Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2019, Vol. 10 Issue (3) : 570-577     DOI: 10.14336/AD.2018.0804
Orginal Article |
Total Burden of Cerebral Small Vessel Disease in Recurrent ICH versus First-ever ICH
Mangmang Xu, Yajun Cheng, Quhong Song, Ruozhen Yuan, Shuting Zhang, Zilong Hao, Ming Liu*
Center of Cerebrovascular Disease, Department of Neurology, West China Hospital, Sichuan University.Chengdu, 610041, Sichuan Province, China
Download: PDF(445 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

The relationship between recurrent intracerebral hemorrhage (ICH) and total burden of cerebral small vessel disease (CSVD) is not completely investigated. We aimed to study whether recurrent intracerebral hemorrhage (ICH) had higher CSVD score than first-ever ICH. Lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), cortical superficial siderosis (cSS) and CSVD score were rated on brain magnetic resonance imaging (MRI) in primary ICH patients. Recurrent ICHs were confirmed by reviewing the medical records and MRI scans. Mixed hematomas were defined as follows: deep + lobar, deep + cerebellar, or deep + lobar + cerebellar. Of the 184 patients with primary ICH enrolled (mean age, 61.0 years; 75.5% men), recurrent ICH was present in 45 (24.5%) patients; 26.1% (48/184) had ≥2 hematomas, 93.8% (45/48) of which exhibited recurrent ICH. Mixed hematomas were identified in 8.7% (16/184) of patients and bilateral hematomas in 17.9% (33/184). All mixed hematomas and bilateral hematomas were from cases of recurrent ICH. Patients with mixed etiology-ICH were more likely to have recurrent ICH than patients with cerebral amyloid angiopathy (CAA) or hypertensive angiopathy (HA)-related ICH (36.8% vs17.8%, p=0.008). Multivariate ordinal regression analysis showed that the presence of recurrent ICH (p=0.001), ≥2 hematomas (p=0.002), mixed hematomas (p<0.00001), and bilateral hematomas (p=0.002) were separately significantly associated with a high CSVD score. Recurrent ICH occurs mostly among patients with mixed etiology-ICH and is associated with a higher CSVD burden than first-ever ICH, which needs to be verified by future larger studies.

Keywords recurrent intracerebral hemorrhage      cerebral small vessel disease      primary intracerebral hemorrhage      white matter hyperintensity      cerebral microbleed     
Corresponding Authors: Liu Ming   
About author:

These authors contributed equally to this study.

Issue Date: 05 February 2018
E-mail this article
E-mail Alert
Articles by authors
Mangmang Xu
Yajun Cheng
Quhong Song
Ruozhen Yuan
Shuting Zhang
Zilong Hao
Ming Liu
Cite this article:   
Mangmang Xu,Yajun Cheng,Quhong Song, et al. Total Burden of Cerebral Small Vessel Disease in Recurrent ICH versus First-ever ICH[J]. Aging and disease, 2019, 10(3): 570-577.
URL:     OR
VariableAll participants
Recurrent ICH
First-ever ICH
P Value
Clinical characteristics
Age, Y, mean (SD)61.0 (12.5)60.8 (10.4)61.0 (13.1)0.902
Sex, male, n (%)139 (75.5)30 (66.7)109 (78.4)0.111
History of hypertension, n (%)122 (66.3)34 (75.6)88 (63.3)0.131
History of DM, n (%)17 (9.2)2 (4.4)15 (10.8)0.250
History of hyperlipidemia, n (%)6 (3.3)3 (6.7)3 (2.2)0.158
Smoking, n (%)61 (33.2)10 (22.2)51 (36.7)0.073
ICH etiology
 CAA-ICH, n (%)26 (14.1)5 (11.1)21 (15.1)0.066
 HA-ICH, n (%)75 (40.8)13 (28.9)62 (44.6)
 Mixed etiology-ICH, n (%)57 (31.0)21 (46.7)36 (25.9)
 Undetermined, n (%)26 (14.1)6 (13.3)20 (14.4)
Neuroimaging characteristics
ICH location,
 Deep, n (%)128 (69.6)28 (62.2)100 (71.9)0.177
 Lobar, n (%)48 (26.1)13 (28.9)35 (25.2)
 Cerebellum, n (%)8 (4.3)4 (8.9)4 (2.9)
Presence of lacunes, n (%)83 (45.1)26 (57.8)57 (41.0)0.049
Presence of WMH, n (%)90 (48.9)33 (73.3)57 (41.0)<0.0001
