Perfusion deficits in thrombolysis-treated acute ischemic stroke patients with negative or positive diffusion-weighted imaging

Objective Magnetic resonance imaging (MRI) and CT perfusion may provide diagnostic information for intravenous tissue-type plasminogen activator (IV t-PA) administration in acute ischemic stroke (AIS) patients. We aimed to compare the clinical features and perfusion deficits of diffusion weighted imaging (DWI)-negative and DWI-positive AIS patients. Methods This retrospective and observational study included thrombolysis-treated AIS patients undergoing multimodel CT imaging before treatment and DWI after treatment between 2021 and 2022. Two experienced neuroradiologists blindly and independently examined the images to identify perfusion deficits in AIS patients. The patients were divided into DWI-positive and DWI-negative groups based on visible hyperintense lesions on DWI. A modified Rankin scale (mRS) score of ≤ 2 indicated good functional outcomes at discharge. Sensitivity analysis was conducted to determine whether CT perfusion was an independent predictor of positive DWI imaging on follow-up. Results This study included 151 patients, of whom 35 (23.2%) patients were DWI-negative on follow-up. These DWI-negative patients were less likely to have a medical history of atrial fibrillation; they had lower triglyceride levels, a shorter admission time, lower National Institutes of Health Stroke Scale (NIHSS) scores after IV t-PA and lower mRS scores at discharge, and had better functional outcomes. A total of 37.1% of DWI-positive and 25.7% of DWI-negative patients had vascular stenosis (P = 0.215). A total of 47.4% of DWI-positive and 37.1% of DWI-negative patients had CT perfusion deficits (P = 0.284). A total of 73.5% of patients with normal CT perfusion had positive DWI, while 19.1% of patients with perfusion deficits had negative DWI. The sensitivity and specificity of NCCT were 14.8% and 97.1% (Kappa = 0.061, P = 0.074), CTP was 47.4% and 62.9% for predicting DWI lesion (Kappa = 0.069, P = 0.284). Conclusions About 23.2% of AIS patients who received intravenous thrombolysis treatment did not have a relevant DWI-MRI lesion on follow-up. Over one-third of patients in the DWI-MRI negative group showed CT perfusion deficits, with a sensitivity of 47.4% for predicting DWI lesions in non-mechanical thrombectomy patients.


Introduction
Intravenous tissue-type plasminogen activator (IV t-PA) was administered to acute ischemic stroke (AIS) patients after screening with a head CT to exclude intracerebral hemorrhage.Magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) is often used to diagnose stroke and guide treatment decisions.However, it is time-consuming and has several limitations.Moreover, previous studies discovered that patients with persistent neurological deficits had false negative DWI.It was reported that 6.8 29% of patients were DWI-negative [1][2][3][4].DWI fails to detect AIS in a substantial minority of patients due to underestimated hyperacute ischemia [1].Several randomized clinical trials have demonstrated that endovascular stroke therapy for acute stroke has significantly improved [5,6].More patients treated with IV t-PA at a later time window benefit from CT perfusion (CTP) imaging-based definitions of eligibility [7].CT angiography (CTA) and CTP can detect intracranial vascular stenosis or occlusion and perfusion deficits in patients with different types of ischemic stroke.The sensitivity of CTP varies significantly due to the heterogeneity in patient characteristics, CTP spatial and temporal resolution, and postprocessing methods [8].CT imaging is superior to MRI in terms of acquisition speed, absence of screening questionnaires, scanner availability, cost, and processing time [9].Evaluating the infarct core volume using CTP could provide a timely assessment of tissue perfusion status in hyperacute stroke and the long-term clinical prognosis of AIS patients.We aimed to determine whether CT imaging provides further diagnostic information for the evaluation of DWI-negative patients with ischemic stroke.
This study aimed to compare the clinical features and CT perfusion deficits of DWI-negative AIS patients to DWI-positive AIS patients.The clinical value of CT perfusion in identifying patients with non-mechanical thrombectomy treatment was also investigated to help decide whether to adopt intravenous thrombolysis in AIS patients.

