Atherosclerosis 240 (2015) 278e283
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Basilar plaque on high-resolution MRI predicts progressive motor deficits after pontine infarction Sung-Hwan Lim a, 1, Hojin Choi a, 1, Hee-Tae Kim a, Juhan Kim a, Sung Hyuk Heo b, Dae-il Chang b, Ji Young Lee c, Young-Jun Lee c, Ji Young Kim d, Hyun Young Kim a, Young Seo Kim a, * a
Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea Department of Neurology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Department of Radiology, College of Medicine, Hanyang University, Seoul, Republic of Korea d Department of Nuclear Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 January 2015 Received in revised form 12 March 2015 Accepted 18 March 2015 Available online 20 March 2015
Background: The association between progressive motor deficits (PMD) in acute pontine infarction and basilar stenosis is unclear. High resolution MRI (HRMRI) is an emerging tool for basilar artery evaluation and might provide more accurate information. We aimed to analyze the association between basilar plaque assessed by HRMRI and PMD after acute pontine infarction. Methods: We identified consecutive patients with unilateral pontine infarction within 24 h of stroke onset. All the patients underwent diffusion weighted MRI, MR angiography and HRMRI within 24 h of admission. PMD was defined as an increase in National Institutes of Health Stroke Scale score by 1 during hospitalization. Factors potentially associated with PMD were validated by multivariate analyses. Results: Of a total of 87 patients, 63 (72%) had paramedian pontine infarction (PPI) and PMD was observed in 28 (32%) patients. Apparent basilar plaque assessed by HRMRI was more frequent in those with PMD than in those without PMD (52% versus 33%, p < 0.001). In contrast, the frequency of basilar stenosis (>30%) assessed by MR angiography was similar regardless of PMD. In the patients with PPI, PMD was associated with hypertension and apparent plaque on HRMRI. After adjusting covariates, PMD was independently associated with apparent plaque on HRMRI (OR, 9.1; 95% CI 1.4e58.9). Conclusions: Our results suggest that basilar plaque assessed by HRMRI is associated with PMD in patients with acute unilateral pontine infarction. Since basilar stenosis may be underestimated by MR angiography, HRMRI may provide additional information for predicting PMD and evaluating basilar artery stenosis. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Pontine infarction Basilar plaque High-resolution MRI Progressive motor deficit
1. Introduction Isolated pontine infarction commonly produces lacunar syndrome and can be classified into paramedian pontine infarction (PPI) and small deep pontine infarction (SDPI) according to the presence of ventral surface involvement [1e4]. The former is known to be associated with basilar artery atherosclerotic disease (BAD) and the latter is known to be associated with lacunar pontine
* Corresponding author. Department of Neurology, College of Medicine, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul 133-792, Republic of Korea. E-mail address: [email protected] (Y.S. Kim). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.029 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
infarction (LPI) [1e3]. However, the recent technique of high resolution MRI (HRMRI), which is more useful for visualizing vessel walls, has revealed the presence of basilar plaque when angiograms obtained by magnetic resonance angiography (MRA) or digital subtraction angiography did not [4e6]. Based on these findings, some authors have proposed that BAD may also be the main pathology of DPI [4,7]. Early neurologic deterioration (END) after ischemic stroke may result in increased mortality and morbidity [8]. Therefore, early determination of END and appropriate treatment is important for better outcomes [9]. The possible predictors of END are initial stroke severity, history of diabetes mellitus, lacunar infarction, atrial fibrillation and large vessel occlusion [9]. However, in patients with pontine infarction, the relationship between basilar
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artery stenosis and END is still unclear. In general, steno-occlusive arterial disease of the basilar artery is known to be associated with END [10,11], but recent studies based on MR angiography (MRA) found no association between BAD and END or the progressive motor deficits (PMD) of pontine infarction [12,13]. Since, HRMRI can give more accurate information about the basilar artery, studies based on HRMRI might yield different results. In this study, we hypothesized that basilar plaque assessed by HRMRI might be associated with PMD in acute unilateral pontine infarction. We therefore compared MRA and HRMRI to see if there was any difference between them. 2. Material and methods 2.1. Study population Between September 2009 and May 2013, we identified in a prospective registry 90 consecutive patients with unilateral isolated pontine infarction who were admitted to two centers (Hanyang University Hospital and Kyung Hee University Hospital) within 24 h of symptom onset. Unilateral isolated pontine infarction was defined as focal neurologic symptoms with relevant lesions on diffusion-weighted images (DWI) and without concurrent infarcts outside the pons [1]. Patients with basilar artery occlusion (n ¼ 1) and anatomical variations (n ¼ 2) were excluded. After excluding these patients, the total study population consisted of 87 patients. We performed a retrospective analysis after approval by the Institutional Review Board of Hanyang University Hospital. 