Contribution of Arterial Blood Pressure to the Clinical Expression of Lacunar Infarction
Background and Purpose The relation between symptomatic lacunar infarction, silent stroke, and arterial hypertension is controversial.
Methods From 500 patients with ischemic or hemorrhagic stroke admitted to the Downtown Barcelona Stroke Registry between July 1992 and December 1994, we evaluated prospectively the prevalence of silent infarction in 249 patients who had a brain MRI. The association of risk factors with silent infarction was investigated with the use of logistic regression analysis. In a selected group of 43 patients with symptomatic lacunes, we performed at stroke follow-up transcranial Doppler sonography and 24-hour continuous blood pressure monitoring to evaluate whether blood pressure, cerebrovascular tone, and cerebral blood flow at rest and after the administration of 1 g acetazolamide correlated with silent infarction.
Results A total of 147 silent infarctions were observed in 83 patients (33%). Most silent infarctions corresponded to small deep lesions in the territory of the lenticulostriate arteries. Patients with silent infarctions had higher systolic and diastolic blood pressure at stroke onset. However, on multivariate analysis, age greater than 60 years was the only risk factor associated with silent infarction. In a subgroup of 43 patients with symptomatic lacunes and patent extracranial vessels, systolic and diastolic pressure at stroke onset and diastolic pressure and vascular resistance at stroke follow-up were higher when silent infarctions coexisted. However, cerebral blood flow at rest and after acetazolamide injection were unrelated to silent infarction.
Conclusions Silent ischemia in patients with symptomatic lacunar and nonlacunar stroke was only associated with aging. However, a history of arterial hypertension was perhaps unrecognized, since hemodynamic testing and continuous blood pressure monitoring in patients with lacunar stroke suggested that the coexistence of silent lesions indicated a more generalized cerebral arteriolosclerosis.
Those infarcts found on neuroimaging or at necropsy without the patient providing a history of stroke are termed SIs. Most SIs correspond to small lesions located in the territory of the lenticulostriate arteries, and they are reported to be associated with vascular risk factors, including arterial hypertension.1 2 3 4 5 Nevertheless, as a consequence of the disparity in clinical criteria and sensitivity of methods applied for brain imaging and blood pressure measurement, the correlation of silent ischemia with arterial hypertension was found controversial in previous studies.1 2 3 4 5 6
To reconcile these discrepancies, the existence of two distinct lacunar infarct entities was recently proposed, namely, single symptomatic lacunar infarcts, secondary to microatheromatous disease, and multiple asymptomatic lacunar infarcts, related to arteriolosclerosis and hypertension.7 Recent clinical series have reinforced the concept of etiologically distinct lacunar infarct subgroups.8 However, whether both lacunar entities differ in their blood pressure characteristics and cerebral hemodynamics remains unproven in longitudinal studies.
In the present study we evaluated in a large cohort of stroke patients the association of SI with arterial hypertension and other stroke risk factors. In a selected group of patients with symptomatic lacunar stroke, we performed continuous blood pressure monitoring and CBF measurements to further investigate whether the coexistence of silent ischemia indicated a more generalized form of hypertensive encephalopathy. If SIs are markers of hypertension and impaired cerebral autoregulation, hemodynamic evaluation of asymptomatic patients with SI could result in better therapeutic strategies aimed at preventing threatening stroke.
Subjects and Methods
From July 1992 to December 1994, 500 consecutive stroke patients admitted to the Neurology Service at our institution were entered into a computerized data bank as part of the Downtown Barcelona Stroke Registry, including 249 patients who had a brain MRI during hospital admission. Two hundred fifty-one patients did not have a brain MRI at the time of stroke for any of the following reasons: age greater than 80 years (n=62), stroke severity 74 or less by the Mathew score scale (n=87), contraindication for brain MRI (n=37), or nonavailability of brain MRI (n=65). As a result of the selection criteria, patients who had a brain MRI were younger and had less severe strokes than those excluded from the study. However, with the exception of a slightly higher prevalence of NVAF, excluded patients shared stroke risk factors similar to those of patients who had a brain MRI (Table 1⇓).
