Synopsis
Stroke
is the second leading cause of death world-wide. Diffusion-weighted MRI (DWI) is
very sensitive to early acute ischemic injury, with mean diffusivity reduced in
the hyperacute stage, but elevated in the chronic stages. In addition, DWI can
potentially be combined with other MRI sequences to stage extent of ischemic
injury and identify potentially salvageable tissue. Diffusion-tensor MRI and
high angular resolution diffusion MRI techniques can be used to evaluate
ultrastructural injury post-stroke. DWI has been shown to critical for
improving the diagnosis, prognosis and management of acute ischemic stroke
patients and for monitoring post-stroke recovery.Target Audience
Clinician research
scientists and translational neuroimaging researchers
Objectives
Discuss
the role of diffusion-weighted imaging (DWI) in experimental animal models and
ischemic stroke patients and how it can be used to provide information on the stage
and extent of tissue damage after stroke and guide patient management decisions.
Purpose
Intravenous
alteplase or recombinant tissue plasminogen activator (rt-PA) is the current
standard of care therapy for acute ischemic stroke patients seen within 3 hours
from stroke onset. Beyond this therapeutic window, rt-PA can increase the risk
of symptomatic intracranial hemorrhage (SICH).
1 As such, in patients
presenting with signs and symptoms of an acute ischemic stroke, rapid and
accurate diagnosis and exclusion of acute hemorrhage are essential. In
addition, stroke imaging researchers have suggested that imaging, in particular
MRI, could provide insight on extent of tissue injury and be used to guide
patient management decisions instead of an oft ill-defined last-known well
time.
Methods
The DWI signal can be
generalized to: $$$S_{DWI}=S_0 \exp^{-bD}$$$ for which b
is the b-value (s/mm2) or diffusion-weighting factor, S0 is the baseline
T2-weighted image without diffusion-weighting (also known as the b0
or low-b image) and D is the apparent
diffusion coefficient (ADC), also known as mean diffusivity (mm2/s).2 By
acquiring images with at least two different b-values (usually one being b0),
the ADC can be calculated to quantify the effects of ischemia on tissue
diffusion over time. For conditions for which the rate of diffusion is
orientation dependent, such as in white matter, the diffusion process can be
characterized by a tensor to take into consideration direction dependence.3 To
quantify changes in the shape of the diffusion tensor after acute stroke,
scalar rotationally invariant metrics of anisotropy are typically used, such as
fractional anisotropy (FA).4 The
eigenvectors of the diffusion tensor have also been used to perform tractography
analysis.5 Using
high angular resolution diffusion imaging, the multiple fiber orientations can
be identified within a voxel.3, 6, 7 Multiple b-values allows one
to characterize non-Gaussian diffusion properties using techniques such as
diffusional kurtosis imaging (DKI).8
Results
DWI has been shown to detect physiological changes
due to acute cerebral ischemia within 15 minutes of ischemic injury in both
experimental animal models of ischemia9 and in humans.10 In comparison, conventional MRI and non-contrast CT (NCCT) do not
exhibit abnormalities until approximately 2-3 h post-stroke onset.11, 12 One prospective study of
patients presenting to the emergency department showed that MRI was 83%
sensitive for the diagnosis of stroke, far surpassing CT, for which sensitivity
was only 26%.13 Figure 1 shows an example NCCT, FLAIR and DWI for a 72-year old male acute
ischemic stroke patient acquired within 2 hours from last known well (LKW). In
both experimental animal models of stroke14, 15 and in acute
stroke patients,16, 17 ADC has been observed to
be reduced at the hyperacute stage (0–3 hours), pseudonormal at the sub-acute
phase and elevated in the chronic stage. After reperfusion therapy, the
time-course of ADC is notably sped18 up demonstrating early pseudo-normalization that can be
mistaken as reversal of tissue injury only to be proven infarcted on subsequent
imaging studies.19, 20 This suggests that ADC
alone may not be a suitable marker for inevitable tissue infarction and that
there may be better markers that are more sensitive to ultrastructural changes such
as FA or DKI. Both increases and decreases in FA 21, 22 have been reported after
acute ischemic stroke with increases linked to potentially salvageable tissue.23, 24 Decreases in FA,
thought to reflect early pyramidal tract Wallerian degeneration, have also been
noted in the subacute to chronic stage.25 DKI was observed to
increase both in gray matter and white matter.26-28 Structural connectivity
analysis using probabilistic tractography have been used to understand stroke
recovery processes.29
Beyond
diagnosis, DWI is currently under investigation to identify those patients who
may benefit from extended time window treatment with intravenous thrombolysis. Studies
have shown that patients with large acute DWI lesion volumes did poorly
regardless of whether reperfusion was achieved.30, 31 DWI may therefore be
useful for screening out patients who are at high risk of SICH, especially for
extended time-window therapies. DWI may also be used
as an imaging surrogate for clinical outcome in the context of lesion expansion
with respect to follow-up lesion volumes.32-34 Findings from animal
experiments support the hypothesis that mismatches between lesions observed in
DWI and FLAIR15 or DWI and perfusion-weighted MRI (PWI)35 can be used to stage the extent of ischemic injury. The
recently completed MR WITNESS trial showed that it was safe to treat patients
with unwitnessed strokes who were last known to be well within 24 hours, but within
4.5 hours of symptom discovery and had mismatches between DWI and FLAIR.36, 37 The Extending the Time
for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA)
trial showed that using DWI and PWI mismatch criteria could select patients for
treatment with endovascular therapy within 4.5 hours since they were last known
to be well.38
Discussion
DWI
plays a key role in diagnosis of acute ischemic stroke. In combination with
other MRI techniques, the role of DWI in stroke patient management becomes even
more significant. DWI in combination with FLAIR MRI can be used to identify
patients who can be treated safely with rt-PA even if their symptom onset was
unwitnessed. In conjunction with PWI, DWI can be used to select patients who
will likely respond favorably to rt-PA or endovascular treatment despite being
evaluated outside the therapeutic time window. Other diffusion techniques, such
as diffusion tensor imaging or fiber tracking hold great promise for providing
additional insight into monitoring and understanding chronic stroke
pathophysiology.
Acknowledgements
This
study was supported in part by PHS grants P50NS051343, R01NS059775,
R01NS063925, and NIBIB P41EB015896.References
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