2.2. Demographic characteristics and risk factors Demographic and clinical information was recorded on admission. The data included age, gender, risk factors for stroke (hypertension, diabetes mellitus, hyperlipidemia, smoking, and atrial fibrillation), and history of medication (anti-hypertensives, antiplatelets and statins). Hypertension was defined as a history of using antihypertensive medication, or systolic blood pressure (BP) 140 mm Hg or diastolic BP 90 mm Hg at discharge. Diabetes was defined as the use of hypoglycemic agents, fasting blood glucose 126 mg/dl, random blood glucose 200 mg/dl, or glycosylated hemoglobin >6.4% on admission. Hyperlipidemia was defined as previous use of lipid-lowering agents, or fasting serum total cholesterol level 240 mg/dl and/or low-density lipoprotein level 160 mg/dl. Subjects were classified as either current smokers or non-smokers. To investigate whether the patients have atrial fibrillation, they underwent 24 h Holter monitoring. To assess clinical progression, National Institute of Health Stroke Scale (NIHSS) scores were checked at admission, at discharge, and at the time of maximal neurologic deficit if this was present. Modified Rankin Scale (mRS) scores were obtained at discharge. Systolic blood pressure and diastolic blood pressure were measured from the arm in a supine position on admission. Laboratory tests including white blood cell count and hemoglobin were checked at admission. Lipid profiles, comprising total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides, fasting blood glucose, hemoglobin A1C, high-sensitivity C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and homocysteine were checked on the day after admission after overnight fasting. Progressive motor deficit (PMD) was defined as an increase of their motor NIHSS score of 1 between the initial and maximal neurologic deficit in the first week [12]. 2.3. Image acquisition and analysis All the patients in the two centers (Hanyang University Hospital
279
and Kyung Hee University Hospital) underwent the same imaging protocol within 24 h of admission, using3-Tesla MR machines (Achieva, Philips, Best, The Netherlands) with eight-channel SENSE head coils. The standardized protocol of MRI was performed as previously described [5]. The patients with unilateral pontine infarcts were divided into 2 groups based on the location of the lesion as seen on DWIs: paramedian pontine infarct (PPI) and small deep pontine infarct (SDPI). PPI was defined as a unilateral pontine infarct involving the ventral surface of the pons, and SDPI was defined as unilateral pontine infarct not involving the ventral surface of the pons [2,6]. The volumes of pontine infarcts were calculated by summing the involved infarct areas on DWIs using an image analyzer (MIPAV 7.0, Medical Image Processing Analysis and Visualization; National Institutes of Health, Bethesda, MD, USA). As previously described, the extent of stenosis on MRA was estimated from the maximum intensity projection (MIP) images (MRA analysis), and the degree of stenosis on HRMRI was calculated from proton-density weighted HRMRIs (HRMRI analysis) [5]. Two trained neurologists (YSK and SHL), blind to all the clinical information, evaluated the degree of stenosis and calculated averages for the final data. Basilar plaques were categorized into three groups (no plaque, minimal plaque and apparent plaque) as previously described [5]. The k statistics for the concordance rate showed excellent agreement (k ¼ 0.86, P < 0.05). Any discrepancies between the 2 readers were resolved by consensus with another neuroradiologist (YJL). 2.4. Statistical analysis Patients were initially divided into two groups by the presence or absence of PMD, and differences between variables were tested with Pearson's chi-square test, Fisher's exact test, Student's t-test, or the ManneWhitney U test as appropriate. Since, PMD has been encountered only in patients with PPI, additional analyses were restricted to the patients with PPI based on the presence of PMD. Finally, predictive factors associated with PMD in patients with PPI were analyzed using multivariable logistic regression analysis. The adjusted variables were selected from the results of the univariate analysis with P < 0.2. Values of p < 0.05 were considered statistically significant and all statistical analyses were carried out with the SPSS 21.0 package for Windows (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Baseline characteristics according to PMD A total of 87 patients were included in this study, and baseline characteristics of the patients according to the presence of PMD are shown in Table 1. PMD occurred in 28 (32%) of the 87 patients. Twelve (43%) patients were male, and the mean age (±SD) was 68.3 (±10.5) years. Baseline characteristics such as demographics, risk factors, clinical findings, laboratory findings and medication history were not significantly different in the two groups. However PMD only occurred in patients with PPI. The patients with SDPI did not experience any PMD during the first week. Initial large infarct volume was marginally associated with PMD but did not reach statistical significance. 3.2. Location of pontine infarction and detection of basilar plaque Baseline characteristics according to the location of pontine infarction are shown in Supplemental Table 1. The occurrence of PPI was associated with higher cholesterol and low-density lipoprotein levels. Data on the presence of basilar plaques
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Table 1 Baseline characteristics of patients according to presence of progressive motor deficits (PMD). PMD
Demographics Age, years Gender, male (%) Risk factors Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Current smoking (%) Atrial fibrillation (%) Clinical findings Initial NIHSS, score Initial SBP (mmHg) Initial DBP (mmHg) Laboratory findings White blood cell (103/mm3) Hemoglobin (g/dl) Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglyceride (mg/dl) Fasting blood glucose (mg/dl) Hemoglobin A1c (%) C-reactive protein (mg/dl) Erythrocyte sedimentation rate (mm/hr) Homocysteine (umol/l) Previous medication history Anti-hypertensive use (%) Anti-platelet use (%) Statin use (%) Lesion location Paramedian pontine infarction (%) Small deep pontine infarction (%) Infarction volume (mm3)
p
Without (n ¼ 59)
With (n ¼ 28)
65.9 ± 10.7 35 (59)
68.3 ± 10.5 12 (43)
0.790 0.150*
43 (73) 21 (36) 23 (39) 21 (36) 3 (5)
24 (86) 15 (54) 13 (46) 4 (14) 3 (11)
0.184* 0.112* 0.510* 0.065¶ 0.382¶
3.7 ± 4.0 151.6 ± 25.9 89.8 ± 13.3
3.6 ± 3.1 161.3 ± 28.7 84.2 ± 15.8
0.755y 0.118 0.089
7.2 ± 1.9 13.7 ± 1.6 175.9 ± 36.9 43.0 ± 12.1 109.0 ± 32.4 139.0 ± 127.4 115.8 ± 39.6 6.7 ± 1.4 0.5 ± 1.0 16.3 ± 15.1 12.6 ± 4.4
7.6 ± 2.6 13.9 ± 1.7 181.8 ± 54.1 43.0 ± 9.9 114.4 ± 40.5 119.5 ± 54.7 128.7 ± 40.5 7.0 ± 1.7 0.5 ± 0.9 22.9 ± 21.0 10.8 ± 4.2
0.404 0.600 0.608 0.989 0.504 0.440 0.163 0.268 0.917 0.109 0.113
34 (58) 22 (37) 12 (20)
21 (75) 11 (39) 4 (14)
0.116* 0.858* 0.496¶ 50%) on HRMRI was detected in 12 of PPI group (19%), and 30e50% stenosis was found in 13 patients (21%) in this group. There were no patients in the SDPI group with significant stenosis (>50%) but 6 (25%) had 30e50% stenosis. However, in the MRA analysis, there were 11 patients (17%) with more than 30% stenosis in the PPI group and 3 (13%) in SDPI group. The detection rate of basilar stenosis was thus more than twice as high by HRMRI than MRA.