On admission, all patients were given a detailed neurological examination with the use of the Mathew score scale (normal=100) and the Mini-Mental State Examination (normal=30). At discharge (mean, 14±7 days), neurological status was reassessed with the Mathew score scale. The most likely stroke mechanism was used to classify symptomatic infarctions into cardioembolic, atherosclerotic, lacunar, undetermined cause, and hemorrhagic, according to the criteria used by the Stroke Data Bank, with slight modifications.9 History of transient ischemic attacks was not used as a clinical criterion for stroke subtyping. The diagnostic workup was performed as appropriate for the better identification of stroke subtypes. Standard blood tests, chest roentgenography, and electrocardiography were performed in all patients. In addition, carotid ultrasound was carried out in 60% of patients, cerebral angiography in 18%, MR angiography in 22%, and transthoracic or transesophageal echocardiography in 34%.
According to standard definitions, the following risk factors were considered: age (<50, 50 to 60, 61 to 70, >70 years), sex, current smoking, arterial hypertension (treated or >160 mm Hg systolic or >90 mm Hg diastolic), angina, myocardial infarction, left ventricular hypertrophy (abnormally high QRS complex voltage on electrocardiogram), intermittent claudication, diabetes (treated or fasting glucose >110 mg/dL), NVAF (absent P waves and an irregular ventricular response in the electrocardiogram), valve disease (echocardiographic diagnoses of cardiac lesions considered to be potential sources of emboli), and hypercholesterolemia (treated or >240 mg/dL).
All included patients had a brain MRI scan that used a superconducting magnet at a field strength of 1.5 T on proton density, T1-, and T2-weighted images in sagittal, coronal, and axial planes, respectively. All abnormalities located in anatomic regions contralateral to the symptomatic hemisphere or involving ipsilateral or contralateral regions incompatible with current symptoms were labeled as SI if they were hyperintense relative to brain parenchyma on both long repetition time sequences and hypointense on T1-weighted imaging.10 Two types of SI were defined: small deep SI, compatible with lacunar infarctions, and territorial SI, consistent with atherosclerotic or cardioembolic infarctions or those of undetermined cause. To avoid misclassification of état criblé as small deep SI, lesions identified on successive axial sections whose appearance was hypointense relative to brain parenchyma on proton density and hyperintense on T2 were excluded.11 Periventricular hyperintense areas in the T2-weighted scan were defined as infarctions only if they were well demarcated, wedge-shaped, or extended to the cortex and followed a specific vascular territory. Abnormal areas in the T2-weighted scan were defined as leukoaraiosis if they were ill defined, patchy, diffuse, and localized in white matter only.10 The volume of the symptomatic infarction was calculated in most subjects with the use of the templates created by the Stroke Data Bank,9 and the vascular topography of the infarctions was identified according to a standard brain atlas.
Six months after stroke onset, 43 patients with symptomatic lacunar infarction, free of cortical infarctions on MRI or proximal carotid disease on Doppler ultrasound or MR angiography, which could interfere with the correct interpretation of CBF values, were readmitted for hemodynamic testing. Patients with recurrent symptoms at follow-up were considered ineligible. At hospital readmission, blood pressure was measured noninvasively in the right arm at intervals of 15 minutes during the day and at intervals of 20 minutes during the night with an ambulatory monitor (SpaceLabs ABP monitor 90207). The average diurnal values were calculated between 6 am and 10 pm and the average nocturnal values between 10 pm and 6 am. Systolic, diastolic, and mean blood pressures were registered. Systolic and diastolic fall was defined as the average percent change between the values obtained during the day compared with the night values. The onset of sleep was identified as the time patients went to bed.
CBF was measured between 9 and 10 am with the use of a transcranial Doppler ultrasound machine fitted with a 2-MHz probe (TC2-Plus, EME), and we used the mean values of 60 cardiac cycles in our calculations. Both right and left MCAs were insonated at a depth of 45 to 55 mm while subjects were lying in a semirecumbent position in a quiet, semidark room and breathing room air. Mean flow velocity (V) and pulsatility index (PI) were recorded. The latter was calculated as (maximum systolic V−maximum diastolic V)/mean V. Cerebrovascular reactivity was evaluated 10 minutes after the injection of 1 g acetazolamide, and the vasodilatory response was calculated from the formula [(VMCA acetazolamide−VMCA basal)/VMCA basal]×100. CRI was obtained from mean arterial pressure (MAP) in the brachial artery and flow velocity in the MCA, according to the formula CRI=MAP/mean V.12 Increasing values of CRI were thought to reflect increasing vascular tone in the cerebral circulation as a consequence of arteriosclerotic changes. Blood pressure and CBF monitoring were performed on the same day and at least 24 hours after all antihypertensive drugs had been discontinued.
At clinical follow-up, all patients were given several tests of attention and mental speed with validated sensitivity in the detection of subcortical lesions13 to rule out the possibility that patients with SI had more severe deficits. For the simple visual reaction time task, patients were required to press a key whenever a visual stimulus appeared on a computer screen. For the simple acoustic reaction time task, patients were also requested to press a key whenever they heard a beep. Reaction times were recorded in a computer for off-line analysis.
For statistical analysis, categorical variables were analyzed with the use of χ2 and crude odds ratios with 95% confidence intervals. Continuous variables with normal distribution were correlated with the presence or absence of SI with the use of ANOVA. With “all SI” and “small deep SI” as dependent variables, stepwise logistic regression models were performed to determine the independent association of age, sex, hypertension, diabetes mellitus, history of myocardial infarction, angina, smoking, NVAF, hypercholesterolemia, and index stroke subtype. Entry values of 0.05 and remove values of 0.10 were used in the model. Multicollinearity between variables was evaluated by analyzing the coefficients in the correlation matrix. A level of P<.05 was accepted as statistically significant.
Analysis of Risk Factors in the Total Cohort of Subjects Studied With MRI (n=249)
A total of 147 SIs were detected in 83 patients (33%), and their characteristics are represented in Table 2⇓. Table 3⇓ shows that age was the only factor associated with the presence of SI. On the contrary, there were no significant differences in the prevalence of stroke risk factors, stroke subtypes, and neurological severity at hospital admission or at hospital discharge between subjects with or without SI. At stroke onset, systolic and diastolic pressure were significantly higher in patients with SI, and in normotensive patients, systolic pressure at clinical onset was also higher in patients with SI (Table 4⇓). On logistic regression analysis, age was also the only variable that remained in the models of all SI and small deep SI (Table 5⇓).
Hemodynamic Findings at Follow-up in Patients With Lacunar Infarction (n=43)
The subgroup of 43 patients with lacunar infarction and hemodynamic testing had similar neuropsychological involvement at follow-up (≥6 months). Thus, visual (336±172 milliseconds) and acoustic (336±138 milliseconds) reaction times in patients with SI (n=21) were similar to visual (333±82 milliseconds) and acoustic (318±102 milliseconds) reaction times in patients without SI (n=22). Continuous monitoring of blood pressure disclosed that diurnal and nocturnal values were higher in patients with SI, although only diurnal diastolic pressure reached statistical significance (Table 6⇓). However, systolic and diastolic nocturnal fall were unrelated to the presence of SI. As shown in Table 7⇓, the vasodilatory capacity was significantly lower in the MCA ipsilateral to clinical symptoms in all patients. The vasodilatory capacity was also lower in patients with SI, although probably because of wide standard deviations or an insufficient number of patients, differences did not reach statistical significance. CRI was higher in both hemispheres in patients with SI.
We found in a large series of stroke patients studied with brain MRI that age but not history of hypertension was independently associated with the presence of asymptomatic lesions. In a subgroup of patients with symptomatic lacunes, those who had coexistent SI showed at stroke onset higher systolic and diastolic pressure than patients without these lesions. At follow-up, diurnal diastolic pressure remained higher in patients with SI, and hemodynamic evaluation of this subgroup of patients revealed that CBF values at rest and after the administration of acetazolamide were unrelated to SI. However, the presence of asymptomatic lesions was associated with a higher cerebrovascular tone of the resistance vessels in the territory of the MCA.
