The Neuroradiology Journal 26: 573-578, 2013

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Wake-up (or Wake-up for) Stroke:
a Treatable Stroke
Sandra Bracco1, Rossana Tassi2, Paola Gennari1, Irene Grazzini3,
Sara Leonini1, Paolo D’Andrea2, Giuseppe Martini2, Alfonso Cerase1
Unit NINT Neuroimaging and Neurointervention, 2 Stroke Unit, Department of Neurological and Sensorineural
Sciences, Siena Hospital Trust, “Santa Maria alle Scotte Hospital”; Siena, Italy
3
School of Diagnostic Imaging, University of Siena; Siena, Italy
1

Key words: neuroendovascular treatment, neuroimaging-based reperfusion therapy, thrombolysis, unclear onset-stroke,
wake-up stroke

SUMMARY – A 74-year-old man was admitted to the Emergency Room of our institution with
worsening dysarthria, left-side weakness and hypoesthesia (NIHSS score: 5) since his awakening at
7:30 a.m. The evening before, he had gone to sleep at 10:30 p.m. Brain computed tomography (CT)
and cervicocranial CT angiography showed low density attenuation of the right caudate nucleus
head and lenticular nucleus and sub-total occlusion of ipsilateral middle cerebral artery (MCA) prebi/trifurcation M1 segment. Brain CT perfusion showed an ischemic core in the right striatal region, surrounded by a wide region of ischemic penumbra. Although the onset of symptoms, defined
as “time last-seen well”, was 14 hours before presentation, the following worsening of neurological
conditions (NIHSS score: 12) and the evidence of cerebral blood flow / cerebral blood volume mismatch at CT perfusion led us to propose neuroendovascular treatment on the basis of an off-label
use. Neuroendovascular treatment by Penumbra system was achieved and the right MCA was only
partially recanalized. The patient was discharged with NIHSS score of 12. At six months, modified
Rankin scale score was 3. To the best of our knowledge, this is the first Italian case report describing
a patient who underwent successful neuroendovascular treatment for a “wake-up stroke” without
clinical worsening nor major complications and an acceptable clinical outcome. This was possible
thanks to an extension of the therapeutic window guided by CT perfusion.

Introduction
Approximately 25% of patients with ischemic
stroke awake with neurological deficits. In
these wake-up strokes (WUS), the onset of
symptoms is defined as “time last-seen well”
(TLSW). Current guidelines do not recommend
thrombolysis or neuroendovascular treatment
in patients with WUS or in patients with unclear-onset stroke, since the actual time of onset is often unknown 1,2.
Modern multimodal neuroimaging, including
computed tomography (CT), CT angiography,
CT perfusion, magnetic resonance (MR) imaging, MR angiography, diffusion-weighted imaging, and MR perfusion, may guide reperfusion
therapies, allowing the treatment of patients
eight hours from onset 3,4. Notably, several

trials 5-7 report the safety and efficacy of both
intravenous and intra-arterial neuroimagingguided reperfusion therapies in patients with
WUS or unclear-onset strokes.
The purpose of this case report is to describe
a patient who underwent successful neuroendovascular treatment for a WUS without major
complications and with an acceptable clinical
outcome, thanks to an extension of the therapeutic window guided by CT perfusion.
Case Report
A 74-year-old man was admitted in the
Emergency Room of our institution at 9:10
a.m. for dysarthria, left-side weakness and hypoesthesia since awakening at 7:30 a.m. The
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Wake-up (or Wake-up for) Stroke: a Treatable Stroke

Sandra Bracco

E

Figure 1  Computed tomography (CT) of the brain obtained at diagnosis. Serial consecutive (A,B) and nonconsecutive (C,D) unenhanced axial CT images show (black arrows) subtle high density attenuation and dot sign in the right middle cerebral artery
(MCA), associated with subtle low-density attenuation (white arrows) in the ipsilateral fronto-insular region, head of caudate nucleus, and lenticular nucleus, while a scan through the coronae radiatae (D) was negative. Anteroposterior multi-intensity projection CT angiography shows partial occlusion of the right MCA, soon before its genu (E). Axial perfusion CT maps obtained at the
level of images A (F) and B (G), indicating Tmax (1), mean transit time (2), capillary permeability (3), cerebral blood flow (4), and
cerebral blood volume (5) show a clear ischemic core (asterisk) and a wide area of ischemic penumbra (black arrowheads). Note also
that capillary permeability shows alteration (white arrowhead) in the right superficial frontal territory.

evening before, he had gone to sleep at 10:30
p.m. Neurological examination showed slight
left VII cranial nerve palsy, dysarthria, left
hemiparesis and hypoesthesia (National Institute of Health Stroke Scale score, NIHSSs = 5).
History revealed silent myocardial infarction
20 years ago and dyslipidemia. The patient had
stopped clopidogrel therapy ten days before admission. A standard 12 lead electrocardiogram
displayed bradycardia. Two hours after admission, he underwent brain CT and CTA (Figure
1), that showed subtle high density attenuation
and dot signs (Figure 1A,B), in the right middle cerebral artery (MCA) low density attenuation of the right caudate nucleus head and lenticular nucleus (Figure 1C,D), thereby fulfilling
an Alberta stroke program early CT score 8 of 8,
and occlusion of ipsilateral MCA pre-bi/trifurcation M1 segment (Figure 1E).
Neurological conditions worsened and the
patient became lethargic, with increased left
574

sensitive deficits and hemiparesis (NIHSSs =
12). Brain CT perfusion (Figure 1F,G) showed
an ischemic core in the right lenticular region,
surrounded by a wide area of ischemic penumbra. An increased area of capillary permeability was also evident.
All primary data were acquired using a
LightSpeed VCT scanner and post-processed in
an Advantage Workstation 4.6 (General Electric Healthcare, Fairfield, CT, USA). Perfusion
CT data were analysed by CT perfusion 4D
imaging software, evaluating regions of interest on cerebral blood volume (CBV) and cerebral blood flow (CBF) maps 9,10. A CBF of 12.7
mL/100 g/min and CBV of 2.2 mL/100 g/min
were considered threshold levels predictive of
the infarct core 11. All the remaining perfusiondeficient territory compared to the contralateral hemisphere was considered potentially
salvageable. Namely, the penumbra was defined by normal CBV but decreased CBF, i.e.

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The Neuroradiology Journal 26: 573-578, 2013

A

B

Figure 2  Neuroendovascular treatment. Anteroposterior (left) and lateral (right) early angiograms obtained at 2.30 p.m. (A) and
after thrombectomy at 4.10 p.m. (B) show only a subtle reperfusion of the right middle cerebral artery.

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Wake-up (or Wake-up for) Stroke: a Treatable Stroke

A

Sandra Bracco

B

Figure 3  Computed tomography (CT) of the brain obtained 9 days later. Serial nonconsecutive unenhanced axial CT images obtained at the levels of Figures 1C (A) and 1D (B) show sparing of most of the low perfusion area in the right cerebral hemisphere
and only uncertain partial subtle hemorrhagic transformation.

a “mismatch” between the CBV and CBF lesion size 9,10. Although the TLSW was 14 hours,
the patient’s worsening of neurological conditions and the evidence of “mismatch” between
CBV and CBF lesion size at CT perfusion led
to rule out systemic thrombolysis and propose
neuroendovascular treatment on the basis of
an off-label use. Cerebral angiography (Figure 2A), performed by a digital biplanar rotational angiographic suite (Innova 3131IQ, General Electric Healthcare, Fairfield, CT, USA),
showed a thrombus in the right MCA M1 segment. Neuroendovascular treatment by the Penumbra system (Penumbra, Inc, Alameda, CA,
USA) was performed 70 minutes later (Figure
2B) and the right MCA was only partially recanalized. Then, the patient was treated by
oral clopidogrel (75 mg/die). At day 9, brain
CT (Figure 3) showed frontoparietal infarction
with uncertain hemorrhagic transformation,
however a wide frontal region was spared. At
day 13, the patient was discharged to rehabilitation for left sensory-motor hemiparesis.
NIHSSs was 12. Six-month follow-up modified
Rankin scale score was 3. Ten months later,
the patient was readmitted to our Stroke Unit
for a transient ischemic attack characterized
576