3.3. Potential predictors of PMD in PPI patients Since PMD was only seen in patients with PPI, we further analyzed the latter. PMD was significantly associated with NIHSS and mRS scores at discharge (p < 0.001). Among the PMD patients, 2 had “no plaque” (18%), 4 had “minimal plaque” (22%) and 22 had “apparent plaque” (67%). The baseline characteristics of the PPI patients according to the presence of PMD are described in Table 3. In the univariate analysis, the presence of hypertension was the only significant variable associated with PMD (p ¼ 0.042). There were no significant differences in volume of infarct or laboratory findings between the patients with and without PMD. Finally, we performed multivariable logistic regression analyses separately based on the HRMRI and MRA results (Table 4). Apparent basilar
Table 2 Comparison of basilar plaques and severity of basilar artery stenosis by MRA and HRMRI according to location of pontine infarction. Degree of stenosis
None 1e29% 30e49% 50e99%
Paramedian pontine infarction (n ¼ 63)
Small deep pontine infarction (n ¼ 24)
No plaque (n ¼ 11)
Minimal plaque (n ¼ 19)
Apparent plaque (n ¼ 33)
MRA analysis
MRA analysis
MRA analysis
HRMRI analysis
p
11 (100) 0 0 0
7 (37) 12 (63) 0 0
5 17 8 3
0 8 (24) 13 (40) 12 (36)
0.001 6 (100) 0 0 0
(15) (52) (24) (9)
No plaque (n ¼ 6)
Minimal plaque (n ¼ 10)
Apparent plaque (n ¼ 8)
MRA analysis
MRA analysis
MRA analysis
HRMRI analysis
p
9 (90) 1 (10) 0 0
2 3 2 1
0 2 (25) 6 (75) 0
0.184
(25) (37) (25) (13)
Data are numbers of patients (%), Fisher's exact test were used to compare MRA analysis and HRMRI analysis in each group with apparent plaque.
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281
Table 3 Clinical characteristics of PPI patients according to presence of PMD. PMD
Demographics Age, years Gender, female (%) Risk factors Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Current smoking (%) Atrial fibrillation (%) Clinical findings Initial NIHSS, score Initial SBP (mmHg) Initial DBP (mmHg) Laboratory findings White blood cell (103/mm3) Hemoglobin (g/dl) Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglyceride (mg/dl) Fasting blood glucose (mg/dl) Hemoglobin A1c (%) High sensitivity C-reactive protein (mg/dl) Erythrocyte sedimentation rate (mm/hr) Homocysteine (umol/l) Medication history Anti-hypertensive use (%) Anti-platelet use (%) Statin use (%) Infarction volume (mm3)
p
Without (n ¼ 35)
With (n ¼ 28)
67.1 ± 11.3 17 (49)
68.3 ± 10.5 16 (57)
0.666 0.498*
22 (63) 11 (31) 17 (49) 9 (26) 2 (6)
24 (86) 15 (54) 13 (46) 4 (14) 3 (11)
0.042* 0.076* 0.866* 0.426¶ 0.648¶
4.4 ± 2.7 150.7 ± 28.8 88.7 ± 14.1
4.4 ± 2.9 161.3 ± 28.7 84.2 ± 15.8
0.935y 0.151 0.243
7.1 ± 1.8 13.6 ± 1.6 185.3 ± 27.4 43.0 ± 10.1 134.2 ± 143.6 118.0 ± 26.7 114.3 ± 36.9 6.5 ± 1.4 0.4 ± 0.7 16.1 ± 13.3 12.0 ± 4.8
7.6 ± 2.6 13.9 ± 1.7 181.8 ± 54.1 43.0 ± 9.9 1119.5 ± 54.7 114.4 ± 40.5 128.7 ± 40.5 7.0 ± 1.7 0.5 ± 0.9 22.9 ± 21.0 10.8 ± 4.2
0.353 0.489 0.758 0.998 0.609 0.674 0.145 0.162 0.635 0.135 0.356
9 (26) 18 (51) 5 (14) 579.9 ± 453.0
21 (75) 11 (39) 4 (14) 613.6 ± 514.9
0.056* 0.250* 1.000¶ 0.784
Data are presented as mean ± SD or number (%). NIHSS, National Institute of Health Stroke Scale; SBP, systolic blood pressure; DBP, diastolic blood pressure; Student’s t- test, *Pearson chi-square test, ythe Mann-Whitney U test, and ¶Fisher’s exact test were used.
