Neurol Sci DOI 10.1007/s10072-015-2267-1
ORIGINAL ARTICLE
Lesion patterns of single small subcortical infarct and its association with early neurological deterioration Zuowei Duan1 • Changbiao Fu1 • Bin Chen1 • Gang Xu1 • Lihong Tao1 • Tieyu Tang1 • Hongling Hou1 • Xuetao Fu1 • Ming Yang1 • Zhensheng Liu2 Xinjiang Zhang1
•
Received: 16 December 2014 / Accepted: 22 May 2015 Ó Springer-Verlag Italia 2015
Abstract Early neurological deterioration (END), happening in the acute phase of infarct, is not rare in patients with single small subcortical infarction (SSSI). The aim of this study was to investigate the lesion patterns of SSSI and its association with END as well as functional outcome at 90 days after onset. 227 patients with acute SSSI in the perforator territory of MCA were prospectively recruited from Yangzhou No.1 People’s Hospital between May 2010 and Jan 2014 and divided into proximal SSSI (pSSSI) and distal SSSI (dSSSI) according to the lesion patterns. END was defined as a change in National Institutes of Health Stroke Scale score C2 points in the first 72 h after admission. Functional outcome at 90 days after onset was assessed using the modified Rankin Score (mRS) and dichotomized as good (0–2) and poor (C3). Of them, 93 (40.97 %) patients had pSSSI and 134 (59.03 %) patients had dSSSI. Univariate analysis found that the risk factors profiles differ significantly between patients with pSSSI and those with dSSSI (P \ 0.05). During hospitalization, 60 (26.43 %) patients experienced END during the first 72 h after admission, and 46 (22.01 %) patients had poor outcome at 90 days after onset. After adjusting for potential confounders, pSSSI pattern (OR 2.242, 95 % CI Z. Duan and C. Fu contributed equally to this work. & Xinjiang Zhang [email protected] Zuowei Duan [email protected] 1
Department of Neurology, Yangzhou No.1 People’s Hospital, 45 Taizhou Road, Yangzhou 225001, Jiangsu Province, People’s Republic of China
2
Department of Radiology, Yangzhou No.1 People’s Hospital, Yangzhou 225001, People’s Republic of China
1.165–4.313, P = 0.016) was an independent predictor of END and that the END (OR 2.637, 95 % CI 1.208–5.759, P = 0.015) independently predicted the poor outcome at 90 days after onset. The pSSSI patterns might predict END for patients with SSSI in the MCA perforating territory. Keywords Single small subcortical infarction Early neurological deterioration Lesion pattern Middle cerebral artery Perforating artery
Introduction The mechanisms underlying single small subcortical infarction (SSSI) in the perforator territory are poorly elucidated. Compared with large-territory infarct, SSSI usually has a fair outcome [1, 2]. However, early neurological deterioration (END), a relatively bad clinical course in the acute phase of infarction, is common in these patients [3, 4]. END often occurs in hours or even days following symptom onset and usually leads to unexpectedly severe disability and even death [5–7]. Therefore, identifying presentation features that predict END is important, because they could help to screen patients who are at high risk of worsening. Although a few studies have reported that several clinical and biological factors, such as older age, the initial neurological severity, diabetes mellitus, bleed levels of glucose and homocysteine may influence the development of END [7–12]. However, few studies have investigated the relationship between diffusionweighted imaging (DWI) findings and END. Recently, a study found that SSSI located in the proximal region near the parent artery had a higher prevalence of atherosclerosis indicators (cerebral atherosclerosis and coronary heart disease), while those located in a more distal area had a
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Subjects and methods
and 3D time-of-flight magnetic resonance angiography (MRA). According to a previously published study, the DWI-defined lesion patterns of SSSI were divided into proximal SSSI (pSSSI) pattern and distal SSSI (dSSSI) pattern based on the relationship between lesion location and the parent artery [13]: pSSSI pattern was defined as an infarction located in the proximal region near the parent artery (extending to the basal surface of the parent artery) and dSSSI pattern defined as an infarction located in a more distal area (not extending to the basal surface of the parent artery, as shown in Figs. 1, 2). The largest infarction size on axial DWI was also analyzed. Two investigators who were blind to the clinical details defined the categorization of SSSI. If there was a dispute, the final result was reached through consultation.
Patient selection
Arterial study
Between May 2010 and Jan 2014, 227 patients with acute SSSI were prospectively recruited from Yangzhou No.1 People’s Hospital. Inclusion criteria were age C18 years; the time-period between symptom onset and admission time B24 h; MRI conducted during the first 24 h after admission; acute isolated infarction located in the MCA perforating territory; the largest diameter of lesion on axial DWI B20 mm. Exclusion criteria were treated with thrombolytic agents and interventional therapy; history of stroke; significant stenosis (C50 %) in responsible extracranial internal carotid artery; potential cardiac embolic sources; and early discharge. The study was approved by Ethics Committees of Yangzhou No.1 People’s Hospital and written informed consent was obtained from each patient.
For each patient, we evaluated the status of cerebrocervical artery using either MRA or computer tomography angiography (CTA). In this study, stenosis C50 % in the M1 segment of ipsilateral MCA was regarded as a significant cause of SSSI. Concomitant intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS), that is, any intracranial or extracranial atherosclerotic disease unrelated to the new SSSI, was also analyzed. Generally, the ICAS was degreed using WASID criteria, while ECAS using NASCET criteria [15, 16]. The presence and the degree of cerebrocervical artery stenosis were analyzed by consensus among two physicians who were blinded to the lesion patterns.
greater frequency of small artery disease indicators (leukoaraiosis and microbleeds), which suggests that the SSSI might have a heterogeneous pathogenesis according to the imaging-defined lesion patterns [13, 14]. Based on the results above, we hypothesized that the DWI-defined lesion patterns could be associated with END as well as poor outcome at 90 days after onset. In this present study, we attempted to identify predictors for END as well as functional outcome at 90 days after onset in patients with acute SSSI in the perforator territory of middle cerebral artery (MCA) using DWI findings on admission.
