A New Classification System for Postinterventional Cerebral Hyperdensity: The Influence on Hemorrhagic Transformation and Clinical Prognosis in Acute Stroke

Background Postinterventional cerebral hyperdensity (PCHD) is commonly seen in acute ischemic patients after mechanical thrombectomy. We propose a new classification of PCHD to investigate its correlation with hemorrhagic transformation (HT). The clinical prognosis of PCHD was further studied. Methods Data from 189 acute stroke patients were analyzed retrospectively. According to the European Cooperative Acute Stroke Study criteria (ECASS), HT was classified as hemorrhagic infarction (HI-1 and HI-2) and parenchymal hematoma (pH-1 and pH-2). Referring to the classification of HT, PCHD was classified as PCHD-1, PCHD-2, PCHD-3, and PCHD-4. The prognosis included early neurological deterioration (END) and the modified Rankin Scale (mRS) score at 3 months. Results The incidence of HT was 14.8% (12/81) in the no-PCHD group and 77.8% (84/108) in the PCHD group. PCHD was highly correlated with HT (r = 0.751, p < 0.01). After stepwise regression analysis, PCHD and the National Institutes of Health Stroke Scale (NIHSS) score at admission were found to be independent factors for END (p < 0.001, p = 0.015, respectively). The area of curves (AUC) of PCHD, the NIHSS at admission, and the combined model were 0.810, 0.667, and 0.832, respectively. The optimal diagnostic cutoff of PCHD for END was PCHD > 2. PCHD, the NIHSS score at admission, and good vascular recanalization (VR) were independently associated with 3-month mRS (all p < 0.05). The AUC of PCHD, the NIHSS at admission, good VR, and the combined model were 0.779, 0.733, 0.565, and 0.867, respectively. And the best cutoff of PCHD for the mRS was PCHD > 1. Conclusion The relationship of PCHD and HT suggested PCHD was an early risk indicator for HT. The occurrence of PCHD-3 and PCHD-4 was a strong predictor for END. PCHD-1 is considered to be relatively benign in relation to the 3-month mRS.


Introduction
Postinterventional cerebral hyperdensity (PCHD) is fairly commonly seen in patients with acute ischemic stroke following intra-arterial treatment [1][2][3]. Recently, with advances in technology, intravascular stents have been widely used for acute stroke patients; however, there have been few studies on patients with PCHD after mechanical thrombectomy. Previous small-sample studies revealed that PCHD was a strong predictor for final infarction size [4,5] but was not a risk factor for symptomatic hemorrhage or poor prognosis [5,6]. This low predictive efficiency may be due to the analysis of only the occurrence of PCHD, rather than the classification of PCHD. Later, Xu et al. found that "metallic hyperdensities" with a CT density of over 90 HU and a larger volume with a bulging contour could predict the occurrence of parenchymal hemorrhage at 24 h [7]. However, there were no further investigations into the effect on clinical prognosis in that study. The classification standard of CT values was formulated in clinical trials evaluating arterial thrombolysis [3], and a later study of intra-arterial revascularization suggested that a CT value of >90 poorly predicted hemorrhagic transformation (HT) with low sensitivity (23%) [8]. There were no further studies of PCHD on clinical prognosis in people with mechanical thrombectomy.
According to the European Cooperative Acute Stroke Study (ECASS) criteria, HT was further divided into four levels [9]. Different types of HT after stroke require corresponding targeted treatment and are closely related to prognosis [10,11]. However, the correlation between various degrees of HT and PHCD was not clear. Thus, we proposed a new classification of PCHD, which divides PCHD into four levels according to the definition of HT, to provide a more direct and pragmatic early reference sign. The influence and the optimal diagnostic threshold of PCHD subtypes on clinical prognosis were further analyzed.
The aim of our study was to predict HT and clinical prognosis by evaluating the new classification system for PCHD and to provide a theoretical and experimental basis for the formulation of a treatment plan after intra-arterial intervention.

