(Stroke. 1999;30:2296-2301.)
© 1999 American Heart Association, Inc.
Original Contributions |
Impaired Cerebrovascular Reactivity as a Risk Marker for First-Ever Lacunar Infarction
A Case-Control Study
From the Cerebrovascular Unit (C.M., J.A.S., J.M., S.A., A.C.) and Magnetic Resonance Unit (A.R.), Hospital Vall d`Hebrón, Barcelona, Spain.
Correspondence to Carlos Molina, MD, Cerebrovascular Unit, Department of Neurology, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. E-mail cmolc{at}meridian.es
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Abstract |
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Background and Purpose—Functional assessment of small arteries and arterioles could provide valuable information regarding the extent of diffuse arteriolosclerosis in patients with small-vessel disease. Therefore we attempted to clarify the role of cerebrovascular reactivity (CVR) as a risk marker for first-ever symptomatic lacunar infarction.
Methods—Forty-six patients with lacunar infarction and 46 sex- and age-matched control subjects were prospectively evaluated. Cerebral hemodynamics were studied with transcranial Doppler ultrasonography. CVR was examined by calculating the percent increase in mean flow velocity occurring after 15 mg/kg acetazolamide administration (Diamox test).
Results—CVR was significantly (P<0.0001, Student's t test) lower in cases (50.0±12.7%) as compared with control subjects (65.2±12.4%). A multiple logistic regression analysis identified male sex (odds ratio [OR] 2.3, P=0.02), age (OR 3.6, P<0.005), and the presence of lacunar infarction on magnetic resonance imaging (OR 5.3, P<0.001) as significant and independent factors associated with a reduction of CVR. Moreover, a cut-point of 55.6% (sensitivity 67%, specificity 82%) was established as the threshold value for distinguishing between pathological and normal CVR. CVR was significantly (P=0.02) lower in patients with multiple (46.38±12.6%) than with single (54.83±11.58%) lacunar infarction. In addition, a trend of negative correlation was found between CVR and the number of lacunar infarctions (r=-0.26, P=0.08). In the multiple logistic model, history of hypertension (OR 7.24; 95% confidence interval 2.95 to 17.79) and CVR (OR 0.8; 95% confidence interval 0.81 to 0.93) emerge as significant and independent predictors of first-ever lacunar infarction.
Conclusions—These data suggest that impaired CVR is a risk marker for first-ever lacunar infarction.
Key Words: cerebrovascular reactivity • lacunar infarction • ultrasonography, Doppler, transcranial
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Lipohialynosis and microatheromatosis are the main underlying arterial lesions in patients with lacunar infarction (LI).1 2 These microangiopathic changes are believed to be responsible for the LI and white matter hyperintensities (WMHIs) seen on magnetic resonance imaging (MRI). Therefore MRI has been proposed as a gold standard technique for the in vivo evaluation of the severity of microangiopathy.3 4 5 6 However, functional assessment of small arteries and arterioles could provide valuable information regarding the extent of diffuse arteriolosclerosis in patients with small-vessel disease.
Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus such as carbon dioxide or acetazolamide.7 In the absence of major arterial stenosis, an impaired CVR may reflect increased rigidity of the arteriolar walls8 and has been associated with a higher risk of stroke.9 10
Decreased CVR has been observed in patients with hypertension and in patients with insulin-dependent diabetes mellitus.11 12 13 Moreover, impaired CVR in young hypertensive subjects appears to improve after the initiation of antihypertensive treatment, suggesting that hypertensive microangiopathic changes could be, at least initially, reversible.13 In addition, long-standing and effective treatment of hypertension is associated with a strong reduction in the risk of cerebrovascular events.14 15 Therefore CVR could be used to monitor the effect of antihypertensive therapy on the cerebral microcirculation.
Several studies focusing on the hemodynamic evaluation of patients with cerebral microangiopathy have shown contradictory results.8 16 17 18 19 20 Differences may be related to selection and methodological bias such as inclusion of patients with carotid artery stenosis,18 19 20 patient selection on the basis of radiological findings only, different methods used for CVR measurement, and the absence of a control group without MRI evidence of cerebral microangiopathy.19 20 Moreover, to our knowledge, the condition of CVR as a potential risk factor for LI has never been tested.
