Clinical features and imaging markers of small vessel disease in symptomatic acute subcortical cerebral microinfarcts

doi:10.21203/rs.3.rs-1500799/v1

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Clinical features and imaging markers of small vessel disease in symptomatic acute subcortical cerebral microinfarcts

https://doi.org/10.21203/rs.3.rs-1500799/v1

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Background: Acute cerebral microinfarct (A-CMI) is presumed to be of ischemic origin and can be detected as small diffusion-weighted imaging (DWI) lesions in any parenchymal region of the brain (diameter<5 mm). Since the recent small subcortical infarcts (RSSI) not having a lower size cutoff according to their definition, whether the lesion with size compatible with A-CMI in subcortical area (As-CMI) has distinct clinical and imaging features are largely unknown.

Methods: Patients were selected with a magnetic resonance DWI-confirmed RSSI between January 2010 and November 2020 in a consecutive cohort. We measured axial infarct diameter and classified patients into two groups: As-CMI group (diameter<5mm) versus Larger RSSI group (diameter 5-20mm). Clinical variables, including vascular risk factors, clinical symptoms/signs, lesion locations and radiological markers of cerebral small vessel disease (SVD) on MRI were analyzed between the two groups. Patients were followed up for 12-months and functional outcomes were measured by the modified ranking scale (mRS).

Results: A total of 23 (3.9%) were As-CMI in 584 patients with RSSI. The most common neurological deficits with As-CMI were hemiparalysis (n=20), followed by central facial/lingual palsy (n=10) and hemidysesthesia (n=10). Most As-CMIs were located in the basal ganglia (n=11), followed by the thalamus (n=5) and centrum semiovale (n=4). No different regional distributions and symptoms/signs frequencies were found between the two groups except a lower percentage of dysarthria in As-CMI group (p=0.008). In multivariate analysis, patients with As-CMI were independently associated with lacunes (presence of lacunes and multiple lacunes) (adjusted odds ratio [aOR] 2.88; 95% confidence interval [CI] 1.21-6.84 and aOR 3.5, CI 1.29-9.48) and higher total SVD burden (aOR 1.68, CI 1.11-2.53). Patients with As-CMI did not show a better functional outcome after 12-months of follow-up.

Conclusions: Patients with As-CMI had non-specific clinical profile but a higher burden of SVD, indicating As-CMI might be s sign of more severe small vascular injury. Whether its vascular features are associated with worse cognitive outcomes requires further investigation.

microinfarcts

recent small subcortical infarcts

small vessel disease

acute lacunar stroke

DWI

outcomes

Cerebral microinfarcts (CMIs) are small lesions presumed to be of ischemic origin [1]. The lesions, small and often not visible to the naked eyes on autopsy, have been found incidentally in older individuals with cognitive impairment or other manifestations of cerebrovascular disease, indicating damage to brain structure and a poor clinical outcome[2, 3].

CMIs in the acute stage can be detected as small incidental diffusion-weighted imaging (DWI) lesions. DWI has been verified with high sensitivity in detecting very small infarcts, including those 1–2 mm in diameters in any brain parenchymal location[4]. Due to the blooming effects, the maximum diameter on acute DWI might overestimate the true infarct size [5]. The defined diameter of acute CMI varied among investigators, from a few mm to ≤ 10mm[6]. The majority of studies on incidental small DWI lesions did not report their actual size, and usually adopt a cut off with axial diameter less than 5mm instead[7, 8]. Based on available evidence, experts propose a size criterion of less than 5 mm for an acute cerebral microinfarct (A-CMI) [1]. However, confusion arises when diagnosing small DWI lesion in subcortical area of ischemic stroke patients. If perforating arterioles are affected, it will cause RSSI, formerly termed ‘acute lacunar stroke’. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria for RSSI applied an upper size cutoff of 20 mm, a criterion designed to identify lacunar infarcts in their acute stage, without providing a lower size cutoff [9]. Due to the definition of recent small subcortical infarct (RSSI) that includes the lesion size of acute subcortical cerebral microinfarcts (As-CMI), whether DWI lesions compatible with As-CMI could be distinguished from larger size of RSSI in the aspect of clinical and imaging features is unclear.