by motor aphasia lasting ten minutes. A paroxysmal atrial fibrillation was diagnosed and oral
anticoagulant therapy was started.
Discussion
More than one third of ischemic strokes occur during sleep and generally these WUS are
excluded from thrombolytic therapy, since the
actual time from symptom onset is often unknown 1,2. However, in daily clinical practice it
has been noted that evaluation of the potential
benefits and risks of reperfusion therapy results not only from the clinical assessment and
the optimization of stroke-to-hospital or doorto-needle times, but also from multimodal advanced neuroimaging, that allows the extension
of the time window for therapy. Notably, non
contrast-enhanced CT, MR imaging including
diffusion-weighted imaging, CT and/or MR angiography and perfusion will identify the volume
of the ischemic lesion, the presence and site of
intracranial arterial occlusion and potentially
salvageable brain tissue, as well as the risk for
hemorrhagic transformation after reperfusion
3,5-7
. This is possible without treatment delay 4.

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Within this context, several papers have
demonstrated that CT perfusion can accurately
detect the ischemic core and penumbra, thus
representing a useful tool for identifying acute
stroke patients suitable for treatment 9,10. However, there is still controversy about the accuracy (and thus, the need for) of CT perfusion
imaging in acute ischemic stroke imaging in
daily clinical practice 12-15.
A recent review 15 from the experience and
evidence-based approach of The Massachusetts
General Hospital acute stroke imaging algorithm questioned the role of CT perfusion in
patients with anterior circulation occlusion in
whom the primary indications for intravenous
thrombolysis are an elapsed time since onset of
4.5 h or less and an absence of hemorrhage or
large infarct on neuroimaging. In this subset of
patients, CT perfusion is considered a Level 3/
Class IIb method for early estimation of both
the infarct core and penumbra, mainly for a
not yet standardized method of acquisition
and post-processing and the great variability
in the interpretation of results. Notably, perfusion CT is considered to have no proven role
in selecting patients with anterior circulation
occlusion for intravenous thrombolysis or neuroendovascular therapy, but to be limited to i)
research patients, ii) patients for whom diffusion-weighted imaging is not available, and iii)
other purposes such as hypertensive therapy,
although there are still scant data on this application 15.
However, trials on WUS or unclear-onset
strokes, including multimodal neuroimaging,
proved that the actual onset time of WUS is
close to the wake-up time and that stroke may
be the cause of wake-up 1. Furthermore, both

The Neuroradiology Journal 26: 573-578, 2013

intravenous 5 and intra-arterial 6,7 neuroimaging-guided reperfusion therapies have been
demonstrated to be safe and feasible more than
eight hours from TLSW in patients with WUS
or unclear-onset strokes, such as occurred in
the patient reported herein. Finally, ultraearly diffusion-weighted imaging is not available at our institution as the MRI magnet is
not placed in the Emergency Department, and
thus in many cases we have to shift to the potential offered by CT perfusion.
To the best of our knowledge, this is the first
Italian case report describing a patient who
underwent neuroendovascular treatment for
WUS by a CT perfusion-guided wide extension
of the therapeutic window for neuroendovascular therapy. This occurred without clinical
worsening nor major complications and resulted in an acceptable clinical outcome.
Conclusions
We have confirmed the role of neuroimagingguided neuroendovascular therapy in a patient
with WUS beyond eight hours after TLSW.
Only a few years ago, this patient would have
been considered not eligible for reperfusion. Although this is a single case report, we believe
that in future patients with WUS or unclearonset stroke will be candidates for neuroimaging-guided reperfusion therapies, and notably
neuroendovascular treatment. Prospective randomized controlled studies comprising large
series of patients are required to determine if
this strategy is really feasible. We agree that
this is the era in which we are shifting from
“time is brain” to “physiology is brain” 3,10,15.

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Wake-up (or Wake-up for) Stroke: a Treatable Stroke

Sandra Bracco

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Alfonso Cerase, MD
Unit NINT Neuroimaging and Neurointervention
Department of Neurological and Sensorineural Sciences
Azienda Ospedaliera Universitaria Senese
Policlinico “Santa Maria alle Scotte”
Viale Mario Bracci, 16
53100 Siena, Italy
Tel.: +390577585040/4
Fax: +390577586197
E-mail: alfonsocerase@gmail.com
a.cerase@ao-siena.toscana.it