The purpose of the present study was to evaluate whether CVR is reduced in patients with LI compared with sex- and age-matched control subjects without MRI evidence of microangiopathy and to determine the role of decreased CVR as a risk factor for first-ever symptomatic LI.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From January 1997 to June 1998, we prospectively evaluated 67 consecutive patients with a first-ever symptomatic LI confirmed by standard MRI. Of these 67 patients we excluded those with carotid stenosis >50% (n=5), patients with intracranial stenosis on transcranial Doppler (TCD; n=7), and patients with an inadequate temporal bone window (n=9). Finally, 46 patients were included in the study.
LI was defined as an acute classic lacunar syndrome with an MRI showing an ischemic lesion of <15 mm located in the arterial territory of the lenticulostriate, thalamoperforant, or pontineperforant arteries according to previously published criteria.21
All patients underwent a careful neurological and cardiological examination, ECG, transthoracic echocardiography, blood chemistry, and a clinical history with particular attention to previous cerebrovascular events.
Control subjects were selected from consecutive subjects who underwent MRI studies in the evaluation of hypoacousia or dizziness. Subjects with vertigo possibly caused by brain stem or cerebellar dysfunction, history of migraine, transient ischemic attack, or stroke and those with LI on MRI were excluded. From a total of 59 subjects evaluated, 46 age- (±2 years) and sex-matched control subjects were selected. Informed consent was obtained for all patients and control subjects before the study. The study was approved by the local ethics committee.
On the basis of standard definitions, the presence of vascular risk factors was recorded including age, sex, hypertension (systolic blood pressure values >160 mm Hg and/or diastolic blood pressure >90 mm Hg on 2 different determinations before stroke or after the first week of stroke or use of antihypertensive medication), condition of treatment for hypertension (regularly treated, irregularly treated, or untreated hypertension), diabetes mellitus (treated or fasting glucose levels >110 mg/dL), cigarette smoking, and hypercholesterolemia (treated or cholesterol levels >240 mg/dL).
Hemodynamic Protocol
To avoid changes in vasomotor tone related to the acute phase of
cerebral ischemia, hemodynamic evaluation was
delayed in all patients until 1 month after the acute stroke. In
control subjects, hemodynamic assessment was carried
out within 2 weeks after MRI examination.
Carotid artery sonography was performed in all patients and control subjects by means of a high-resolution, real-time scanner equipped with a 7.5-MHz imaging transducer and a 4-MHz pulse-wave Doppler transducer. Carotid artery stenosis was defined according to the standardized criteria.22 The vertebrobasilar system was assessed as described by Bartels.23 Those patients with carotid stenosis >50% were excluded.
To exclude the presence of intracranial stenosis that may interfere in the measuring of CVR, TCD examinations were performed in all patients and control subjects with the use of a 2-MHz pulse-wave probe. Intracranial stenosis was defined according to Ley-Pozo and Ringelstein.24
CVR studies were performed by the same neurologist between 3 and 5 PM. Medications such as cerebral vasodilators were discontinued 48 hours before hemodynamic evaluation. Mean flow velocity (MFV) on the middle cerebral artery was continuously monitored by means of a Multi-Dop X/TCD transcranial Doppler instrument (DWL Elektroniche Systeme GmbH). One dual 2-MHz transducer fitted on a headband and placed on the temporal bone window was used to obtain continuous measurements. The highest signal was sought at a depth ranging from 45 to 55 mm. This unit allows for continuous-wave Doppler recording of the intracranial artery with on-line calculation of MFV in centimeters per second. By activating the record function, it is possible to save the Doppler spectra during the entire period of each study. Reactivity was examined by calculating the percent increase in MFV occurring after 15 mg/kg acetazolamide (ACZ) administration (Diamox test). The study was carried out in a quiet room with the patient lying in a comfortable supine position without any visual or auditory stimulation. The MFV at rest was obtained by continuous recording during a 5-minute period followed by ACZ infusion during 3 minutes. Fifteen minutes after ACZ administration, the maximal increase in MFV over 2 minutes was recorded. CVR was calculated from the formula MFV-ACZ-MFVbasal/MFVbasalx100. Systolic and diastolic blood pressure and heart rate were recorded before and after the Diamox test.
