Analysis of factors influencing recurrent stroke due to symptomatic non-acute middle cerebral artery occlusion and prediction modelling

Abstract

Background

Stroke recurrence after symptomatic non-acute middle cerebral artery occlusion (SNMCAO) remains difficult to predict, with existing models showing limited accuracy.

Objective

To investigate the factors associated with recurrent stroke in SNMCAO and validate a prediction model.

Methods

This retrospective study included 150 patients with SNMCAO admitted to our hospital between August 2023 and October 2024. Data were obtained from the electronic medical record system. Patients were divided into recurrent (n = 35) and non-recurrent groups (n = 115) based on stroke recurrence. Risk factors were screened using univariate analysis, least absolute shrinkage and selection operator (LASSO) regression, and multifactorial logistic analysis. A nomogram prediction model was established and validated using R software.

Results

Hypertension (yes/no, 25/10 vs. 46/69; 71.4% vs. 40.0%), smoking (yes/no, 9/26 vs. 9/106; 25.7% vs. 7.8%), mRS score (≤ 2/>2, 20/15 vs. 93/22; 57.1% vs. 80.9%), deep tiny flow voids (DTFV) (yes/no, 18/17 vs. 89/26; 51.4% vs. 77.4%), intraplaque hemorrhage (yes/no, 21/14 vs. 36/79; 60.0% vs. 31.3%), and incomplete anterior circulation (yes/no, 22/13 vs. 38/77; 62.9% vs. 33.0%) showed significant differences. LASSO regression identified hypertension, smoking, DTFV, and incomplete anterior circulation without multicollinearity. Logistic regression showed these were risk factors for recurrent stroke (OR = 3.750, 4.077, 3.233, 3.653, P < 0.05). The nomogram showed an AUC of 0.684 (95% CI: 0.586–0.782), with good calibration (Brier Score: 0.163, p = 1) and positive clinical decision curve analysis.

Conclusion

Hypertension, smoking, DTFV, and incomplete anterior circulation are risk factors for recurrent stroke in SNMCAO. The nomogram provides moderate predictive performance for risk stratification.

Introduction

Stroke recurrence after symptomatic non-acute middle cerebral artery occlusion (SNMCAO) remains difficult to predict. Cerebrovascular disease has become the third leading cause of death in China, and the prevalence of intracranial vascular occlusive lesions is higher in Chinese compared with Caucasians [1, 2]. SNMCAO is defined as atherosclerotic occlusion of the middle cerebral artery with symptomatic fluctuation or deterioration despite aggressive medical treatment, which, as an important subtype of ischemic stroke, has become a focus of research in the field of cerebrovascular disease due to its high risk of recurrence and complex pathophysiological mechanisms [3, 4]. Xia J et al. [5] indicated that with the prevalence of population aging, the SNMCAO incidence shows an increasing trend year by year, accounting for about 40% of ischemic stroke causes in Asian populations. SNMCAO has complex pathological features, which can lead to large infarcts in its blood-supplying region, resulting in severe clinical symptoms and poor prognosis [5]. Although modern medicine has reduced the risk of stroke recurrence in some patients by means of antiplatelet therapy and intensive risk factor management, the recurrence rate of SNMCAO patients within 1 year is still as high as 20%−30% even under strict pharmacological treatment [6].

Stroke is a cerebral blood circulation disorder of sudden onset, mostly caused by intracerebral arterial stenosis, which can lead to cerebral arterial occlusion or rupture [7, 8]. Cao J et al. [9] stated that the cumulative prevalence of stroke was 11.2%, of which one-fourth were recurrent strokes, and the morbidity, mortality, disability, and treatment costs of recurrent strokes were higher than those of first-onset patients. Therefore, it is clinically important to actively analyze the factors associated with recurrent stroke in SNMCAO and construct a prediction model.

Existing prediction models for SNMCAO recurrence rely primarily on clinical parameters, with insufficient integration of imaging features. Most literature focuses on single variable associations rather than systematic multidimensional analysis. Traditional models lack incorporation of important imaging markers such as deep tiny flow voids (DTFV) and intraplaque hemorrhage, resulting in limited identification of high-risk groups. This study addresses these gaps by integrating clinical data, imaging features, and constructing a machine-learning-driven dynamic prediction model.