In vivo detection, imaging characteristics of small DWI hyperintense lesions have been reported in patients with cerebral amyloid angiopathy, stroke or memory loss [10–14]. These studies indicated it was associated with SVD MRI markers, such as white matter hyperintensities, cerebral microbleeds and enlarged perivascular spaces, but the association between different sizes of small subcortical DWI lesions and SVD neuroimaging markers has not been thoroughly investigated. In addition, data from autopsy or DWI-based studies reported that the clinical symptom most clearly related to multiple microinfarcts was cognitive dysfunction. In subcortical area, the acute microinfarct could act as lacunar stroke syndrome, but whether it has similar symptoms/signs distribution compared to larger RSSI was rarely known. Better understanding of the varied clinical features of As-CMI and larger RSSI could extend an emerging literature from previous studies and provide further evidence concerning the diagnostic classification of acute SVD.

Hence, we aimed to clarify the distinct characteristics of acute subcortical cerebral infarcts (As-CMI) as compared to larger size of RSSI regarding vascular risk factors, clinical manifestation, radiological markers of SVD distribution and outcomes.

We declare that all supporting data are available within the article and in the Data Supplement.

Patients

A total of 7536 patients with acute ischemic stroke were consecutively recruited from the Chengdu stroke registry between January 2010 and November 2020. Among them, 584 patients with symptomatic magnetic resonance DWI-confirmed recent small subcortical infarcts of ≤20 mm in axial diameter were included in the final analysis. The patients’ selection process was shown in Figure 1. Details of inclusion/exclusion criteria and data collection are described in the Data Supplement.

Patients were followed-up through telephone interview at 3 and 12-months after ischemic stroke. Functional outcome was measured by modified Ranking scale (mRS) score[15].

The study was approved by the Medical Ethics Committee of West China Hospital, Sichuan University. The ethical principles involved in this research were strictly in accordance with the “Declaration of Helsinki”. The requirement for written informed consent was waived by the Medical Ethics Committee of West China Hospital, Sichuan University because of the retrospective study design.

Neuroimaging

MRI was performed according to a standardized protocol as part of routine clinical assessments. Imaging was performed on a 3-T MR scanner with an acquisition that consisted of T1 and T2-weighted, fluid-attenuated inversion recovery (FLAIR), axial trace DWI with b-values of 0 and 1,000, and apparent diffusion coefficient (ADC) sequences. The MRI parameters were described in Data Supplement.

Assessment of As-CMI and Larger RSSI in RSSI patients

Two experienced raters blinded to demographic and clinical data independently reviewed the MRI studies to identify RSSI on MRI. RSSI was defined as hyperintense lesions on DWI in regions supplied by a penetrating artery, with a corresponding reduced diffusivity on ADC maps in subcortical area, with a diameter≤20 mm on axial sections. Of note, according to the proposed detection criteria for As-CMI [1], a few very small DWI lesions had a corresponding isointense signal in ADC at the same location. Subcortical lesion location was classified into four regions (basal ganglia, centrum semiovale, thalamus, and pons). We measured axial infarct diameter and classified infarcts as As-CMI group (0<diameter<5mm, shown in Figure 2) and Larger RSSI group (5mm≤diameter ≤20 mm) . Larger RSSI subjects were further divided into median-size (5mm≤diameter <15mm) and large-size (15mm≤diameter≤20mm) subgroups.

Assessment of SVD MRI markers

Lacunes, white matter hyperintensity (WMH) and enlarged perivascular spaces (EPVS) in basal ganglia (BG) and centrum semiovale (CSO)were rated according to the STRIVE consensus criteria [9]. Details of image evaluation are available in the Data Supplement.

Data analysis

Continuous variables expressed as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. Comparison between the groups was performed using a chi-squared test or Fisher exact test for categorical variables, and independent sample t-test or Mann-Whitney U test for continuous variables, as appropriate. Binary logistic regression methods were used to analyze the odds (with 95% confidence interval) of As-CMI and SVD imaging markers. In supplementary analysis, when larger RSSI group was divided into large-size and medium-size subgroups, multinomial logistic regression were used to test the association between As-CMI and SVD imaging markers. All p values were two sided and values <0.05 were considered statistically significant. All analyzes were performed using SPSS (version 23, SPSS Inc).

Of the 584 patients finally included, 23(3.9%) were defined as As-CMI. Five patients in Larger RSSI group had multiple DWI small lesions.