MRI Examinations
All patients included in the study underwent a brain MRI scan
within the first 15 days after stroke, with the use of the following
scanning units: 1/1.5-T Magnetom SP63, (Siemens) and 2/1.0-T Magnetom
Impact (Siemens). The studies were performed with a quadrature
transmitter/receiver head coil, obtaining a dual-echo (proton density
and T2-weighted) spin-echo axial scan with repetition time (TR) of 2200
to 2500 ms, an echo time (TE) of 12 to 80 ms, and 1 acquisition and a
T1-weighted spin-echo axial scan using a TR of 550 ms, a TE of 12 ms,
and 2 acquisitions. Both sequences were obtained with 5 mm of
slice thickness, 1.5 mm of interslice gap, 192 to 256x256 matrix,
and 230-mm field of view.
All MRIs were reviewed by the same neuroradiologist blinded to the clinical data. WMHIs on T2-weighted and proton density–weighted images in contact with the ventricular wall were defined as periventricular white matter hyperintensities (PWMHIs), whereas those separated from the ventricular wall by a strip of normal-appearing white matter situated in the deep white matter were defined as deep white matter hyperintensities (DWMHIs). Hyperintensities on T2-weighted images equivalent to cerebrospinal fluid on proton-density and T1-weighted images were regarded as old infarcts; hyperintensities on T2-weighted and proton density–weighted images that were isointense on T1-weighted images and located in a known subcortical or deep gray matter arterial distribution (lacunar) were regarded as acute infarcts. LIs were evaluated separately from the WMHIs. Perivascular (Virchow-Robin) spaces were considered a normal finding and not included in the evaluation of WMHIs or infarcts.
Periventricular hyperintensities were classified on the basis of size and shape in 4 groups: (1) small, rounded hyperintensities limited to the frontal or occipital periventricular white matter, (2) extending hyperintensities around the long axis of the lateral ventricular wall with regular margins and <5 mm in width, (3) extending hyperintensities with regular margins and 5 to 10 mm in width, and (4) extending hyperintensities with irregular margins and >10 mm in width. Only groups 3 and 4 were considered abnormal.
DWMHIs were classified on the basis of size (greatest diameter) and shape into 3 groups: (1) small, focal, punctate hyperintensities with a diameter <5 mm, (2) large, focal, mostly rounded hyperintensities with a diameter between 5 and 10 mm, and (3) large, mostly irregular and diffusely confluent or with a diameter >10 mm.
Statistical Analysis
For statistical purposes, CVR for the right and left sides were
averaged, resulting in a single CVR value for each individual.
Statistical significance for intergroup differences were assessed by
the 2-tailed Fisher's exact test and 
2 test
for categorical variables and the Mann-Whitney U test
and Student's t test for continuous variables. Multiple
linear regression analysis was performed to identify the
variables that independently contributed to a reduction in CVR. To
determinate a threshold of CVR, a logistic regression model was applied
to calculate the sensitivity and specificity for each value of CVR
configuring a receiver operator characteristic (ROC) curve. Logistic
regression analysis was conducted to determine the factors that
could be considered as independent predictors of first-ever
symptomatic LI. Pearson's 
coefficient was applied to
verify correlation between examined variables. The analyses
were performed with the use of SPSS 6.0 software (SPSS Inc). A level of
P<0.05 was accepted as statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty-six patients (men/women, 32:14) with a first-ever LI and 46 age- and sex-matched control subjects were included in the study. Demographic data and risk factor profiles of the series are presented in Table 1
. The
mean age of patients was 56.6±13.4 years (range 25 to 77 years),
similar to 58.3±12 years (range 27 to 77 years) of the control group.
Patients with LI were significantly more often hypertensives and
cigarette smokers than their matched control subjects.
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Pure motor hemiparesis was the more frequent lacunar syndrome, being observed in 17 (36%) patients, followed by sensorimotor syndrome in 14 (34%), ataxic hemiparesis in 5 (10.6%), pure sensory syndrome in 5 (10.6%), dysarthria–clumsy hand syndrome in 2 (4.2%), and isolated dysarthria–facial palsy in 3 (6.3%) patients. Acute LI was located on the right side in 20 (43%) and on the left side in 26 (57%) cases. Lesions involved the capsulothalamic region in 10 (22%) patients, limited to the corona radiata in 11 (23%), the pons in 10 (21%), the internal capsule in 6 (12.2%), the thalamus in 6 (12.2%), and the lenticular nucleus in 3 (6.3%) patients.