For patients with non-acute occlusion more than 24 h after onset, interventions should be stratified according to hemodynamic status: those with low perfusion should be prioritized for revascularization, while those with good compensation should receive optimized pharmacological therapy [10, 11]. Recent developments in endovascular recanalization techniques have provided new treatment options for SNMCAO, though screening criteria remain controversial. This study aims to provide a theoretical basis for precise stratified treatment of SNMCAO and promote innovation in secondary stroke prevention strategies.

Materials and methods

Statement of ethics

This study was approved by our Institutional Review Board and Ethics Committee. Given that this study was retrospective and only de-identified patient data were used, informed consent was not required as there were no risks or adverse effects to patients. This waiver is in line with regulatory and ethical guidelines related to retrospective studies.

Study design

This retrospective study included 150 patients who received SNMCAO treatment at our hospital between August 2023 and October 2024 as study subjects, with all patients’ data coming from the electronic medical record system and divided into a recurrent group (n = 35) and a non-recurrent group (n = 115), using recurrent stroke as the outcome indicator.

Inclusion criteria

SNMCAO was defined as symptomatic occlusion of the middle cerebral artery M1 segment confirmed by head CT angiography (CTA), with symptoms persisting despite medical therapy for more than 24 h but less than 60 days.

Inclusion criteria: (1) symptoms occurred within 14-60d; (2) occlusion of the M1 segment of the middle cerebral artery, and head CT angiography (CTA) showed the presence of vascular beds at the end of the middle cerebral artery; (3) head MRI confirmed that the new infarct foci farther away from the occluded vessel were small, and the volume of cerebral infarction was not more than 1/5 of the volume of the arteries that supplied the blood; (4) a large low-perfusion area, and CT perfusion (CTP) imaging had a low-perfusion mismatch with the infarct core of more than 50%; (5) failure of dual antiplatelet therapy and statin within 14 days, defined as NIHSS worsening ≥ 2 or new DWI lesion.

Exclusion criteria: (1) known allergies or contraindications to aspirin, clopidogrel, statins, heparin, anesthetic drugs, contrast agents, and stenting system materials; (2) active peptic ulcer disease; (3) bleeding from a vital organ within 30 d; (4) active bleeding constitution; (5) combination of severe liver, kidney, and other organ diseases; and (6) incomplete clinical data.

General information

Clinical data of patients who met the criteria were collected through the hospital information management system, including age, gender, previous stroke history, hypertension (in accordance with the diagnostic criteria for hypertension in The Japanese Society of Hypertension Guidelines for Self-monitoring of Blood Pressure at Home (Second Edition) [12]), diabetes mellitus (in accordance with the diagnostic criteria for diabetes mellitus in Application of the Chinese Expert Consensus on Diabetes Classification in clinical practice [13]), systolic blood pressure, diastolic blood pressure, smoking (ensuring that the number of cigarettes smoked is > 1 cigarettes/d for > 1 year or < 1 year of abstinence), alcohol consumption (alcohol consumption is > 1 drink/d for > 1 year or < 1 year of abstinence (1 drink of 45mL white wine/360mL of beer/120mL of fruit wine)), and body mass index (BMI).

Lipid metabolism indexes

Triacylglycerol (TG), cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were collected from all the study subjects. 5 ml of fasting peripheral venous blood was extracted, centrifuged at 5000 r/min for 8 min with a centrifugation radius of 10 cm, and the supernatant was retained and preserved at −20 °C for examination. Detected by biochemistry instrument (Model: HITACHI Hitachi 7600, Manufacturer: DIRUI MEDICAL TECHNOLOGY CO., LTD.).

