Wake-up stroke and CT perfusion: effectiveness and safety of reperfusion therapy
Ischemic stroke is a neuroemergency condition highly treatable with thrombolysis and thrombectomy. Recently, observational studies have brought insights into clinical and imaging characteristics of wake-up stroke, which interested up to 25% of ischemic stroke patients. In clinical practice, wake-up strokes are usually not considered for reperfusion therapy. The aim of this study was to investigate the use CT perfusion imaging in patients with wake-up stroke and to assess the effect of neuroimaging information provided by CT perfusion maps on the efficacy and safety of thrombolysis and thrombectomy.
Patients and method
We studied 22 wake-up stroke (WUS) patients (13F/9M mean age) who underwent reperfusion therapy after the eligibility assessed by the CT perfusion imaging (< 50% core-to-penumbra ratio and negative CT perfusion).
Mean National Institutes of Health Stroke Scale (NIHSS) was 8.1 ± 4.9 at admission while 3.3 ± 5.1 at discharge, significantly different from admission (p < 0.001). As many as ten patients had mRS lower than 3 at discharge. Intracranial hemorrhage occurred in five patients and caused symptoms worsening only in two patients (decrease of NIHSS score of 4 points) of which one patient died.
The main finding of this study is that wake-up stroke with adequate selection by CT perfusion may benefit reperfusion treatment.
KeywordsWake-up stroke Reperfusion therapy Intravenous thrombolysis CT perfusion NIHSS
Despite advances in preventive strategies and acute therapy for stroke, one of the leading causes of disability and death among adults, the burden of this pathology is still very high. Ischemic stroke is a neuroemergency condition highly treatable using thrombolysis and thrombectomy . Earlier treatment and prompt recanalization is clearly associated with improved mortality and clinical outcome due to prevention of neuronal ischemia [2, 3, 4]. Several “gray points” regarding exclusion criteria for rtPA treatment have been discussed over the years. Recently, observational studies have brought insights into clinical and imaging characteristics of wake-up stroke (WUS), which interested up to 25% of ischemic stroke patients. New approaches to guide treatment in WUS patients have been suggested and have reported that selected WUS patients may be eligible for effective and safe treatment with IV rtPA [5, 6, 7, 8].
Different imaging modalities that may guide a patient selection for reperfusion therapy are still under investigation [9, 10, 11]. Among these, CT perfusion (CTP) is very helpful in determining the areas of hypoperfused tissue that can recover in acute stroke patients and help the physicians to individuate WUS patients eligible for treatment.
The aim of our study was to investigate the use of CTP brain scan in WUS patients and the effect of this dynamic neuroimaging information on the efficacy and safety of thrombolysis. We reported this study in the neuro-radiological acute stroke protocol with CTP for WUS patients in our Stroke Unit before and after the improvement of neuroimaging.
Material and methods
This retrospective study was conducted on patients who were admitted to the Stroke Unit of the University Medical Hospital of Trieste (Italy) between January 2016 and December 2016. The patients included in the study showed acute focal neurologic symptoms compatible with ischemic stroke developed at morning awakening and underwent reperfusion therapy. All patients with acute ischemic stroke were admitted to our Emergency Department (ED) within 3 h from awakening. All patients were found in good clinical condition the evening before admission between 20 and 23 PM. The definition of stroke is based on the WHO MONICA criteria (WHO MONICA Project Principal Investigators 1988). Both genders were included in the study sample; no age limit was applied. Standard dose of intravenous rtPA was 0.9 mg/kg.
Each patient underwent 24 h direct CT after hospitalization in order to verify the presence of an ischemic lesion. By visual inspection, CTP core infarction was comparable or smaller than ischemic lesion detected on 24-h CT scan.
