Effect of coincidence of severe extracranial and intracranial artery stenosis or occlusion on cerebral small vessel disease

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Effect of coincidence of severe extracranial and intracranial artery stenosis or occlusion on cerebral small vessel disease

https://doi.org/10.21203/rs.3.rs-4825369/v1

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Objective: There was a significant correlation between the large atherosclerotic extracranial artery stenosis (ECAS) or intracranial artery stenosis (ICAS) and the neuroimaging markers of cerebral small vessel disease (CSVD). Our objective was to investigate the effect of coexistence of severe extracranial and intracranial arterial stenosis or occlusion on CSVD in patients with ischemic stroke.

Methods: A total of 222 patients with LAA infarction with CSVD were included in this retrospective study, including 160 males and 62 females. All enrolled patients were divided into four groups: ECAS, ECAS+ICAS, ICAS and None. The differences between the four groups were evaluated by total CSVD scores, total Fazekas scores, periventricular WMH Fazekas scores and deep WMH Fazekas scores.

Results: There were significant differences between the four groups in terms of total CSVD scores (P< 0.05). But there was no significant difference in the total Fazekas scores, periventricular WMH Fazekas scores and deep WMH Fazekas scores. Further pairwise comparison shows that only the ECAS+ICAS group and the none group had a significant difference in total CSVD scores (P < 0.05).

Conclusion: The coincidence of severe stenosis or occlusion of the extracranial and intracranial artery may increase the incidence of CSVD and aggravate the performance of CSVD in patients with ischemic stroke and mainly reflected in the total CSVD scores. If ECAS and/or ICAS are found in patients, the total CSVD burden should be also actively assessed. To reduce the incidence of stroke and improve outcomes, active clinical intervention should be undertaken for these patients.

Severe extracranial or intracranial artery stenosis

Occlusion

Large atherosclerotic cerebral infarction

Total cerebral small vessel disease scores

Fazekas scores

Cerebral small vessel disease (CSVD) is recognized as a risk factor for stroke and dementia. Atherosclerotic extracranial or intracranial artery stenosis or occlusion is a crucial cause and pathology of ischemic stroke. The evaluation of CSVD mainly depends on MRI image features. With the advancement of MRI technology, especially with the support of high-field MRI technology, more subtle abnormal changes in brain tissue related to CSVD injury can be revealed. These neuroimaging markers have been found in many studies to be associated with the prognosis of LAA stroke ^[2].

Imaging findings of CSVD are generally considered to include lacunae, new subcortical infarction, blood-derived white matter lesions (WML), enlarged perivascular space (EPVS), cerebral microbleeds (CMBs) and cerebral atrophy ^[3]. Extracranial artery stenosis (ECAS) and intracranial artery stenosis (ICAS) have been showed to be associated with the development of CSVD and usually share common vascular risk factors such as hypertension and aging ^[4–6], both of these common risk factors affect the outcome of stroke. Previous studies have found that ICAS was associated with lacunes, increased white matter hyperintensities volume and brain atrophy ^[6]. Other studies have suggested that ICAS may be associated with arteriolar lesions, radiographically manifested as white matter lesions or small chronic infarcts, which are pathologically defined as CSVD ^[7]. Xue-yang Wang ^[8] et al. also founded that severe centrum semiovale perivascular space (CS-PVS) and lacunes were associated with severe stenosis of intracranial large artery disease. In recent years, many studies have explored the relationship between ECAS and total CSVD score or different imaging markers of CSVD from different perspectives. Ultrasound evidence recently described by Lu et al. suggests that severe ECAS in patients with ischemic stroke suspected to have originating in small or large arteries is associated with the presence of concurrent progressive CSVD ^[9]. Müjdat Deniz Benli et al. founded that compared with the 50–69% ICA stenosis group, the number of patients with silent brain infarcts (SBIs) and the number of SBIs in the ipsilateral hemisphere were higher in stenosis ≥ 70% group ^[10]. Another study showed that patients with severe ECAS or occlusion had a significantly higher total CSVD score than those without ^[11].

However, the effect of extracranial or intracranial vascular stenosis, especially coincidence of severe extracranial and intracranial arterial stenosis or occlusion on CSVD in patients with ischemic stroke has yet to be addressed. Therefore, in the present study, we divided four groups according to the presence or absence of severe intracranial or extracranial arterial stenosis to investigate their influence on CSVD.

Recruitment period

This study was designed as a retrospective study and was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University. The ethics review number is KY 2021-039-01. All participants provided signed and informed consent. We enrolled patients between April 1, 2021 and November 1, 2023.