Neurological function

Neurological function was collected before the patients were discharged from the hospital based on the mRS score (score 0–6) to evaluate whether the prognosis of the patients was good or not. 0 was classified as obvious improvement of symptoms and no limitation of activities; 1 indicated that there was no obvious disability after the treatment, and the daily activities could be taken care of; 2 indicated that the patients had a slight disability but could take care of themselves; 3 indicated that there was a moderate disability, and the daily life couldn’t be taken care of by themselves, but they could walk; 4 indicated that the patients had a severe disability, unable to take care of themselves in daily life; 5 indicates that the patient is incontinent and bedridden; and 6 indicates death. mRS score ≤ 2 indicates excellent neurological function, and mRS score > 2 indicates poor neurological function [14].

Imaging features

Incomplete anterior circulation was defined as absence or hypoplasia of the anterior communicating artery or contralateral A1 segment on magnetic resonance angiography (MRA).

Deep tiny flow voids (DTFV), intraplaque hemorrhage, incomplete anterior circulation, incomplete posterior circulation symptomatic side, and proximal stump status were collected from all patients by magnetic resonance imaging (MRI) scanning performed with a Philips 3.0 T scanner (Ingenia, Philips Medical Systems, The Netherlands) and a 16-channel head and neck coil with a high-resolution vessel wall imaging protocol (including pre- and post-contrast T1WI isotropic spin-echo sequences (T1WI-VISTA), T2WI black-blood imaging (BBT2WI), and 3D-TOF-MRA, with all images de-identified and digitally stored, and analyzed for plaque characterization metrics by semi-automated measurement software (tsimaging.Net).

Statistical processing

SPSS 26.0 and R 4.3.2 software were used for statistical analysis and graphing in this study. We limited candidate variables to those with clinical plausibility (n = 20) to avoid overfitting, and applied FDR correction (Benjamini-Hochberg) to univariate p-values. Measured information if it meets the normal distribution, two independent samples t-test, expressed as (x̅±s); if it does not meet it, Mann-Whitney U test, expressed as median and interquartile spacing [M (P25, P75)]; counting information using χ² test, expressed as frequency, P < 0.05 is considered to exist statistically significant.

In order to reduce the influence of multicollinearity on the regression results and avoid overfitting, the screened factors were analyzed by the “glmnet” package of R software based on the regression analysis of the least shrinkage and selection operator (LASSO), and the final screened variables were included in the multifactorial logistic regression to screen the independent risk factors affecting the occurrence of recurrent stroke in SNMCAO. A nomogram prediction model was constructed using the “rms” package in R language. The model was validated by repeating the sampling 1000 times using the Bootstrap method. The area under the curve (AUC) of receiver operating characteristic (ROC) was used to assess the discrimination of the model, the calibration of the model was assessed by plotting standard calibration curves, and the net clinical benefit of the model was assessed by decision curve analysis (DCA). Hosmer-Lemeshow test was performed to assess goodness-of-fit of the logistic regression model.

Results

Comparison between recurrence and non-recurrence groups

Table 1 shows significant differences between groups in hypertension, smoking, mRS score, DTFV, intraplaque hemorrhage, and incomplete anterior circulation (P < 0.05). Other variables showed no significant differences (P > 0.05).

Table 1.

Comparison of general data between groups

Index		Recurrence group (n = 35)	Non-recurrence group (n = 115)	χ²/t	P
Age (years, x̅±s)		56.52 ± 13.54	55.89 ± 14.16	0.233	0.816
Gender (n)	Male	28	95	0.124	0.725
	Female	7	20
Previous stroke (n)	Yes	6	10	2.009	0.156
	No	29	105
Hypertension (n)	Yes	25	46	10.321	0.001
	No	10	69
Diabetes (n)	Yes	3	10	0.001	0.982
	No	32	105
Systolic BP (mmHg, x̅±s)		133.64 ± 13.64	136.14 ± 16.98	0.796	0.427
Diastolic BP (mmHg, x̅±s)		81.45 ± 8.45	83.29 ± 9.15	1.060	0.291
Smoking (n)	Yes	9	9	8.131	0.004
	No	26	106
Alcohol (n)	Yes	4	4	3.359	0.067
	No	31	111
BMI (kg/m², x̅±s)		24.52 ± 1.18	24.39 ± 1.23	0.553	0.581
TG (mmol/L, x̅±s)		1.29 ± 0.20	1.24 ± 0.25	0.032	0.974
TC (mmol/L, x̅±s)		3.21 ± 0.35	3.24 ± 0.37	0.425	0.671
LDL-C (mmol/L, x̅±s)		1.77 ± 0.18	1.85 ± 0.26	1.699	0.091
HDL-C (mmol/L, x̅±s)		0.94 ± 0.13	0.98 ± 0.18	1.220	0.224
mRS Score (n)	≤ 2	20	93	8.129	0.004
	> 2	15	22
DTFV (n)	Yes	18	89	8.845	0.003
	No	17	26
Intraplaque hemorrhage (n)	Yes	21	36	9.378	0.002
	No	14	79
Incomplete anterior circulation (n)	Yes	22	38	9.938	0.002
	No	13	77
Incomplete posterior circulation (n)	Yes	23	74	0.022	0.882
	No	12	41
Proximal stump morphology (n)	Conical	28	70	4.348	0.114
	Blunt	5	31
	No residual	2	14

LASSO regression analysis

Coefficient paths for the six variables as the penalty term (lambda) increases. The vertical dashed line indicates the optimal lambda (0.021) selected by cross-validation. At this lambda, two variables (excluded) have coefficients shrunk to zero and thus are not visible. The remaining four variables (hypertension, smoking, DTFV, and incompleteanterior circulation) Figure 1A.To reduce multicollinearity, LASSO regression was performed on 6 significant variables (Fig. 1). The optimal λ (0.021) identified 4 variables: hypertension, smoking, DTFV, and incomplete anterior circulation. Coefficients of excluded variables shrink to 0 and thus are not visible in Fig. 1A.

Fig. 1.

LASSO regression analysis

Logistic regression analysis

Multifactorial logistic analysis showed hypertension, smoking, DTFV, and incomplete anterior circulation were independent risk factors (Table 2). Hosmer-Lemeshow test showed good fit (χ²=6.12, p = 0.53).

Table 2.

Logistic regression analysis of recurrent stroke in SNMCAO

Factor	β value	SE	Wald χ²	P value	OR	95% CI
Hypertension	1.322	0.420	9.913	0.002	3.750	1.647–8.538
Smoking	1.405	0.520	7.312	0.007	4.077	1.472–11.291
DTFV	1.173	0.405	8.391	0.004	3.233	1.462–7.151
Incomplete anterior circulation	1.296	0.412	9.891	0.002	3.653	1.629–8.191

Hosmer-Lemeshow test χ²=6.12, p = 0.53 indicating good model fit

Nomogram construction

Based on logistic regression, the prediction model was: Logit(P)=−1.932 + 1.322×Hypertension + 1.405×Smoking + 1.173×DTFV + 1.296×Incomplete anterior circulation.

A nomogram was constructed (Fig. 2) with 4 risk factors, each contributing to the total score predicting recurrence probability.

Fig. 2.

Nomogram for risk prediction of recurrent stroke in SNMCAO

Model validation

ROC curve

The AUC was 0.684 (95% CI: 0.586–0.782), indicating moderate discrimination (Fig. 3).

Fig. 3.

ROC curve of the nomogram model

Calibration and decision curves

Bootstrap validation (1000 iterations) showed good calibration (Brier Score: 0.163, p = 1) (Fig. 4). Decision curve analysis showed positive net benefit (Fig. 5).

Fig. 4.

Calibration curve of the nomogram model

Fig. 5.

Decision curve of the nomogram model

Discussion

Studies have reported that the risk of recurrent stroke in SNMCAO patients within 12 months is 12.5%, characterized by poor prognosis, severe neurological deficits, and high morbidity and mortality [15, 16]. Therefore, clinical attention should be paid to SNMCAO patients, and actively analyzing the relevant factors affecting recurrent stroke is key to taking appropriate preventive measures.