Conditions such as a previous stroke, history of epilepsy, migraine, brain neoplasia and previous brain surgery, and seizure at stroke onset were excluded. Exclusion criteria were also inadequate pCTs owing to technical reasons as excessive motion artifacts, bolus suboptimal time, and insufficient post-processing. WUS patients who arrived after 3 h from awakening with wide core (> 50%) on perfusion maps or ASPECT score ≤ 7 were excluded.
Patients’ demographic, clinical, and radiological data
Gender (M, F) (n%)
9.13 (41%, 59%)
Age (median, range)
Risk factors (n%)
Thrombolysis + thrombectomy
Baseline NIHSS (mean; SD)
Pre-hospital mRS (median; range)
Last seen well time (median; range)
10:15 PM (8:00–11:00 PM)
ASPECT score (mean; SD)
70% penumbra 30% core
50% penumbra 50% core
Hemorrhagic transformation (n%)
Hospitalization (mean; SD) (days)
Discharge NIHSS (mean; SD)
3 months mRS (mean; SD)
A standardized protocol for diagnosis and treatment of acute stroke was established between Neurologic Clinic, Neuroradiology, and EDs of the University Hospitals of the province of Trieste. It consists in immediately centralizing at the ED all patients with acute onset of neurological symptoms compatible with suspected cerebrovascular disease and performing general and neurological examination including NIHSS, urgent hematological tests and a multimodal computed tomography (CT) imaging protocol. The CT protocol comprises cerebral non-contrast CT, CT angiography of the supra-aortic and intracranial arteries, and CTP. Thanks to the introduction of CTP in protocol, WUS patients eligible to recanalization treatment were included.
In order to assess the outcome in WUS patients who underwent reperfusion therapy, we have evaluated the following parameters: changing of NIHSS and mRS (during recovery and at discharge and at 3 months), intracerebral hemorrhage, and mortality rate.
Direct CT, CT angiography, and CTP were performed with one of the latest generation CTs (Brilliance iCT 256 slices; Philips Medical Systems, Best, Netherlands). CTP acquisition protocol involves the intravenous injection of 75 ml of contrast medium, followed by a 40-ml saline bolus, both administered at an injection rate of 4 ml/s and three-dimensional axial acquisitions on a whole brain volume with a reconstruction of the slices set to 5 mm using a series of repeated movements of the scanner table. The acquisitions were carried out every 4 s, resulting in a total scanning time of 60 s. The exposure parameters used were 80 kVp and 150 mAs. Analysis of the CTP images raw data were carried out on a separate console (brain perfusion software; Extended Brilliance Workstation v 3.0, Philips Medical System), and the perfusion maps mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were obtained after manually positioning a region of interest in correspondence to an artery and a vein. The brain perfusion software is based on the central volume principle and uses a closed-form, non-iterative, deconvolution for the evaluation of MTT. The areas below the density/time curves are used to determine the CBV. CBF maps are calculated as a ratio between CBV and MTT. Subsequently, specific threshold values were set up in the software to calculate the penumbra areas, highlighted in green on the generated color maps (MTT 145% of the contralateral healthy area and CBV > 2.0 ml/100 g), and the infarcted core areas, highlighted in red (MTT 145% of the contralateral healthy area and CBV < 2.0 ml/100 g), as described by Wintermark et al. (Wintermark, 2006). The software-generated lesions were areas greater than 1 cm2, lesions affecting the cerebral parenchyma, lesions outside the areas affected by motion artifacts, or chronic strokes present on direct scan [12, 13].
Continuous variables were presented as mean ± SD or medians (ranges) depending on their distribution (normal or not) and non-continuous variables as percentages. The differences between NIHSS at admission and discharge were assessed by Wilcoxon signed-rank test. A level of p < 0.01 was regarded as statistically significant.
