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Applications of diffusion-weighted imaging in diagnosis, evaluation, and treatment of acute ischemic stroke

Diffusion-weighted image (DWI) is widely used in acute care hospitals and provides diverse, valuable information about acute stroke. DWI is the gold standard for identifying the infarct core. The DWI infarct pattern is correlated with the pathogenic mechanisms underlying stroke and may predict stroke recurrence and outcome. Therefore, a deeper understanding of DWI is necessary for physicians treating patients with acute ischemic stroke. In this review, the application and interpretation of DWI for acute stroke and future perspectives are discussed.


INTRODUCTION
Magnetic resonance imaging (MRI) is a vital tool for the evaluation of acute stroke patients and has been used since the 1980s. The recent 2018 guidelines recommended that computed tomographic perfusion or diffusion-weighted image (DWI)/magnetic resonance (MR) perfusion scans should be obtained if the patient is past > 6 hours after last known normal status and has large vessel occlusion [1].
Although various MR sequences have recently been developed and used due to their unique clinical value [2], DWI is widely used in acute care hospitals and provides diverse, valuable information about acute stroke. Therefore, a deeper understanding of DWI is necessary for physicians treating patients with acute ischemic stroke. In this review, the application and interpretation of DWI for acute stroke patients and perspectives are discussed.

DIFFUSION-WEIGHTED IMAGING
DWI and apparent diffusion coefficient maps DWI is the most reliable method for early detection of cerebral ischemia, definition of the in-Diffusion-weighted imaging in acute ischemic stroke farct core, and differentiation of acute ischemia from stroke mimics [3]. Within minutes of an ischemic insult, a core region of tissue exhibits profound loss of blood flow and becomes irreversibly damaged, even if blood flow is rapidly restored. DWI detects decreases in the self-diffusion of water molecules as early as 11 minutes after symptom onset [4]; these changes are probably related to cellular energy failure and early cytotoxic edema, reflecting the physiologic consequences of ischemic injury.
In general, the acquisition sequences for DWI generate b-1000 DWIs (typically utilized as the infarct core), b-0 DWIs, and apparent diffusion coefficient (ADC) maps. DWIs should be reviewed with the ADC maps (diffusion-weighted without a T2 component) for proper interpretation. Combined with the ADC map, DWI provides information on the severity, reversibility, and chronology (age of infarcts) of ischemic brain damage. First, the ADC is useful for estimating the lesion age and distinguishing acute from subacute DWI lesions [5].
Acute ischemic lesions can be divided into hyperacute (low ADC and DWI-positive) and subacute (normalized ADC, 1 to 2 weeks after stroke onset) lesions, and chronic lesions can be differentiated from acute lesions by normalization of ADC and DWI. Second, tissues with a higher absolute ADC value have a higher likelihood of reversibility [6,7]. DWI lesions are commonly considered markers of irreversible ischemia, but can, occasionally, be reversed. DWI lesion reversal after reperfusion has been shown to be associated with early neurological improvement [8]. ADC threshold may be useful in distinguishing the ischemic core and penumbra, and the degree of reduction in ADC values may predict DWI lesion reversal after successful reperfusion [9]. However, the prevalence and clinical relevance of DWI reversal are unclear, although, a very low absolute ADC value ( < 550 × 10 -6 mm 2 /sec) and a large DWI lesion volume have been associated with severe, irreversible damage and a high risk of hemorrhagic transformation after thrombolysis [10,11]. Third, DWI with ADC maps can be useful in differentiation between vasogenic (elevated ADC) and cytotoxic (decreased ADC) edema [12].