The mRS score is an internationally recognized tool for assessing neurological recovery and disability in stroke patients [17, 18]. Our results indicated that mRS score > 2 was a risk factor for recurrent stroke in SNMCAO. This may be due to neurological deficits in patients with mRS > 2 being mostly caused by large infarcts or damage to key functional areas. Such patients often have poorly compensated collateral circulation, causing brain tissues distal to occlusion to be in chronic hypoperfusion. Bao Q et al. [19] found that patients with mRS > 2 have reduced remodeling capacity of motor cortex, impaired neuroplasticity, and depleted hemodynamic reserve, making micro thrombus more prone to trigger new infarction.

Hypertension emerged as an independent risk factor for recurrence, consistent with previous studies [20, 21]. Long-term hypertension reduces arterial elasticity and compliance, promotes atherosclerosis with intima-media thickening and lumen narrowing. Small arteries undergo hyaline degeneration and fibrinoid necrosis, increasing vascular resistance and decreasing cerebral blood flow [22]. Hypertension damages endothelial cells, activates the coagulation system, and aggravates atherosclerosis, making collateral circulation formation difficult.

Smoking was identified as a significant risk factor, with higher proportion in the recurrent group, similar to findings by Yao Q et al. [23]. Carbon monoxide in tobacco competes with oxygen for hemoglobin binding, decreasing oxygen transport capacity. This tissue hypoxia stimulates oxidative stress, activates coagulation, and promotes atherosclerosis. Nicotine stimulates sympathetic nerves, causing catecholamine release, vasoconstriction, and reduced cerebral blood flow [24, 25]. Smoking also increases fibrinogen levels, promotes platelet aggregation, and reduces high-density lipoprotein content.

Regarding collateral circulation, we analyzed the role of primary pathways and neovascularization in recurrent stroke [26, 27]. DTFV, intraplaque hemorrhage, and incomplete anterior circulation showed significant differences between groups. Incomplete anterior circulation increased recurrence risk 3.65-fold, consistent with previous studies showing 8.92 times higher risk [28]. When the anterior communicating artery is absent, contralateral blood flow cannot efficiently reach ischemic tissue, and cerebral vasoregulation is imperfect [29].

DTFV represents a complex pathological feature not present around normal middle cerebral arteries but seen in symptomatic patients [30]. Our finding that DTFV was a risk factor may seem paradoxical. Some authors speculate that visible DTFV may reflect adaptive but insufficient collateral channels—providing some perfusion compensation but still correlating with recurrence due to inadequate flow. Further longitudinal studies are needed to clarify this relationship.

Intraplaque hemorrhage showed significance in univariate analysis but lost independence after adjustment. Chen L et al. [31] stated that intraplaque hemorrhage increases plaque volume and luminal stenosis. However, because it lost significance after adjustment, it was not included in the nomogram; its prognostic value may be masked by collinearity with lumen status.

The nomogram achieved an AUC of 0.684, indicating moderate discriminatory ability with 95% CI (0.586–0.782) showing reliability. The calibration curve demonstrated good agreement between predicted and actual outcomes. The clinical decision curve showed positive net benefit for risk stratification. Given the modest AUC, the model should be viewed as a screening aid rather than a definitive diagnostic tool.

Although FDR correction was applied, the possibility of residual type I error cannot be excluded. The sample size may affect statistical stability and model reliability. External validation with multi-center cohorts is warranted before clinical deployment. Future work should incorporate perfusion imaging and genetic markers to enhance discrimination.

Conclusion

Hypertension, smoking, DTFV, and incomplete anterior circulation are risk factors for recurrent stroke in SNMCAO. The nomogram provides moderate predictive performance and may assist in early risk stratification.

Author contributions

FX and JJS were involved in the conception and design, or analysis and interpretation of the data; XFW and TM the drafting of the paper, revising it critically for intellectual content; FX and QCD the final approval of the version to be published; and that all authors agree to be accountable for all aspects of the work.

Funding

No funding was received.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics statement

All research is in strict accordance with and adheres to the Declaration of Helsinki.

The study was approved by the Ethics Committee of Baoji Hospital of Traditional Chinese Medicine.

Consent to participate

Not applicable.

Consent for publication

All authors have agreed to publish.All authors have read and approved the final work.

Competing interests

The authors declare no competing interests.