Between January 2016 and December 2016, 469 patients were admitted to our Neurological Department for an ischemic stroke. Patients’ demographic, clinical, and radiological data are summarized in Table 1. Among them, 136 patients were treated with reperfusion therapy (136 patients with IV rtPA, of those, 13 patients received also endovascular treatment, three patients primary thrombectomy). Of these, 22 patients (16%; 13 female, 9 male) were admitted due to WUS. All patients were admitted to the ED early in the morning between 5 and 8 AM; last seen well time was documented between 20 and 23 PM of the preceding evening. Mean patients’ age was 63.5 years (range 41–89). Main risk factors were systolic hypertension and dyslipidemia (19 and 12 patients respectively), three patients showed positive anamnesis for diabetes mellitus, five patients showed atrial fibrillation, and nine patients were current smoker at admission. Mean NIHSS at admission was 8.1 ± 4.9. mRS of 2 and 1 were reported in two patients each, while other patients presented an mRS of 0. Mean ASPECT estimated on direct CT brain scans was 9.45 ± 1.1 (17 of 22 had ASPECT 10). On CTP images, 100% penumbra-to-core ratio was found in seven of them, while eight and two of them had 70 and 50%, respectively. In five subjects, CTP imaging was negative, with non-significate hypoperfusion identified on the CTP maps. WUS patients received intravenous thrombolysis, while one patient received only thrombectomy treatment. Three patients who received thrombolysis underwent thrombectomy at a later point. Intracranial hemorrhage occurred in five patients and caused symptoms worsening (SICH) in two patients (decrease of NIHSS score of 4 points).
Mean NIHSS at discharge was 3.3 ± 5.1, significantly different from NIHSS at admission. In seven patents, NIHSS at discharge was 0. Moreover, the benefits in terms of NIHSS decrease from admission to discharge was evident both for younger and for aged (over 65 years) patients: mean NIHSS decrease 4.08 (72% decrease from admission) and 5.33 (60% decrease) respectively. For older subjects (over 80 years), the mean decrease of NIHSS was 5.75 (45% decrease). Patients with 100% penumbra-to-core ratio presented mean NIHSS decrease of 4 (73% decrease) while in patients with 70 and 50% of penumbra the NIHSS decrease was 4.3 (50% decrease) and 4 (54% decrease). In patients with negative CTP, mean NIHSS decreased 4.6 (77% decrease).
Mean length of hospital stay in our study population was 11.6 ± 6.9 days. Ten patients were discharged and sent home, six patients were admitted to intensive rehabilitation institute, two patients were discharged and sent to rehabilitation institute for chronic condition, three patients were admitted to another neurological or internist department, and one patient died. Mean mRS score at 3 months was 2.36 ± 1.68 and ten patients had an mRS lower than 3 at discharge.
The aim of this study was to investigate the use of CTP imaging in patients with WUS and to assess the effect of neuroimaging information provided by CTP maps on the efficacy and safety of thrombolysis and thrombectomy. The main finding of this study is that WUS can benefit from reperfusion treatment. Moreover, both in younger and older patients, treatment was effective and safe.
Therefore, our results show that extending the number of patients with acute stroke that may benefit from reperfusion therapy is possible. The use of advanced neuroimaging techniques guides clinicians to properly select subjects for aggressive treatment and prevent stroke-related disability. Actually, in the clinical practice, a huge number of patients who developed a WUS do not receive reperfusion therapy due to the unavailability of radiological functional neuroimaging in numerous hospitals. At the same time, neuroimaging helps clinicians to exclude WUS patients without penumbra tissue and large ischemic core from reperfusion therapy, due to the high risk of hemorrhagic complication. We found that selected WUS patients with identifiable penumbral tissue benefit from thrombolysis, showing significant good outcome and no increase of bleeding risk. Precise criteria of patient selection may contribute to identify those subjects that can benefit from “off-label” rtPA administration. Across several clinical trials and different studies, WUS treated with IV rtPA has significantly good clinical outcomes and moderate incidence of intracranial bleeding [15, 16, 17].