Vascular risk factors MRI analysis MRI examination was performed during the first 24 h after admission. Included in the imaging protocol were T1WI, T2WI, DWI, fluid-attenuated inversion recovery (FLAIR),
Vascular risk factors were recorded at hospital admission and defined as follows: hypertension, defined as blood pressure C140/90 mmHg, or use of antihypertensive medications; diabetes mellitus, defined as a fasting blood
Fig. 1 Example of pSSSI: the infarction extending to the basal surface of the parent artery
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glucose C126 mg/dl, positive 75 g oral glucose tolerance test result, or use of insulin or oral hypoglycemic agents; hyperlipidemia, defined as a serum total cholesterol level C240 mg/dl, or use of cholesterol-reducing medications; current cigarette smoking, defined as current or quit smoking B6 months prior; drinking, defined as intake more than 80 g/day or quit drinking B6 months prior; and a history of ischemic heart disease.
Neurological severity and END definition Once admitted in the stroke unit, patients were treated with antiplatelets (mono-antiplatelet or dual antiplatelet therapy) and stain. And the management of blood level of glucose and lipids, blood pressure was also carried out based on careful monitoring according to diagnostic and therapeutic criteria. The National Institutes of Health Stroke Scale
Fig. 2 Example of dSSSI: the infarction not extending to the basal surface of the parent artery Table 1 Comparison of demographic and clinical characteristics between patients with pSSSI and those with dSSSI
Characteristics
Proximal SSSI (N = 93)
Distal SSSI (N = 134)
P
Age, years, mean (SD)
62.14 ± 13.17
63.65 ± 13.03
0.394
Female sex, N (%)
27 (29.0)
42 (31.3)
0.710
Hypertension, N (%)
62 (66.7)
107 (79.9)
0.025
Onset to initial MRI, h, mean (SD)
9.66 ± 3.72
10.36 ± 4.20
0.196
Length-of-hospital stay, days, mean (SD)
7.70 ± 2.64
6.93 ± 2.22
0.011
Diabetes mellitus, N (%)
26 (28.0)
19 (14.2)
0.010
Hyperlipidemia, N (%)
31 (33.3)
28 (20.9)
0.036
Ischemic heart disease, N (%)
9 (9.7)
12 (9.0)
0.853
Smoking, N (%)
32 (34.4)
52 (38.8)
0.500
Drinking, N (%)
23 (24.7)
33 (24.6)
0.986
LA (Fazekas scale C2), N (%)
23 (24.7)
65 (48.5)
0.000
SBP, mmHg, mean (SD)
137.31 ± 26.43
140.87 ± 26.20
0.307 0.714
DBP, mmHg, mean (SD)
85.01 ± 13.73
85.70 ± 14.08
Initial NIHSS, median (IQR)
4 (2–5)
3 (2–4)
0.165
Lesion diameter, mm, mean (SD)
13.49 ± 3.21
12.08 ± 3.24
0.001
Previous antiplatelet, N (%) Previous stain, N (%)
10 (10.8) 7 (7.5)
8 (6.0) 14 (10.4)
0.190 0.455
Current medications Mono-antiplatelet treatment, N (%)
80 (86.0)
117 (87.3)
0.777
Acute stain treatment N (%)
35 (37.6)
51 (38.1)
0.948
Atherosclerosis Ipsilateral MCA stenosis, N (%)
40 (43.0)
27 (20.1)
0.000
ICAS, N (%)
41 (44.1)
30 (22.4)
0.001
ECAS, N (%)
25 (26.9)
19 (14.2)
0.017
IQR indicates interquartile range, SSSI single small subcortical infarcts, NIHSS National Institutes of Health Stroke Scale, LA leukoaraiosis, SBP systolic blood pressure, DBP diastolic blood pressure, MCA middle cerebral artery, ICAS intracranial atherosclerotic stenosis, ECAS extracranial atherosclerotic stenosis
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(NIHSS) was applied to evaluate the neurological deficits. END was defined as a change in NIHSS score C2 points in the first 72 h after admission in comparison with baseline NIHSS at admission [11, 17]. The functional outcome at 90 days after onset was noted as the modified Rankin Score (mRS), which was dichotomized as good (0–2) and poor (C3). The evaluation of END and the functional outcome was conducted by investigators who were blinded to the imaging information. Data analysis For statistics, univariate parametric and nonparametric comparisons of clinical characteristics were performed with Student’s t test, Mann–Whitney test, v2 test or Fisher’s exact test as appropriate. Then, multiple logistic regression model was performed using variables with P value B0.1 in univariate analysis to determine the independent predictors of END or poor outcome. The SPSS package 16.0 for windows were performed for all statistical analysis and P values \0.05 were considered significant.
