Association between cerebral small vessel disease burden and early neurological deterioration in isolated pontine infarction

doi:10.21203/rs.3.rs-4127758/v1

Objective

To investigate the association between cerebral small vessel disease burden and early neurological deterioration (END) in stroke patients with isolated pontine infarction.

Methods

A total of 107 acute isolated pontine infarct patients within 24 hours of symptoms onset were included from a comprehensive stroke center, the mean age is 67 years old. Cerebral small vessel disease burden on brain MRI including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMB), and enlarged perivascular spaces (EPVS) were evaluated in each patient. END was defined as an increase of ≥ 1 point on the motor National Institutes of Health Stroke Scale (NIHSS) or ≥ 2 points on the total NIHSS score within 72 hours from admission. T-test, chi-square test, and logistic regression were used for statistical analysis.

Results

33.6% (36/107) of them occurred END. Patients in the END group have a higher percentage of hyperlipidemia (66.7% vs. 43.7%, p = 0.024). over 50% of infarction mechanism can be attributed to basilar artery branch disease in both groups (58.3% in the END group and 50.7% in the non-END group). In multivariate regression, neither cerebral small vessel disease total burden nor WMH, CMB, lacunes, and EPVS were associated with END (all P >0.05). Basilar artery intraplaque hemorrhage on vessel wall imaging is associated with END independently (OR = 3.233, 95% CI 1.032–10.123, p = 0.044).

Conclusion

Neither cerebral small vessel disease burden nor its individual imaging features were associated with END in isolated pontine infarction patients. Basilar artery intraplaque hemorrhage is an independent predictor of END in this population.

ischemic stroke

isolated pontine infarction

early neurological deterioration

cerebral small vessel disease

Isolated pontine infarction is the most common types of posterior circulation stroke, and about 1/3 of them occur early neurological deterioration (END)(1), patients with END usually have a poor outcome(2). The predefined mechanism of isolated pontine infarction can be classified as basilar artery branch disease (BABD), small-artery disease (SAD) and large-artery-occlusive disease (LAOD)(3). To identify the predictors of END in these patients is critically important for risk prediction and further precision intervention.

Cerebral small vessel disease (CSVD) is a complex of clinical syndrome, and features by lacunes, white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds (CMB), and brain atrophy on brain imaging(4). CSVD could possibly impact stroke prognosis by comprised dynamic cerebral autoregulation(5). The burden of CSVD has been regarded as a predictor of stroke outcome in previous studies(6). One study suggested that a higher cerebral small vessel disease score is associated with poor prognosis and recurrence in acute ischemic stroke(7). While other study in mild ischemic stroke demonstrated that imaging markers of cerebral small vessel disease did not correlate with END (8). Another study of small sample size investigated the association between WMH and END in patients with isolated pontine infarction, and the results demonstrated that both periventricular and subcortical WMH were useful to predict END in patients with isolated pontine infarction(9). However, in their study, only WMH was analyzed, other features of cerebral small vessel disease including lacunar, CMB, and EPVS were not included.

Thus, the correlation between CSVD burden and END in isolated pontine infarct still need further study. The objective of this study was to investigate the association between cerebral small vessel disease total burden, as well as its individual imaging features, and END in subjects with isolated pontine infarction.

This is a retrospective study conducted in a comprehensive stroke center. Ischemic stroke patients with isolated pontine infarction from January 2020 to December 2022 were screened by two neurologists independently. Subjects were included if: (1) age ≥ 18 years old;(2) subjects presented with focal neurological symptoms and corresponding pontine infarction validated on Diffusion Weighted Imaging (DWI); (3) admission within 24 hours after symptoms onset; Subjects were excluded if who were on intravenous thrombosis, endovascular thrombectomy, missing recordings of neurological change or NIHSS after admission.

