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Page 2 of 9 Lim et al. Vessel Plus 2021;5:34 https://dx.doi.org/10.20517/2574-1209.2021.44

Keywords: Stroke, reperfusion, thrombectomy, tissue plasminogen activator, fibrinolytic agents, computed
tomography, magnetic resonance imaging

INTRODUCTION
The evaluation and treatment of acute ischemic stroke has advanced rapidly in the last three decades. New
knowledge in reperfusion timing and techniques, advanced imaging, and improved patient selection
continues to translate to better outcomes. Early paradigms regarding time-based approaches to treatment
have been challenged by positive trials that use advanced imaging criteria to select patients for
reperfusion . In this paper, we will review the initial studies that introduced the clinical efficacy of
[1-4]
systemic reperfusion, a brief history of the penumbra and its imaging, and the four seminal trials. We will
then explore the implications and clinical benefit of these trials, introduce an alternative application of
imaging-guided selection to transient ischemic attack and minor stroke, and outline future direction.

TIME-BASED TARGET OF THROMBOLYSIS
The first major advance in acute reperfusion therapy occurred in the 1990s when alteplase (rrtPA) became
the first approved drug to treat acute ischemic stroke. At the time, the National Institute of Neurological
Disorders and Stroke rt-PA Stroke Study Group demonstrated that, despite a small increased incidence of
symptomatic intracranial haemorrhage, treatment with rtPA within 3 h of onset of symptoms improved
clinical outcome . This represented the beginning of a line of clinical inquiry to increase the time window
[5]
[6]
of therapy. Further success came in 2008 when the ECASS III trial demonstrated the safety and efficacy of
alteplase administered between 3 and 4.5 h after stroke onset. The pooled analyses of clinical trials
[7,8]
suggested a loss of efficacy after this 4.5 h mark. It is likely that the choice of non-contrast computed
tomography prevented the use of rtPA beyond this 4.5 h window. Such imaging modality does not capture
the presence of salvageable ischemic tissue (ischemic penumbra) nor vessel occlusion. Methods for imaging
the ischemic penumbra will be explored in the next section.

THE PENUMBRA AND THE EVOLUTION OF BRAIN IMAGING
Since the 1970s, early mammalian experiments have noted that when a major artery of the brain was
occluded, a rate of cerebral blood flow could be reached that preserved neuronal structure but produced
functional inactivity . Neurons could actually survive in this state of functional incapacity, and then be
[9]
normalized again if cerebral blood flow was restored . Such a cerebral blood flow zone between the upper
[9]
threshold of electrical failure and the lower threshold of energy and pump failure was defined as the
ischemic penumbra . Beyond this zone is a region of hypoperfusion but normal cerebral function
[10]
experiencing benign oligemia . Hence, this early classical model demonstrated that there was a zone of
[9]
electrical silence in ischemic cerebral tissue that remained potentially salvageable.

There are several modalities for imaging the ischemic penumbra including positron emission tomography
(PET), magnetic resonance imaging (MRI) and computed tomography perfusion (CTP) . While PET with
[11]
15 O tracer is regarded as the gold standard method to produce quantitative measurements , PET is
[12]
unfortunately best suited as a research tool rather than use in routine clinical practice . Using the hypoxic
[11]
tissue ligand FMISO ( F-fluoromisonidazole) ischemic penumbral tissue was demonstrated to exist for up
18
[13]
to 48 h from stroke onset and its survival was associated with improved functional outcome . The early
1990s saw researchers experimenting with dynamic MRI studies that compared perfusion-weighted imaging
(PWI) and diffusion-weighted imaging (DWI) to image the ischemic penumbra. PWI measures cerebral
blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and delay
in tracer arrival (T ).
max