Results Demographic and general characteristics The 227 consecutive patients with acute SSSI (mean age ± SD = 61.99 ± 12.91 years; 69 female) in the perforating territory of MCA were recruited. Of them, 169 (74.45 %) patients had hypertension, 45 (19.82 %) patients had diabetes mellitus, 59 (25.99 %) patients had hyperlipidemia, 84 (37.00 %) patients had current smoking and 56 (24.67 %) patients had drinking, 21 (9.25 %) patients had a histories of ischemic heart disease. 67 (29.52 %) patients had ipsilateral MCA stenosis. 71 (31.28 %) had concomitant ICAS and 44 (19.38 %) had ECAS. 88 (38.77 %) patients had significant LA with Fazekas scores of 2 and 3. Risk factor profiles between pSSSI and dSSSI Of the 227 patients, pSSSI pattern was found in 93 (40.97 %) patients and dSSSI pattern found in 134
Table 2 Comparison between patients with early neurological deterioration and those without Characteristics
END
P
Yes (N = 60)
No (N = 167)
Age, years, mean (SD)
65.22 ± 3.11
62.25 ± 13.02
Female, N (%)
27 (45.0)
42 (25.1)
Logistic regression OR
95 % CI
P
0.132
–
–
–
0.004
2.978
1.524–5.819
0.001
Onset to initial MRI, h, mean (SD)
9.63 ± 3.96
10.23 ± 4.04
0.327
–
–
–
Length-of-hospital stay, days, mean (SD)
8.02 ± 2.31
6.96 ± 2.19
0.002
–
–
–
Hypertension, N (%)
46 (76.7)
123 (73.7)
0.646
–
–
–
Diabetes mellitus, N (%)
13 (21.7)
32 (19.2)
0.676
–
–
–
Hyperlipidemia, N (%)
18 (30.0)
41 (24.6)
0.409
–
–
–
Ischemic heart disease, N (%)
8 (13.3)
13 (7.8)
0.203
–
–
–
Smoking, N (%)
21 (35.0)
63 (37.7)
0.708
–
–
–
Drinking, N (%)
13 (21.7)
43 (25.7)
0.529
–
–
–
LA (Fazekas scale C2), N (%)
23 (38.3)
65 (38.9)
0.936
–
–
–
Proximal SSSI pattern, N (%)
35 (58.3)
58 (34.7)
0.001
2.242
1.165–4.313
0.016
SBP, mmHg, mean (SD)
140.73 ± 22.74
138.93 ± 26.75
0.643
–
–
–
DBP, mmHg, mean (SD)
84.05 ± 12.01
85.91 ± 14.53
0.375
–
–
–
Initial NIHSS, median (IQR) Lesion diameter, mm, mean (SD)
4 (3–5) 13.24 ± 3.01
3 (2–5) 12.45 ± 3.38
0.004 0.111
1.143 –
0.963–1.357 –
0.127 –
–
–
–
–
–
–
–
–
–
1.779
0.886–3.571
0.105
Previous antiplatelet, N (%)
7 (11.7)
11 (6.6)
0.212
Previous stain, N (%)
7 (11.7)
14 (8.4)
0.452
Mono-antiplatelet treatment, N (%)
54 (90.0)
143 (85.6)
0.391
Acute stain treatment N (%)
21 (35.0)
65 (38.9)
0.591
26 (43.3)
41 (24.6)
0.006
Current medications
Atherosclerosis Ipsilateral MCA stenosis, N (%) ICAS, N (%)
25 (41.7)
46 (27.5)
0.043
1.257
0.640–2.470
0.507
ECAS, N (%)
16 (26.7)
28 (16.8)
0.096
1.339
0.584–3.068
0.490
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(59.03 %) patients. Compared with patients with dSSSI, patients with pSSSI had a lager lesion diameter (P = 0.001), higher prevalence of hyperlipidemia (P = 0.036), ipsilateral MCA stenosis (P \ 0.001), ICAS (P = 0.001), ECAS (P = 0.017) and diabetes mellitus (P = 0.010), and lower prevalence of hypertension (P = 0.025) and LA (P \ 0.001), as shown in Table 1. Factors associated with END Sixty patients (35 pSSSI vs 25 dSSSI) had END during the first 72 h after admission. The pSSSI pattern (P = 0.001), female sex (P = 0.004), initial NIHSS (P = 0.004), and ipsilateral MCA stenosis (P = 0.006) and ICAS (P = 0.043) were significantly different between patients with END and those without. After adjusting for potential confounders (including female, proximal SSSI pattern, initial NIHSS, ipsilateral MCA stenosis, ICAS and ECAS, whose P value B0.1 in univariate analysis), pSSSI pattern (OR 2.242, 95 % CI 1.165-4.313, P = 0.016) and female
sex (OR 2.978, 95 %CI 1.524–5.819, P = 0.001) remained independent, as shown in Table 2. Factors associated with functional outcome Of the 209 patients who could contact at 90 days after admission, 46 patients showed poor outcome represented by an mRS score C3. The poor outcome was significantly associated with female sex (P = 0.012), diabetes mellitus (P = 0.045), pSSSI pattern (P = 0.008), initial NIHSS (P \ 0.001), ipsilateral MCA stenosis (P = 0.020) and ECAS (P = 0.034), and END (P \ 0.001). After logistic regression analysis contained variables with P B 0.1 in univariate analysis, the END (OR 2.637, 95 % CI 1.208–5.759, P = 0.015), female sex (OR 2.509, 95 % CI 1.159–5.430, P = 0.020), and initial NIHSS (OR 1.404, 95 % CI 1.133–1.741, P = 0.002) were the important independent predictors of the poor outcome at 90 days after admission, as shown in Table 3.
Table 3 Comparison between patients with poor outcome and those with good outcome at 90 days after onset Characteristics
Functional outcome Poor outcome (N = 46)
P Good outcome (N = 163)
Logistic regression OR
95 % CI
P –
Age, years, mean (SD)
63.07 ± 11.17
62.10 ± 13.46
0.658
–
–
Female, N (%)
21 (45.7)
43 (26.4)
0.012
2.509
1.159–5.430
0.020
Onset to initial MRI, h, mean (SD)
10.02 ± 3.68
10.11 ± 4.19
0.897
–
–
– –
Length-of-hospital stay, days, mean (SD)
8.30 ± 2.40
6.94 ± 2.15
0.000
–
–
Hypertension, N (%)
37 (80.4)
123 (75.5)
0.482
–
–
–
Diabetes mellitus, N (%)
13 (28.3)
25 (15.3)
0.045
1.892
0.795–4.503
0.150
Hyperlipidemia, N (%)
10 (21.7)
42 (25.8)
0.577
–
–
–
Ischemic Heart Disease, N (%)
2 (4.3)
15 (9.2)
0.289
–
–
–
Smoking, N (%)
14 (30.4)
63 (38.7)
0.308
–
–
–
Drinking, N (%)
8 (17.4)
43 (26.4)
0.210
–
–
–
Proximal SSSI pattern, N (%)
26 (56.5)
57 (35.0)
0.008
1.621
0.745–3.526
0.223
SBP, mmHg, mean (SD)
141.70 ± 19.25
139.85 ± 16.61
0.522
–
–
–
DBP, mmHg, mean (SD)
84.96 ± 9.35
83.76 ± 10.44
0.488
–
–
–
Initial NIHSS, median (IQR)
4 (3–6)
3 (2–4)
0.000
1.404
1.133–1.741
0.002
Lesion diameter, mm, mean (SD) LA (Fazekas scale C2), N (%)
13.38 ± 3.07 16 (34.8)
12.51 ± 3.29 67 (41.1)
0.113 0.439
– –
– –
– –
0.431
Previous antiplatelet, N (%)
4 (8.7)
9 (5.5)
Previous stain, N (%)
5 (10.9)
12 (7.4)
Current medications Mono-antiplatelet treatment, N (%)
41 (89.1)
140 (85.9)
0.569
Acute stain treatment N (%)
18 (39.1)
63 (38.7)
0.953
Ipsilateral MCA stenosis, N (%)
20 (43.5)
42 (25.8)
0.020
1.435
0.626–3.287
0.393
ICAS, N (%)
17 (37.0)
47 (28.8)
0.291
–
–
–
Atherosclerosis
ECAS, N (%) END, N (%)
13 (28.3)
24 (14.7)
0.034
1.244
0.477–3.243
0.655
22 (47.8)
31 (19.0)
0.000
2.637
1.208–5.759
0.015
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Discussion Consistent with previous results [13, 14], we found that patients with pSSSI had higher prevalence of atherosclerosis indicators (diabetes mellitus, hyperlipidemia and atherosclerotic disease), while those patients with dSSSI had higher prevalence of small artery disease indicators (hypertension and leukoaraiosis). The risk factor profiles between the two patterns of patients were different. Moreover, we also found that pSSSI pattern was the independent predictor of END and the END independently predicted the subsequent poor outcome at 90 days after onset. To our best knowledge, few studies had focused on the relationship between lesion patterns and functional outcome to date. As we all know, END was a known complication of stroke in general and subcortical stroke in particular [17]. It was reported that subcortical infarcts occurred when a vessel supplying the subcortex becomes occluded or suffers from critical hypoperfusion. And for subcortical infarcts, the higher number of vessels with intracranial atherosderosis, the more likely the patients to develop END [11, 18–20]. That is to say, the atherosderotic burden was significantly associated with the presence of END in patients with subcortical infarct. In line with that, branch atheromatous disease resulting from occlusion of the mouth of the branch which was also reported to be more prone to show worsening or fluctuating symptoms during hospitalization [21]. In addition, according to a recent study, hypoperfusion was also reported to be associated with poor outcome after stroke [22–24]. Compared with dSSSI, pSSSI showed remarkable atherosclerosis features and had few collateral vessels in the infarct area. Therefore, the higher atherosderotic burden and the hypoperfusion might play a role in the development of END. The potential pathogenesis might be: thrombus propagation leading to progressive occlusion of lateral branches, or embolus dropped from the active atherosderotic plaques and traveled distally to the cortical branches, or educed perfusion in the proximal tissue area, which might lead to new infarct or infarct expansion [3, 19–24]. Some other pathogenesis, such as inflammation and edema, etc., were poorly elucidated and needed to be further studied [3]. We also found that female sex was an independent risk factor of END as well as poor outcome. However, the reason for such findings still remained unexplained, and further exploration was required [25, 26]. Previous reports demonstrated that stenosis of any degree in the parent artery was regarded as a significant cause of SSSI; however, mild degree of parent artery disease was not analyzed in our study, that might be why we did not find the independent association between parent artery and END. We
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might thus underestimate the predictive value of parent artery disease for END in patients with SSSI [27, 28]. Moreover, we also did not find the independent association between initial NIHSS and END, despite the fact that the initial NIHSS was an independent risk factor of poor functional outcome at 90 days after admission. Some limitations of our study should be emphasized. First, this study was a single hospital-based study with small sample size, the findings needed to be further confirmed in multicenter prospective studies with large sample. Second, the second MRI after worsening was not regularly performed, so the specific pathophysiology of worsening was not evidently demonstrated. Third, we just analyzed the short-term prognosis of SSSI in this study, the prognosis of long-term prognosis of SSSI was not analyzed according to the lesion patterns; further researches were needed. In conclusion, the pattern of pSSSI was significantly associated with the presence of END and the END predicted the subsequent poor outcome. Conflict of interest
No conflict of interest.
