Impact of First-pass Effect for M2 Segment of Middle Cerebral Artery Occlusion

Abstract

Although the efficacy of endovascular therapy for large-vessel occlusion is well-established, its effectiveness in the M2 segment of middle cerebral artery occlusion remains uncertain. This study aimed to identify which M2 segment of middle cerebral artery occlusion cases may benefit from endovascular therapy by focusing on the first-pass effect, which refers to patients who underwent endovascular therapy and achieved complete reperfusion after 1 pass. The study analyzed computed tomography perfusion imaging using the Rapid Processing of Perfusion and Diffusion software. In this retrospective study, we analyzed 71 patients with M2 segment of middle cerebral artery occlusion who underwent endovascular therapy after computed tomography perfusion imaging using the Rapid Processing of Perfusion and Diffusion software. The patients were divided into 2 groups: the first-pass effect group (n = 15) and the No first-pass effect group (n = 56). The first-pass effect group showed a significantly higher proportion of patients with a modified Rankin Scale score of 0-2 at 90 days than the No first-pass effect group (80.0% vs. 39.3%; adjusted odds ratio: 12.6, 95% confidence interval: 1.27-125.5). Among Rapid Processing of Perfusion and Diffusion-derived parameters, a median Hypoperfusion Intensity Ratio, an index of collateral status, was significantly lower in the first-pass effect group, with a suggested threshold of <0.22. In patients with M2 segment of middle cerebral artery occlusion, achieving first-pass effect was associated with better neurological outcomes. First-pass effect was more likely when Hypoperfusion Intensity Ratio was ≤ 0.22, suggesting this parameter may guide treatment decisions.

Introduction

In recent years, endovascular therapy (EVT) for large-vessel occlusion (LVO) has been developed, and the indications for EVT have expanded depending on the time from onset.^1,2) However, recent reports have shown that EVT for medium vessel occlusion (MeVO) does not demonstrate superiority over the best medical treatment,³⁾ because it has been reported that EVT in MeVO is associated with a higher risk of intracranial hemorrhage than in LVO, due to the small diameter of the vessels targeted for treatment.⁴⁾

Although evidence for mechanical thrombectomy in MeVOs remains limited, several studies have suggested its potential efficacy, particularly in cases of M2 segment middle cerebral artery occlusion (M2O).^5,6) Furthermore, mechanical thrombectomy may be an effective treatment option when appropriate patient selection criteria are applied.

On the other hand, there have been reports that achieving the first-pass effect (FPE), which means complete reperfusion after a single pass, is associated with favorable outcomes.⁷⁾ Therefore, we focused on FPE, considering it a potential key factor in the success of EVT for M2O.

Additionally, the use of computed tomography (CT) perfusion imaging analyzed by Rapid Processing of Perfusion and Diffusion (RAPID) software has enabled faster and more reliable identification of the penumbral region, allowing for more accurate and timely determination of treatment eligibility.^1,8)

Therefore, we investigated the clinical impact of FPE in patients with M2O and its association with imaging parameters using RAPID software.

Materials and Methods

Data collection and definitions

This was a single-center, retrospective registry study including all consecutive eligible cases during the study period at Hyogo Medical University. Among patients with stroke who underwent CT perfusion (CTP) imaging using RAPID software, those who were considered to have M2O were extracted and analyzed. This study was approved by the Hyogo Medical University Ethics Committee (Approval Number 4818) and complied with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The requirement for written informed consent was waived due to the retrospective design of the study.

Baseline characteristics and risk factors of interest included age, sex (male), premorbid modified Rankin Scale (mRS) score of ≤ 2,⁹⁾ antithrombotic therapy before admission, atrial fibrillation, heart failure, hypertension, diabetes mellitus, and hyperlipidemia; onset-to-door time within 360 mins; and use of intravenous recombinant tissue-type plasminogen activator. The baseline National Institutes of Health Stroke Scale (NIHSS) score was used to indicate stroke severity at the time of admission.¹⁰⁾ For imaging analysis of patients with ischemic stroke, the Alberta Stroke Program Early Computed Tomography Score (ASPECTS),¹¹⁾ automatically calculated using RAPID software, was used.