Study design and patients
The design of this study was approved by the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University, and was performed in accordance with the declaration of Helsinki.A retrospective review of consecutive patients admitted to the stroke unit of our hospital who presented with AIS or transient ischemic attack (TIA) and received IV t-PA treatment between January 2021 and August 2022 was performed.AIS was diagnosed using WHO criteria (acute episode of neurological deficit, lasting less than 24 h in the case of TIA, more than 24 h in the case of an ischemic stroke) [10].
The subtype of ischemic stroke was diagnosed by an experienced neurologist according to the established criteria of TOAST [11].The inclusion criteria for this study were: (1) acute stroke symptoms within 4.5 h; (2) received intravenous thrombolysis treatment but not mechanical thrombectomy; (3) multimodal CT examination dataset including non-contrast CT brain (NCCT), supra-aortic CTA and CTP performed on admission before treatment; (4) MRI performed < 72 h after symptom onset.Exclusion criteria were: (1) Patients diagnosed as TIA or stroke mimics; (2) Patients who had incomplete clinical data.(Fig. 1).

Demographic data
Data were recorded on demographic characteristics and vascular risk factors that included age, sex, systolic and diastolic blood pressure (BP) at presentation, body mass index, duration of admission in days, history of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, ischemic stroke, and coronary artery disease, current smoking and drinking status and time of symptom onset.Neurological deficit symptoms were recorded by admission and after treatment National Institutes of Health Stroke Scale (NIHSS) score [12], Modified Rankin Scale (mRS) score [13] at discharge.The mRS scores of 3-6 were used to define poor functional outcomes at discharge.Laboratory data included cholesterol, triglycerides, HDL-C, LDL-C, Lipoprotein (a), creatinine, HbA1c, Homocysteine (Hcy), and uric acid).

CTP and DWI acquisition and postprocessing
Multimodal CT examinations including NCCT, CTP, and CTA were performed on a 64-section multidetector scanner (Revolution Frontier, GE Healthcare, Siemens) [14].Standard NCCT was acquired (5 mm slices) followed by CTP using a SOMATOM Emotion 16 (Siemens GE Healthcare).Perfusion maps including cerebral blood flow (CBF), cerebral blood volume (CBV), time to peak (TTP), and mean transit time (MTT) were produced by using the fast-processing of ischemic stroke (F-STROKE) software [15].MRI examinations including conventional T1-weighted, T2-weighted, fluid-attenuated inversion recovery imaging, susceptibility weighted imaging (SWI), and DWI were performed on a 3.0-T MRI scanner (Prisma; Siemens AG, Erlangen, Germany) with a 32-channel array head coil.We rated the total MRI burden of cerebral small vessel disease (CSVD) on an ordinal scale from 0 to 4 [16], by counting the presence of each of the 4 MRI features of CSVD presence of lacunes and cerebral microbleeds (CMBs) were defined as the presence of one or more lacunes (1 point if present) or any CMB (1 point if present).Presence of perivascular spaces (PVS) was counted if there were moderate to severe

Image review and interpretation
The imaging data included DWI, NCCT, CTA, and CTP (CBV, CBF, MTT, and TTP) images was performed blindly and independently by two experienced neuroradiologists.Ischemic core volume was defined as relative CBF < 30% and penumbra volume as T-max > 6s in normal tissue [17].Perfusion deficits were defined as regions with abnormality of CTP map, decreased of CBF or CBV, or/and increased T-max or MTT compared with the contra-lateral side [14].Using visible hyperintense lesion on DWI as the criterion standard, patients were divided into DWI-positive and DWI-negative groups.DWI-negative patients were defined as persistent focal neurological dysfunction for more than 24 h but no areas of hyperintensity observed on DWI.Fluid-attenuated inversion recovery (FLAIR) images were reviewed to ensure that the perfusion deficits did not correspond to a region of old infarction.Supra-aortic CT angiography (CTA) was evaluated for the presence of underlying vascular stenosis that corresponded to the regional perfusion deficits.Vascular stenosis was presented as > 50% stenosis of intracranial and extracranial large vessels of CTA.In cases of discrepancies, a consensus read was performed with both readers and a senior and more experienced reviewer who was not involved in the initial grading.Inter-observer agreement on quantitative perfusion parameters were assessed in terms of the intraclass correlation coefficient (95% confidence interval), which was 0.80.