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ORIGINAL ARTICLE
Lesion patterns of single small subcortical infarct and its association with early neurological deterioration Zuowei Duan1 • Changbiao Fu1 • Bin Chen1 • Gang Xu1 • Lihong Tao1 • Tieyu Tang1 • Hongling Hou1 • Xuetao Fu1 • Ming Yang1 • Zhensheng Liu2 Xinjiang Zhang1
•
Received: 16 December 2014 / Accepted: 22 May 2015 Ó Springer-Verlag Italia 2015
Abstract Early neurological deterioration (END), happening in the acute phase of infarct, is not rare in patients with single small subcortical infarction (SSSI). The aim of this study was to investigate the lesion patterns of SSSI and its association with END as well as functional outcome at 90 days after onset. 227 patients with acute SSSI in the perforator territory of MCA were prospectively recruited from Yangzhou No.1 People’s Hospital between May 2010 and Jan 2014 and divided into proximal SSSI (pSSSI) and distal SSSI (dSSSI) according to the lesion patterns. END was defined as a change in National Institutes of Health Stroke Scale score C2 points in the first 72 h after admission. Functional outcome at 90 days after onset was assessed using the modified Rankin Score (mRS) and dichotomized as good (0–2) and poor (C3). Of them, 93 (40.97 %) patients had pSSSI and 134 (59.03 %) patients had dSSSI. Univariate analysis found that the risk factors profiles differ significantly between patients with pSSSI and those with dSSSI (P \ 0.05). During hospitalization, 60 (26.43 %) patients experienced END during the first 72 h after admission, and 46 (22.01 %) patients had poor outcome at 90 days after onset. After adjusting for potential confounders, pSSSI pattern (OR 2.242, 95 % CI Z. Duan and C. Fu contributed equally to this work. & Xinjiang Zhang [email protected] Zuowei Duan [email protected] 1
Department of Neurology, Yangzhou No.1 People’s Hospital, 45 Taizhou Road, Yangzhou 225001, Jiangsu Province, People’s Republic of China
2
Department of Radiology, Yangzhou No.1 People’s Hospital, Yangzhou 225001, People’s Republic of China
1.165–4.313, P = 0.016) was an independent predictor of END and that the END (OR 2.637, 95 % CI 1.208–5.759, P = 0.015) independently predicted the poor outcome at 90 days after onset. The pSSSI patterns might predict END for patients with SSSI in the MCA perforating territory. Keywords Single small subcortical infarction Early neurological deterioration Lesion pattern Middle cerebral artery Perforating artery
Introduction The mechanisms underlying single small subcortical infarction (SSSI) in the perforator territory are poorly elucidated. Compared with large-territory infarct, SSSI usually has a fair outcome [1, 2]. However, early neurological deterioration (END), a relatively bad clinical course in the acute phase of infarction, is common in these patients [3, 4]. END often occurs in hours or even days following symptom onset and usually leads to unexpectedly severe disability and even death [5–7]. Therefore, identifying presentation features that predict END is important, because they could help to screen patients who are at high risk of worsening. Although a few studies have reported that several clinical and biological factors, such as older age, the initial neurological severity, diabetes mellitus, bleed levels of glucose and homocysteine may influence the development of END [7–12]. However, few studies have investigated the relationship between diffusionweighted imaging (DWI) findings and END. Recently, a study found that SSSI located in the proximal region near the parent artery had a higher prevalence of atherosclerosis indicators (cerebral atherosclerosis and coronary heart disease), while those located in a more distal area had a
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Subjects and methods
and 3D time-of-flight magnetic resonance angiography (MRA). According to a previously published study, the DWI-defined lesion patterns of SSSI were divided into proximal SSSI (pSSSI) pattern and distal SSSI (dSSSI) pattern based on the relationship between lesion location and the parent artery [13]: pSSSI pattern was defined as an infarction located in the proximal region near the parent artery (extending to the basal surface of the parent artery) and dSSSI pattern defined as an infarction located in a more distal area (not extending to the basal surface of the parent artery, as shown in Figs. 1, 2). The largest infarction size on axial DWI was also analyzed. Two investigators who were blind to the clinical details defined the categorization of SSSI. If there was a dispute, the final result was reached through consultation.
Patient selection
Arterial study
Between May 2010 and Jan 2014, 227 patients with acute SSSI were prospectively recruited from Yangzhou No.1 People’s Hospital. Inclusion criteria were age C18 years; the time-period between symptom onset and admission time B24 h; MRI conducted during the first 24 h after admission; acute isolated infarction located in the MCA perforating territory; the largest diameter of lesion on axial DWI B20 mm. Exclusion criteria were treated with thrombolytic agents and interventional therapy; history of stroke; significant stenosis (C50 %) in responsible extracranial internal carotid artery; potential cardiac embolic sources; and early discharge. The study was approved by Ethics Committees of Yangzhou No.1 People’s Hospital and written informed consent was obtained from each patient.
For each patient, we evaluated the status of cerebrocervical artery using either MRA or computer tomography angiography (CTA). In this study, stenosis C50 % in the M1 segment of ipsilateral MCA was regarded as a significant cause of SSSI. Concomitant intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS), that is, any intracranial or extracranial atherosclerotic disease unrelated to the new SSSI, was also analyzed. Generally, the ICAS was degreed using WASID criteria, while ECAS using NASCET criteria [15, 16]. The presence and the degree of cerebrocervical artery stenosis were analyzed by consensus among two physicians who were blinded to the lesion patterns.
greater frequency of small artery disease indicators (leukoaraiosis and microbleeds), which suggests that the SSSI might have a heterogeneous pathogenesis according to the imaging-defined lesion patterns [13, 14]. Based on the results above, we hypothesized that the DWI-defined lesion patterns could be associated with END as well as poor outcome at 90 days after onset. In this present study, we attempted to identify predictors for END as well as functional outcome at 90 days after onset in patients with acute SSSI in the perforator territory of middle cerebral artery (MCA) using DWI findings on admission.