Demographic and vascular risk factors in patients of As-CMIs and Larger RSSI

The mean age of patients in the study population was 62.2 (SD12.4) years and 71.9% were male. A higher frequency of a history of coronary artery disease was observed in the As-CMI subjects (p = 0.020). However, no significant differences were seen in other demographic or vascular risk factors between patients of As-CMI compared to Larger RSSI (Table 1).

Table 1

Demographics and vascular risk factors between acute subcortical cerebral microinfarcts (As-CMI) and Larger RSSI subjects
Characteristics	As-CMI, n = 23	Larger RSSI, n = 561	P value
Age,yr	67.2 ± 13.0	62.0 ± 12.4	0.050
Male	15(65.2)	405(72.2)	0.466
Interval between stroke onset to imaging scanning			0.590
< 24hrs	1(4.3)	9(1.6)
1-7days	19(82.6)	467 (83.2)
8-14days	3(13.0)	85(15.2)
Prestroke mRS 0–1, n (%)	20(87.0)	542(96.6)	0.068
NIHSS at admission	2(1–4)	3(2–5)	0.080
SBP (mmHg)	161.2 ± 21.7	160.1 ± 22.6	0.826
DBP (mmHg)	91.5 ± 14.5	93.9 ± 15.4	0.462
Vascular risk factors
Hypertension	17(73.9)	407(72.5)	0.886
Diabetes Mellitus	8(34.8)	206(36.7)	0.850
Hyperlipidemia	5(21.7)	206(36.7)	0.143
Coronary artery disease	4(17.4)	24(4.3)	0.020
Previous ischemic stroke	5(21.7)	51(9.1)	0.059
Current drinking	4(17.4)	158(28.2)	0.258
Current smoking	8(34.8)	225(40.2)	0.605
Data are n (%), mean (SD) or median (IQR)
Abbreviation: mRS, modified ranking scale, NIHSS, national institutes of health stroke scale; SBP, systolic blood pressure; DBP, diastolic blood pressure;

Clinical manifestations and lesion location in patients of As-CMI and Larger RSSI

In As-CMI patients, hemiparalysis (n = 20) was the most common neurological deficit, followed by central facial/lingual palsy (n = 10) and hemidysesthesia (n = 10). Most As-CMI lesions were in the basal ganglia (n = 11), followed by the thalamus (n = 5) and centrum semiovale (n = 4). Patients with As-CMI and Larger RSSI did not differ with respect to clinical manifestations and lesion location generally, except for a lower percentage of dysarthria in the As-CMI (p = 0.008) (Fig. 3 and Table S1).

SVD neuroimaging markers in patients of As-CMI and Larger RSSI

After adjusting for age, sex, coronary artery disease, As-CMI was associated with lacunes (presence of lacunes and multiple lacunes) (odds ratio [OR] 2.88; 95% confidence interval [CI] 1.21–6.84 and OR 3.5, CI 1.29–9.48) and higher total SVD burden (OR 1.68, CI 1.11–2.53). No association was found between As-CMI and the severity of WMH and BG-EPVS or CSO-EPVS (Table 2).

Table 2: Neuroimaging markers of SVD in acute subcortical cerebral microinfarcts (As-CMI) and Non As-CMI subjects

	As-CMI, n=23	Larger RSSI, n=561	Fully-adjusted* OR(95%CI)	P value
Lacunes	14(60.9)	188(33.5)	2.88(1.21-6.84)	0.016
Lacunes number				0.039
0	9(39.1)	373(66.5)	Reference
1	6(26.1)	102(18.2)	2.34(0.81-6.79)	0.115
>1	8(34.8)	86(15.3)	3.50(1.29-9.48)	0.013
The severity of WMH				0.060
0-2	11(47.8)	310(55.3)	Reference
3-4	3(13.0)	154(27.5)	0.52(0.14-1.90)	0.323
5-6	9(39.1)	97(17.3)	2.29(0.90-5.80)	0.081
The severity of EPVS in BG				0.391
≤10	5(21.7)	227(40.5)	Reference
11-20	13(56.5)	220(39.2)	2.07(0.68-6.28)	0.198
>20	5(21.7))	114(20.3)	1.38(0.34-5.59)	0.645
The severity of EPVS in CSO				0.559
≤10	4(17.4)	76(13.5)	Reference
11-20	10(43.5)	287(51.2)	0.51(0.14-1.75)	0.285
>20	9(39.1)	198(35.3)	0.56(0.15-2.05)	0.383
Total CVSD Burden	2(1-3)	1 (0-2)	1.68(1.11-2.53)	0.013

Abbreviation: SVD, cerebral small vessel disease; WMH, white matter hyperintensity; EPVS, enlarged perivascular spaces; BG: basal ganglia; CSO, centrum semiovale.