Statistical analysis
Categorical variables were presented as percentages and continuous variables as mean with standard deviation or median with interquartile range.For categorial variables, chi-square or Fisher's exact test was used to compare baseline characteristics between negative and positive DWI lesion test results.The t-test or Mann-Whitney U test was performed for continuous variables.The sensitivity and specificity of CTP results for predicting positive DWI lesions were determined using Paired chi-square test and Kappa consistency checking.Statistical analyses were performed using SPSS 26.0.P < 0.05 was considered statistically significant.

Demographic profile
In the present study, 200 patients with acute stroke symptoms completed multimodal CT examination within 4.5 h of symptom onset, and MRI examination within 72 h of symptom onset from Jan 2021 to Aug 2022.A total of 151 patients with the final diagnosis of stroke were included in this study after excluding patients with TIA, stroke mimics, and other causes.The mean age was 64.8 ± 11.4 years, and 102 (67.5%) patients were male.There were 35 (23.2%) patients with negative DWI on follow-up.DWI-negative patients were less likely to have a history of atrial fibrillation, had lower triglyceride levels, had shorter admission duration, had a lower NIHSS score after IV t-PA and mRS score at discharge, and better function outcomes compared to DWI-positive patients (Table 1).There was no significant difference in age and gender between the negative and positive DWI groups.

Clinical features of different CT perfusion results
A total of 68 (45.0%) patients had CT perfusion deficits with a median age of 62.0 (55.5.70.5) years (Table 2).A total of 83 (55.0%) patients had normal CT perfusion with a median age of 65.0 (59.0 75.0).There were 51 (61.4%) patients in normal CT perfusion and 57 (83.8%) patients in the CT perfusion deficits group diagnosed with anterior circulation AIS.There were 61 (73.5%)DWI-positive patients in normal CT perfusion and 13 (19.1%)DWI-negative patients in CT perfusion deficits group.Patients with perfusion deficits were older, more likely to have history of diabetes and atrial fibrillation, have a longer hospital stay, and have poor function outcomes compared to patients with normal CT perfusion.There were statistically significant differences in age and gender between the two groups.

Imaging results of CTP and CSVD score
Table 3 showed the results of CTP and CSVD score in patients with negative and positive DWI groups.There was no significant difference in vascular stenosis, CT perfusion deficits, and CSVD score between positive and negative DWI groups.It showed that 37.1% of DWI-positive patients and 25.7% of DWI-negative patients had vascular stenosis.There were 47.4% of DWIpositive patients and 37.1% of DWI-negative patients had CT perfusion deficits.The 73.7% of patients with