In clinical practice, more than 15–20% of all cases of stroke occur during sleep and generally they are excluded from thrombolytic therapy owing to the unknown time of symptom onset . Similarly to acute myocardial infarction and sudden cardiac death, diurnal variation in the onset of ischemic stroke has been hypnotized, with a higher frequency of strokes occurring in the morning . The incidence of early-morning strokes is around 50% higher compared to nocturnal incidence (regardless of the type of stroke, ischemic, hemorrhagic and transient ischemic attacks) [20, 21]. The mechanisms underlying this diurnal variation in cerebrovascular events are not exactly known. Endogenous factors such as increase in blood pressure, increase in platelet aggregation, and peak in prothrombotic factors may play a role in the early-morning dominance of cardiovascular events. An increase in Lp(a) and fibrinogen during morning hours has also been documented, as has been for sunrise endothelial dysfunction [22, 23, 24]. Exogenous factors can play an additional role, as an association was found between obstructive sleep apnea syndrome (OSA) and strokes . All these data may support the hypothesis of stroke onset in the early morning, thus making WUS eligible for acute treatment.
Different neuroimaging techniques may identify salvageable tissue. Significant demarcation of the irreversibly damaged infarct core as well as the ischemic but still viable and thus salvageable tissue at risk of infarction can be seen by DWI/PWI/MRA (diffusion-weighted magnetic resonance, perfusion-weighted MR, MR angiography), or alternatively by CT/CTA/CTA-SI (computer tomography/CT angiography/CTA source images), while SPECT and especially positron emission tomography (PET) may render semi-quantitative and quantitative hemodynamic data. Yet, despite the high level of performance and the important information offered by all these techniques, they are not feasible for an emergency setting where rapid decision and management are required [26, 27, 28, 29, 30].
MRI has showed to provide precise information about penumbral tissue and is therefore increasingly used in patient selection for IVT therapy including WUS .
The diffusion-weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch concept indirectly estimates time of the ischemic event. Similarly, the lesion on DWI representing the infarct core is identified, while the area calculated from perfusion imaging (PWI) in the time to peak map identifies the area of critically hypoperfused tissue. The mismatch between the two volumes represents the tissue at risk of infraction and thus the target tissue for reperfusion treatment.
In acute stroke patients, MRI is not the first and more comfortable examination and it is not reliable in emergency setting while brain CT scan and application CTP maps have the advantages of wider availability, faster performance, and easily provided quantitative perfusion metrics . In patients with acute cerebral ischemia, CTP provides the means to distinguish infarct core/nonviable tissue from penumbra/tissue at risk. On PCT mapping, the penumbra manifests as increased MTT, decreased CBF, and normal or increased CBV. In contrast, infarcted tissue demonstrates significantly decreased CBF and CBV. The absence of extended TTP or MTT is usually a reliable indication that ischemia is not present.
Moreover, an accurate interpretation of the CTP parameters may be difficult in the presence of a cerebrovascular anatomic variant or various physiologic conditions that produce changes in CBF and MTT leading to a false appearance of penumbra. There are many pitfalls and artifacts in acquiring the data, calculation of maps, and choosing arterial input function. The knowledge of mimics and pitfalls in acute stroke imaging can be helpful in accurate interpretation of these examinations.
In our case, WUS patients treated with rtPA had a good outcome with a mRS score < 2 at 3 months and with a short length of stay comparable to other stroke patients treated with reperfusion therapy. Moreover, mean net benefit in terms of NIHSS from admission to discharge was evident both for “younger” patients (< 65 years old), 4.08 (72% of benefit), compared to older patients (particularly subject > 80 years old), 5.75 (45%). Meaning that thrombolysis is safe and effective also in older patients, a high number of patients were discharged at home with healthy conditions and good ADL/IADL performance.