*Adjusted for age, sex, coronary artery disease.

Follow-up

Data for 3-month and 1-year follow-up were obtained from 526 of 584 (90.0%) and 513 of 584(87.8%) eligible patients. The As-CMI group did not show a better functional outcome at 3-months follow-up (median mRS 1.0 vs.1.0; p = 0.924) and 12-months (median mRS 0 vs.1.0; p = 0.791). Twenty patients (86.9%) in the As-CMI subjects completed 3 and 12-months follow-up, of whom 8 patients (40%) had an improvement, 11 unaltered and 1 unfavorable shift in mRS score, which were comparable to Larger RSSI subjects (p = 0.820) (Table 3).

Table 3

Follow-up for acute subcortical cerebral microinfarcts (As-CMI) and Larger RSSI subjects
	As-CMI	Larger RSSI	P value
3-months follow-up, n(%)	506(90.1)	20(86.9)
mRS score, median(IQR)	1(0–2)	1(1–2)	0.924
12-months follow-up, n(%)	492(87.7)	21(91.3)
mRS score, median(IQR)	0(0-1.5)	1(0–1)	0.791
mRS shifts more than 1 point after12-months follow-up, n(%)	484(86.2)	20(86.9)	0.820
Favorable, n(%)	161(33.3)	8(40.0)
Unaltered, n(%)	294(60.7)	11(55.0)
Unfavoable, n(%)	29(6.0)	1(5.0)

Subgroup Analyses

As shown in table S2-5, clinical profile and SVD imaging markers were assessed among As-CMI and two subgroups (medium-size and large-size) of Larger RSSI subjects. The results of univariate analysis were similar to the main analysis, except for a lower NIHSS score on admission, but higher percentage of prestroke mRS > 1 and history of previous ischemic stroke in As-CMI group compared to large-size subjects (all p < 0.05)(Table S2). In the multivariate analysis, adjusted for confounding factors, the association between As-CMI and lacunes (presence of lacunes and multiple lacunes) remained unvaried. Furthermore, As-CMI was still associated with a higher total SVD burden (OR 1.85, CI 1.11–3.08, large-size subgroup as reference) (Table S5).

To the best of our knowledge, the present study is the first to examine As-CMI in a large series of consecutive patients in whom DWI has also shown RSSI. In our current study, we found As-CMI was identified in 3.9% of RSSI patients. We found a similar distribution among risk factors, common symptoms/signs as well as lesion location. Second, we assessed the association between As-CMI and SVD markers, and observed that the As-CMI was associated with lacunes and a higher total SVD burden. Third, we demonstrated that the As-CMI subjects did not have a better functional outcome compared to the Larger RSSI subjects. These findings emphasize the fact that although As-CMI has a smaller lesion size than RSSI, the clinical features and outcome were similar. Given the small size of As-CMI patients, consideration was given to further divide the larger RSSI group into medium-size and large-size subgroups with 15mm as a lesion size cutoff. After subgroup comparisons, we found similar results compared to main findings.

In our series, dichotomization of RSSI according to the axial diameter (༜/≥5 mm) did not result in quite different regional distributions and symptoms/signs frequencies. In patients with symptomatic As-CMI, nearly half of the lesions were located in the basal ganglia, followed by the thalamus, centrum semiovale (CSO) and brainstem. In addition, hemiparalysis was the most common neurological deficits, followed by central facial/lingual palsy and hemidysesthesia. These are common symptoms in acute lacunar stroke according to the widely used OCSP classification[16]. In other words, the clinical symptoms/signs poorly discriminate the size of subcortical infarcts. Our finding showed that even the small lesion size of As-CMI could cause overt neurological symptoms. Noticeably, As-CMI could also contribute to other low frequency symptoms such as dysphagia, aphasia or ataxia.

Another novel finding was the association between subcortical As-CMI and the presence of multiple lacunes and a high total SVD burden. Previous studies reported a higher SVD burden in patients with RSSI or As-CMI who presented with possible vascular cognitive impairment [7, 17]. However, the relation between RSSI size and SVD burden was not explored. As-CMI located in the white matter mostly occur in relationship to distal branches of perforating arteries[18]. The increased frequency of lacunes and SVD burden in As-CMI showed that As-CMI might be a significant sign for active small vessel disease. The anatomical and hemodynamic characteristics of these smaller and distal branches of medullary or lenticulostriate arteries may partly explain an increased vulnerability of these territories to hypoperfusion injury and other pathophysiological mechanisms such as arteriosclerosis, endothelial injury or blood brain barrier dysfunction[18, 19].

In long-term follow up, our data did not show that As-CMI patients had a better functional outcome and recovery. The mRS score we applied is good at measuring the degree of disability or dependence in the daily activities of patients after stroke. However, the majority of lacunar infarcts would cause minor stroke related deficits. Among lacunar stroke, the mRS might not be a subtle tool to evaluate the degree of rehabilitation. A previous study indicated brain frailty was associated with worse cognitive score with a stronger effect in lacunar stroke [20]. As-CMI was found to increase odds of lacunes and SVD burden, implying a correlation with worse cognitive outcome that merits further investigation.

Our study has several strengths such as the large hospital-based sample with MR-DWI, comprehensive evaluation of clinical symptoms/signs, and the assessment of SVD markers and outcomes. However, we would like to acknowledge some limitations. First, there is an ongoing discussion on whether different RSSI lesion sizes are associated with a distinct etiology. Thus, the present study excluded patients with potential embolic sources or undetermined causative mechanisms in order to focus on small vessel arteriopathy. Second, cerebral microbleeds were not included in the total SVD burden evaluation since a large proportion of patients did not undergo gradient-echo T2*-weighted imaging. Third, because of its retrospective nature, we cannot avoid selection bias. Also the number of As-CMI is relatively small.

In conclusion, we add to the increasing body of evidence that patients with As-CMI had non-specific clinical profile but a higher burden of SVD, indicating As-CMI might be s sign of more severe small vascular injury. Whether its vascular features are associated with worse cognitive outcomes requires further investigation.

As-CMI: acute subcortical microinfarct; RSSI: recent small subcortical infarcts; DWI: diffusion-weighted imaging; STRIVE: The STandards for ReportIng Vascular changes on nEuroimaging; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; ADC: apparent diffusion coefficient; WMH: white matter hyperintensity; EPVS: enlarged perivascular spaces; BG: basal ganglia; CSO: centrum semiovale; mRS: modified Ranking scale.

Ethics approval and consent to participate

All authors consented to and approved this manuscript. All methods in this study were carried out in accordance with relevant guidelines and regulations. This study strictly followed the ethical principles set out in the “Declaration of Helsinki”. The study protocol was approved by the Medical Ethics Committee of West China Hospital, Sichuan University [2014(69)]. The requirement for written informed consent was waived by the Medical Ethics Committee of West China Hospital, Sichuan University because of the retrospective study design.

Consent for publication

Not applicable.

Availability of data and materials

Original data to support the results of this study are not publicly available due to privacy reasons of patients, but are available from the corresponding author on reasonable request.

Competing interests

There are no competing interests.

Funding

This work was funded by The National Natural Science Foundation of China (Grant No.81601022), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18009) and the National Key Research and Development Program of China of the Ministry of Science and Technology of China (2016YFC1300500-505).

Authors’ Contributions

WD T and YJ C contributed equally to this study. WD T: study concept, data analysis, statistics, and writing the paper. YJ C: patient recruitment and imaging data analysis. W G: imaging data analysis. WR K: study protocol design. C Y and B W: imaging data interpretation and guidance: ST Z: patient recruitment and study protocol development. M L: study concept and guidance. All authors reviewed and approved the manuscript.

Acknowledgements

We appreciate for all the patients participating in our study. We are thankful to Prof.Marc Fisher for his linguistic assistance during the preparation of this manuscript.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

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Clinical features and imaging markers of small vessel disease in symptomatic acute subcortical cerebral microinfarcts

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Abstract

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Introduction

Methods

Results

Demographic and vascular risk factors in patients of As-CMIs and Larger RSSI

Clinical manifestations and lesion location in patients of As-CMI and Larger RSSI

SVD neuroimaging markers in patients of As-CMI and Larger RSSI

Follow-up

Discussion

Abbreviations

Declarations

References

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Supplementary Files

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