We also examined the frequency of thrombectomy strategies used, including a combined technique (aspiration plus stent retriever), aspiration catheter alone, stent retriever alone, and other techniques. Of note, a balloon-guiding catheter was used in all cases.

In addition, the following CTP-related parameters calculated using the RAPID software were collected: volumes with time-to-maximum (T_max) >4, >6 (critically hypoperfused ischemic region), >8, and >10 sec; volumes with relative cerebral blood flow (rCBF) <30% (ischemic core); and mismatch volume. The mismatch volume corresponding to the ischemic penumbra was defined as T_max >6 sec-rCBF <30% (ischemic core), and Hypoperfusion Intensity Ratio (HIR).¹²⁾

Neurovascular imaging

When a patient with stroke symptoms is transferred, we usually perform CT, CT angiography, and CTP using the RAPID software for diagnosis in our institution. We used a 128-slice multidetector CT system (Siemens Somatom Definition AS+) for stroke imaging. The CTP was performed with a z-axis coverage of 96 mm using 2 continuous slabs. The scan was conducted with a tube voltage of 80 kVp, tube current of 230 mAs, 5-sec delay, and a cycle time of 1.5 sec. A total of 40 mL contrast medium was injected at a flow rate of 5 mL/sec, followed by a 30 mL saline flush at the same rate. The CTP images were acquired using periodic spiral scanning. The acquired CTP data were post-processed using commercial software (RAPID, iSchemaView, Menlo Park, CA, USA), and parametric maps were automatically generated.

Outcome definitions

The primary outcome was defined as a score of 0-2 on the mRS 90 days after onset, while the secondary outcomes included the mortality rate at 90 days, any intracranial hemorrhage within 72 hours of onset, and symptomatic intracranial hemorrhage within 72 hours. Regarding intracranial hemorrhage, 1 of the postoperative complications, symptomatic intracranial hemorrhage, was defined as a worsening of the NIHSS score by 4 points or more.¹³⁾

The outcomes were compared between the FPE and No FPE groups. The FPE group was defined as the group in which successful recanalization of Thrombolysis in Cerebral Infarction (TICI 3) was achieved with a single thrombectomy pass,¹⁴⁾ whereas the No FPE group was defined as all other cases. Additionally, we visualized and compared the differences in mRS scores at 3 months between the FPE and No FPE groups using a graph.

Statistical analysis

The clinical characteristics and outcomes were compared between the FPE and No FPE groups. Continuous variables are presented as means, standard deviations, medians, and interquartile ranges, while categorical variables are presented as numbers and percentages. Additionally, we present the number of missing observations. After visual assessment of the distributions, continuous variables were compared using the Student's t-test or the Wilcoxon rank-sum test based on their distribution. Categorical variables were examined using the chi-square test, as appropriate. We constructed a multivariate logistic regression model to estimate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the primary and secondary outcomes, comparing the FPE group to the No FPE group. We used a parsimonious multivariate logistic regression model aOR of age, baseline NIHSS score, premorbid mRS score, CT-ASPECTS score, and use of intravenous recombinant tissue-type plasminogen activator.

In addition, receiver operating characteristic (ROC) curves indicating the threshold to identify FPE were created for the HIR, and the area under the curve (AUC) was measured because the HIR reflects the extent of collateral circulation development.^12,15)

All statistical analyses were conducted using JMP Pro version 17 software (SAS Institute Inc., Cary, NC, USA). All tests were 2-sided, and p values <0.05 were considered statistically significant.

Results

Patient characteristics

Between April 2019 and April 2024, at the Department of Neurosurgery, Hyogo Medical University, we performed head perfusion CT scans using RAPID software in 857 cases. Of these, 161 patients met the criteria for MeVO. Eighteen cases were excluded because of RAPID software errors. Subsequently, 45 non-M2O cases were excluded, and 98 M2O cases were included in the analysis. Of the 98 remaining M2O cases, 27 that did not undergo EVT were excluded, resulting in 71 M2O cases that underwent EVT. These cases were classified into the FPE group (15 cases) and the No FPE group (56 cases) (Figure 1).

Figure 1.

Study flow chart.

EVT: endovascular treatment; M2O: M2 segment of middle cerebral artery occlusion; MeVO: medium vessel occlusion; RAPID: Rapid processing of Perfusion and Diffusion

We analyzed 71 patients, comprising 15 in the FPE group and 56 in the No FPE group. The average age of the participants was 77 years, and 53.5% were male.

