cmbs are regarded as one of the indicators of cerebral small vessel disease , especially when located in the deep gray matter or infratentorial area .
risk factors associated with cmbs in the lobar area are different than those associated with deep cmbs .
a different pathomechanism of cortical microangiopathy by amyloid deposition ( i.e. , cerebral amyloid angiopathy ) is regarded as the major cause of lobar cmb .
in addition , lobar cmbs are also predominantly observed in patients with a cardioembolic source of septic emboli , which may cause small mycotic aneurysms in their cerebral arteries .
the prevalence of cmbs in stroke patients differs according to the subtype of ischemic stroke .
the prevalence has been found to be highest in patients with small lacunar infarctions [ 9 - 11 ] ; however , cmbs in other subtypes of stroke are also common .
in fact , up to one - third of cardioembolic stroke ( ce ) cases demonstrate cmbs [ 14 - 16 ] . considering that patients with ce require long - term anticoagulation , and that anticoagulation increases the risk of intracerebral hemorrhage , especially in patients with multiple cmbs , understanding the pathomechanism of cmbs according to ischemic stroke subtype or location may be important in determining the treatment strategy for secondary stroke prevention . in our current study
, we investigated the risk factors and locations of cmbs in patients with different ischemic stroke subtypes , and the risk factors for cmbs in different locations .
ischemic stroke patients who were admitted within 1 week of stroke onset to the stroke center at asan medical center ( seoul , korea ) between january 2007 and january 2010 were retrospectively reviewed from a prospectively collected database . among these cases ,
patients classified as having large artery atherosclerosis ( laa ) , small vessel occlusion ( svo ) , or ce were consecutively enrolled after excluding other etiologies .
the ischemic stroke subtypes in this population were classified in accordance with the toast ( trial of org 10172 in acute stroke treatment ) system .
holter monitoring , and transthoracic and/or transesophageal echocardiography were performed in selected patients who ( 1 ) had a history of heart disease or arrhythmia on electrocardiography , ( 2 ) were young ( < 50 years of age ) , or ( 3 ) had any cortical lesion on diffusion - weighted image without evidence of the embolic source on magnetic resonance angiography .
patients classified as undetermined or other determined etiology and patients with poor quality image that were not amenable to analysis were excluded from the study .
the requirement for obtaining informed consent was waived because of the retrospective nature of the analysis .
the demographic characteristics of the study patients , including their vascular risk factors and previous use of antithrombotic agents ( antiplatelet agent and anticoagulants ) were collected from medical records .
the risk factors included hypertension ( defined as receiving medications for hypertension or blood pressure > 140/90 mmhg on repeated measurements ) , diabetes mellitus ( defined as receiving medications for diabetes mellitus , fasting blood sugar 126 mg / dl or hba1c 6.5% , or a casual plasma glucose > 200 mg / dl ) , previous heart disease , hypercholesterolemia ( defined as receiving cholesterol - reducing agents or an overnight fasting cholesterol level 240 mg / dl , 200 mg / dl triglycerides , or low density lipoprotein ( ldl ) cholesterol 160 mg / dl ) , and current cigarette smokin .
mri scans were obtained within one week of stroke onset using either a 1.5 t or 3.0 t mr imaging unit .
all the enrolled patients underwent diffusion - weighted image , gre , and magnetic resonance angiography .
the common parameters for diffusion - weighted image were a slice thickness of 5 mm , an inter - slice gap of 2 mm , 20 axial slices , and a field of view of 250 mm .
the mri parameters for gre were a slice of thickness of 5 mm , an inter - slice gap of 2 mm , 20 axial slices , a field of view of 250 mm , a 400-ms repetition time , 30-ms echo time , 20 flip angle , and a 256192 matrix .
common magnetic resonance angiography parameters included a flip angle of 20 , a 512512 matrix , and a field of view of 250 mm .
cmbs were defined as lesions with homogeneous round signal loss and a diameter 5 mm on gre .
however , hypointense lesions within the subarachnoid space and areas of symmetrical hypointensity in the globus pallidus on gre were considered likely to represent adjacent pial blood vessels and calcifications , respectively .
cmbs located at the cortico - subcortical area of each lobe ( i.e. , frontal , parietal , temporal , or occipital ) were regarded as lobar cmbs .
cmbs in the basal ganglia , thalamus , brainstem , and cerebellum were categorized as deep cmbs .