Study Population

We collected clinical data from 222 patients in our rehabilitation department for analysis.

Inclusion criteria

① Aged between 50 and 80 years;

② According to the TOAST classification scheme, the patients were diagnosed as ischemic stroke caused by atherosclerosis of the large arteries ^[1];

③ Patients with onset within 2 to 4 weeks when admission;

④ All patients signed informed consent when admission.

Exclusion criteria

① Cardiogenic embolism, arteriole occlusion, et al. other types of TOAST etiological classification scheme were not included;

② Patients with leukoencephalopathy due to multiple sclerosis, genetic diseases, Alzheimer's disease (AD) and other factors were excluded;

③ Patients who were unable to provide all sequences of head MRIs were also excluded.

Imaging Assessment

All enrolled patients underwent brain MRIs before admission. The patient's bilateral ECASs were assessed by color Doppler ultrasonography, including the common carotid arteries, the extracranial internal carotid arteries and the proximal vertebral arteries (ostium, V2-3). Bilateral ICASs were assessed by MR Angiography or CT angiography, including the middle cerebral arteries, anterior cerebral arteries, posterior cerebral arteries and distal vertebral arteries (segment V4).

We used the total CSVD score and the Fazekas score to evaluate the CSVD burden. As there are some differences between periventricular WMH and deep WMH, we further evaluated the Fazekas scores of periventricular WMH and deep WMH respectively in this study.

Assessment of Total CSVD Score

It mainly included lacunes, EPVS, CMBs and WML scores. The score ranges from 0 to 4, and higher scores indicated more severe CSVD ^[12]. The scoring method involved several aspects: (1) Lacunae: 1 point was given when 1 or more asymptomatic lacunes were present. (2) CMBs: 1 point was awarded when there is 1 or more microbleeds. (3) EPVS: based on the number of EPVS in the basal ganglia, a semi-quantitative scale from 0 to 4 points is used: grade 0, no EPVS; grade 1, 10 or fewer EPVS; grade 2, 11–20 EPVS; grade 3, 21–40 EPVS; grade 4, more than 40 EPVS. 1 point is given for moderate to severe EPVS (grade 2–4) ^[13]. (4): WML: WMLs are graded according to the Fazekas scale. 1 point is awarded for a Fazekas score of 3 for periventricular white matter lesions (irregular hyperintensities extending into deep white matter) and/or a Fazekas score of 2 or 3 for deep WMLs (confluent WMH) ^[14].

The Fazekas Scale (0–6)

The Fazekas score ranges from 0 to 6 and is the sum of scores for periventricular and deep WMLs. Periventricular hyperintensity scores: 0 indicates no obvious white matter change; 1 indicates that WMLs are cap-like or pencil-like thin-layer lesions; 2 refers to a smooth halo; and 3 indicates that the irregular periventricular hyperintensities extended into the deep WM. Deep WM scores: 0 indicates no obvious WML; 1 indicates punctate WML; 2 indicates the fusion of WMLs; and 3 indicates large lesion fusion ^[14].

In the North American Symptomatic Carotid Endarterectomy (NASCET) criteria ^[15], vascular stenosis was classified into the following five grades: no stenosis, mild stenosis (less than 30%), moderate stenosis (30%-69%), severe stenosis (70%-99%), or occlusive (100%).

Grouping

The study design was showed in Fig. 1 and we performed several different comparisons as following:

First, we compared total CSVD scores, total Fazekas scores and Fazekas scores of periventricular WMH and deep WMH respectively between the four groups (including ECAS, ECAS + ICAS, ICAS and None).

Next, we made further pairwise comparison between ECAS and ECAS + ICAS, ECAS and ICAS, ECAS and None, ECAS + ICAS and ICAS, ECAS + ICAS and None, ICAS and None for total CSVD scores.

Statistical Analysis

We compared baseline factors (including age, sex, the history of hypertension, diabetes and stroke) between patients of group ECAS, group ECAS + ICAS, group ICAS and group None. The comparison of age was performed with t test; other comparisons were performed with Fisher’s exact test (for percentages). Statistical analysis and graphing were performed by GraphPad Prism 8.0 (GraphPad Software, Inc., San Diego, California, USA). All data in this study basically conform to normal distribution, and continuous variables such as age are expressed as mean ± standard deviation; independent sample t test was applied for comparison between groups. A P value < 0.05 was considered statistically significant.