Table 4 Multivariable analysis: factors associated with PMD in PPI patients. HRMRI analysis
MRA analysis
Variable
Unadjusted OR
Adjusted OR
p
Variable
Unadjusted OR
Adjusted OR
p
Hypertension Diabetes mellitus ESR Basilar plaque No Minimal Apparent
3.5 (1.0e12.5) 2.5 (0.9e7.0) 1.0 (0.9e1.1)
3.2 (0.7e15.6) 1.4 (0.4e5.4) 1.0 (0.9e1.1)
0.149 0.604 0.293
3.8 (1.1e13.2) 2.2 (0.8e6.1) 1.0 (0.9e1.1)
4.8 (1.0e22.2) 2.3 (0.7e7.9) 1.0 (0.9e1.1)
0.045 0.189 0.346
(reference) 1.2 (0.2e7.9) 9.0 (1.6e49.0)
(reference) 1.2 (0.2e8.4) 9.1 (1.4e58.9)
0.863 0.020
Hypertension Diabetes mellitus ESR Basilar stenosis None 1e29% 30e49% 50e99%
(reference) 2.5 (0.8e7.7) 2.3 (0.4e11.9) 4.6 (0.4e59.1)
(reference) 3.0 (0.8e11.6) 2.2 (0.3e15.6) 4.3 (0.3e61.1)
0.110 0.448 0.280
p for multivariate models; Data are presented as odds ratios (95% confidence interval). Adjusted variables with P < 0.2 were selected from the results of univariate analysis.
plaque on HRMRI was significantly associated with PMD in the patients with PPI (p ¼ 0.020). However, the analysis based on MRA did not detect a significant relationship between basilar artery stenosis and PMD.
4. Discussion In the present study we found that PMD only occurred in the patients with PPI and it was independently associated with basilar artery stenosis evaluated by HRMRI but not with basilar artery stenosis on MRA. These findings are of interest because HRMRI has been recently shown to reveal basilar artery wall status more accurately, and our results differ from previous studies that were based on MRA [12,13]. Although, definitions of PMD and END vary, progression of
motor symptoms and early neurological deterioration after pontine infarction are relatively common, ranging from 22% to 31% [11e15]. In our study, PMD only occurred in the PPI patients and its prevalence was 32%. Since we defined PMD as an increment of at least 1 point in the NIHSS motor score [12], it was not encountered among the patients with DPI since they had sensory symptoms, gaze abnormalities and/or ataxia, with only minor motor symptoms. Our definition of PMD may have contributed to the greater prevalence of PMD in this study than in previous studies. The prevalence would be lower using other definitions such >2 or 4 points on NIHSS score, as in other reports [11,13e15]. Since, a large number of patients with acute pontine infarction experience neurological deterioration, many studies have investigated predictors of END, and lower pontine lesion [12], larger lesion volume [13], and longer basilar artery diameter [14] were found to be associated with END. In
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terms of basilar artery steno-occlusive lesions, some reports have revealed an association [10,11], others not [12,13]. However, these studies evaluated the basilar artery by MRA without assessing basilar wall status. HRMRI is an emerging tool for evaluating intracranial arterial disease because it can visualize vessel walls, permitting assessment of both luminal stenosis and vessel wall pathology [16,17]. It has been reported that HRMRI can reliably identify plaque features such as plaque vulnerability, intraplaque hemorrhage and arterial remodeling [17e19]. It was also found that atherosclerotic plaques that were missed by luminal angiographies could be detected by HRMRI [5,19]. Recently, HRMRI has been used to differentiate atherosclerosis, inflammation, vasospasm, Moyamoya disease and primary CNS angiitis, which have different treatment implications [20e23]. Therefore, we considered that evaluation of the intracranial stenosis by HRMRI might provide more information than luminal angiographies, and indeed we failed above to find any association between PMD and basilar artery stenosis based on MRA, but detected a highly significant association when assessed by HRMRI. Since the major cause of progressive pontine infarction is known to be associated with stepwise occlusion of the branches of small penetrating arteries and decreased blood flow [24], the basilar plaque on HRMRI may reflect at least one mechanism underlying the progressive pontine infarction. Although our methods have not been validated by many studies, we speculate that basilar plaque on HRMRI may be an important predictor of PMD in isolated pontine infarction. It could be important because many patients have apparent basilar artery plaque without significant stenosis according to luminal angiography. Previous studies in patients with isolated pontine infarction demonstrated that PPIs are associated with basilar artery stenosis and DPIs with lacunar infarction [1e3]. However, recent studies based on HRMRI have revealed basilar plaques in DPI patients and have stressed that DPI could also be a branch atheromatous disease [4,7]. In addition, one study showed that the frequencies of basilar artery atherosclerosis by HRMRI and small vessel disease were similar in patients with PPI and DPI [25]. In our study, we found apparent plaques in 33% of the DPI patients, a lower proportion than among the PPI patients (52%). Although a number of DPI patients had apparent basilar plaque, more consideration needs to be paid to whether basilar plaque is the real culprit in DPI patients. In a previous study we identified 26 apparent plaques (22%) and 40 minimal plaques (34%) in patients with 117 anterior circulation infarcts [5]. This suggests that the basilar plaque that is seen in DPI may not be the cause of the disease but an innocent bystander. Therefore, we suggest that basilar plaque in patients with DPI should be more cautiously considered a type of occlusive disease. The present study had several limitations. First, the design of the study was retrospective and it had a small sample size. Thus, a study with a larger sample to allow calculation of relative risks is needed to confirm the predictive value of basilar plaque for PMD. Second, we only included unilateral pontine infarction patients and excluded basilar artery-occluded patients, which may have underestimated the frequency of motor progression. Finally, we only used proton density weighted images without evaluating other sequences including contrast enhancement. Since contrast enhancement of vessel walls may represent vascular inflammation or hemorrhage, further studies using these methods are needed to clarify the relationship between basilar plaque and PMD. In conclusion, PMD among patients with acute isolated pontine infarction is more common in PPI patients with apparent basilar plaques on HRMRI. Therefore, assessment of basilar plaques could be a useful tool for predicting PMD and outcomes in pontine infarction patients.