Systolic and diastolic blood pressures determined
at the time of hemodynamic evaluation were
significantly higher in patients compared with control subjects (mean
systolic blood pressure 143.4±22 mm Hg and
131.3±15 mm Hg, P<0.05; mean diastolic
blood pressure 83±11 mm Hg and 70.5±11 mm Hg,
P<0.02, respectively). There was no significant difference
in middle cerebral artery resting MFV between cases and control
subjects (MFV 51.3±12 cm/s and 49.3±13 cm/s, respectively). However,
CVR was significantly (P<0.0001, Student's t
test) lower in cases (50.0±12.7%) as compared with control subjects
(65.2±12.4%) (Table 2). To evaluate the
possible effect of symptomatic LI on side-to-side
differences in CVR measurement, we compared CVR between
symptomatic and asymptomatic sides among 36
hemispheric LIs. The CVR on the symptomatic side
(49.3±13.6 cm/s) was not significantly (P=0.3) different
from that on the asymptomatic side (51.14±14 cm/s).
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In univariate analysis, age <65 years
(P=0.01), male sex (P<0.002), smoking habit
(P=0.024), the presence of LI on MRI (P<0.001),
and untreated hypertension (P=0.039) significantly
contributed to a reduction of CVR. A multiple linear regression
analysis identified male sex (odds ratio [OR] 2.3,
P=0.02), age (OR 3.6, P<0.005), and the presence
of LI on MRI (OR 5.3, P<0,001) as significant and
independent factors associated with a reduction of CVR. On the basis of
ACZ-CVR values obtained in control subjects, we tried to determine a
cut-point for the ACZ-CVR value under which a subject should be
considered as having a pathological CVR. For this purpose, an ROC curve
was applied to obtain a threshold that better distinguishes LI patients
from control subjects. This approach provided a cut-point of 55.6%
(sensitivity 67%, specificity 82%) as the threshold value for ACZ-CVR
(Figure). Thirty-seven (80%) control
subjects and 15 (33%) LI patients had ACZ-CVR values above, whereas 9
(20%) control subjects and 31 (66%) LI patients had values below the
threshold.
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The MRI examinations revealed the presence of a single lacunar
infarction (SLI) in 20 (43%) patients and multiple lacunar infarctions
(MLI) in 26 (57%) patients. The risk factor profile of patients with
SLI and MLI is presented in Table 3. CVR was significantly
(P=0.02) lower in patients with MLI (46.38±12.6%) as
compared with SLI (54.83±11.58%). In addition, a trend of negative
correlation was found between CVR and the number of LI
(r=-0.26, P=0.08; Pearson's coefficient).
PWMHIs and DWMHIs were present in 33 (72%) patients. PWMHIs
were scored as grade 1 to 2 in 26 (78%) and 3 to 4 in 7 (22%)
patients, whereas DWMHIs were scored as grade 1 to 2 in 28 (84%) and 3
in 5 (15%). However, there was no difference in CVR between scores
greater and lower than 2 in both PWMHs and DWMHIs. In addition, CVR was
unrelated neither with the extent of PWMHI (r=-0,3;
P=0.1, Pearson's coefficient) nor with the extent of
DWMHI (r=-0.001; P=0.9).
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The relative contribution of different variables for first-ever LI
on univariate analysis is shown in Table 4. By the replacement of the CVR as
continuous variable with CVR as dichotomous factor (pathological
<55%; normal >55%), history of hypertension (OR 18.2; 95%
confidence interval [CI] 5.8 to 56.9), CVR <55% (OR 9.5, 95% CI
3.4 to 26.5), and smoking habit (OR 3.42; 95% CI 1.3 to 8.6) were
associated with a significantly increased risk for first-ever LI. Age,
sex, diabetes mellitus, hypercholesterolemia,
and blood pressure at the time of investigation were not associated
with an increased risk for first-ever LI.
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In a multiple logistic regression model, only history of hypertension
(OR 7.24; 95% CI 2.95 to 17.79) and CVR (OR 0.8; 95% CI 0.81 to 0.93)
emerge as significant and independent predictors of first-ever LI
(Table 5). Moreover, untreated and
irregularly treated hypertensive patients had a higher risk (OR 4.42;
95% CI 1.58 to 33.66) than those regularly treated, and the regularly
treated had a higher risk (OR 2.24; 95% CI 1.55 to 9.17) than the
normotensives. The remaining variables that were found significant
with univariate analysis did not enter into the
model.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Prior studies have shown a decreased vasodilatory capacity in subjects with risk factors for arteriolosclerosis.12 13 25 CVR appears to be reduced in patients with long-term insulin-dependent diabetes11 and in those with proliferative diabetic retinopathy.26 Furthermore, vasomotor tone appears to be increased in severe, noncontrolled hypertensives as compared with controlled hypertensives and normotensive subjects, and an inverse association was found between ACZ-CVR and the degree of echocardiographic left atrial enlargement.12 CVR has also been noted to be markedly decreased in cerebrovascular diseases, especially in patients with large-vessel occlusive disease.8 27 28 However, reports on hemodynamic reserve capacity in patients with symptomatic LI are scarce,8 19 29 and its role as a risk factor for first-ever LI has not been previously evaluated.
Our results demonstrate a significantly impaired CVR in patients with first-ever symptomatic LI as compared with sex- and age-matched control subjects. These findings strongly support the assumption that microangiopathic changes (arteriolosclerosis) may be an independent contributor to impaired reactivity unrelated to the presence of carotid stenosis.8 29 Unlike prior studies,8 19 20 we compared CVR in patients with LI with subjects without MRI evidence of microangiopathy, establishing an ACZ-CVR value of 55.6% as a threshold for differentiating patients from control subjects. However, an overlap was observed between patients and control subjects regarding ACZ-CVR values, resulting in 33% of patients with LI above the threshold and 20% of control subjects below the threshold. Normal values of ACZ-CVR reported range from 35% to 60%.11 30 The relatively higher ACZ-CVR in our control group (65%) may be due to exclusion of subjects with large-vessel stenosis and those with asymptomatic LI on MRI. Furthermore, to our knowledge this is the first time that CVR has been tested in subjects without MRI evidence of cerebral microangiopathy. The unexpected direct association observed between age and CVR could be related to bias, such as the relatively younger population studied (mean age 55 years) and small number of patients older than 70 years.
In the present case-control study, CVR was significantly lower in patients with MLI than in SLI, and a trend of negative correlation was found between CVR and the number of symptomatic and asymptomatic LI seen on MRI. These results support the hypothesis that single symptomatic LI may be related to microatheromatosis, and multiple, usually silent LI may represent a widespread arteriolosclerotic disease.31 Therefore CVR could be a useful test to evaluate the degree of diffuse arteriolosclerosis. Our results contradict a previously reported study19 in which no correlation was found between vasomotor tone and the presence of silent LI on MRI but are in agreement with a recent study in which cerebral blood flow and ACZ-CVR were significantly more reduced in patients with MLI than in those with SLI.32 Unlike previous studies,17 18 33 we found that in patients with first-ever LI, vasodilatory capacity was not related to the extent of both PWMHI and DWMHI. Although these results may be related to a type II error in view of the small number of patients with higher grades of abnormalities, both clinical20 and pathological3 studies have shown a great variation in the extent of PWMHI among patients with LI. Our findings are in line with recent observations in which blood flow and acetazolamide reactivity in the cerebral cortex were significantly lower in patients with leukoaraiosis with LI than in those with leukoaraiosis without LI,29 suggesting that a reduction of reactivity in patients with leukoaraiosis mainly depends on the presence of LI. Kobayashi et al34 reported a decreased cerebral blood flow in patients with lacunes, but no difference in PWMH was found between patients with and those without lacunes, indicating that lacunes may be more related to severe cerebral arteriosclerosis than to PWMHI. Systemic hemodynamic factors such as an excessive fall in nocturnal blood pressure,35 36 systolic hypertension,19 heart disease19 whereas diabetes mellitus36 may contribute to the progression and extent of white matter lesions on MRI.
Arterial hypertension is the strongest risk factor for first-ever and recurrent LI.14 15 Uncontrolled hypertension has been shown to produce arteriosclerosis in cerebral small vessels of experimental hypertensive animals.37 We observed that CVR was lower in untreated as compared with treated hypertensive patients and that untreated hypertensives had a higher risk for first-ever LI than treated hypertensives. These findings suggest that a more severe arteriolar damage exists in uncontrolled hypertension and that CVR allows estimation of the degree of diffuse arteriolosclerosis. In the present study, history of hypertension and CVR <55% emerge as strong and independent markers of increased risk for first-ever symptomatic LI. Prospective studies are needed to elucidate the role of a decreased CVR as a risk factor for first-ever and recurrent LI.
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Acknowledgments |
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We would like to thank Dr Wouter Schoneville for critically reading the manuscript and Dr Carmen Vidal for statistical support.
Received May 31, 1999; revision received July 19, 1999; accepted August 4, 1999.
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