Demographic characteristics, atherosclerotic risk factors (hypertension, diabetes, hyperlipidemia, previous stroke history, coronary artery disease, chronic kidney disease, etc), blood test, blood pressure at admission, National Institutes of Health Stroke Scale (NIHSS) at admission and after deterioration, were all obtained from the medical report. Infarct mechanism was categorized as basilar artery branch disease (BABD), small-artery disease (SAD) and large-artery-occlusive disease (LAOD) according to the infarct location and vascular lesion(3). In this study, END was defined as an increase of ≥ 1 point on the motor NIHSS or ≥ 2 points on the total NIHSS score within 72 h from after admission (9).

This study was approved by the local ethic committee, and informed consent was waived due to the retrospective data analysis.

Imaging protocol

All patients were scanned on a 3.0 T MR scanner (Discovery 750, GE Healthcare, Milwaukee, USA) with 8-channel head coil. The protocol including brain MRI followed by MRA. The detailed sequence and its parameters were as follows: (1) T1W, FSE, TR/TE 1750/24 msec, FOV 24 cm×24 cm, matrix 320×256, thickness = 5mm; (2) T2W, FSE, TR/TE 5000/95 msec, FOV 24 cm×24 cm, matrix 512×512, thickness = 5mm; (3) T2-fluid attenuated inversion recovery (FLAIR), FSE, TR/TE 9000/145 msec, FOV 24 cm×24 cm, matrix 256×256, thickness = 5mm; (4) DWI, echo plannar imaging, TR/TE 3000/65 msec, FOV 24 cm×24 cm, matrix 160×160, thickness = 5mm; (5) apparent diffusion coefficient (ADC): EPI, TR/TE 3000/65.7–84; (6) susceptibility weighted imaging (SWI): Gradient echo (GRE), TR/TE 80-15000/45.

MRA was followed by routine brain MRI including 3D time-of-flight (TOF) MRA, and Cube T1-weighted imaging. 3D TOF MRA was obtained by axial, fast-spin echo (FSE): TR / TE 22/2.5 msec, FOV 22×21cm, flip angle(FA)=20°, spatial resolution 0.6×1.0×1.2mm³;3D Cube T1W: SE, TR /TE 800/16 msec, FOV 23×18cm, FA = 90°, spatial resolution = 0.7×0.6×0.6mm³.

Image analysis

All images were evaluated by two experienced radiologists who were blinded to clinical information. A new pontine infarct was defined as a hyperintense area on DWI with corresponding decreased signal on ADC.

Cerebral small vessel disease burden was evaluated by two independent neurologists according to the criteria previously(10). The total CSVD score were calculated by each features below, with 1 points for ≥ 1 lacunes, deep WMH (dWMH) ≥ 2 and (or) periventricular WMH (pWMH) = 3, ≥ 1 CMB, and moderate to severe (2–4) PVS, individually. Of which, lacunes were defined as rounded or ovoid lesions, 3–20 mm diameter, in the basal ganglia, internal capsule, centrum semiovale, or brainstem, of CSF signal intensity on T2 and FLAIR, generally with a hyperintense rim on FLAIR and no increased signal on DWI. CMB was evaluated on SWI and defined as small (5 mm), homogeneous, round foci of low signal intensity on gradient echo images in cerebellum, brainstem, basal ganglia, white matter, or cortico-subcortical junction, differentiated from vessel flow voids and mineral depositions in the globi pallidi. Deep and periventricular WMH were both evaluated according to the Fazekas scale from 0 to 3. PVS was defined as small (mm) punctate (if perpendicular) and linear (if longitudinal to the plane of scan) hyperintensities on T2 images in the basal ganglia or centrum semiovale, and they were rated on a previously described, validated semiquantitative scale from 0 to 4.

In addition, intracranial artery stenosis was also recorded in each vessel, and the degree of stenosis was divided as <30%, 30–49%, 50–69%, and ≥ 70%. Intraplaque hemorrhage (IPH) on basilar artery was obtained on Cube T1WI, defined as T1-hyperintensity plaque with signal intensity higher than that of the surrounding brain parenchyma or muscle(11).

Statistical analysis

SPSS 19.0 was used to statistical analysis, Variables with normal distribution were presented as mean ± SD, skewed distribution as Median(Interquartile Range, IQR), t-test and chi-square were used to variables comparison between END and non-END groups. Logistic regression was used to adjust confoundings, and locate the association between cerebral small vessel disease burden and END in these patients. All statistical difference was set at 0.05.

A total of 107 subjects satisfying the criteria above were included in this study, the mean age is 67 years old, male dominant with a prevalence of 77.6% (83/107). Of them, 33.6% (36/107) occurred END within 72h hours after admission, most symptoms deteriorated within 48 hours. The demographic and risk factors comparison between END and non-END group was shown in Table 1. Patients with END have a higher percentage of hyperlipidemia (66.7% vs. 43.7% in each group, p = 0.024), and more patients were on dual-platelet therapy in END group (63.9% VS. 36.6%, p = 0.007). The infarct mechanism between END and non-END group was also statistically different, BABD contribute to over 50% in both groups (58.3% in END group and 50.7% in non-END group), LAOD is much higher in END group, while SAD is more prevalent in non-END group. No difference in other atherosclerotic risk factors was found statistically significant between groups.

Table 1

Baseline characteristics of subjects between END and non-END group
Variables M ± SD or n (%)	END group (n = 36)	Non-END group (n = 71)	P-value
Age, years	64.86 ± 11.34	68.62 ± 10.05	0.083
Male	31 (86.1)	52 (73.2)	0.132
Hypertension	30 (83.3)	51 (71.8)	0.190
Diabetes	21 (58.3)	49 (69.0)	0.272
Hyperlipidemia	24 (66.7)	31 (43.7)	0.024
CAD	6 (16.7)	17 (24.3)	0.367
CKD	1 (2.9)	10 (14.3)	0.143
Previous stroke	15 (41.7)	34 (47.9)	0.542
SBP	155.5 ± 15.3	154.2 ± 21.1	0.725
DBP	83.9 ± 8.7	83.4 ± 14.4	0.841
Glucose (mmol/L)	8.89 ± 3.46	8.53 ± 3.44	0.620
HbA1C (%)	7.39 ± 1.92	7.02 ± 1.65	0.337
TC (mmol/L)	4.52 ± 1.01	4.30 ± 1.00	0.322
TG (mmol/L)	1.77 ± 1.10	1.58 ± 0.83	0.343
HDL-C (mmol/L)	0.98 ± 0.23	1.07 ± 0.27	0.106
LDL-C (mmol/L)	2.88 ± 0.78	2.57 ± 0.88	0.093
Intensive statin	3 (8.3)	3 (4.2)	0.669
Dual-antiplatelet	23(63.9)	26 (36.6)	0.007
NIHSS at admission*	2 (1, 4)	2 (1, 3)	0.598
Infarct mechanism			0.003
BABD	21(58.3)	35 (50.7)
SAD	8 (22.2)	32 (46.4)
LAOD	7 (19.4)	2 (2.9)
*: M[IQR], Mann-Whitney test. (CAD: coronary artery disease; CKD: chronic kidney disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol)

As shown in Table 2, cerebral small vessel disease features including lacune, white matter hyperintensity, microbleeds, and EPVS were compared between END and non-END groups. However, neither total CVSD burden no its individual features demonstrated any difference between groups (all P>0.05). In addition, the prevalence of basilar artery (BA) stenosis, internal Carotid Artery (ICA)/Middle Cerebral Artery (MCA) stenosis, and basilar artery IPH were also compared between groups, and the results indicated that patients with END were more likely to have basilar artery IPH (31.3% in END group vs. 12.3% in non-END group, p = 0.024).

Table 2

Image features comparison between END and non-END group
Variables	END group (n = 36)	Non-END group (n = 71)	P-value
Total CSVD scale	1 (0, 2)	2 (1, 2)	0.157
Lacune	22 (61.1)	55 (77.5)	0.075
WMH-total score	2 (2, 4)	3 (2, 4)	0.093
pWMH	2 (1, 2)	2 (1, 3)	0.057
dWMH	1 (0, 2)	1 (1, 2)	0.282
CMB	11 (30.6)	25 (35.2)	0.630
EPVS	4 (11.1)	8 (11.3)	1.000
BA ≥ 50% stenosis ICA/MCA ≥ 50% stenosis Basilar artery IPH	16 (44.4) 17 (48.6) 10 (31.3)	25 (35.7) 20 (30.3) 8 (12.3)	0.382 0.070 0.024

BA: basilar artery; ICA: internal carotid artery; MCA: middle cerebral artery.

In multivariate regression, after adjusted confoundings, we didn’t see any positive result for the association between CVSD burden and END, nor any relationship between CVSD features and END, all p values>0.05. Basilar artery IPH were associated with END independently in multivariate regression analysis, OR = 3.233, 95% CI (1.032, 10.123).

Table 3 Predictors of END in logistic regression analysis

	Multivariate regression
	OR	95% CI	P-value
Total CSVD scale	0.881	0.585-1.327	0.544
Lacune	0.596	0.231-1.535	0.283
WMH-total score	0.876	0.624-1.230	0.444
pWMH	0.736	0.420-1.290	0.284
dWMH	0.946	0.547-1.636	0.842
CMB	0.976	0.395-2.411	0.959
EPVS	1.029	0.275-3.847	0.966
BA ≥50% stenosis	1.711	0.694-4.219	0.244
ICA/MCA ≥50% stenosis	2.319	0.928-5.797	0.072
Basilar artery IPH	3.233	1.032-10.123	0.044

Adjusted for age，hyperlipidemia in multivariate regression analysis.

Our study demonstrates negative correlations between cerebral small vessel disease burden and early neurological deterioration in isolated pontine infarction patients. However, basilar artery IPH is independently correlated with END in these patients. The result in our study could help us have a better understanding of END in isolated pontine infarction.

Prevalence of END in isolated pontine infarction and possible mechanism

One third patients presented END in our study, and most of the END occurred within 48 hours after symptoms onset. Patients with isolated pontine infarction may present dizziness, limb numbness at first, but have a lower NIHSS score. And in most cases the dizziness is non-specific and difficult to distinguish with other causes. The most common mechanism of isolated pontine infarction in our study is basilar artery branch disease, which is consistent with a previous study. In their study, BABD was the most frequent cause of isolated pontine ischemia (43%), followed by SAD (34%) and LAOD (21%)(3). The result suggests that patients with sudden dizziness or other mild posterior circulation symptoms deserve much more attention, especially at the first several days, they are much more likely to occur symptoms deterioration. Moreover, there are also study indicated that patients with branch atheromatous disease-induced index pontine infarction were more likely to recur at the same site and with the same mechanism(12). Therefore, rapid evaluation on the etiology and mechanism is necessary, which will provide more evidence for optimal medical management in this population.

CSVD and END in isolated pontine infarction

Association between CSVD and stroke outcome has been studied extensively, but still inconclusive(7, 13–15). While its predictive value in early neurological deterioration has not been comprehensively investigated. A study with 82 patients revealed that severe WMH is associated with END in isolated pontine infarction, both severe pWMH (OR = 6.17; 95% CI 1.93–19.75, p = 0.002) and dWMH (OR = 3.19; 95% CI 1.10–9.23, p = 0.032) remained independent predictors of END after adjusted confoundings (9). However, we didn’t detect any positive result between WMH and END in our study. The possible reason could be that the population in our study is younger than their patients, since WMH is an age-related imaging features; Moreover, no other CSVD imaging biomarker was involved in their study, and the sample size is also not large enough to draw the conclusion.