In all the 222 patients with LAA cerebral infarctions, 160 were males and 62 were females. 35 patients had severe ECAS or occlusion, 28 patients had both severe extracranial and intracranial arterial stenosis or occlusion, 39 patients had severe ICAS or occlusion and 120 patients didn’t have any severe extracranial or intracranial arterial stenosis or occlusion. Among the four groups (ECAS, ECAS+ICAS, ICAS and None), there was no significant differences in terms of age, gender, the history of hypertension, diabetes or stroke (P > 0.05) (Table 1).

1. Total CSVD scores，total Fazekas scores, periventricular WMH Fazekas scores

and deep WMH Fazekas scores between the four groups. We found significant difference between the four groups in terms of total CSVD scores (P = 0.048, Figure 2A); but there was no significant difference in the total Fazekas scores, periventricular WMH Fazekas scores and deep WMH Fazekas scores.

2. Pairwise comparisons between the groups (including ECAS and ECAS+ICAS,

ECAS and ICAS, ECAS and NONE, ECAS+ICAS and ICAS, ECAS+ICAS and NONE, ICAS and NONE). Further pairwise comparison shows that only the ECAS+ICAS and NONE group had a significant difference in total CSVD scores (P =0.026, Figure 3E).

In our study, we found that there were significant differences between the four groups (including ECAS, ECAS+ICAS, ICAS and None) in terms of total CSVD scores. But no significant difference in the total Fazekas scores, periventricular WMH Fazekas scores and deep WMH Fazekas scores were found. The main results of the present study show that with severe stenosis or occlusion of extracranial or intracranial artery can promote the occurrence and development of CSVD and mainly reflected in the total CSVD score rather than total Fazekas scores, periventricular WMH Fazekas scores and deep WMH Fazekas scores. Further pairwise comparison shows that only the ECAS+ICAS group and the none group had a significant difference in total CSVD scores. But there was no significant difference in group ECAS and ECAS+ICAS, ECAS and ICAS, ECAS and None, ECAS+ICAS and ICAS, and also, ICAS and None.

The imaging hallmarks of CSVD include lacunae, small new subcortical infarcts, WML, EPVS, CMBs and brain atrophy ^[16]. Staals et al. proposed that total CSVD scores is more powerful and persuasive in assessing the overall impact of CSVD on brain function than a single imaging phenotype ^[12]. Many studies explored the relationships between total CSVD scores and clinics. Total CSVD scores were found to be independently associated with cognitive impairment in patients with CSVD ^[17]. Xuanting Li et al. ^[18] also found that total CSVD scores was associated with the overall cognitive impairment among middle-aged and elderly Chinese adults. In a study, total CSVD scores were also shown to be independently associated with clinical outcomes in patients with acute ischemic stroke (AIS) treated with intra-arterial thrombectomy (IAT), and a higher total CSVD score may be a reliable predictor of poor outcomes in AIS patients treated with IAT ^[19]. It appears that ECAS or/and ICAS may affect stroke outcomes by affecting CSVD. Based on some previous studies on the relationships between ECAS or/and ICAS and CSVD, in our study, severe intracranial or/and extracranial arterial stenosis or occlusion was shown to be more associated with total CSVD scores than the Fazekas scores (including total Fazekas scores, periventricular WMH Fazekas scores and deep WMH Fazekas scores). WML is the most common manifestation compared with other hallmarks of CSVD such as lacunae, small new subcortical infarcts, EPVS and CMBs. Many studies confirmed the relationship between extracranial or/and intracranial arterial stenosis and WMH ^[20,21]. However, in our study, we didn’t find any significant difference in the Fazekas scores between the four groups. This may be because ECAS or/and ICAS are more likely to cause varying degrees of brain function impairment by affecting multiple CSVD imaging phenotypes, rather than just white matter damage.

Further pairwise comparisons were made for exploring the relationship between severe extracranial or/and intracranial arterial stenosis or occlusion and CSVD. It showed that only the ECAS+ICAS group had higher total CSVD scores than NONE group. There was no significant difference between other groups (ECAS and ECAS+ICAS, ECAS and ICAS, ECAS and NONE, ECAS+ICAS and ICAS, ECAS+ICAS and NONE, ICAS and NONE), however. We speculated that this may be because both severe extracranial and intracranial arterial stenosis or occlusion have contributed to the occurrence and development of CSVD in various degrees. Compared with group NONE, the coexistence of severe extracranial and intracranial arterial stenosis or occlusion might lead to more severe CSVD burden. This result is consistent with previous studies. For example, Lu et al. found that high levels of ECAS were associated with coexisting advanced CSVD in ischemic stroke patients ^[9]. Wang et al. concluded that in multivariate analysis of their study, severe centrum semiovale centrum semiovale PVS and lacunes were associated with severe stenosis of intracranial large artery disease ^[8]. CSVD has a significant effect on the occurrence, development, prognosis and recurrence of LAA cerebral infarction. Clinically, active, appropriate and effective intervention for extracranial and/or intracranial arterial stenosis may help to reduce or prevent the occurrence and progression of CSVD, and further reduce the adverse effects of CSVD on brain function.