Mean decrease of NIHSS of 4 (54% decrease) was observed in patients with 50% penumbra to core ratio, while in patients with 70 and 100% of penumbra NIHSS decrease was 4.3 (50% decrease) and 4 (73% decrease) respectively. In patients with negative CTP mean, NIHSS decreased 4.6 (77% decrease). The high improvement of NIHSS in negative CTP patients is probably due to small size of hypoperfused area which is usually undetectable by CTP [33, 34].
Several studies using either plain CT, multiparametric CT [17, 32], or multiparametric stroke MRI [30, 31] reported safety of advanced treatment in WUS. No difference in eligibility and response for CTP-based thrombolysis was shown between WUS and known onset time of stroke. All these studies demonstrate the feasibility of imaging-guided thrombolysis in WUS patients while there was no excess in ICH. Moreover, outcome appeared largely similar compared to patients treated with thrombolysis within 4.5 h from known symptom onset [35, 36, 37, 38].
Our data supports that WUS patients should be considered for treatment. Efforts are ongoing to develop better methods of identifying those patients who can benefit from treatment at the minimum risk. This is of great importance considering that WUS makes for a significant percentage of ischemic strokes. To sum up, neuroimaging-guided decision-making for thrombolysis may extend the time window for therapy in individual patients by detecting the salvageable penumbra, tailoring treatment to patients in order to maximize the potential benefit and minimize risks.
Identifying a safe and effective selection strategy may allow WUS patients to receive thrombolysis and open new research strategies to move away from the rigid time window approach.
The authors thank Matteo di Franza for the editorial assistance.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Hacke W, Kaste M, Bluhmki ED, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, ECASS Investigators. ; ECASS investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317–1329CrossRefPubMedGoogle Scholar
- 4.Berkhemer OA, Fransen PS, Beumer D, van den Berg L, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen M, Staals J, Hofmeijer J, van Oostayen J, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk L, Kappelle LJ, Lo RH, van Dijk E, de Vries J, de Kort PL, van Rooij W, van den Berg J, van Hasselt B, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog H, Gerrits DG, van den Berg-Vos R, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam W, Roos YB, van der Lugt A, van Oostenbrugge R, Majoie CB, Dippel DW, MR CLEAN Investigators. ; MR CLEAN investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11–20Google Scholar
- 18.Wouters A, Lemmens R, Dupont P, Thijs V (2014) Wake-up stroke and stroke of unknown onset: a critical review. Front Neurol 5. https://doi.org/10.3389/fneur.2014.00153
- 26.Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, Wu O, Kim JS, Breuer L, Singer OC, Warach S, Christensen S, Treszl A, Forkert ND, Galinovic I, Rosenkranz M, Engelhorn T, Köhrmann M, Endres M, Kang DW, Dousset V, Sorensen AG, Liebeskind DS, Fiebach JB, Fiehler J, Gerloff C, STIR and VISTA Imaging Investigators (2011) 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 10:978–986CrossRefPubMedGoogle Scholar
- 31.Kang DW, Sohn SI, Hong KS, Yu KH, Hwang YH, Han MK, Lee J, Park JM, Cho AH, Kim HJ, Kim DE, Cho YJ, Koo J, Yun SC, Kwon SU, Bae HJ, Kim JS (2012) Reperfusion therapy in unclear-onset stroke based on MRI evaluation (RESTORE): a prospective multicenter study. Stroke 43:3278–3283CrossRefPubMedGoogle Scholar
- 34.Furlanis G, Ajčević M, Stragapede L, Lugnan C, Ridolfi M, Caruso P, Naccarato M, Ukmar M, Manganotti P (2018) Ischemic volume and neurological deficit: correlation of computed tomography perfusion with the National Institutes of Health Stroke Scale Score in acute ischemic stroke. J Stroke Cerebrovasc Dis. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.04.003 CrossRefPubMedGoogle Scholar
- 35.Rimmele DL, Thomalla G (2014) Wake-up stroke: clinical characteristics, imaging findings, and treatment option—an update. Front Neurol 5. https://doi.org/10.3389/fneur.2014.00035