Diagnosis of stroke
Diagnosis of stroke largely depends on clinical presentation.
Stroke-mimics account for 19% to 30% of suspected stroke presentations, with diverse underlying etiology [13]. With advances in MRI technology, ischemic lesion can be identified with high accuracy using DWI (88% to 100% sensitivity, 95% to 100% specificity). A false-negative DWI result is possible, and a meta-analysis including 3,236 acute ischemic stroke patients showed that the prevalence of DWI-negative acute ischemic stroke is 6.8% [14]. False-negative DWI was associated with less severe strokes, a longer time from onset to scan, small vessel disease, and localization in the posterior circulation, such as patients with small punctate infarcts located within the brainstem (e.g., as medulla) or deep gray nuclei (e.g., thalamus) [15]. In addition, 1.5-T DWI was better than One-third of individuals with traditionally-defined transient ischemic attack (TIA) exhibit the signature of new infarction by DWI [18,19], and application of DWI in TIA patients would reduce estimates of the annual incidence of TIA by 33% and increase estimates of the annual incidence of stroke in the United States by 7% [20]. The percentage of TIA patients with a DWI lesion increases with increasing total symptom duration [21] and with increasing duration between TIA symptom onset and performance of the initial DWI [22]. TIA is now defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without signs of acute infarction by neuroimaging [19].
Similarly, even in patients with transient neurological attacks, episodes of acute atypical or non-focal neurological symptoms, DWI showed acute ischemia in 23% [23]. DWI lesions were associated with greater risk for stroke during the first 3 months after TIA [24]. Although the ABCD 2 score is widely used for TIA patients, the ABCD 3 -I score, which incorporates the presence of DWI lesions, has shown a higher predictive value for assessing the risk of early stroke after TIA [25,26].  [27,28].
As clots from the left atrium or left atrial appendage are usually large (fibrin-containing, organized) and can occlude the distal internal carotid artery, proximal middle cerebral artery, or distal basilar artery, atrial fibrillation is associated with more severe ischemic stroke or longer ( > 60 minutes)

DWI AND STROKE OUTCOMES
Stroke functional outcome: prediction of prognosis on admission DWI lesion volume determines the prognosis of patients with acute ischemic stroke, regardless of revascularization treatment/perfusion status [34]. There is emerging evidence that patients with a DWI lesion volume greater than approximately 70 mL do poorly [35]. Other than DWI lesion volume, the location of infarcts, as imaged by DWI, could influence functional outcome and stroke progression [36,37].
DWI lesion pattern may help in the recognition of differences in early prognostic endpoints after ischemic stroke, and may also guide targeted interventions to prevent negative outcomes (Fig. 2). In a prospective analysis of 426 patients   [38]. Changes in DWI lesion volumes at follow-up (72 to 96 hours) were varied, but large, in internal border zone infarcts, compared with other DWI lesion patterns (226% vs. 143%, compared with initial DWI lesion volume). Recurrent strokes after the index stroke were common in those who had small superficial infarcts [38]. The were multiple and small, located in cortical/superficial areas, and within areas of mild perfusion deficit, whereas infarct growth generally occurred within regions with more severe perfusion deficits, suggesting differential therapeutic approaches for these two types of stroke evolution. Most patients who showed infarct growth had a territory/lobar-or internal border zone-type DWI lesion pattern; while patients with new lesions showed small cortical or cortical border zone infarct patterns. Collateral status determines outcome after stroke [41], and it differs between DWI lesion patterns.
Compared to territorial/lobar type DWI lesion patterns, deep or small superficial patterns are associated with good collateral status [42].
In addition, DWI lesion volume (and extent of perfusion deficits) determines the speed of clinical recovery after revascularization therapy. Not all patients show dramatic improvement after revascularization therapy, and a significant proportion of patients who lack early clinical improvement after days of successful revascularization still achieved good outcomes at 3 months (Stunned brain syndrome) [43]. In consecutive patients who underwent pretreatment DWI, a significant correlation was noted between the time to > 40% reduction in National Institutes of Health Stroke Scale score and initial DWI lesion volumes [44]. In this study, pretreat- Corp., Grapevine, TX, USA), an automated software package for performing quantitative evaluation of ADC to estimate the ischemic core and perfusion-weighted image thresholding of T max > 6 seconds for defining critical hypoperfusion, has been used in several randomized clinical trials (RCTs) [48].
Second, until now, no clinical trials involving acute stroke patients have used DWI as a surrogate endpoint. Very recently, incidence of new DWI lesions were used as the primary endpoint in a randomized trial comparing the effects of clopidogrel and ticlopidine/ginkgo in clopidogrel-resistant patients undergoing carotid artery stenting [49]. With advances in fast-scanning and automatic measurement of DWI values [2], DWI could be used as an inclusion endpoint and surrogate outcome endpoint in acute stroke RCTs. Third, application of artificial intelligence in the acute stroke field is increasing. It can be particularly helpful in decision-making in every step of revascularization therapy for acute ischemic stroke: in clinical and imaging recognition of acute ischemic stroke in the ambulance or emergency room and in predicting the outcome after endovascular therapy [50][51][52]. Lastly, a quantitative radiomics approach for a more detailed analysis of DWI features, such as signal intensity or lesion texture (e.g., surface area and sphericity), could be helpful in differentiation of stroke subtypes [53].

CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.