The severity of WMH
 Total WMH 0-2, n (%)81 (44.0)10 (22.2)71 (51.1)0.002
 Total WMH 3-4, n (%)50 (27.2)15 (33.3)35 (25.2)
 Total WMH 5-6, n (%)53 (28.8)20 (44.4)33 (23.7)
Presence of CMBs, n (%)135 (73.4)40 (88.9)95 (68.3)0.007
The severity of CMBs,
 0, n (%)49 (26.6)5 (11.1)44 (31.7)0.014
 1-4, n (%)63 (34.2)16 (35.6)47 (33.8)
 ≥5, n (%)72 (39.1)24 (53.3)48 (34.5)
Strictly deep CMBs, n (%)45 (24.5)11 (24.4)34 (24.5)0.998
Strictly lobar CMBs, n (%)27 (14.7)7 (15.6)20 (14.4)0.848
Mixed location CMBs, n (%)63 (34.2)22 (48.9)41 (29.5)0.017
The presence of cSS, n (%)44 (23.9)14 (31.1)30 (21.6)0.193
The presence of disseminated cSS, n (%)20 (10.9)6 (13.3)14 (10.1)0.584
Presence of EPVS>10 in BG, n (%)92 (50.0)23 (51.1)69 (49.6)0.864
The severity of EPVS in BG
 ≤10, n (%)92 (50.0)22 (48.9)70 (50.4)0.686
 11-20, n (%)49 (26.6)14 (31.1)35 (25.2)
 >20, n (%)43 (23.4)9 (20.0)34 (24.5)
The severity of EPVS in CSO
 ≤10, n (%)78 (42.4)15 (33.3)63 (45.3)0.069
 11-20, n (%)46 (25.009 (20.0)37 (26.6)
 >20, n (%)60 (32.6)21 (46.7)39 (28.1)
CSVD score, median (IQR)2 (1-3)3 (2-4)2 (1-3)0.002
Table 1  Clinical and neuroimaging characteristics of the study population.
Figure 1.  Flow gram of patient selection.
CSVD scoreAll participants (n=184)Recurrent ICH (n=45)First-ever ICH (n=139)
0, n (%)25 (13.6)2 (4.4)23 (16.5)
1, n (%)36 (19.6)8 (17.8)28 (20.1)
2, n (%)41 (22.3)8 (17.8)33 (23.7)
3, n (%)46 (25.0)10 (22.2)36 (25.9)
4, n (%)36 (19.6)17 (37.8)19 (13.7)
Table 2  Total CSVD score for patients with recurrent ICH and first-ever ICH.
Figure 2.  Hematoma characteristics and CSVD score. A) the presence of recurrent ICH and CSVD score. B) The number of hematomas and CSVD score. C) the presence of mixed hematomas and CSVD score. D) the presence of bilateral hematomas and CSVD score.
VariableUnadjustedAge- + sex-adjustedFully adjusted
OR (95% CI)pOR (95% CI)pOR (95% CI)p
Recurrent ICH0.361 (0.195 to 0.668)0.0010.313 (0.167 to 0.587)<0.0010.332 (0.174 to 0.632)0.001
≥2 hematomas0.375 (0.206 to 0.685)0.0010.334 (0.181 to 0.616)<0.0010.365 (0.195 to 0.683)0.002
Mixed hematomas0.093 (0.034 to 0.258)<0.000010.064 (0.022 to 0.187)<0.0000010.073 (0.024 to 0.216)<0.00001
Bilateral hematomas0.354 (0.178 to 0.705)0.0030.288 (0.142 to 0.582)0.0010.322 (0.156 to 0.664)0.002
Table 3  Association between ICH and total burden of CSVD in ordinal regression analysis.
[1] Pantoni L, Fierini F, Poggesi A (2014). Thrombolysis in acute stroke patients with cerebral small vessel disease. Cerebrovasc Dis, 37:5-13.
[2] Pantoni L (2010). Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol, 9:689-701.
[3] van der Flier WM, van Straaten EC, Barkhof F, Verdelho A, Madureira S, Pantoni L, et al. (2005). Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke, 36:2116-2120.
[4] Herrmann LL, Le Masurier M, Ebmeier KP (2008). White matter hyperintensities in late life depression: a systematic review. J Neurol Neurosurg Psychiatry, 79:619-624.
[5] Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. (2011). Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke, 42:2672-2713.
[6] Wardlaw JM, Smith C, Dichgans M (2013). Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol, 12:483-497.
[7] Roongpiboonsopit D, Charidimou A, William CM, Lauer A, Falcone GJ, Martinez-Ramirez S, et al. (2016). Cortical superficial siderosis predicts early recurrent lobar hemorrhage. Neurology, 87:1863-1870.
[8] Klarenbeek P, van Oostenbrugge RJ, Rouhl RP, Knottnerus IL, Staals J (2013). Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease. Stroke, 44:2995-2999.
[9] Staals J, Makin SD, Doubal FN, Dennis MS, Wardlaw JM (2014). Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology, 83:1228-1234.
