Silent brain infarctions and leuko-araiosis in Chinese patients with first-ever acute lacunar strokes

doi:10.4236/jbise.2010.35061

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J. Biomedical Science and Engineering, 2010, 3, 443-447

doi:10.4236/jbise.2010.35061 Published Online May 2010 (http://www.SciRP.org/journal/jbise/

JBiSE

Published Online May 2010 in SciRes. http://www.scirp.org/journal/jbise

Silent brain infarctions and leuko-araiosis in Chinese patients

with first-ever acute lacunar strokes

Peterus Thajeb1,2,3,4*, Wen-Yuan Lee2, Chung-Hung Shih5, Teguh Thajeb6, James Davis3, Rosanne

Harrigan3, Linda Chang3

1Center for Stroke Care and Prevention, Cathay General Hospital Sijhih, Sijhih, Taiwan, China;

2Section of Neurosurgery and Neurology, China Medical University Hospital, Taipei, Taiwan, China;

3Biomedical Science, Graduate Division, John A Burns School of Medicine, University of Hawaii at Manoa, Hawaii, USA;

4Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, China;

5Institute of Respiratory Therapy, Taipei Medical University, Taipei, Taiwan, China;

6Department of Internal Medicine, Landseed Hospital, Pingjen, Taiwan, China.

Email: [email protected]; [email protected]

Received 3 January 2010; revised 12 January 2010; accepted 15 January 2010.

ABSTRACT

We report on silent brain infarction (SBI) and leuko-

araiosis (LA) of 23 patients with clinically diagnosed

“first-ever” acute ischemic lacunar stroke. The lacu-

nar syndromes were pure motor hemiparesis (10),

pure sensory syndrome (2), ataxic hemiparesis (3),

dysarthria clumsy hand syndrome (3), and sensory-

motor deficit (5). Nineteen out of the 23 patients pre-

sented with completed strokes on arrival to the hospi-

tal, and 4 (17%) developed evolving-stroke within 24

hours of stroke onset. A lacune corresponded to the

acute stroke could be found in all patients on brain

magnetic resonance imaging (MRI), and in 18 (78%)

on brain computed tomography (CT). MRI showed

additional subclinical or asymptomatic “silent brain

infarctions or lacunes” (SBI) in 19 (83%) of 23 pa-

tients, and leuko-araiosis (LA) of moderate to severe

degree (> grade 2) was present in 61% of patients al-

though dementia was absent. Hypertension is the risk

factor in 78% of cases followed by diabetes mellitus,

smoking, and elevated plasma cholesterol level. Inde-

pendence of the types of lacunar syndromes, patients

with hypertension and diabetes mellitus are associated

with high grade LA. None with normal blood pressure

and plasma glucose had grade 3 or grade 4 LA (p <

0.05). In conclusion, evolving-stroke occurs in one-

fifth of patients with “first-ever” lacunar infarct

within the first 24 hours of stroke onset. SBI was

found in 83% of cases. Hypertension and diabetes

mellitus are associated with additional SBI and high

grade LA. The severity of leuko-araiosis per se dic-

tates the cerebrovascular risks.

Keywords: Computed Tomography; First-Ever Stroke;

Lacune; Leuko-Araiosis; Magnetic Resonance Imaging;

MRI; Silent Brain Infarction

1. INTRODUCTION

Elegant study on 1042 routine autopsied brains by Fisher

in 1965 [1,2], and data from 2,859 necropsied cases re-

ported by Tuszynski et al. [3] suggest that lacunes occur

in between 6% [3] and 11% [1,2] of cases, respectively.

Approximately, eighty percent of these lacunes had no

history of stroke and neurological deficit, and thus called

“asymptomatic” or “silent” lacunes [3,4]. During life,

the diagnosis of asymptomatic or subclinical silent lacu-

nes in the pre-era of MRI has been a difficult task for

several reasons. First, ethically a neurological healthy

subject would not justify having an intensive laboratory

work-up for any possible reason of unexpected intracra-

nial silent lesion. Second, in the earlier days, before the

advent of MRI technique, a brain CT would not sensitive

enough to detect a small lesion of less than 15 mm in a

clinically overt lacunar stroke. Therefore, the actual in-

cidence of subclinical silent lacunes in the general

population, and in asymptomatic patients with cere-

brovascular risk factors remains conjectural. Extensive

use of brain MRI in the past decade had suggested that

prevalence of MRI-based diagnosis of silent brain in-

farction (SBI) ranged from 8% [5] to 28% [6]. These

SBIs included silent lacunes and silent non-lacunar in-

farctions [5-8]. A screening health examination in Japan

on 246 neurologically normal adults revealed 13% had

possible silent lacunar lesions on brain MRI [9]. But

nothing is known about SBI in Chinese/Taiwanese with

“first-ever” acute ischemic lacunar syndromes. This is-

sue will be addressed herein.