multiple cmbs that were distributed throughout both the lobar and deep areas were defined as diffuse cmbs .
if at least one cmb existed at lobar area or deep area , the patient was regarded to have any lobar or any deep cmb .
classification of stroke subtype and detection of the cmbs were performed by two independent neurologists ( y.y and h.s ) who were blind to the clinical data , and any discrepancies were reevaluated at a consensus meeting .
pearson chi - square test , student t test , or mann - whitney test was appropriately used .
in addition , multivariable logistic regression analysis was performed to estimate the independent contributions of various factors on the presence of cmbs in different stroke subtypes and locations .
variables were selected for entry into the model based on the results of univariable analysis ( p0.2 ) ; svo group : age , hypertension and previous stroke history , laa group : hypertension and previous stroke history , ce group : hypertension and previous use of antithrombotic agents were entered . for locations , factors associated with any lobar , lobar ,
spss for windows was used for these analyses ( version 18.0 ; spss inc . ,
ischemic stroke patients who were admitted within 1 week of stroke onset to the stroke center at asan medical center ( seoul , korea ) between january 2007 and january 2010 were retrospectively reviewed from a prospectively collected database . among these cases ,
patients classified as having large artery atherosclerosis ( laa ) , small vessel occlusion ( svo ) , or ce were consecutively enrolled after excluding other etiologies .
the ischemic stroke subtypes in this population were classified in accordance with the toast ( trial of org 10172 in acute stroke treatment ) system .
holter monitoring , and transthoracic and/or transesophageal echocardiography were performed in selected patients who ( 1 ) had a history of heart disease or arrhythmia on electrocardiography , ( 2 ) were young ( < 50 years of age ) , or ( 3 ) had any cortical lesion on diffusion - weighted image without evidence of the embolic source on magnetic resonance angiography .
patients classified as undetermined or other determined etiology and patients with poor quality image that were not amenable to analysis were excluded from the study .
the requirement for obtaining informed consent was waived because of the retrospective nature of the analysis .
the demographic characteristics of the study patients , including their vascular risk factors and previous use of antithrombotic agents ( antiplatelet agent and anticoagulants ) were collected from medical records .
the risk factors included hypertension ( defined as receiving medications for hypertension or blood pressure > 140/90 mmhg on repeated measurements ) , diabetes mellitus ( defined as receiving medications for diabetes mellitus , fasting blood sugar 126 mg / dl or hba1c 6.5% , or a casual plasma glucose > 200 mg / dl ) , previous heart disease , hypercholesterolemia ( defined as receiving cholesterol - reducing agents or an overnight fasting cholesterol level 240 mg / dl , 200 mg / dl triglycerides , or low density lipoprotein ( ldl ) cholesterol 160 mg / dl ) , and current cigarette smokin .
mri scans were obtained within one week of stroke onset using either a 1.5 t or 3.0 t mr imaging unit .
all the enrolled patients underwent diffusion - weighted image , gre , and magnetic resonance angiography .
the common parameters for diffusion - weighted image were a slice thickness of 5 mm , an inter - slice gap of 2 mm , 20 axial slices , and a field of view of 250 mm .
the mri parameters for gre were a slice of thickness of 5 mm , an inter - slice gap of 2 mm , 20 axial slices , a field of view of 250 mm , a 400-ms repetition time , 30-ms echo time , 20 flip angle , and a 256192 matrix .
common magnetic resonance angiography parameters included a flip angle of 20 , a 512512 matrix , and a field of view of 250 mm .
cmbs were defined as lesions with homogeneous round signal loss and a diameter 5 mm on gre .
however , hypointense lesions within the subarachnoid space and areas of symmetrical hypointensity in the globus pallidus on gre were considered likely to represent adjacent pial blood vessels and calcifications , respectively .
cmbs located at the cortico - subcortical area of each lobe ( i.e. , frontal , parietal , temporal , or occipital ) were regarded as lobar cmbs .
cmbs in the basal ganglia , thalamus , brainstem , and cerebellum were categorized as deep cmbs .
multiple cmbs that were distributed throughout both the lobar and deep areas were defined as diffuse cmbs .
if at least one cmb existed at lobar area or deep area , the patient was regarded to have any lobar or any deep cmb .
classification of stroke subtype and detection of the cmbs were performed by two independent neurologists ( y.y and h.s ) who were blind to the clinical data , and any discrepancies were reevaluated at a consensus meeting .
pearson chi - square test , student t test , or mann - whitney test was appropriately used .
in addition , multivariable logistic regression analysis was performed to estimate the independent contributions of various factors on the presence of cmbs in different stroke subtypes and locations .
variables were selected for entry into the model based on the results of univariable analysis ( p0.2 ) ; svo group : age , hypertension and previous stroke history , laa group : hypertension and previous stroke history , ce group : hypertension and previous use of antithrombotic agents were entered . for locations , factors associated with any lobar , lobar ,
spss for windows was used for these analyses ( version 18.0 ; spss inc . ,
during the study period , 1,357 patients within 7 days from ischemic stroke onset were registered to the database during the study period . among them , 169 patients with undetermined etiology and 64 patients with other determined etiology were excluded . of them , 1,124 patients were initially determined to be eligible to participate and were screened . however , 91 patients were excluded due to suboptimal image quality and a final study population of 1,033 patients was included . the ischemic stroke subtypes were laa ( n=432 ; 41.8% ) , svo ( n=304 ; 29.4% ) , and ce ( n=297 ; 28.8% ; figure 1 ) .
the demographic features and vascular risk factors were significantly different between patients with different ischemic stroke subtypes . compared with laa or svo patients ,
most of the vascular risk factors , including hypertension , diabetes mellitus , hyperlipidemia , and smoking , were less frequent in ce patients .
however , the proportion of ce patients who had previously used antithrombotic agents was significantly higher than the other subtypes ( table 1 ) .
the prevalence and mean number of cmbs were significantly different between the various ischemic stroke subtypes : prevalence , svo ( 40.5% ) , ce ( 33.0% ) , and laa ( 24.8% ; p<0.001 ; table 1 ) ; mean number of cmbs , svo ( meanstandard deviation : 4.657.40 ) , ce ( 3.093.49 ) , and laa ( 3.123.63 ; p=0.041 ) .
as indicated in table 1 and figure 1 , the location of the cmbs also differed according to the subtype of ischemic stroke ( p=0.004 ) .
the presence of any lobar cmb was high in svo and ce patients , whereas deep cmb was frequently observed from svo patients ( figure 2 ) .
finally , the ratio of patients with any cmbs in the lobar area to that of deep area was relatively high in patients with ce ( 63/71 ; 88.7% ) compared to svo ( 71/97 ; 73.2% ) or laa ( 43/85 ; 50.6% ) cases ( figure 2 ) .
the concordance rate between the two investigators for the location of cmbs was 90.4% , and the kappa value was 0.71 .
the clinical characteristics of patients with and without cmb for each ischemic stroke subtype are presented in table 2 . in patients categorized as svo or laa ,
the prevalence of hypertension and previous stroke history were higher in patients with cmbs than in those without .
patients with cmbs were older ( 66.011.0 vs. 63.113.0 ; p<0.05 ) than those without cmbs in the svo group . by multivariate
analysis , hypertension ( or=1.956 [ 95% confidence interval=1.0643.594 ] ; p=0.031 ) and a previous history of stroke ( or=1.929 [ 1.1253.309 ] ; p=0.017 ) were independent risk factors for cmbs in svo patients .
similarly , hypertension ( or=3.656 [ 1.7607.594 ] ; p=0.001 ) and a previous history of stroke ( or=1.663 [ 1.0362.669 ] p=0.035 ) were also independent risk factors for cmbs in laa patients .
however , these factors were not associated with the presence of cmbs in ce patients . in terms of cmb location ,
the results of univariable analysis are demonstrated at table 3 . according to the results of multivariable analysis ,
the presence of strictly lobar cmb was independently associated with ce ( or=1.85 [ 1.023.34 ] ; p=0.042 ) and use of antithrombotic agents ( or=1.80 [ 1.102.94 ] ; p=0.019 ) .
age ( or=1.02 [ 1.001.04 ] ; p=0.015 ) and hypertension ( or=1.61 [ 1.082.40 ] ; p=0.020 ) were independently associated with the presence of deep cmb .
the presence of any lobar cmb was independently associated with the use of antithrombotic agents ( or=1.97 [ 1.263.07 ] ; p=0.003 ) , whereas sex was the only factor associated with the presence of any deep cmb ( male sex : or=0.50 [ 0.290.86 ] ; p=0.013 ) .
during the study period , 1,357 patients within 7 days from ischemic stroke onset were registered to the database during the study period . among them , 169 patients with undetermined etiology and 64 patients with other determined etiology were excluded . of them , 1,124 patients were initially determined to be eligible to participate and were screened . however , 91 patients were excluded due to suboptimal image quality and a final study population of 1,033 patients was included . the ischemic stroke subtypes were laa ( n=432 ; 41.8% ) , svo ( n=304 ; 29.4% ) , and ce ( n=297 ; 28.8% ; figure 1 ) .
the demographic features and vascular risk factors were significantly different between patients with different ischemic stroke subtypes . compared with laa or svo patients ,
most of the vascular risk factors , including hypertension , diabetes mellitus , hyperlipidemia , and smoking , were less frequent in ce patients .
however , the proportion of ce patients who had previously used antithrombotic agents was significantly higher than the other subtypes ( table 1 ) .
the prevalence and mean number of cmbs were significantly different between the various ischemic stroke subtypes : prevalence , svo ( 40.5% ) , ce ( 33.0% ) , and laa ( 24.8% ; p<0.001 ; table 1 ) ; mean number of cmbs , svo ( meanstandard deviation : 4.657.40 ) , ce ( 3.093.49 ) , and laa ( 3.123.63 ; p=0.041 ) .
as indicated in table 1 and figure 1 , the location of the cmbs also differed according to the subtype of ischemic stroke ( p=0.004 ) .
the presence of any lobar cmb was high in svo and ce patients , whereas deep cmb was frequently observed from svo patients ( figure 2 ) .
finally , the ratio of patients with any cmbs in the lobar area to that of deep area was relatively high in patients with ce ( 63/71 ; 88.7% ) compared to svo ( 71/97 ; 73.2% ) or laa ( 43/85 ; 50.6% ) cases ( figure 2 ) .
the concordance rate between the two investigators for the location of cmbs was 90.4% , and the kappa value was 0.71 .
the clinical characteristics of patients with and without cmb for each ischemic stroke subtype are presented in table 2 . in patients categorized as svo or laa ,
the prevalence of hypertension and previous stroke history were higher in patients with cmbs than in those without .
patients with cmbs were older ( 66.011.0 vs. 63.113.0 ; p<0.05 ) than those without cmbs in the svo group . by multivariate
analysis , hypertension ( or=1.956 [ 95% confidence interval=1.0643.594 ] ; p=0.031 ) and a previous history of stroke ( or=1.929 [ 1.1253.309 ] ; p=0.017 ) were independent risk factors for cmbs in svo patients .
similarly , hypertension ( or=3.656 [ 1.7607.594 ] ; p=0.001 ) and a previous history of stroke ( or=1.663 [ 1.0362.669 ] p=0.035 ) were also independent risk factors for cmbs in laa patients .
however , these factors were not associated with the presence of cmbs in ce patients .
in terms of cmb location , the results of univariable analysis are demonstrated at table 3 . according to the results of multivariable analysis ,
the presence of strictly lobar cmb was independently associated with ce ( or=1.85 [ 1.023.34 ] ; p=0.042 ) and use of antithrombotic agents ( or=1.80 [ 1.102.94 ] ; p=0.019 ) .
age ( or=1.02 [ 1.001.04 ] ; p=0.015 ) and hypertension ( or=1.61 [ 1.082.40 ] ; p=0.020 ) were independently associated with the presence of deep cmb .
the presence of any lobar cmb was independently associated with the use of antithrombotic agents ( or=1.97 [ 1.263.07 ] ; p=0.003 ) , whereas sex was the only factor associated with the presence of any deep cmb ( male sex : or=0.50 [ 0.290.86 ] ; p=0.013 ) .
our present findings indicate that the prevalence , location , and risk factors associated with cmbs differ significantly according to ischemic stroke subtype .
cmbs were most frequently observed in svo patients , followed by ce and laa patients .
the distribution of cmbs was mostly in deep areas in svo and laa patients , whereas the cmbs were found in the lobar area relatively more frequently in ce patients compared to svo and laa patients .
the presence of cmbs was associated with hypertension and previous stroke history in svo or laa cases , whereas there was no significant association between those factors and the presence of cmbs in patients with ce .
prior use of antithrombotics was associated with the presence of any lobar cmb , which was relatively frequent in ce patients .