[10] Huijts M, Duits A, van Oostenbrugge RJ, Kroon AA, de Leeuw PW, Staals J (2013). Accumulation of MRI Markers of Cerebral Small Vessel Disease is Associated with Decreased Cognitive Function. A Study in First-Ever Lacunar Stroke and Hypertensive Patients. Front Aging Neurosci, 5:72.
[11] Song TJ, Kim J, Song D, Yoo J, Lee HS, Kim YJ, et al. (2017). Total Cerebral Small-Vessel Disease Score is Associated with Mortality during Follow-Up after Acute Ischemic Stroke. J Clin Neurol, 13:187-195.
[12] Uiterwijk R, van Oostenbrugge RJ, Huijts M, De Leeuw PW, Kroon AA, Staals J (2016). Total Cerebral Small Vessel Disease MRI Score Is Associated with Cognitive Decline in Executive Function in Patients with Hypertension. Front Aging Neurosci, 8:301.
[13] Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. (2013). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol, 12:822-838.
[14] Lau KK, Li L, Schulz U, Simoni M, Chan KH, Ho SL, et al. (2017). Total small vessel disease score and risk of recurrent stroke: Validation in 2 large cohorts. Neurology, 88:2260-2267.
[15] Charidimou A, Imaizumi T, Moulin S, Biffi A, Samarasekera N, Yakushiji Y, et al. (2017). Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis. Neurology, 89:820-829.
[16] Charidimou A, Werring DJ (2014). Cerebral microbleeds as a predictor of macrobleeds: what is the evidence? Int J Stroke, 9:457-459.
[17] Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, et al. (2010). Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology, 74:1346-1350.
[18] Charidimou A, Boulouis G, Haley K, Auriel E, van Etten ES, Fotiadis P, et al. (2016). White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy. Neurology, 86:505-511.
[19] Pasi M, Boulouis G, Fotiadis P, Auriel E, Charidimou A, Haley K, et al. (2017). Distribution of lacunes in cerebral amyloid angiopathy and hypertensive small vessel disease. Neurology, 88:2162-2168.
[20] Wu B, Yao X, Lei C, Liu M, Selim MH (2015). Enlarged perivascular spaces and small diffusion-weighted lesions in intracerebral hemorrhage. Neurology, 85:2045-2052.
[21] Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. (2009). Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol, 8:165-174.
[22] Charidimou A, Boulouis G, Xiong L, Jessel MJ, Roongpiboonsopit D, Ayres A, et al. (2017). Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy. Neurology, 88:1607-1614.
[23] Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987). MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol, 149:351-356.
[24] Charidimou A, Meegahage R, Fox Z, Peeters A, Vandermeeren Y, Laloux P, et al. (2013). Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study. J Neurol Neurosurg Psychiatry, 84:624-629.
[25] Imaizumi T, Inamura S, Nomura T (2014). The severities of white matter lesions possibly influence the recurrences of several stroke types. J Stroke Cerebrovasc Dis, 23:1897-1902.
[26] Pasi M, Charidimou A, Boulouis G, Auriel E, Ayres A, Schwab KM, et al. (2018). Mixed-location cerebral hemorrhage/microbleeds: Underlying microangiopathy and recurrence risk. Neurology, 90:e119-e126.
[1] Supplementary data Download
[1] Zhu Shuzhen, Wei Xiaobo, Yang Xiaohua, Huang Zifeng, Chang Zihan, Xie Fen, Yang Qin, Ding Changhai, Xiang Wei, Yang Hongjun, Xia Ying, Feng Zhong-Ping, Sun Hong-Shuo, Yenari Midori A, Shi Lin, Mok Vincent CT, Wang Qing. Plasma Lipoprotein-associated Phospholipase A2 and Superoxide Dismutase are Independent Predicators of Cognitive Impairment in Cerebral Small Vessel Disease Patients: Diagnosis and Assessment[J]. Aging and disease, 2019, 10(4): 834-846.
[2] Yamanaka Takehiko, Uchida Yuto, Sakurai Keita, Kato Daisuke, Mizuno Masayuki, Sato Toyohiro, Madokoro Yuta, Kondo Yuko, Suzuki Ayuko, Ueki Yoshino, Ishii Fumiyasu, Borlongan Cesar V, Matsukawa Noriyuki. Anatomical Links between White Matter Hyperintensity and Medial Temporal Atrophy Reveal Impairment of Executive Functions[J]. Aging and disease, 2019, 10(4): 711-718.
[3] Liu Junfeng, Wang Deren, Xiong Yao, Liu Bian, Lin Jing, Zhang Shihong, Wu Bo, Wei Chenchen, Liu Ming. Association between Coagulation Function and Cerebral Microbleeds in Ischemic Stroke Patients with Atrial Fibrillation and/or Rheumatic Heart Disease[J]. Aging and disease, 2017, 8(2): 131-135.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd