amazed to be calling in a stroke alert on such a young patient. While en route to Jackson Memorial Hospital, a comprehensive stroke center, they noted the patient was improving.

The stroke team met EMS at the door. The team assessed her initial National Institutes of Health Stroke Scale (NIHSS) score at 6, and the patient showed improved arm and leg movement but persistent aphasia.

A CT scan of this otherwise healthy young woman showed an unexpected result: There was a hyperdense left middle cerebral artery (MCA) sign—a major clot was blocking the major artery supplying blood to the dominant side of her brain.

IV tPA was started 18 minutes after arrival at the ED, but the chance of opening up this critical artery with IV tPA alone was small. Even in a case where stroke symptoms seem to be improving, the patient may actually have a very high-risk blockage.

The stroke team moved the patient to angiography, where the interventional neurologist confirmed the total left MCA occlusion and removed the clot by performing the thrombectomy with a special retrieval device. The patient woke up from the sedation fully able to speak and move normally. Her ED door-to-groin puncture (i.e., angiography) time was just 41 minutes, and her left MCA perfusion was fully restored 71 minutes after her arrival. Her follow-up NIHSS was zero—back to normal.

Why did a healthy young woman have a total blockage of a major artery? She had no history of stroke in her family and the only medication she took was oral contraceptives, which can lead to venous blood clots.

A transesophageal echocardiogram revealed a patent foramen ovale (PFO), an abnormal connection between her right and left atrium. She was born with this defect, and it had never caused her a problem before. However, if a blood clot forms in a vein in some part of the body and a small piece breaks off, the PFO will let that clot move straight into the left side of the heart to be pumped out via the aorta. This one went to her brain.

This is a great example of how a coordinated approach to stroke—including 9-1-1 dispatchers, EMS, ED staff and the hospital stroke team—can effectively race against time to achieve positive patient outcomes.

Angiogram showing blocked blood flow in the left middle cerebral artery. Photos courtesy Polk County Fire Rescue/Jackson Memorial Hospital

Angiogram showing left middle cerebral artery opened by clot retriever.

Clot that was captured and removed from the patient via mechanical thrombectomy.