the prevalence of cmb according to ischemic stroke subtype in our current series was consistent with the findings of previous reports .
not only the prevalence , but also the cmb location , differed according to ischemic stroke subtype .
svo patients more frequently demonstrated cmbs in deep areas , where the deep perforating arteries exist .
previously , cmbs located in deep areas were found to be associated with high blood pressure , renal impairment , and heavy alcohol consumption [ 21 - 23 ] . from our present study findings ,
cmbs in those areas are suggested to be caused by hypertensive arteriopathy , which affects the perforators .
cmbs in lobar areas have been associated with smoking , apoe 4 , and low cholesterol levels .
recently , several studies revealed lobar cmbs in specific lobar areas to be associated with various degenerative diseases ( e.g. alzheimer s disease , parkinson s disease and diffuse lewy body disease ) [ 26 - 28 ] . however , age , which is the strongest risk factor for degenerative diseases , was not found to be associated with lobar cmbs in our present study with stroke population .
instead , we found that ce and the previous use of antithrombotics were associated with the presence of lobar cmb .
cmbs have previously been associated with the use of anticoagulants , and this relationship was reported to be stronger in patients from the general population with a greater fluctuation of prothrombin time .
furthermore , among patients with ischemic stroke , cmbs were found to be common in patients with atrial fibrillation , and the use of antithrombotics was independently associated with the presence of lobar but not deep cmbs . in our present study ,
lobar cmbs were more frequent in ce patients , and the presence of lobar cmb was associated with a prior use of antithrombotics .
patients with ce generally show small asymptomatic cortical infarctions , higher spontaneous recanalization rates , and concomitant hemorrhagic transformations . considering that patients under oral anticoagulation are more likely to develop cmbs , the use of antithrombotics may enhance micro - hemorrhages occurring as a result of recanalization of small arterioles obstructed by an asymptomatic embolus originating from the heart [ 32 - 34 ] .
the characteristics of lobar cmbs developed through such a mechanism may differ from cmbs caused by degenerative disease .
first , due to its retrospective design , there was a risk of selection bias , which could have impacted on our findings of cause and effect .
however , our patients were consecutively recruited from a single center , and most of these cases underwent brain mri using an established protocol .
second , we used both 1.5 t and 3.0 t mri , although 1.5 t mri is inferior for the detection of cmbs .
notwithstanding the above limitations , our present study demonstrated that the distribution and risk factors associated with cmbs differed by stroke subtype , especially in patients with ce compared with svo or laa .
our results suggest different pathogenic mechanisms for the development of cmbs of each subtype and that the previous use of antithrombotic agents is related to cmb location .
 background and purposethe location of cerebral microbleeds ( cmbs ) may differ according to ischemic stroke subtype , and the underlying pathomechanism may differ by their location . here , 
 we investigated the characteristics of cmbs according to various ischemic stroke subtypes to verify this issue.methodspatients with acute ischemic stroke were consecutively included . 
 the presence of cmbs was determined by gradient echo image sequence . 
 the distribution of cmbs was classified as deep , lobar , or diffuse ( both deep and lobar ) . 
 the prevalence , risk factors , and distribution of cmbs were compared among patients with different stroke subtypes . 
 factors associated with the distribution of cmbs were investigated.resultsamong the 1033 patients included in this study , ischemic stroke subtypes were classified as large artery atherosclerosis ( laa ; n=432 ) , small vessel occlusion ( svo ; n=304 ) , and cardioembolism ( ce ; n=297 ) . 
 the prevalence of cmbs was highest in patients with svo ( 40.5% ) , followed by ce ( 33.0% ) and laa ( 24.8% ; p<0.001 ) . 
 the locations of cmbs was different according to subtype ( p=0.004 ) . 
 ce [ odds ratio ( or)=1.85 ( 1.02 - 3.34 ) ; p=0.042 ] and the use of antithrombotics [ or=1.80 ( 1.10 - 2.94 ) ; p=0.019 ] were associated with lobar cmbs , and old age [ or=1.02 ( 1.00 - 1.04 ) ; p=0.015 ] and hypertension [ or=1.61 ( 1.08 - 2.40 ) ; p=0.020 ] were associated with deep cmbs.conclusionscmbs were frequently located in the lobar area in patients with ce . 
 previous use of antithrombotic agents is associated with lobar cmbs . 
 the pathogenic mechanism of cmb may differ according to ischemic stroke subtype and location . 