Materials and Methods
2.1. Subjects. The study was approved by the local Ethics Committee, and the requirement for informed consent of every patient was waived.
The data of 777 patients with acute cerebral infarction from 2016 to 2019 were retrospectively analyzed in the PACS. Among these patients, 189 patients treated with intravascular intervention were enrolled in this study. A flowchart of participant recruitment is shown in Figure 1. According to whether a hyperdensity was found on noncontrast CT scans (NCCT) after intravascular intervention, the patients were divided into a no-PCHD group (n = 81) and a PCHD group (n = 108). Referring to the new PCHD classification standard, the PCHD group was further divided into PCHD-1, PCHD-2, PCHD-3, and PCHD-4.
Early neurological deterioration (END) was indicated when the NIHSS score increased ≥4 points within 72 h of onset [12].
The mRS score at 3 months: 0-2 scores indicated a good prognosis (no symptoms or mild disability); 3-6 scores indicated a poor prognosis (moderate to severe disability or death) [13,14].
2.3. Image Data Acquisition. Intravascular intervention: for patients without contraindications of venous thrombolysis, mechanical thrombolysis was administered after venous thrombolysis. The time window for anterior circulation strokes was up to 8 h after symptom onset, and that for posterior circulation strokes was 24 h. The time window could be extended appropriately according to ischemic core/penumbra mismatch. The femoral artery was selected for puncture, and the thrombus was removed using a Solitaire stent (Medtronic). Digital subtraction angiography (Allura Xper Fd20 by Philips, Netherlands) was used during mechanical thrombectomy. The sequence included the anterior and lateral positions of each artery. The exposure was automatically adjusted with a delay of 0.5 s, and images of the arterial, parenchymal, and venous phases were collected at a rate of 6 frames per second. Successful recanalization was defined as grade 2b-3 of the modified   Axial NCCT reexamination scan: the SIEMENS Definition AS 128 CT scanner was used. The routine head scan protocol: the tube voltage = 120 kV, the reference current = 400 mA, the actual current can be adjusted by using the combined applications reduce exposure dose 4 dimensions (CARE dose 4D) technology, acquisition matrix = 512 × 512 , rebuild field of view ðFOVÞ = 300 mm × 300 mm, layer thickness = 1 mm, and interslice gap = 0. The emergency head scan protocol: the tube voltage = 120 kV, the reference current = 400 mA, the actual current can be adjusted by using the CARE dose 4D technology, acquisition matrix = 512 × 512, rebuild FOV = 300 mm × 300 mm, and pitch = 0:9 mm.
HT was defined as a hyperdensity that persisted or was extended on CT reexamination within 1 week or on a susceptibility-weighted imaging sequence (SWI) that showed a low signal in the infarct range. HT was classified according to the ECASS definition. HI means hemorrhagic infarction, and pH means parenchymal hemorrhage.

Neural Plasticity
(ii) HI-2: more confluent petechiae without a spaceoccupying effect or nonsolid (iii) pH-1: less than 30% of the infarcted area has a mild mass effect (iv) pH-2: greater than 30% of the infarcted area has a significant space-occupying effect PCHD was defined by visually distinctive parenchymal hyperdense areas diagnosed within 24 h after intravascular intervention, with a diameter of at least 0.1 cm 2 and an increased density of at least 5 HU (HUmax) compared to the unaffected contralateral area. The example diagram of PCHD is shown in Figure 2.
(i) PCHD-1: small area of hyperdensity without spaceoccupying effects (ii) PCHD-2: more confluent hyperdensity without space-occupying effects (iii) PCHD-3: less than 30% of the infarcted area has a mild mass effect (iv) PCHD-4: greater than 30% of the infarcted area has a significant space-occupying effect Imaging indexes (the Alberta Stroke Program Early CT (ASPECT) score and the classification of PCHD and HT) were evaluated by two neuroradiologists (Dr. Shao, who has 3 years of experience, and Dr. He, who has 13 years of experience). The two doctors first evaluate independently and finally reach a consensus through discussion where there is disagreement.