However, our study still has some limitations that need to be addressed. First, we performed a retrospective analysis of 222 patients with ischemic stroke. But the occurrence and development of CSVD are long-term and chronic. Many factors may affect the development and change of CSVD. As a cross-sectional or baseline analysis alone, it may not provide the most accurate description of the relationship between ECAS or/and ICAS and CSVD. Thus, longitudinal follow-up in the future should be involved. Second, few of the enrolled patient received active intravascular intervention. We speculate that the severity of CSVD will improve in the future after appropriate ECAS and/or ICAS intervention. In fact, given that severe extracranial or intracranial arterial stenosis or occlusion may increase the incidence of CSVD or exacerbate the presentation of CSVD, active intravascular intervention of ECAS and/or ICAS in such patients may be beneficial for the improvement of overall brain function. Third, severe stenosis or occlusion of the extracranial or intracranial artery may be closely related to a specific phenotype of CSVD. However, this study only focused on the total CSVD scores and the Fazekas scores, which only represents white matter lesions. The influence of ECAS or/and ICAS on other phenotypes of CSVD should also be concerned in the future.

In conclusion, the coexistence of severe stenosis or occlusion of the extracranial and intracranial artery may increase the incidence or exacerbate the presentation of CSVD in patients with LAA cerebral infarction. active intravascular intervention of ECAS and/or ICAS in such patients may be beneficial for the improvement of overall brain function. If ECAS and/or ICAS are found in patients, the total CSVD burden should be also actively assessed. Intervention at the early stage of CSVD may have an important impact on stroke treatment, prognosis and recurrence, and may also reduce morbidity and mortality, especially for patients with both severe extracranial and intracranial arterial stenosis or occlusion.

ECAS extracranial artery stenosis

ICAS intracranial artery stenosis

CSVD cerebral small vessel disease

WML blood-derived white matter lesions

EPVS enlarged perivascular space

CMBs cerebral microbleeds

CS-PVS centrum semiovale perivascular space

SBIs silent brain infarcts

AD Alzheimer's disease

NASCET North American Symptomatic Carotid Endarterectomy

Ethical statement and consent to participate

This research was conducted in agreement with the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University. All participants provided signed and informed consent. The ethics review number is KY 2021-039-01. The informed consent was obtained from all subjects and/or their legal guardian(s) for minor and uneducated participants.

Consent for publication

Not applicable

Availability of data and materials

The data that support the findings of this study are available from the corresponding author.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This research was supported by the National Natural Science Foundation of China (grant number: 82072532).

Acknowledgment

The authors wish to thank their colleagues for mentorship, help and guidance in experimental design.

Author contributions

Pei Dai: Conceptualization, Methodology, Formal analysis, Data Curation, Writing - Original Draft; Ya-na Fang: Formal analysis; Hui-xian Yu: Methodology; Zhao-xia Wang: Methodology, Data Curation; Si-hao Liu: Data Curation; Da-wei Zang: Writing-Review & Editing, supervision, funding. All authors read and approved the final manuscript.

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Table 1 Patient comparisons

Group	Age（±𝑠）	Sex（n）		Hypertension（n）		Diabetes（n）		Stroke（n）
		M	F	Yes	No	Yes	No	Yes	No
ECAS	62.80±9.83	28	7	28	7	20	15	10	25
ECAS+ICAS	65.07±8.76	24	4	22	6	17	11	4	24
ICAS	62.92±8.50	30	9	32	7	25	14	14	25
NONE	62.17±9.74	78	42	98	22	52	68	27	93

ECAS, extracranial arterial stenosis; ICAS, intracranial artery stenosis; M, male, F, female.

P＞0.05

No competing interests reported.

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Effect of coincidence of severe extracranial and intracranial artery stenosis or occlusion on cerebral small vessel disease

Status:

Version 1

Abstract

Figures

INTRODUCTION

MATERIALS AND METHODS

Recruitment period

Study Population

Imaging Assessment

Assessment of Total CSVD Score

The Fazekas Scale (0–6)

Grouping

Statistical Analysis

RESULTS

DISCUSSION

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

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