Another study of intracranial branch atheromatous disease demonstrated that culprit plaques of large parent arteries, rather than cerebral small vessel disease, contribute to early neurological deterioration in stroke patients with intracranial branch atheromatous disease(16). This is consistent with our study. Nearly half of subjects’ infarction mechanism can be attributed to BABD in our study. And our results also suggest that basilar artery vulnerable plaque is an independent predictor of END in multi-variate regression. While in our study, another possible explanation for the negative result between CSVD and END in isolated pontine infarction could be that the CSVD burden were evaluated mostly in anterior circulation, which cannot completely reflect the vascular autoregulation capability in posterior circulation.

Other imaging predictors of END in isolated pontine infarction

Most of previous studies about imaging biomarker in isolated pontine infarction focus on the topological morphology characteristics, including the infarct location, volume, and signal intensity on ADC. Ventral pontine infarct(2), infarct volume (maximum length multiplied by thickness) (17), and mean rADC value within the ischemic lesion had been verified to closely related with early neurological deterioration in patients with isolated pontine infarcts(18). We didn’t include those features in our study, since not all infarcts on imaging could be reflected on NIHSS score, especially when it comes to complicated pontine anatomy.

Another interesting finding in our study is that anterior circulation vascular stenosis could possibly be a predictor of END in this population, but with marginal statistical significance in both univariate and multivariate regression. We speculated that patients with heavier atherosclerotic burden usually suffer from some dysfunction in cerebral autoregulation, but the conclusion deserve further study.

Advantages and Limitations

Our study comprehensively investigated the association between cerebral small vessel disease burden, as well as its independent features, and END in isolated pontine infarction, despite no positive findings. This study provides some information on the mechanism of isolated pontine infarction, the result revealed that BABD is the most common mechanism of isolated pontine infarction, and basilar artery intraplaque hemorrhage is the independent factor of END in these patients. Which will also add some new knowledge about the imaging features in predicting posterior circulation END.

Some limitations should also be purposed here. First, the sample size in our study is not large enough to finalize the conclusion, a large sample study is still needed in the future to validate our result. Second, semi-quantitative scoring was used to evaluate CSVD burden, no quantitative imaging features were used in this study, such as the infarct volume, white matter hyperintensity volume, perfusion index, and etc.

In conclusion, early neurological deterioration in isolated pontine infarction is not uncommon, the mechanism of END and related factors deserve further exploration. Our study demonstrated negative correlation between cerebral small vessel disease and END in isolated pontine infarction, however, basilar artery vulnerable plaque as a predictor of END in these patients deserve further attention.

Human Ethics and Consent to Participate declarations

This study was approved by Beijing Tsinghua Changgung ethic committee (22028-0-02), and informed consent was waived due to the retrospective data analysis.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Competing interest

The authors declare that they have no competing interests.

Funding

This study is supported by National Key R&D Program of China (2023YFC2506600), Tsinghua Precision Medicine, Tsinghua University (20219990033), and Capital’s Funds for Health Improvement and Research (2020-1-2241)

Author Contributions

Xiaowei Song: purpose the idea and design the study, writing the manuscript; Duoduo Hou and Hongliang Zhao: data acquisition; Siyuan Zhang: statistical analysis, and result interpretation.

Zhuoma Pengmao: data acquisition; Jian Wu: funding support, manuscript revision.

Acknowledgements

Not applicable.

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No competing interests reported.

Association between cerebral small vessel disease burden and early neurological deterioration in isolated pontine infarction

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Introduction

Methods

Imaging protocol

Image analysis

Statistical analysis

Results

Discussion

Prevalence of END in isolated pontine infarction and possible mechanism

CSVD and END in isolated pontine infarction

Other imaging predictors of END in isolated pontine infarction

Advantages and Limitations

Declarations

References

Additional Declarations

Status:

Version 1