Statistical Analysis.
Statistical analysis was performed with SPSS 20.0 (IBM, Chicago, IL, United States). Comparisons of the basic clinical characteristics were conducted with a t-test, the chi-square test, or the Mann-Whitney U test, depending on the circumstances. The Crosstabs test and ANOVA were used for the four subtypes of PCHD. The intraclass correlation coefficient was calculated to evaluate the consistency between the two observers. The Spearman rank correlation test was used to analyze the correlation between PCHD and HT, and r > 0:75 was considered to be a good correlation. Univariate logistic regression analysis was used to explore the relationship between dependent variables and independent variables. A forest plot was established to show the relationship. Then, through multivariate logistic regression analysis, the independent factors that were associated with END and mRS were further identified. Finally, a receiver-operating characteristic (ROC) curve was constructed. The area of curves (AUC) was used to evaluate the diagnostic efficacy of the independent risk factors for END and mRS at 3 months. Cutoff value was used to identify the threshold that predicts clinical outcomes. Statistical significance was set at p ≤ 0:05.
As shown in Table 1, there were significant differences in the history of hypertension, APTT, the NIHSS score at admission, and the ASPECT score between the no-PCHD group and the PCHD group (p < 0:05). There was no significant difference in the location of occluded artery between the two groups (p > 0:05).
As shown in Table 2, there were significant differences in the ASPECT score among the four PCHD subgroups (p = 0:009). The CT value of the high-density PCHD-4 group was higher than that of the PCHD-1 and PCHD-2 groups (p = 0:002), but no difference was found between these three subgroups and the PCHD-3 group. Patients in the PCHD-1/2 group lacked intraventricular hyperdensity, which was significantly different from that in PCHD-3/4 group (p = 0:002). Moreover, there were significant differences in clinical prognosis among the four groups (HT, END, and mRS, all p < 0:05).
The two observers performed radiographic evaluations with a high degree of consistency. The intraclass correlation coefficients of the ASPECT score, PCHD and HT were 0.950, 0.986, and 0.978, respectively, all p < 0:01.

Predicting Early Neurological Deterioration (END).
The image and clinical data of END-and END+ group were shown in Table s1. The univariate analysis revealed there were significant differences in the NIHSS score, the the CT value of the high-density PCHD-4 group was higher than that of the PCHD-1 and PCHD-2 groups, but no difference was found between these three subgroups and the PCHD-3 group. 6 Neural Plasticity ASPECT score, PCHD classification, and interventricular hyperdensity between the two groups (p < 0:05, illustrated Figure 4). After the multivariate regression analysis, the NIHSS score at admission and PCHD were independent factors for END (p = 0:015, p < 0:001, respectively), as in Table 3. Figure 5 showed that AUC of PCHD was 0.810, and the optimal diagnostic cutoff value was PCHD > 2.
The AUC of the NIHSS score at admission was 0.667. The AUC of the combined model was 0.832.     Table s2. Univariate analysis revealed that the NIHSS score at admission, the ASPECT score, PCHD classification, and good vascular recanalization were associated with the 3month mRS (all p < 0:05), as shown in Figure 6. The multivariate analysis revealed that the NIHSS score, PCHD, and good vascular recanalization were independently associated with the mRS score at 3 months (all p < 0:05). Good vascular recanalization was a protective factor (OR = 0:256, 0.070-0.933), but the predictive efficiency was lower (AUC = 0:565), as in Table 4. Figure 7 showed that AUC of PCHD was 0.779, and the optimal diagnostic cutoff value was PCHD > 1. The AUC of the NIHSS score at admission, good vascular recanalization, and the combined model were 0.733, 0.565, and 0.867, respectively.

Discussion
This study shows that there was a good correlation between the new classification system for PCHD and HT. The patients with PCHD-3 and PCHD-4 were more likely to have early neurological deterioration. The 3-month mRS was poorer in patients with PCHD classified as PCHD-2, PCHD-3, and PCHD-4, but PCHD-1 was considered to be relatively benign.
In our study, the incidence of PCHD after intra-arterial reperfusion therapy was 57.1%, which was consistent with the incidence of PCHD reported by others (32.9% to 84.2%) [1][2][3]15]. The incidence of HT in our study was 50.8% (HI = 31:2%; pH = 19:6%). The incidence of pH was higher than that in several published multicenter randomized clinical trials, ranging from 3.6% to 11% [16][17][18][19][20]. However, our rate was determined from real-world data after mechanical thrombectomy. The lack of strict control over the time window, which was extended according to ischemic core/penumbra mismatch, may be one of the reasons for this discrepancy. Another reason may be the use of SWI to detect HT, which may result in a visual overestimation of hematoma size due to susceptibility effects [21].
This study is the first to classify PCHD according to the ECASS definition in an attempt to develop a simpler and more intuitive method to predict different types of HT.  The probability of END in the high-risk group was significantly higher than that in the low-risk group, and the optimal diagnostic cutoff value was PCHD > 2.  Figure 6: Univariate predictors of the mRS score at 3 months.

Neural Plasticity
Our results showed that there was a good correlation between the subtypes of PCHD and HT. Therefore, we propose that both of these occurrences have a similar pathological basis, resulting from microvascular damage and increased permeability of the BBB. A scholar proposed that when the BBB loss is small, the main extravasation content is contrast agent, which will be absorbed during follow-up. Larger red blood cells also leak out when BBB breakdown is evident. A large number of red blood cells in the brain parenchyma can cause a significant mass effect, resulting in poor clinical prognosis [15,22,23]. The treatment and clinical prognosis of different types of HT vary, and this study provides a theoretical basis for selecting the appropriate subsequent treatment through the early evaluation of PCHD. In this study, we also found that the CT values in the PCHD-3 group were not well differentiated from those in the other three groups, which may explain the low predictive ability of CT values for HT [8].
Previous studies have shown that the presence of hyperdensity in patients with arterial thrombolysis has no significant effect on the clinical prognosis [5,6]. There were no further studies of PCHD on clinical prognosis in patients with mechanical thrombectomy. In our study, hyperdensity was classified into more detailed grades, and our results suggested that there were different cutoff points for early or long-term clinical prognosis. The finding of space-occupying, intervention-related PCHD 3 and PCHD-4 was associated with a high likelihood of END. This suggests that in patients with large-vessel infarction, the accumulation of mass effects may lead to further deterioration of neurological function [23].
PCHD and the NIHSS score at admission were independent risk factors for mRS at 3 months, while good vascular recanalization was a protective factor. Our results suggested that PCHD-2, PCHD-3, and PCHD-4 had a negative impact on the long-term functional outcome compared with PCHD-1. Our finding was similar to that of a previous study [11], which demonstrated the influence of hemorrhagic transformation on long-term prognosis after thrombolysis, confirming the greater clinical relevance of the new classification system for PCHD and HT.

Limitations.
This study was a single-center retrospective analysis. HT was diagnosed by two imaging methods, followup CT or SWI. Although both diagnostic methods have been used in other studies, some bias may still be present [24,25].

Conclusions
There was a good correlation between HT and PCHD after intravascular intervention in ischemic stroke patients. PCHD was an independent factor for END and the mRS score at 3 months with different cutoff points. The new classification system for PCHD was suggested to have some clinical significance for predicting both the subtypes of HT and clinical prognosis.

Data Availability
Data can be accessed by inquiring the corresponding author.

Conflicts of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.  Figure 7: Evaluation of the accuracy of the mRS score at 3 months. (a) ROC curves for good vascular recanalization (VR), the NIHSS score at admission, and PCHD in predicting the mRS+ (≥3 score) at 3 months. (b) The probability of the mRS+ at 3 months in the high-risk group was significantly higher than that in the low-risk group, and the optimal diagnostic cutoff value was PCHD > 1.