Wake Up Stroke: A Brief Literature Review

By John Henry Dreyfuss, MDalert.com staff.

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  • About 25% to 30% of ischemic strokes occur during sleep.
  • Tissue-plasminogen activator is the only specific stroke treatment proven effective in large randomized trials.
  • Without knowledge of exact time of symptom onset, this large group of patients is excluded from treatment with tissue-plasminogen activator.
  • Clinical and imaging studies suggest that many wake-up strokes occur close to awakening and these patients might be within the approved time-window for thrombolysis upon arrival at the emergency department.

The following is a brief review of the recent medical literature on the phenomenon of wake-up stroke. This literature review is intended to accompany our full article on the topic available here.

Figure. Recombinant tissue plasminogen activator.

​1. Wake-up stroke in a young woman with rotational vertebral artery occlusion due to far-lateral cervical disc herniation. Okawa M, Amamoto T, Abe H, Yoshimura S, Higashi T, Inoue T. J Neurosurg Spine. 2015 May 1:1-4. [Epub ahead of print]. PMID: 25932602

“Brain MRI showed acute infarction in the posterior fossa. Cerebral angiography showed thrombus in the distal top of the basilar artery and the bilateral posterior cerebral arteries. During angiography, the thrombus size decreased with heparinization. There was severe stenosis of the right vertebral artery (VA) at C5-6, and head rotation to the right resulted in complete occlusion of the right VA. Neck MRI showed far-lateral intervertebral disc herniation. Surgical decompression of the VA was performed via the anterior cervical approach. Histological examination showed a degenerative intervertebral disc. Postoperative angiography confirmed successful decompression of the VA,” concluded Okawa et al.

2. Are the current MRI criteria using the DWI-FLAIR mismatch concept for selection of patients with wake-up stroke to thrombolysis excluding too many patients? Odland A, Særvoll P, Advani R, Kurz MW, Kurz KD. Scand J Trauma Resusc Emerg Med. 2015 Feb 19;23:22. doi: 10.1186/s13049-015-0101-7. PMID: 25888410.

“Up to 25% of stroke patients wake up with a neurological deficit, so called wake-up stroke (WUS). Different imaging approaches that may aid in the selection of patients likely to benefit from reperfusion therapy are currently under investigation. The magnetic resonance imaging (MRI) diffusion weighted imaging -- fluid attenuated inversion recovery (DWI-FLAIR) mismatch concept is one proposed method for identifying patients presenting within 4.5 hours of the ischemic event,” the researchers wrote.

“In this small series DWI-FLAIR mismatch was not associated with worse outcome or ICH. This suggests that selecting WUS patients using DWI-FLAIR mismatch in clinical trials may exclude a large group of patients who might benefit,” concluded Odland et al.

3. Time-resolved MR angiography in wake-up stroke: an innovative application of a proven technique. Balaji R. Acad Radiol. 2015 Apr;22(4):411-2. doi: 10.1016/j.acra.2015.01.004. PMID: 25753592.

“Stroke is a common disorder with high incidence of disability and death. Cerebral ischemia for even a minute leads to extensive neuronal death with catastrophic results for patients. Treatment strategies focus on minimizing neuronal loss and reviving neurons on the brink of ischemia. Imaging plays a critical role in assessing the cause of acute and transient ischemic strokes and extent of neuroparenchymal involvement. Accuracy and speed of diagnosis are important for initiating treatment within the golden hours or the window period to reduce morbidity and mortality,” Dr. Balaji wrote.

4. Endovascular therapy of wake-up strokes in the modern era of stent retriever thrombectomy. Mokin M, Kan P, Sivakanthan S, Veznedaroglu E, Binning MJ, Liebman KM, Jethwa PR, Turner RD 4th, Turk AS, Natarajan SK, Siddiqui AH, Levy EI. J Neurointerv Surg. 2015 Jan 29. pii: neurintsurg-2014-011586. doi: 10.1136/neurintsurg-2014-011586. [Epub ahead of print]. PMID: 25634902. 

“Our study indicates that endovascular treatment of WUS with stent retrievers and aspiration thrombectomy is safe and effective,” the researchers wrote in the Journal of Neurointerventional Surgery. 

5. Acute stroke imaging: feasibility and value of MR angiography with high spatial and temporal resolution for vessel assessment and perfusion analysis in patients with wake-up stroke. Seeger A, Klose U, Poli S, Kramer U, Ernemann U, Hauser TK. Acad Radiol. 2015 Apr;22(4):413-22. doi: 10.1016/j.acra.2014.11.013. Epub 2015 Jan 15. PMID: 25601301.