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Basilar plaque on high-resolution MRI predicts progressive motor deficits after pontine infarction Sung-Hwan Lim a, 1, Hojin Choi a, 1, Hee-Tae Kim a, Juhan Kim a, Sung Hyuk Heo b, Dae-il Chang b, Ji Young Lee c, Young-Jun Lee c, Ji Young Kim d, Hyun Young Kim a, Young Seo Kim a, * a
Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea Department of Neurology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Department of Radiology, College of Medicine, Hanyang University, Seoul, Republic of Korea d Department of Nuclear Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 January 2015 Received in revised form 12 March 2015 Accepted 18 March 2015 Available online 20 March 2015
Background: The association between progressive motor deficits (PMD) in acute pontine infarction and basilar stenosis is unclear. High resolution MRI (HRMRI) is an emerging tool for basilar artery evaluation and might provide more accurate information. We aimed to analyze the association between basilar plaque assessed by HRMRI and PMD after acute pontine infarction. Methods: We identified consecutive patients with unilateral pontine infarction within 24 h of stroke onset. All the patients underwent diffusion weighted MRI, MR angiography and HRMRI within 24 h of admission. PMD was defined as an increase in National Institutes of Health Stroke Scale score by 1 during hospitalization. Factors potentially associated with PMD were validated by multivariate analyses. Results: Of a total of 87 patients, 63 (72%) had paramedian pontine infarction (PPI) and PMD was observed in 28 (32%) patients. Apparent basilar plaque assessed by HRMRI was more frequent in those with PMD than in those without PMD (52% versus 33%, p < 0.001). In contrast, the frequency of basilar stenosis (>30%) assessed by MR angiography was similar regardless of PMD. In the patients with PPI, PMD was associated with hypertension and apparent plaque on HRMRI. After adjusting covariates, PMD was independently associated with apparent plaque on HRMRI (OR, 9.1; 95% CI 1.4e58.9). Conclusions: Our results suggest that basilar plaque assessed by HRMRI is associated with PMD in patients with acute unilateral pontine infarction. Since basilar stenosis may be underestimated by MR angiography, HRMRI may provide additional information for predicting PMD and evaluating basilar artery stenosis. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Pontine infarction Basilar plaque High-resolution MRI Progressive motor deficit
1. Introduction Isolated pontine infarction commonly produces lacunar syndrome and can be classified into paramedian pontine infarction (PPI) and small deep pontine infarction (SDPI) according to the presence of ventral surface involvement [1e4]. The former is known to be associated with basilar artery atherosclerotic disease (BAD) and the latter is known to be associated with lacunar pontine
* Corresponding author. Department of Neurology, College of Medicine, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul 133-792, Republic of Korea. E-mail address: [email protected] (Y.S. Kim). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.029 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
infarction (LPI) [1e3]. However, the recent technique of high resolution MRI (HRMRI), which is more useful for visualizing vessel walls, has revealed the presence of basilar plaque when angiograms obtained by magnetic resonance angiography (MRA) or digital subtraction angiography did not [4e6]. Based on these findings, some authors have proposed that BAD may also be the main pathology of DPI [4,7]. Early neurologic deterioration (END) after ischemic stroke may result in increased mortality and morbidity [8]. Therefore, early determination of END and appropriate treatment is important for better outcomes [9]. The possible predictors of END are initial stroke severity, history of diabetes mellitus, lacunar infarction, atrial fibrillation and large vessel occlusion [9]. However, in patients with pontine infarction, the relationship between basilar
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artery stenosis and END is still unclear. In general, steno-occlusive arterial disease of the basilar artery is known to be associated with END [10,11], but recent studies based on MR angiography (MRA) found no association between BAD and END or the progressive motor deficits (PMD) of pontine infarction [12,13]. Since, HRMRI can give more accurate information about the basilar artery, studies based on HRMRI might yield different results. In this study, we hypothesized that basilar plaque assessed by HRMRI might be associated with PMD in acute unilateral pontine infarction. We therefore compared MRA and HRMRI to see if there was any difference between them. 2. Material and methods 2.1. Study population Between September 2009 and May 2013, we identified in a prospective registry 90 consecutive patients with unilateral isolated pontine infarction who were admitted to two centers (Hanyang University Hospital and Kyung Hee University Hospital) within 24 h of symptom onset. Unilateral isolated pontine infarction was defined as focal neurologic symptoms with relevant lesions on diffusion-weighted images (DWI) and without concurrent infarcts outside the pons [1]. Patients with basilar artery occlusion (n ¼ 1) and anatomical variations (n ¼ 2) were excluded. After excluding these patients, the total study population consisted of 87 patients. We performed a retrospective analysis after approval by the Institutional Review Board of Hanyang University Hospital. 