2. PATIENTS AND METHODS

Patients recruited in this study were a subset from the

444 P. Thajeb et al. / J. Biomedical Science and Engineering 3 (2010) 443-447

authors’ consecutive stroke registry between January 1,

2007 and December 31, 2008. Subjects with a lacunar

infarction due to small penetrating artery occlusion are

often considered “minor” stroke by both laymen and

many clinicians. Good recovery of symptoms and signs

in certain proportion of cases leads to underestimation of

the prevalence of lacunar infarction and silent brain in-

farction. In order to obtain a homogeneous study popula-

tion, we address the question that how often a silent

brain infarction (SBI) can be seen in patients with clini-

cally “first-ever” lacunar stroke? Therefore, patients with

non-lacunar infarction were excluded from the study.

Only those fulfilling all diagnostic criteria set below for

acute first-ever lacunar infarction and those with com-

plete clinical data and available brain CT and MRI

within 5 days of stroke onset will be analyzed. The di-

agnostic criteria of “first-ever” acute lacunar infarction

were: 1) acute stroke with clinical manifestation of one

of the 5 typical clinical lacunar syndromes described by

Fisher [1,2]; 2) absence of past history of presumed

stroke or transient ischemic attack (TIA), including

amourosis fugax; 3) normal electroencephalography

(EEG); 4) neuroimaging studies (brain MRI or CT or

both) showing a corresponded acute brain infarction in

the territory of the penetrating artery and of the size of a

“lacune” (diameter of 15 mm or less); and 5) exclusion

of those with presumed vascular dementia on

mini-mental state examination (MMSE) [10] or modified

mini-mental test (MMT) [11], or both, and on Hatchinski

ischemic score [12]. Twenty-three patients thus recruited

consisted of 6 women and 17 men. The age at stroke

onset ranged from 51 to 85 years (mean 65 years).

MRI was performed by using either one of the fol-

lowing protocol. The old MRI machine (0.5 Tesla su-

perconductive unit, MRI-50 A, manufactured by Toshiba

Corporation) was a multiple-spin-echo T1-weighted im-

age with TR 500 msec/TE 15 msec, T2-weighted images

with TR 3000 msec/TE 120 msec, and proton density

images (PDI) with TR 3000 msec/TE 30 msec. The le-

sions could be round or oval in shape. The single lesion

that matched completely to the clinical presentation (one

of the 5 lacunar syndromes) was called the correspond-

ing lesion. Other unexpected additional (old) lesions or

lacunes were called additional lesions or “silent” lacunes.

A smaller “dot-like”, or spotty high signal intensity on

T2WI and PDI at the cerebal subcortical region that be-

yond the territory of the penetrating arteries, may or may

not be seen on T1WI MRI or brain CT were considered

“etat crible” [13]. The hyperintense poorly demarcated

pathches of irregular border surrounding the lateral ven-

tricles were designated as “leuko-araiosis” (LA) or peri-

ventricular “caps” or “rims” [14]. The grading of sever-

ity of LA was as follows: LA grade 0 (no leuko-araiosis),

LA grade 1 (mild leuko-araiosis at the frontal horn sub-

cortical white matter), LA grade 2 (moderate LA involv-

ing the frontal and posterior horn white matter), LA

grade 3 (severe LA involving the whole rims of lateral

ventricular white matter), and LA grade 4 (advanced LA,

grade 3 LA plus involvement of the centrum semiovale).

The new MRI machine has T1WI [TI 860.0/TR

2,200.0/TE 11.0], T2WI [TR 3,300.0/TE 113.0], FLAIR

[TI 2,500.0/TR 9,000.0/TE 113.0], diffusion weighted

images (DWI) [TR 3,600.0/TE 84.0], ADC map, and

magnetic resonance angiogram (MRA) [TR 37.0/TE 7.0].

MRI definition of a lacune remains the same for T1WI

and T2WI. Additional imaging parameters for acute la-

cunar infarction were lesion of high signal on T2FLAIR,

and DWI, and low signal on ADC map. Asymptomatic

or subclinical “silent” (old) cerebral infarctions were

characterized by signal intensity of iso-or low-signal on

DWI and iso-or high signal on ADC map.

Statistical analyses: Categorical Chi-square or Fisher’s

exact test (for n < 5) were used for statistical analyses.

Probability of < 0.05 was considered statistical signifi-

cance.

3. RESULTS

Mean age at onset was 65 years (range 51 to 85 years)

with men to women ratio of 2.8. There was no statistical

difference between gender and types of lacunar syn-

dromes. Additional lesions suggesting silent cerebral la-

cunar infarctions were encountered in 83% of patients on

MRI (Table 1) as compared to 43% on CT (p < 0.005).

Hypertension was top one risk factor in 78% of patients.

Other risk factors were diabetes mellitus (11 cases,)

(48%), high cholesterol level (> 200 mg/dL) or/and low

HDL-cholesterol level (10 cases), smoking (10 cases),

hyperfibrinogenemia (> 400 mg/dL) (6 cases), high he-

matocrit (4), and hyperuricemia (> 7.5 mg/dL) (4 cases).

The initial manifestations of lacunar syndromes were

pure motor hemiparesis (PMH) in 10 patients, sensoy-

motor deficit (SM) in 5, ataxic hemiparesis (AH) in 3,

dysarthria clumsy hand syndrome (DCH) in 3, and pure

sensory syndrome (PS) in 2. Nineteen of the 23 patients

presented with completed strokes on arrival to the hospi-

tal. Four patients (17%) developed evolving stroke in the

subsequent 24 hours of stroke onset. The frequencies of

abnormalities found on brain CT and MRI were shown in

Table 1. Hyperintense lesions on T2WI and PDI of brain

MRI included the lacunes and etat cribles, were most

commonly encountered at the corona radiata or periven-

tricular white matter (PVWM), followed by internal

Table 1. Frequencies of abnormalities found on brain CT and

MRI of 23 patients with “first-ever” lacunar infarction.

Number (%) of Patients

Detectable abnormalities Brain CT Brain MRI

Corresponding single lesion

of acute infarction 18 (78) 23 (100)

Additional lesions 10 (43) 19 ( 83)*

Leuko-araiosis 2 (9) 14 (61)*

* p < 0.05

P. Thajeb et al. / J. Biomedical Science and Engineering 3 (2010) 443-447 445

capsule, basal ganglia, thalamus, and brain stem (Table

2 and Figure 1). Severity of leuko-araiosis in different

subgroups was shown in Table 3. Regardless of the

types of lacunar syndromes, patients with hypertension

or diabetes mellitus were likely having moderate to se-

vere LA (grade 2 to 3) (13 of the 18 patients) (72%, in

contrast to 20% for those without these risk factors).

Combination of hypertension and DM strengthened this

effect from severe to advanced LA (grade 3 to 4). None

of patient with normotension and euglycemia had LA >

grade 2 (p < 0.05).

Table 2. Frequency and locations of additional silent lacunes

and etat crible in 23 patients with various types of acute first-

ever brain lacunar infarctions.

Location of Silent Number (%) of Patients with Positive CT/MRI

Lacunes PMH

(10)

(5)

(3)

DCH

(3)

(2)

Corona radiata* 4 / 7 2 / 3 0 / 1 0 / 21 / 2

Internal capsule 3 / 5 2 / 2 1 / 2 2 / 30 / 1

Basal ganglia 1 / 4 0 / 2 1 / 1 0 / 00 / 0

Thalamus 0 / 2 2 / 3 0 / 1 1 / 11 / 1

Brainstem 1 / 3 0 / 2 1 / 2 0 / 10 / 0

* p < 0.05

(a)

(b)

(c)

(d)

(e)

Figure 1. (a) Brain CT of an acute lacunar infarction

involving the left thalamus, and old silent lacunes at

left anterior basal ganglion, and right thalamus; (b-e)

Brain MRI of another patient with acute lacunar in-

farction involving the left internal capsule; (b) Diffu-

sion-weighted images (DWI) [TR 3,600.0/TE 84.0];

“silent brain infarctions” involving bilateral paraven-

tricular white matter/corona radiata, basal ganglia,

and thalami. MR angiogram; (e) shows mild athero-

sclerotic change with segmental narrowing of the

anterior and middle cerebral arteries (white arrows);

the internal carotid arteries and basilar artery are

relatively normal.

4. DISCUSSION

Previous association studies on various risk factors such

as hypertension, diabetes mellitus, cardiovascular dis-

ease, atrial fibrillation, carotid stenosis, and carotid inti-

ma-media thickness, and MRI-diagnosis of silent brain

infarctions (SBI) were contradictory [4,5,9]. Regional

cerebral blood flow in bilateral frontotemporal regions

of brain measured by Xenon-133 inhalation method has

been shown to reduce remarkably in neurologically nor-

mal adults with brain MRI evidence of silent lacunes [9].

But only less than half of the silent lacunes were seen on

T1WI [9]. The autopsied data showed higher (81 %)

frequency of SBI [3]. Recent advance in MRI technol-

ogy improves the detection rate of SBI [4]. SBI was

found more frequently than expected in subjects with no

history of transient ischemic attack or stroke [4]. Hyper-

tension was present in 72% of subjects with SBI [4,6]

that was in accord with our study. Prevalence of SBI

even steeply increases after age of 65 years [4,6-8].

However, hypercholesterolemia, hyperglycemia (fasting

446 P. Thajeb et al. / J. Biomedical Science and Engineering 3 (2010) 443-447

plasma glucose > 110 mg/dL), and high hematocrit (Hct

> 50%) or hypercoagulability were not risk factors of

silent lacunes in several studies, but they were reported

to be risk factors in another study [8,15]. Low-grade

inflammation of cerebral vessel can be another risk fac-

tor of SBI or lacunes [16]. Among 40 patients with la-

cunes, 30% of cases showed single lesion on MRI [17]

and these patients may have neuropsychological abnor-

mality in certain aspect of cognitive domain, even

though cognitive function in general remains normal

[17]. Our data showed that simple neuropsychological

tests such as MMSE, MMT, and Hachinski’s score re-

mained normal in patients with first-ever lacune, regard-

less whether they had or had not SBI [10-12]. A recent

study working on more sophisticated neuropsychological

tests performed at 1 month after acute lacunar infarction

showed that 57.5% of patients had mild cognitive im-

pairment (MCI) that was reflected on lower MMSE

score (mean 28.4) [17]. MMSE score of 28 remains at

the normal range of our healthy controls [11]. Further-

more, Grau and colleagues [17] included subjects with

so called “atypical lacunes” in their study, and this part

constituted more than a half of silent brain lacunes lo-

cated in the striatothalamic region of the brain [17].

Atypical lacunes and pure motor hemiparesis accounted

for most of the subjects with MCI [17]. Thalamic lesion

constituted 44% of PS, 25% of PMH, and 25% of atypi-

cal lacune [17]. Nothing was known about unilaterality

or bilaterality of the thalamic lesion and exact locations

of the involvement of the different thalamic nuclei. A

“typical thalamic lacune” usually located at the lateral

tier of thalamic nucleus and frequently manifested with

PS. However, a medially located thalamic infarction can

be as small as a lacune, either unilateral or bilateral, and

sometimes may be mistakenly considered as a “thalamic

lacune” or an “atypical lacune”. They are actually an is-

chemic stroke involving the paramedian mesencephalic

arteries (PMAS) rather than the deep penetrating arteries

of lacunar infarction [18]. PMAS is a branched or a

trunk disease that frequently manifests itself with cogni-

tive impairment, neurobehavioral dysfunction, and ocu-

lar signs [18]. It is a variant of the top-of-basilar artery

syndrome. Therefore, more delicate test for various do-

mains of cognition and higher brain functions might be

needed to detect trivial abnormality in patients with la-

cunar stroke.

In addition, severe periventricular white matter (WM)

change with higher grade (> 2) of leuko-araiosis corre-

lates with the presence of hypertension (13/18 patients,

in contrast to 1/5 in subjects with normal blood pressure)

(Table 3). This is consistent with the previous studies

[4-7]. Austrian Stroke Prevention Study (ASPS) looking

at a community-based population on elderly normal

subjects over 3-year follow-up [5] have shown that dia-

stolic blood pressure and early-confluent white matter

hyperintensities (WMH) at baseline MRI predicted best

the white matter hyperintensity progression. This was

also confirmed by a 6-year ASPS follow-up study [19].