“Time-resolved MRA is a valuable technique in patients with WUS with high sensitivity and high negative predictive value. Cerebral perfusion estimation can be performed in selected cases for therapy decision but can be hampered by patient movement,” concluded Seeger et al. in Academic Radiology.

6.) Proximal aortic distensibility is an independent predictor of all-cause mortality and incident CV events: the MESA study. Redheuil A, Wu CO, Kachenoura N, Ohyama Y, Yan RT, Bertoni AG, Hundley GW, Duprez DA, Jacobs DR Jr, Daniels LB, Darwin C, Sibley C, Bluemke DA, Lima JA. J Am Coll Cardiol. 2014 Dec 23;64(24):2619-29. doi: 10.1016/j.jacc.2014.09.060. PMID: 25524341.

Redheuil et al found that “Decreased proximal aorta distensibility significantly predicted all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low- to intermediate-risk individuals”

7. Differences in wake-up and unknown onset stroke examined in a stroke registry. Reid JM, Dai D, Cheripelli B, Christian C, Reidy Y, Gubitz GJ, Phillips SJ. Int J Stroke. 2015 Apr;10(3):331-5. doi: 10.1111/ijs.12388. Epub 2014 Oct 22. PMID: 25338933.

“Wake-up stroke has lower rates of inrtracrainial hemorrhage” wrote Cheripelli, et al, “but similar stroke severity and outcomes to awake-onset stroke. Unknown onset stroke prevalence appears to be increasing, with higher stroke severity and worse prognosis,” the researchers concluded.

8. Outcomes after endovascular treatment for anterior circulation stroke presenting as wake-up strokes are not different than those with witnessed onset beyond 8 hours. Aghaebrahim A, Leiva-Salinas C, Jadhav AP, Jankowitz B, Zaidi S, Jumaa M, Urra X, Amorim E, Zhu G, Giurgiutiu DV, Horev A, Reddy V, Hammer M, Wechsler L, Wintermark M, Jovin T. J Neurointerv Surg. 2014 Oct 17. pii: neurintsurg-2014-011316. doi: 10.1136/neurintsurg-2014-011316

“Rates of good outcomes, parenchymal hematoma, and final infarct volumes following endovascular treatment may not be different in patients with [wake up stroke] compared with patients with witnessed onset of symptoms beyond 8h,” the researchers asserted.

9.) Coronary artery calcium and risk of atrial fibrillation (from the multi-ethnic study of atherosclerosis). O'Neal WT1, Efird JT2, Dawood FZ3, Yeboah J3, Alonso A4, Heckbert SR5, Soliman EZ6. Am J Cardiol. 2014 Dec 1;114(11):1707-12. doi: 10.1016/j.amjcard.2014.09.005. Epub 2014 Sep 16.

“Calcified coronary arteries are associated with the development of cardiovascular disease and stroke. It is currently unknown whether coronary artery calcium (CAC) is associated with an increased risk for atrial fibrillation (AF). The aim of this study was to address this question in 6,641 participants (mean age 62 ± 10 years, 53% women, 62% nonwhites) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of baseline clinical cardiovascular disease and AF.

“In conclusion, CAC is independently associated with increased risk for AF,” the researchers wrote in the American Journal of Cardiology.

10.) THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg (THAWS) Trial. Koga M, Toyoda K, Kimura K, Yamamoto H, Sasaki M, Hamasaki T, Kitazono T, Aoki J, Seki K, Homma K, Sato S, Minematsu K; THAWS investigators. Int J Stroke. 2014 Dec;9(8):1117-24. doi: 10.1111/ijs.12360. Epub 2014 Aug 4. PMID: 25088843

Patients with unclear-onset time of stroke symptoms beyond 4.5 h and within 12h after the time of the last-known-well period and within 4·5 h after symptom recognition, who showed a negative fluid-attenuated inversion recovery pattern, were randomly assigned to either intravenous thrombolysis or standard treatment.

“The primary efficacy end-point was modified Rankin Scale 0-1 at 90 days. The safety outcome measures were symptomatic intracranial hemorrhage at 22-36 h, and major bleeding and mortality at 90 days, the researchers wrote in the.

“This trial may help determine if low-dose alteplase at 0·6 mg/kg should be recommended as a routine clinical strategy for ischemic stroke patients with unclear-onset time.”