2.2. Demographic characteristics and risk factors Demographic and clinical information was recorded on admission. The data included age, gender, risk factors for stroke (hypertension, diabetes mellitus, hyperlipidemia, smoking, and atrial fibrillation), and history of medication (anti-hypertensives, antiplatelets and statins). Hypertension was defined as a history of using antihypertensive medication, or systolic blood pressure (BP) 140 mm Hg or diastolic BP 90 mm Hg at discharge. Diabetes was defined as the use of hypoglycemic agents, fasting blood glucose 126 mg/dl, random blood glucose 200 mg/dl, or glycosylated hemoglobin >6.4% on admission. Hyperlipidemia was defined as previous use of lipid-lowering agents, or fasting serum total cholesterol level 240 mg/dl and/or low-density lipoprotein level 160 mg/dl. Subjects were classified as either current smokers or non-smokers. To investigate whether the patients have atrial fibrillation, they underwent 24 h Holter monitoring. To assess clinical progression, National Institute of Health Stroke Scale (NIHSS) scores were checked at admission, at discharge, and at the time of maximal neurologic deficit if this was present. Modified Rankin Scale (mRS) scores were obtained at discharge. Systolic blood pressure and diastolic blood pressure were measured from the arm in a supine position on admission. Laboratory tests including white blood cell count and hemoglobin were checked at admission. Lipid profiles, comprising total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides, fasting blood glucose, hemoglobin A1C, high-sensitivity C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and homocysteine were checked on the day after admission after overnight fasting. Progressive motor deficit (PMD) was defined as an increase of their motor NIHSS score of 1 between the initial and maximal neurologic deficit in the first week [12]. 2.3. Image acquisition and analysis All the patients in the two centers (Hanyang University Hospital
279
and Kyung Hee University Hospital) underwent the same imaging protocol within 24 h of admission, using3-Tesla MR machines (Achieva, Philips, Best, The Netherlands) with eight-channel SENSE head coils. The standardized protocol of MRI was performed as previously described [5]. The patients with unilateral pontine infarcts were divided into 2 groups based on the location of the lesion as seen on DWIs: paramedian pontine infarct (PPI) and small deep pontine infarct (SDPI). PPI was defined as a unilateral pontine infarct involving the ventral surface of the pons, and SDPI was defined as unilateral pontine infarct not involving the ventral surface of the pons [2,6]. The volumes of pontine infarcts were calculated by summing the involved infarct areas on DWIs using an image analyzer (MIPAV 7.0, Medical Image Processing Analysis and Visualization; National Institutes of Health, Bethesda, MD, USA). As previously described, the extent of stenosis on MRA was estimated from the maximum intensity projection (MIP) images (MRA analysis), and the degree of stenosis on HRMRI was calculated from proton-density weighted HRMRIs (HRMRI analysis) [5]. Two trained neurologists (YSK and SHL), blind to all the clinical information, evaluated the degree of stenosis and calculated averages for the final data. Basilar plaques were categorized into three groups (no plaque, minimal plaque and apparent plaque) as previously described [5]. The k statistics for the concordance rate showed excellent agreement (k ¼ 0.86, P < 0.05). Any discrepancies between the 2 readers were resolved by consensus with another neuroradiologist (YJL). 2.4. Statistical analysis Patients were initially divided into two groups by the presence or absence of PMD, and differences between variables were tested with Pearson's chi-square test, Fisher's exact test, Student's t-test, or the ManneWhitney U test as appropriate. Since, PMD has been encountered only in patients with PPI, additional analyses were restricted to the patients with PPI based on the presence of PMD. Finally, predictive factors associated with PMD in patients with PPI were analyzed using multivariable logistic regression analysis. The adjusted variables were selected from the results of the univariate analysis with P < 0.2. Values of p < 0.05 were considered statistically significant and all statistical analyses were carried out with the SPSS 21.0 package for Windows (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Baseline characteristics according to PMD A total of 87 patients were included in this study, and baseline characteristics of the patients according to the presence of PMD are shown in Table 1. PMD occurred in 28 (32%) of the 87 patients. Twelve (43%) patients were male, and the mean age (±SD) was 68.3 (±10.5) years. Baseline characteristics such as demographics, risk factors, clinical findings, laboratory findings and medication history were not significantly different in the two groups. However PMD only occurred in patients with PPI. The patients with SDPI did not experience any PMD during the first week. Initial large infarct volume was marginally associated with PMD but did not reach statistical significance. 3.2. Location of pontine infarction and detection of basilar plaque Baseline characteristics according to the location of pontine infarction are shown in Supplemental Table 1. The occurrence of PPI was associated with higher cholesterol and low-density lipoprotein levels. Data on the presence of basilar plaques
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Table 1 Baseline characteristics of patients according to presence of progressive motor deficits (PMD). PMD
Demographics Age, years Gender, male (%) Risk factors Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Current smoking (%) Atrial fibrillation (%) Clinical findings Initial NIHSS, score Initial SBP (mmHg) Initial DBP (mmHg) Laboratory findings White blood cell (103/mm3) Hemoglobin (g/dl) Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglyceride (mg/dl) Fasting blood glucose (mg/dl) Hemoglobin A1c (%) C-reactive protein (mg/dl) Erythrocyte sedimentation rate (mm/hr) Homocysteine (umol/l) Previous medication history Anti-hypertensive use (%) Anti-platelet use (%) Statin use (%) Lesion location Paramedian pontine infarction (%) Small deep pontine infarction (%) Infarction volume (mm3)
p
Without (n ¼ 59)
With (n ¼ 28)
65.9 ± 10.7 35 (59)
68.3 ± 10.5 12 (43)
0.790 0.150*
43 (73) 21 (36) 23 (39) 21 (36) 3 (5)
24 (86) 15 (54) 13 (46) 4 (14) 3 (11)
0.184* 0.112* 0.510* 0.065¶ 0.382¶
3.7 ± 4.0 151.6 ± 25.9 89.8 ± 13.3
3.6 ± 3.1 161.3 ± 28.7 84.2 ± 15.8
0.755y 0.118 0.089
7.2 ± 1.9 13.7 ± 1.6 175.9 ± 36.9 43.0 ± 12.1 109.0 ± 32.4 139.0 ± 127.4 115.8 ± 39.6 6.7 ± 1.4 0.5 ± 1.0 16.3 ± 15.1 12.6 ± 4.4
7.6 ± 2.6 13.9 ± 1.7 181.8 ± 54.1 43.0 ± 9.9 114.4 ± 40.5 119.5 ± 54.7 128.7 ± 40.5 7.0 ± 1.7 0.5 ± 0.9 22.9 ± 21.0 10.8 ± 4.2
0.404 0.600 0.608 0.989 0.504 0.440 0.163 0.268 0.917 0.109 0.113
34 (58) 22 (37) 12 (20)
21 (75) 11 (39) 4 (14)
0.116* 0.858* 0.496¶ 50%) on HRMRI was detected in 12 of PPI group (19%), and 30e50% stenosis was found in 13 patients (21%) in this group. There were no patients in the SDPI group with significant stenosis (>50%) but 6 (25%) had 30e50% stenosis. However, in the MRA analysis, there were 11 patients (17%) with more than 30% stenosis in the PPI group and 3 (13%) in SDPI group. The detection rate of basilar stenosis was thus more than twice as high by HRMRI than MRA.