Vascular risk factors MRI analysis MRI examination was performed during the first 24 h after admission. Included in the imaging protocol were T1WI, T2WI, DWI, fluid-attenuated inversion recovery (FLAIR),
Vascular risk factors were recorded at hospital admission and defined as follows: hypertension, defined as blood pressure C140/90 mmHg, or use of antihypertensive medications; diabetes mellitus, defined as a fasting blood
Fig. 1 Example of pSSSI: the infarction extending to the basal surface of the parent artery
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glucose C126 mg/dl, positive 75 g oral glucose tolerance test result, or use of insulin or oral hypoglycemic agents; hyperlipidemia, defined as a serum total cholesterol level C240 mg/dl, or use of cholesterol-reducing medications; current cigarette smoking, defined as current or quit smoking B6 months prior; drinking, defined as intake more than 80 g/day or quit drinking B6 months prior; and a history of ischemic heart disease.
Neurological severity and END definition Once admitted in the stroke unit, patients were treated with antiplatelets (mono-antiplatelet or dual antiplatelet therapy) and stain. And the management of blood level of glucose and lipids, blood pressure was also carried out based on careful monitoring according to diagnostic and therapeutic criteria. The National Institutes of Health Stroke Scale
Fig. 2 Example of dSSSI: the infarction not extending to the basal surface of the parent artery Table 1 Comparison of demographic and clinical characteristics between patients with pSSSI and those with dSSSI
Characteristics
Proximal SSSI (N = 93)
Distal SSSI (N = 134)
P
Age, years, mean (SD)
62.14 ± 13.17
63.65 ± 13.03
0.394
Female sex, N (%)
27 (29.0)
42 (31.3)
0.710
Hypertension, N (%)
62 (66.7)
107 (79.9)
0.025
Onset to initial MRI, h, mean (SD)
9.66 ± 3.72
10.36 ± 4.20
0.196
Length-of-hospital stay, days, mean (SD)
7.70 ± 2.64
6.93 ± 2.22
0.011
Diabetes mellitus, N (%)
26 (28.0)
19 (14.2)
0.010
Hyperlipidemia, N (%)
31 (33.3)
28 (20.9)
0.036
Ischemic heart disease, N (%)
9 (9.7)
12 (9.0)
0.853
Smoking, N (%)
32 (34.4)
52 (38.8)
0.500
Drinking, N (%)
23 (24.7)
33 (24.6)
0.986
LA (Fazekas scale C2), N (%)
23 (24.7)
65 (48.5)
0.000
SBP, mmHg, mean (SD)
137.31 ± 26.43
140.87 ± 26.20
0.307 0.714
DBP, mmHg, mean (SD)
85.01 ± 13.73
85.70 ± 14.08
Initial NIHSS, median (IQR)
4 (2–5)
3 (2–4)
0.165
Lesion diameter, mm, mean (SD)
13.49 ± 3.21
12.08 ± 3.24
0.001
Previous antiplatelet, N (%) Previous stain, N (%)
10 (10.8) 7 (7.5)
8 (6.0) 14 (10.4)
0.190 0.455
Current medications Mono-antiplatelet treatment, N (%)
80 (86.0)
117 (87.3)
0.777
Acute stain treatment N (%)
35 (37.6)
51 (38.1)
0.948
Atherosclerosis Ipsilateral MCA stenosis, N (%)
40 (43.0)
27 (20.1)
0.000
ICAS, N (%)
41 (44.1)
30 (22.4)
0.001
ECAS, N (%)
25 (26.9)
19 (14.2)
0.017
IQR indicates interquartile range, SSSI single small subcortical infarcts, NIHSS National Institutes of Health Stroke Scale, LA leukoaraiosis, SBP systolic blood pressure, DBP diastolic blood pressure, MCA middle cerebral artery, ICAS intracranial atherosclerotic stenosis, ECAS extracranial atherosclerotic stenosis
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(NIHSS) was applied to evaluate the neurological deficits. END was defined as a change in NIHSS score C2 points in the first 72 h after admission in comparison with baseline NIHSS at admission [11, 17]. The functional outcome at 90 days after onset was noted as the modified Rankin Score (mRS), which was dichotomized as good (0–2) and poor (C3). The evaluation of END and the functional outcome was conducted by investigators who were blinded to the imaging information. Data analysis For statistics, univariate parametric and nonparametric comparisons of clinical characteristics were performed with Student’s t test, Mann–Whitney test, v2 test or Fisher’s exact test as appropriate. Then, multiple logistic regression model was performed using variables with P value B0.1 in univariate analysis to determine the independent predictors of END or poor outcome. The SPSS package 16.0 for windows were performed for all statistical analysis and P values \0.05 were considered significant.
Results Demographic and general characteristics The 227 consecutive patients with acute SSSI (mean age ± SD = 61.99 ± 12.91 years; 69 female) in the perforating territory of MCA were recruited. Of them, 169 (74.45 %) patients had hypertension, 45 (19.82 %) patients had diabetes mellitus, 59 (25.99 %) patients had hyperlipidemia, 84 (37.00 %) patients had current smoking and 56 (24.67 %) patients had drinking, 21 (9.25 %) patients had a histories of ischemic heart disease. 67 (29.52 %) patients had ipsilateral MCA stenosis. 71 (31.28 %) had concomitant ICAS and 44 (19.38 %) had ECAS. 88 (38.77 %) patients had significant LA with Fazekas scores of 2 and 3. Risk factor profiles between pSSSI and dSSSI Of the 227 patients, pSSSI pattern was found in 93 (40.97 %) patients and dSSSI pattern found in 134
Table 2 Comparison between patients with early neurological deterioration and those without Characteristics
END
P
Yes (N = 60)
No (N = 167)
Age, years, mean (SD)
65.22 ± 3.11
62.25 ± 13.02
Female, N (%)
27 (45.0)
42 (25.1)
Logistic regression OR
95 % CI
P
0.132
–
–
–
0.004
2.978
1.524–5.819
0.001
Onset to initial MRI, h, mean (SD)
9.63 ± 3.96
10.23 ± 4.04
0.327
–
–
–
Length-of-hospital stay, days, mean (SD)
8.02 ± 2.31
6.96 ± 2.19
0.002
–
–
–
Hypertension, N (%)
46 (76.7)
123 (73.7)
0.646
–
–
–
Diabetes mellitus, N (%)
13 (21.7)
32 (19.2)
0.676
–
–
–
Hyperlipidemia, N (%)
18 (30.0)
41 (24.6)
0.409
–
–
–
Ischemic heart disease, N (%)
8 (13.3)
13 (7.8)
0.203
–
–
–
Smoking, N (%)
21 (35.0)
63 (37.7)
0.708
–
–
–
Drinking, N (%)
13 (21.7)
43 (25.7)
0.529
–
–
–
LA (Fazekas scale C2), N (%)
23 (38.3)
65 (38.9)
0.936
–
–
–
Proximal SSSI pattern, N (%)
35 (58.3)
58 (34.7)
0.001
2.242
1.165–4.313
0.016
SBP, mmHg, mean (SD)
140.73 ± 22.74
138.93 ± 26.75
0.643
–
–
–
DBP, mmHg, mean (SD)
84.05 ± 12.01
85.91 ± 14.53
0.375
–
–
–
Initial NIHSS, median (IQR) Lesion diameter, mm, mean (SD)
4 (3–5) 13.24 ± 3.01
3 (2–5) 12.45 ± 3.38
0.004 0.111
1.143 –
0.963–1.357 –
0.127 –
–
–
–
–
–
–
–
–
–
1.779
0.886–3.571
0.105
Previous antiplatelet, N (%)
7 (11.7)
11 (6.6)
0.212
Previous stain, N (%)
7 (11.7)
14 (8.4)
0.452
Mono-antiplatelet treatment, N (%)
54 (90.0)
143 (85.6)
0.391
Acute stain treatment N (%)
21 (35.0)
65 (38.9)
0.591
26 (43.3)
41 (24.6)
0.006
Current medications
Atherosclerosis Ipsilateral MCA stenosis, N (%) ICAS, N (%)
25 (41.7)
46 (27.5)
0.043
1.257
0.640–2.470
0.507
ECAS, N (%)
16 (26.7)
28 (16.8)
0.096
1.339
0.584–3.068
0.490
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(59.03 %) patients. Compared with patients with dSSSI, patients with pSSSI had a lager lesion diameter (P = 0.001), higher prevalence of hyperlipidemia (P = 0.036), ipsilateral MCA stenosis (P \ 0.001), ICAS (P = 0.001), ECAS (P = 0.017) and diabetes mellitus (P = 0.010), and lower prevalence of hypertension (P = 0.025) and LA (P \ 0.001), as shown in Table 1. Factors associated with END Sixty patients (35 pSSSI vs 25 dSSSI) had END during the first 72 h after admission. The pSSSI pattern (P = 0.001), female sex (P = 0.004), initial NIHSS (P = 0.004), and ipsilateral MCA stenosis (P = 0.006) and ICAS (P = 0.043) were significantly different between patients with END and those without. After adjusting for potential confounders (including female, proximal SSSI pattern, initial NIHSS, ipsilateral MCA stenosis, ICAS and ECAS, whose P value B0.1 in univariate analysis), pSSSI pattern (OR 2.242, 95 % CI 1.165-4.313, P = 0.016) and female
sex (OR 2.978, 95 %CI 1.524–5.819, P = 0.001) remained independent, as shown in Table 2. Factors associated with functional outcome Of the 209 patients who could contact at 90 days after admission, 46 patients showed poor outcome represented by an mRS score C3. The poor outcome was significantly associated with female sex (P = 0.012), diabetes mellitus (P = 0.045), pSSSI pattern (P = 0.008), initial NIHSS (P \ 0.001), ipsilateral MCA stenosis (P = 0.020) and ECAS (P = 0.034), and END (P \ 0.001). After logistic regression analysis contained variables with P B 0.1 in univariate analysis, the END (OR 2.637, 95 % CI 1.208–5.759, P = 0.015), female sex (OR 2.509, 95 % CI 1.159–5.430, P = 0.020), and initial NIHSS (OR 1.404, 95 % CI 1.133–1.741, P = 0.002) were the important independent predictors of the poor outcome at 90 days after admission, as shown in Table 3.