Discussion
In our retrospective study of 151 patients with AIS who were treated with intravenous thrombolysis, 23.2% of patients were DWI-negative on follow-up, of whom 37.1% had perfusion deficits on CTP imaging.Our results showed that DWI-positive patients had a longer admission duration, higher NIHSS scores after IV t-PA and mRS scores at discharge, and poor functional outcomes than DWI-negative patients.More than one-third of DWI-negative patients had perfusion deficits.Our study revealed a low concordance between the proportion of patients with perfusion deficits on CTP at admission and 72-hour DWI.The reason may be that CTP imaging failed to identify 38.6% patients with posterior circulation.Moreover, 19.1% of patients with lacunar infracts were difficult to detect using CTP imaging.Lacunar strokes and posterior circulation had smaller infarcts that could be missed in DWI imaging with large slice thickness [18].Previous studies indicate that perfusion imaging may have prognostic value in anterior circulation acute ischemic stroke and aid in the selection of patients outside the time window for intravenous thrombolysis (IVT) or mechanical thrombectomy [19].
Our study revealed that 73.5% of patients had positive DWI in normal CT perfusion, while 19.1% of patients with perfusion deficits had negative DWI. CTP imaging revealed that 45% of AIS patients who received intravenous thrombolysis treatment had perfusion deficits.CTP imaging could help in the diagnosis of perfusion deficits in DWI-negative patients.In our study, 37.1% of ischemic stroke patients with negative DWI had perfusion deficits, involving anterior circulation in 84.6% and posterior circulation in 15.4% of patients.A previous study numerically and visually confirmed that CTP provides a stronger ischemic infarct core signal than NCCT [20].CTP can select eligible AIS patients for reperfusion therapy based on the ischemic core and penumbra [21].Whole-brain CT perfusion was used in a study to examine volumetric perfusion deficits in AIS patients, and discovered that perfusion deficits had the highest absolute volumes in MTT and T-max maps [22].
The DWI slice thickness and any slice gap must be reported to determine whether some DWI-negative cases were overlooked.In our study, 23.2% of ischemic stroke patients who received intravenous thrombolysis treatment were DWI-negative on follow-up, comparable to the previous 12.36 to 26% of patients treated with IV t-PA lacking imaging evidence of acute infarction on follow-up [23,24].A study on posterior circulation reported that 26% of acute lateral medullary infarction patients had negative DWI-MRI [25].Our study discovered that DWI-negative patients had lower NIHSS scores after IV t-PA and mRS scores at discharge and better functional outcomes.These results were consistent with the observations of a nationwide prospective registry, the CNSR-III [26].A previous study revealed that mild to moderate cerebral ischemia can cause isolated persistent synaptic failure without neuronal death [27].This could explain why DWI-negative patients had lower NIHSS scores.A lower NIHSS score and small DWI lesion volume before IV t-PA was reported to be associated with a favorable outcomes [28,29].

Limitations
Our study had several limitations.The single-centre retrospective design and relatively small sample size could undermine the generalizability of our findings.Patients who underwent mechanical thrombectomy following intravenous thrombolysis or did not receive thrombolysis treatment were excluded.Our study showed no significant difference in CSVD scores between the two groups.Patients with large vessel occlusion and ischemic core volumes can be easily identified through CT imaging.More accurate imaging techniques and prevention follow-up for small lacunar infarcts need to be investigated.Further research is necessary to evaluate the significance of neurological examinations in a more comprehensive stroke population, including patients who received mechanical thrombectomy.

Conclusion
On follow-up DWI-MRI, 23.2% of AIS patients who underwent intravenous thrombolysis had no relevant lesion.However, we discovered that over one-third of patients in the DWI-MRI negative group had CT perfusion deficits, with a sensitivity of 47.4% for predicting DWI lesions in non-mechanical thrombectomy patients.The use of CT perfusion evaluation in non-mechanical thrombectomy AIS patients before IV t-PA ensures acute treatment based on a valid diagnosis with a decreased risk of treating stroke mimics.

Table 2
Clinical features of different CT perfusion results Abbreviations: CTP CT perfusion, DWI diffusion weighting imaging, SD standard deviation, NIHSS National Institutes of Health Stroke Scale, IVT Intravenous thrombolysis, NCCT non-contrast CT brain, HT hypertension, DM diabetes, CHD coronary heart disease, AF atrial fibrillation, CI cerebral infarction, LI lacunar infarcts, WMH white matter hyperintensities, CMB cerebral microbleeds, PVC perivascular space, mRS modified Rankin scale

Table 3
The results of CTP and CSVD score in two group patients Abbreviations: CTP CT perfusion, DWI diffusion weighting imaging, CSVD cerebral small vessel disease, CBV cerebral blood volume, CBF cerebral blood flow, MTT mean transit time, TTP time to peak, LI lacunar infarcts, WMH white matter hyperintensities, CMB cerebral microbleeds, PVC perivascular spaces