3.3. Potential predictors of PMD in PPI patients Since PMD was only seen in patients with PPI, we further analyzed the latter. PMD was significantly associated with NIHSS and mRS scores at discharge (p < 0.001). Among the PMD patients, 2 had “no plaque” (18%), 4 had “minimal plaque” (22%) and 22 had “apparent plaque” (67%). The baseline characteristics of the PPI patients according to the presence of PMD are described in Table 3. In the univariate analysis, the presence of hypertension was the only significant variable associated with PMD (p ¼ 0.042). There were no significant differences in volume of infarct or laboratory findings between the patients with and without PMD. Finally, we performed multivariable logistic regression analyses separately based on the HRMRI and MRA results (Table 4). Apparent basilar
Table 2 Comparison of basilar plaques and severity of basilar artery stenosis by MRA and HRMRI according to location of pontine infarction. Degree of stenosis
None 1e29% 30e49% 50e99%
Paramedian pontine infarction (n ¼ 63)
Small deep pontine infarction (n ¼ 24)
No plaque (n ¼ 11)
Minimal plaque (n ¼ 19)
Apparent plaque (n ¼ 33)
MRA analysis
MRA analysis
MRA analysis
HRMRI analysis
p
11 (100) 0 0 0
7 (37) 12 (63) 0 0
5 17 8 3
0 8 (24) 13 (40) 12 (36)
0.001 6 (100) 0 0 0
(15) (52) (24) (9)
No plaque (n ¼ 6)
Minimal plaque (n ¼ 10)
Apparent plaque (n ¼ 8)
MRA analysis
MRA analysis
MRA analysis
HRMRI analysis
p
9 (90) 1 (10) 0 0
2 3 2 1
0 2 (25) 6 (75) 0
0.184
(25) (37) (25) (13)
Data are numbers of patients (%), Fisher's exact test were used to compare MRA analysis and HRMRI analysis in each group with apparent plaque.
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281
Table 3 Clinical characteristics of PPI patients according to presence of PMD. PMD
Demographics Age, years Gender, female (%) Risk factors Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Current smoking (%) Atrial fibrillation (%) Clinical findings Initial NIHSS, score Initial SBP (mmHg) Initial DBP (mmHg) Laboratory findings White blood cell (103/mm3) Hemoglobin (g/dl) Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglyceride (mg/dl) Fasting blood glucose (mg/dl) Hemoglobin A1c (%) High sensitivity C-reactive protein (mg/dl) Erythrocyte sedimentation rate (mm/hr) Homocysteine (umol/l) Medication history Anti-hypertensive use (%) Anti-platelet use (%) Statin use (%) Infarction volume (mm3)
p
Without (n ¼ 35)
With (n ¼ 28)
67.1 ± 11.3 17 (49)
68.3 ± 10.5 16 (57)
0.666 0.498*
22 (63) 11 (31) 17 (49) 9 (26) 2 (6)
24 (86) 15 (54) 13 (46) 4 (14) 3 (11)
0.042* 0.076* 0.866* 0.426¶ 0.648¶
4.4 ± 2.7 150.7 ± 28.8 88.7 ± 14.1
4.4 ± 2.9 161.3 ± 28.7 84.2 ± 15.8
0.935y 0.151 0.243
7.1 ± 1.8 13.6 ± 1.6 185.3 ± 27.4 43.0 ± 10.1 134.2 ± 143.6 118.0 ± 26.7 114.3 ± 36.9 6.5 ± 1.4 0.4 ± 0.7 16.1 ± 13.3 12.0 ± 4.8
7.6 ± 2.6 13.9 ± 1.7 181.8 ± 54.1 43.0 ± 9.9 1119.5 ± 54.7 114.4 ± 40.5 128.7 ± 40.5 7.0 ± 1.7 0.5 ± 0.9 22.9 ± 21.0 10.8 ± 4.2
0.353 0.489 0.758 0.998 0.609 0.674 0.145 0.162 0.635 0.135 0.356
9 (26) 18 (51) 5 (14) 579.9 ± 453.0
21 (75) 11 (39) 4 (14) 613.6 ± 514.9
0.056* 0.250* 1.000¶ 0.784
Data are presented as mean ± SD or number (%). NIHSS, National Institute of Health Stroke Scale; SBP, systolic blood pressure; DBP, diastolic blood pressure; Student’s t- test, *Pearson chi-square test, ythe Mann-Whitney U test, and ¶Fisher’s exact test were used.