Table 3 Comparison between patients with poor outcome and those with good outcome at 90 days after onset Characteristics
Functional outcome Poor outcome (N = 46)
P Good outcome (N = 163)
Logistic regression OR
95 % CI
P –
Age, years, mean (SD)
63.07 ± 11.17
62.10 ± 13.46
0.658
–
–
Female, N (%)
21 (45.7)
43 (26.4)
0.012
2.509
1.159–5.430
0.020
Onset to initial MRI, h, mean (SD)
10.02 ± 3.68
10.11 ± 4.19
0.897
–
–
– –
Length-of-hospital stay, days, mean (SD)
8.30 ± 2.40
6.94 ± 2.15
0.000
–
–
Hypertension, N (%)
37 (80.4)
123 (75.5)
0.482
–
–
–
Diabetes mellitus, N (%)
13 (28.3)
25 (15.3)
0.045
1.892
0.795–4.503
0.150
Hyperlipidemia, N (%)
10 (21.7)
42 (25.8)
0.577
–
–
–
Ischemic Heart Disease, N (%)
2 (4.3)
15 (9.2)
0.289
–
–
–
Smoking, N (%)
14 (30.4)
63 (38.7)
0.308
–
–
–
Drinking, N (%)
8 (17.4)
43 (26.4)
0.210
–
–
–
Proximal SSSI pattern, N (%)
26 (56.5)
57 (35.0)
0.008
1.621
0.745–3.526
0.223
SBP, mmHg, mean (SD)
141.70 ± 19.25
139.85 ± 16.61
0.522
–
–
–
DBP, mmHg, mean (SD)
84.96 ± 9.35
83.76 ± 10.44
0.488
–
–
–
Initial NIHSS, median (IQR)
4 (3–6)
3 (2–4)
0.000
1.404
1.133–1.741
0.002
Lesion diameter, mm, mean (SD) LA (Fazekas scale C2), N (%)
13.38 ± 3.07 16 (34.8)
12.51 ± 3.29 67 (41.1)
0.113 0.439
– –
– –
– –
0.431
Previous antiplatelet, N (%)
4 (8.7)
9 (5.5)
Previous stain, N (%)
5 (10.9)
12 (7.4)
Current medications Mono-antiplatelet treatment, N (%)
41 (89.1)
140 (85.9)
0.569
Acute stain treatment N (%)
18 (39.1)
63 (38.7)
0.953
Ipsilateral MCA stenosis, N (%)
20 (43.5)
42 (25.8)
0.020
1.435
0.626–3.287
0.393
ICAS, N (%)
17 (37.0)
47 (28.8)
0.291
–
–
–
Atherosclerosis
ECAS, N (%) END, N (%)
13 (28.3)
24 (14.7)
0.034
1.244
0.477–3.243
0.655
22 (47.8)
31 (19.0)
0.000
2.637
1.208–5.759
0.015
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Discussion Consistent with previous results [13, 14], we found that patients with pSSSI had higher prevalence of atherosclerosis indicators (diabetes mellitus, hyperlipidemia and atherosclerotic disease), while those patients with dSSSI had higher prevalence of small artery disease indicators (hypertension and leukoaraiosis). The risk factor profiles between the two patterns of patients were different. Moreover, we also found that pSSSI pattern was the independent predictor of END and the END independently predicted the subsequent poor outcome at 90 days after onset. To our best knowledge, few studies had focused on the relationship between lesion patterns and functional outcome to date. As we all know, END was a known complication of stroke in general and subcortical stroke in particular [17]. It was reported that subcortical infarcts occurred when a vessel supplying the subcortex becomes occluded or suffers from critical hypoperfusion. And for subcortical infarcts, the higher number of vessels with intracranial atherosderosis, the more likely the patients to develop END [11, 18–20]. That is to say, the atherosderotic burden was significantly associated with the presence of END in patients with subcortical infarct. In line with that, branch atheromatous disease resulting from occlusion of the mouth of the branch which was also reported to be more prone to show worsening or fluctuating symptoms during hospitalization [21]. In addition, according to a recent study, hypoperfusion was also reported to be associated with poor outcome after stroke [22–24]. Compared with dSSSI, pSSSI showed remarkable atherosclerosis features and had few collateral vessels in the infarct area. Therefore, the higher atherosderotic burden and the hypoperfusion might play a role in the development of END. The potential pathogenesis might be: thrombus propagation leading to progressive occlusion of lateral branches, or embolus dropped from the active atherosderotic plaques and traveled distally to the cortical branches, or educed perfusion in the proximal tissue area, which might lead to new infarct or infarct expansion [3, 19–24]. Some other pathogenesis, such as inflammation and edema, etc., were poorly elucidated and needed to be further studied [3]. We also found that female sex was an independent risk factor of END as well as poor outcome. However, the reason for such findings still remained unexplained, and further exploration was required [25, 26]. Previous reports demonstrated that stenosis of any degree in the parent artery was regarded as a significant cause of SSSI; however, mild degree of parent artery disease was not analyzed in our study, that might be why we did not find the independent association between parent artery and END. We
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might thus underestimate the predictive value of parent artery disease for END in patients with SSSI [27, 28]. Moreover, we also did not find the independent association between initial NIHSS and END, despite the fact that the initial NIHSS was an independent risk factor of poor functional outcome at 90 days after admission. Some limitations of our study should be emphasized. First, this study was a single hospital-based study with small sample size, the findings needed to be further confirmed in multicenter prospective studies with large sample. Second, the second MRI after worsening was not regularly performed, so the specific pathophysiology of worsening was not evidently demonstrated. Third, we just analyzed the short-term prognosis of SSSI in this study, the prognosis of long-term prognosis of SSSI was not analyzed according to the lesion patterns; further researches were needed. In conclusion, the pattern of pSSSI was significantly associated with the presence of END and the END predicted the subsequent poor outcome. Conflict of interest
No conflict of interest.
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