Moreover, the WMH has been shown to associate with

lower forced expiratory volume in 1 second (FEV1) and

lower income of less than $ 50,000 per year in CHS [6].

WMH progression did not associate with cognitive func-

tioning [5], punctuate WM lesions are considered benign

and not progressive, whereas early-confluent WM ab-

normalities are progressive within 6-year follow-up [19].

This is in contradiction to the CHS study that concluded

that WM findings were associated with impaired cogni-

tive and lower extremity functions [6].

Molecular markers of coagulation activation such as

elevated prothrombin fragment, parameters for endothe-

lial cell damage (thrombomodulin and von Willebrand

factor), and lipoprotein A were significantly higher in

patients with silent lacunes [15]. By contrast, a recently

discovered plasma biomarker, SCUBE1, have been sh-

own to associate with different forms of acute cerebral

infarction and severity of ischemic stroke based on NI-

HSS score. The plasma level of SCUBE1 is remarkably

Table 3. Grading of leuko-araiosis (la) in 23 patients with “first-ever” lacunar infarction, high or normal blood pressure, and high or

normal fasting plasma glucose.

Grade Number (%) of Patients with

Lacunar Syndromes and Positive CT / MRI Associated Risk Factors

LA* PMH (10) SM (5) AH(3) DCH (3) PS (2) HBP(18) NBP(5) HPG(11) NPG(12)

0 ** 7 / 1 2 / 1 2 / 1 1 / 0 1 / 0 0 ** 3 0 ** 3

1 1 / 2 1 / 1 1 / 2 1 / 1 0 / 0 5 1 1 5

2 0 / 3 0 / 1 0 / 0 0 / 0 0 / 1 4 1 2 3

3 1 / 3 1 / 1 0 / 0 1 / 2 1 / 1 7 0 ** 6 1**

4 1 / 1 1 / 1 0 / 0 0 / 0 0 / 0 2 0 ** 2 0 **

*LA: leuko-araiosis; PMH: pure motor hemiparesis; SM: sensorimotor syndrome; AH: ataxic hemiparesis; DCH: dysarthria-clumsy-hand syndrome;

PS: pure sensory stroke; HBP: high blood pressure; NBP: normal blood pressure; HPG: high fasting plasma glucose; NPG: normal fasting plasma

glucose.

grade 0: absent of LA

grade 1: mild, LA confined to the frontal poles of lateral ventricles (“frontal caps”)

grade 2: moderate, LA confined to the frontal and occipital poles of lateral ventricles (“dual caps”)

grade 3: severe, LA involved the whole lateral ventricles (“dual caps” plus “rims”)

grade 4: advanced, confluent LA lesions surround the centrum semiovale

** p < 0.05

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P. Thajeb et al. / J. Biomedical Science and Engineering 3 (2010) 443-447 447

elevated in patients with acute infarction due to a trunkor

branched-vessel disease, and slightly elevated or normal

in patients with acute lacunar infarction [20]. Plasma

level of oxidized small dense low-density lipoprotein

(LDL-3) is an independent predictor of silent lacunar

infarction [21].

In conclusion, evolving-stroke occurs in about one-

fifth of patients with “first-ever” acute lacunar infarction

within the first 24 hours of stroke onset. Eighty-three

percent of Chinese/Taiwanese patients with first-ever

lacunar stroke had additional silent brain infarction on

MRI. The presence of both hypertension and diabetes

mellitus predicts the likelihood of high grade leuko-

araiosis and additional SBI. Use of neuroimage studies

in conjunction with scrutinized clinical assessments,

monitoring stroke risk factors, and measurement of cer-

tain molecular or plasma biomarkers may be a future

strategy for early diagnosis and treatment of patients at

risk for silent brain lacunar infarctions.

5. ACKNOWLEDGEMENTS

The authors thank clinicians and technicians that contributed to the

performance of brain CT and MRI examinations. Prof Rossane Harri-

gan is supported by a grant #1R25RR019321 for Clinical Research

Education and Career Development (CRECD) in Minority Institutions;

and Prof Linda Chang is supported by a grant #IU54 NS56883-03 for

Imaging Studies in Neurotoxicity and Neurodevelopment, University of

Hawaii Clinical Specialized Neuroscience Research Program (SNRP).

Conflict of interest: none to declare.

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