Table 4 Multivariable analysis: factors associated with PMD in PPI patients. HRMRI analysis
MRA analysis
Variable
Unadjusted OR
Adjusted OR
p
Variable
Unadjusted OR
Adjusted OR
p
Hypertension Diabetes mellitus ESR Basilar plaque No Minimal Apparent
3.5 (1.0e12.5) 2.5 (0.9e7.0) 1.0 (0.9e1.1)
3.2 (0.7e15.6) 1.4 (0.4e5.4) 1.0 (0.9e1.1)
0.149 0.604 0.293
3.8 (1.1e13.2) 2.2 (0.8e6.1) 1.0 (0.9e1.1)
4.8 (1.0e22.2) 2.3 (0.7e7.9) 1.0 (0.9e1.1)
0.045 0.189 0.346
(reference) 1.2 (0.2e7.9) 9.0 (1.6e49.0)
(reference) 1.2 (0.2e8.4) 9.1 (1.4e58.9)
0.863 0.020
Hypertension Diabetes mellitus ESR Basilar stenosis None 1e29% 30e49% 50e99%
(reference) 2.5 (0.8e7.7) 2.3 (0.4e11.9) 4.6 (0.4e59.1)
(reference) 3.0 (0.8e11.6) 2.2 (0.3e15.6) 4.3 (0.3e61.1)
0.110 0.448 0.280
p for multivariate models; Data are presented as odds ratios (95% confidence interval). Adjusted variables with P < 0.2 were selected from the results of univariate analysis.
plaque on HRMRI was significantly associated with PMD in the patients with PPI (p ¼ 0.020). However, the analysis based on MRA did not detect a significant relationship between basilar artery stenosis and PMD.
4. Discussion In the present study we found that PMD only occurred in the patients with PPI and it was independently associated with basilar artery stenosis evaluated by HRMRI but not with basilar artery stenosis on MRA. These findings are of interest because HRMRI has been recently shown to reveal basilar artery wall status more accurately, and our results differ from previous studies that were based on MRA [12,13]. Although, definitions of PMD and END vary, progression of
motor symptoms and early neurological deterioration after pontine infarction are relatively common, ranging from 22% to 31% [11e15]. In our study, PMD only occurred in the PPI patients and its prevalence was 32%. Since we defined PMD as an increment of at least 1 point in the NIHSS motor score [12], it was not encountered among the patients with DPI since they had sensory symptoms, gaze abnormalities and/or ataxia, with only minor motor symptoms. Our definition of PMD may have contributed to the greater prevalence of PMD in this study than in previous studies. The prevalence would be lower using other definitions such >2 or 4 points on NIHSS score, as in other reports [11,13e15]. Since, a large number of patients with acute pontine infarction experience neurological deterioration, many studies have investigated predictors of END, and lower pontine lesion [12], larger lesion volume [13], and longer basilar artery diameter [14] were found to be associated with END. In
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terms of basilar artery steno-occlusive lesions, some reports have revealed an association [10,11], others not [12,13]. However, these studies evaluated the basilar artery by MRA without assessing basilar wall status. HRMRI is an emerging tool for evaluating intracranial arterial disease because it can visualize vessel walls, permitting assessment of both luminal stenosis and vessel wall pathology [16,17]. It has been reported that HRMRI can reliably identify plaque features such as plaque vulnerability, intraplaque hemorrhage and arterial remodeling [17e19]. It was also found that atherosclerotic plaques that were missed by luminal angiographies could be detected by HRMRI [5,19]. Recently, HRMRI has been used to differentiate atherosclerosis, inflammation, vasospasm, Moyamoya disease and primary CNS angiitis, which have different treatment implications [20e23]. Therefore, we considered that evaluation of the intracranial stenosis by HRMRI might provide more information than luminal angiographies, and indeed we failed above to find any association between PMD and basilar artery stenosis based on MRA, but detected a highly significant association when assessed by HRMRI. Since the major cause of progressive pontine infarction is known to be associated with stepwise occlusion of the branches of small penetrating arteries and decreased blood flow [24], the basilar plaque on HRMRI may reflect at least one mechanism underlying the progressive pontine infarction. Although our methods have not been validated by many studies, we speculate that basilar plaque on HRMRI may be an important predictor of PMD in isolated pontine infarction. It could be important because many patients have apparent basilar artery plaque without significant stenosis according to luminal angiography. Previous studies in patients with isolated pontine infarction demonstrated that PPIs are associated with basilar artery stenosis and DPIs with lacunar infarction [1e3]. However, recent studies based on HRMRI have revealed basilar plaques in DPI patients and have stressed that DPI could also be a branch atheromatous disease [4,7]. In addition, one study showed that the frequencies of basilar artery atherosclerosis by HRMRI and small vessel disease were similar in patients with PPI and DPI [25]. In our study, we found apparent plaques in 33% of the DPI patients, a lower proportion than among the PPI patients (52%). Although a number of DPI patients had apparent basilar plaque, more consideration needs to be paid to whether basilar plaque is the real culprit in DPI patients. In a previous study we identified 26 apparent plaques (22%) and 40 minimal plaques (34%) in patients with 117 anterior circulation infarcts [5]. This suggests that the basilar plaque that is seen in DPI may not be the cause of the disease but an innocent bystander. Therefore, we suggest that basilar plaque in patients with DPI should be more cautiously considered a type of occlusive disease. The present study had several limitations. First, the design of the study was retrospective and it had a small sample size. Thus, a study with a larger sample to allow calculation of relative risks is needed to confirm the predictive value of basilar plaque for PMD. Second, we only included unilateral pontine infarction patients and excluded basilar artery-occluded patients, which may have underestimated the frequency of motor progression. Finally, we only used proton density weighted images without evaluating other sequences including contrast enhancement. Since contrast enhancement of vessel walls may represent vascular inflammation or hemorrhage, further studies using these methods are needed to clarify the relationship between basilar plaque and PMD. In conclusion, PMD among patients with acute isolated pontine infarction is more common in PPI patients with apparent basilar plaques on HRMRI. Therefore, assessment of basilar plaques could be a useful tool for predicting PMD and outcomes in pontine infarction patients.
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