Patients with hypertension were significantly more common in the FPE group than in the No FPE group (86.7% vs. 58.9%), and the CT-ASPECTS score was significantly higher in the FPE group (median [interquartile range]; 10 [8-10] vs. 8 [7-9]).

Regarding thrombectomy strategies, there were no significant differences between the FPE and No FPE groups in the frequencies of use: combined technique (80.0% vs 83.9%), aspiration catheter alone (13.3% vs 10.7%), stent retriever alone (6.7% vs 1.8%), and other techniques (0% vs 3.6%).

Average RAPID T_max >6 sec volume (39.4 mL vs. 64.3 mL), RAPID T_max >8 sec volume (20.2 mL vs. 44.4 mL), RAPID T_max >10 sec volume (13.7 mL vs. 32.3 mL), and HIR (0.19 vs. 0.46) were significantly lower in the FPE group. On the other hand, no significant differences were observed between the FPE group and the No FPE group in RAPID CBF < 30% volume (5.5 mL vs. 15.6 mL), RAPID T_max >4 sec volume (98.5 mL vs. 131.2 mL), and mismatch volume (33.9 mL vs. 46.7 mL) (Table 1).

Table 1.

Patient Characteristics

	FPE (n = 15)	No FPE (n = 56)	p-Value
Age, y, mean (SD)	79.0 (13.6)	76.7 (9.9)	0.47
Sex, male, n (%)	8 (53.3)	30 (53.6)	0.99
Pre-mRS score of ≤2, n (%)	13 (86.7)	40 (71.4)	0.32
Medical history
Antithrombotic therapy before admission, n (%)	6 (41.0)	25 (44.6)	0.75
Atrial fibrillation, n (%)	7 (46.7)	35 (62.5)	0.27
Heart failure, n (%)	0 (0.0)	8 (14.3)	0.19
Hypertension, n (%)	13 (86.7)	33 (58.9)	0.046
Diabetes mellitus, n (%)	4 (26.7)	14 (25.0)	1.0
Hyperlipidemia, n (%)	9 (60.0)	30 (53.6)	0.66
Baseline NIHSS, median (IQR)	6 (4-17)	15 (7-22)	0.06
CT-ASPECTS score, median (IQR)	10 (8-10)	8 (7-9)	0.02
Onset to door time within 360 minutes, n (%)	10 (66.7)	44 (78.6)	0.33
Use of intravenous recombinant tissue-type plasminogen activator, n (%)	4 (26.7)	25 (44.6)	0.21
Thrombectomy strategy
Combined technique (aspiration + stent), n (%)	12 (80.0)	47 (83.9)	0.71
Aspiration catheter alone, n (%)	2 (13.3)	6 (10.7)	0.67
Stent retriever alone, n (%)	1 (6.7)	1 (1.8)	0.38
Other techniques, n (%)	0 (0.0)	2 (3.6)	1.0
Volume of RAPID
CBF <30%, mL, median (IQR)	0 (0-7)	9.5 (0-25.5)	0.08
Tmax >4 sec, mL, median (IQR)	68 (54-101)	116 (71.3-162.8)	0.17
Tmax >6 sec, mL, median (IQR)	36 (15-46)	60.5 (37.3-90.5)	0.02
Tmax >8 sec, mL, median (IQR)	15 (0-28)	41.5 (14.5-65.3)	0.009
Tmax >10 sec, mL, median (IQR)	9 (0-24)	30 (7-49.8)	0.02
Mismatch volume, mL, median (IQR)	35 (15-41)	41 (24-67.8)	0.13
Hypoperfusion Intensity Ratio, median (IQR)	0.19 (0-0.57)	0.46 (0.20-0.66)	0.044

CBF: cerebral blood flow, CT ASPECTS: Computed Tomography Alberta Stroke Program Early Computed Tomography Score, IQR: interquartile range, mRS: modified Rankin Scale, NIHSS: National Institutes of Health Stroke Scale, RAPID: rapid processing of perfusion and diffusion, SD: standard deviation, T_max: time to maximum of the residue function

Primary outcome

Regarding the outcome of an mRS score of 0-2 at 90 days after the onset, the FPE group showed significantly better outcomes compared to the No FPE group (12 [80.0%] vs. 22 [39.3%], aOR^*: 12.6 [95% CI: 1.27-125.5] and aOR^**: 21.3 [95% CI: 1.93-234.09]) (Table 2; Figure 2).

Table 2.

Outcomes

	FPE(n = 15)	No FPE(n = 56)	Crude odds ratio (95% CI)	p-Value	Adjusted odds ratio* (95% CI)	P-Value	Adjusted odds ratio**(95% CI)	p-Value
Primary outcome
modified Rankin Scale score of 0-2 at 90 d, n (%)	12 (80.0)	22 (39.3)	6.18(1.56-24.4)	0.009	12.6(1.27-125.5)	0.03	21.27(1.93-234.1)	0.01
Secondary outcomes
Mortality at 90 d, n (%)	0 (0.0)	9 (16.1)	NA	NA	NA	NA	NA	NA
Any intracranial hemorrhage within 72 hrs, n (%)	1 (6.7)	29 (51.8)	0.07 (0.008-0.54)	0.01	0.08(0.009-0.67)	0.02	0.05(0.006-0.44)	0.007
Symptomatic intracranial hemorrhage within 72 hrs, n (%)	0 (0.0)	4 (7.1)	NA	NA	NA	NA	NA	NA

CI: confidence interval, CT ASPECTS: Computed Tomography Alberta Stroke Program Early Computed Tomography Score, FPE: first-pass effect; mRS: modified Rankin Scale, NA: not applicable; NIHSS: National Institutes of Health Stroke Scale

*Adjusted for age, baseline NIHSS, pre-mRS, CT-ASPECTS score.

**Adjusted for age, baseline NIHSS, pre-mRS, and use of intravenous recombinant tissue-type plasminogen activator.

Figure 2.

Distribution of modified Rankin Scale score after 3 months.

FPE: First pass effect; mRS: modified Rankin Scale

Secondary outcome

In terms of mortality at 90 days and symptomatic intracranial hemorrhage within 72 hours, since the number of cases in the FPE group was 0, no significant difference was observed between the 2 groups.

However, intracranial hemorrhage within 72 hours of onset was significantly lower in the FPE group (1 [6.7%] vs. 29 [51.8%], aOR^*: 0.08 [95% CI: 0.009-0.67] and aOR^**: 0.049 [95% CI: 0.006-0.44]).

To assess the association between collateral flow and FPE, we performed ROC curve analysis. AUC values for HIR were 0.69, and FPE was more likely to be achieved when the HIR was ≤0.22 (Figure 3).

Figure 3.

Discriminatory ability of the Hypoperfusion Intensity Ratio for the first-pass effect.

AUC: area under the curve

Discussion

The results of this study demonstrated that in thrombectomy for M2 occlusion, FPE increased the proportion of patients with an mRS of 0-2 at 90 days and significantly improved outcomes. In terms of safety, FPE was associated with a lower risk of intracranial hemorrhage compared to No FPE. This finding suggests that achieving FPE is a key factor in safely improving the outcomes of thrombectomy for M2O.

We also investigated the factors that facilitate FPE during thrombectomy for M2 occlusion. Our analysis revealed that RAPID T_max >6 sec, RAPID T_max >8 sec, RAPID T_max >10 sec, and the HIR were significantly lower in the FPE group than in the No FPE group. Among these, the HIR is known to be an indicator of collateral circulation in thrombectomy for LVO, and it has also been previously reported that an HIR of less than 0.4 is associated with a favorable response to thrombectomy.¹²⁾ Therefore, we focused on the HIR, which is commonly used in clinical practice, and investigated its relationship with FPE. By focusing on the HIR (the ratio of the volume of T_max > 10 sec to the volume of T_max > 6 sec), a widely recognized indicator of collateral circulation, we examined whether HIR could help determine the suitability of thrombectomy for patients with M2O. Our analysis identified an HIR threshold of 0.22, below which patients were more likely to achieve FPE. This finding suggests that thrombectomy in M2O cases with an HIR ≤ 0.22 is associated with improved clinical outcomes and may serve as a valuable criterion for guiding treatment decisions. Previous studies investigating the relationship between HIR and thrombectomy for LVO have shown that an HIR ≤ 0.4 is associated with favorable collateral circulation and better treatment efficacy.^12,15) There have been no prior reports demonstrating that a low HIR is associated with a higher likelihood of achieving FPE; we regard this as the main novelty of our study. However, our study showed that in M2O cases, an HIR of ≤0.22 was associated with a higher rate of FPE and contributed to improved clinical outcomes. Although a direct comparison is difficult, the reason why the threshold of HIR for predicting favorable neurological outcomes appears to be stricter in M2O cases than in LVO cases may be that M2O involves more distal vessels, which are more prone to hemorrhagic complications compared to LVO. Therefore, the therapeutic benefit of thrombectomy in M2O may only be observed under well-developed collateral flows.

Since there were no cases of mortality at 3 months or symptomatic intracranial hemorrhage within 72 hours in the FPE group, these outcomes could not be analyzed. However, our results demonstrated that an increased number of passes was associated with a higher incidence of any intracranial hemorrhage within 72 hours. Some studies have reported that an increased number of EVT passes is associated with a higher risk of intracranial hemorrhage.¹⁶⁾ This suggests that when performing thrombectomy in patients with M2O, consideration may be given to discontinuing the procedure when multiple passes are reached.

This was a retrospective analysis of cases from a single institution, and the volume was small, and the FPE group was small (n = 15), and the 95% CIs around the odds ratios were wide. Accordingly, the estimates have limited precision, and the findings should be interpreted with caution to avoid overestimation. We believe that conclusions should not be based on p values alone. Given the limited number of cases, further prospective studies with larger sample sizes are required to accumulate data and determine the precise threshold values. Moreover, future work should compare FPE and No FPE cohorts with similar baseline characteristics to ensure fair assessment.

In this study, the FPE group showed a significantly lower baseline CT-ASPECTS and more favorable RAPID-based perfusion status than the No FPE group, therefore, comparing functional outcomes may not be fair. Furthermore, ROC analysis yielded an AUC of 0.69, indicating only modest discrimination. It should not be used by itself to make treatment decisions; instead, it should be used together with clinical data such as age, NIHSS, ASPECTS, and core volume.

However, as endovascular thrombectomy for M2O is increasingly performed in clinical practice, the findings of this study may provide a promising step toward establishing evidence for its effectiveness, which remains to be fully clarified. Specifically, performing thrombectomy in M2O cases with small ischemic core volumes and aiming for successful reperfusion with fewer device passes may help establish more robust evidence of its efficacy. Based on these findings, we aimed to pursue further research in this field.

Currently, the treatment window for EVT is extended to 24 hours after stroke onset.¹⁾ Moreover, in the Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke trials (HERMES) Collaboration's meta-analysis of M2O, EVT improved functional independence compared with medical management, with the greatest effect in proximal and dominant M2 lesions and no increase in symptomatic intracranial hemorrhage. Although partial, these findings suggest emerging evidence for the efficacy of EVT in M2O.¹⁷⁾ However, there are no clear criteria for EVT eligibility based on the sizes of the ischemic core and penumbra, and this uncertainty applies to M2O cases. In M2O cases, symptoms are often milder than in LVO cases,¹⁷⁾ making it especially important to focus on treating “salvageable regions.” Therefore, we used the RAPID software, which can sensitively identify “salvageable regions,” and found that the FPE, specifically a HIR ≤ 0.22, was associated with favorable outcomes in patients with M2O. We believe that this study provides valuable insights for identifying patients with M2O who may benefit from EVT.

Conclusions

In patients with M2O, achieving FPE is associated with improved clinical outcomes. Furthermore, FPE was associated with HIR ≤ 0.22.

Conflicts of Interest Disclosure

Dr Uchida has received lecturer fees from Daiichi Sankyo, Bristol Myers Squibb, Stryker, and Medtronic. Dr Shirakawa has received lecturer fees from Stryker, Terumo, Johnson & Johnson, and Medtronic. Dr Yoshimura has received research grants from Medico's Hirata, Medtronic, and Terumo; and has received lecturer fees from Medtronic, Kaneka, Stryker, Daiichi Sankyo, Bristol Myers Squibb, and Johnson & Johnson. Other co-authors have no conflict of interest for this manuscript.