The relationship between arterial hypertension and symptomatic or asymptomatic lacunar infarction is controversial, since it varies across studies.6 7 8 14 Although in the present study we could not find an independent association of SI with history of arterial hypertension, several findings suggest that hypertension was more prevalent in our series than was implied by clinical history. First, we found most SIs located in the territory of the lenticulostriate arteries, where vascular lesions most specific to arterial hypertension are described.15 Second, in agreement with human16 and experimental17 models which found that arterial hypertension progressively increased the cerebrovascular tone at the microcirculation, we also observed higher vascular resistance values in those patients with SI. Finally, when we used more sensitive methods for blood pressure monitoring,18 our results concurred with previous clinical8 and autopsy19 studies that found an association of diastolic blood pressure with multiple lacunes. Blood pressure measurements were limited in previous studies to the acute phase of stroke, and therefore we further confirm the persistence of this association during the chronic phase of stroke.
We gathered some insight on the complex relationship between symptomatic and asymptomatic lacunar infarctions.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 First, we did not find an additional impairment of resting or hypercapnic flow in symptomatic patients attributable to the coexistence of silent ischemia, despite previous studies indicating decreased CBF23 and cerebrovascular reactivity24 in neurologically intact adults with SIs. However, we observed a higher cerebrovascular tone in symptomatic patients with SIs, in agreement with previous studies that demonstrated higher CRI in asymptomatic hypertensive and normotensive patients with lacunar SIs.25 It could be argued that abnormal hemodynamics were secondary to chronic brain dysfunction, since they were more striking in symptomatic hemispheres.26 However, such a mechanism seems unlikely so late after stroke onset, in particular if we did not observe the increased hypercapnic response described in areas of diaschisis secondary to lacunar infarction.20 Rather, since appropriate tests were performed to rule out the existence of cortical infarctions or extracranial atherosclerosis, which might have swayed the hemodynamic response, we contend that symptomatic stroke had supervened because these patients harbored a more severe form of cerebral arteriolosclerosis.
The results of this study could present some limitations that mainly depend on the methods used. First, we only analyzed the risk factor profile of those patients who had an MRI at the time of stroke. At our institution, very old patients and those patients with very severe clinical deficits are generally not studied with MRI. As might be expected from these criteria, we observed that the group of patients included in the study were younger and manifested less severe neurological clinical syndromes. However, additional comparisons between included and excluded patients disclosed no significant differences in the prevalence of stroke risk factors, with the exception of a higher prevalence of NVAF in the group who did not undergo a brain MRI. The inclusion of older patients would have probably resulted in a higher prevalence of SIs. However, the aim of the study was to analyze the relationship between SIs and risk factors and not to estimate the prevalence of SIs in the stroke population. Thus, we are confident that the representability of the selected group is warranted by the close similarities in epidemiological and clinical characteristics observed in the patients who underwent MRI and in those who were not included in the study. Another limitation might derive from the smaller group of patients who were evaluated at a chronic phase after stroke. Although we cannot exclude a type II error, we emphasize that this subgroup of patients represented a homogeneous population free of extracranial disease or cortical lesions that could have flawed the correct interpretation of the hemodynamic findings. Finally, the variability in blood pressure was calculated from a relatively low number of blood pressure values compared with continuous intra-arterial recording. However, it has been shown that for the time intervals used in our measurements, there is not too much difference from values derived by continuous intra-arterial blood pressure recording.27
In summary, in patients with symptomatic stroke the coexistence of silent ischemia is associated with aging and higher blood pressure values at stroke onset. Silent ischemia in the subgroup of patients with lacunar infarction is also associated at stroke follow-up with higher diastolic blood pressure and cerebrovascular resistance in both hemispheres, possibly due to a more generalized cerebral arteriolosclerosis. Nevertheless, larger longitudinal studies performed in normal adults with SIs are needed to confirm whether hemodynamic testing and continuous blood pressure monitoring are useful in the prediction of impending stroke.
Selected Abbreviations and Acronyms
|CBF||=||cerebral blood flow|
|CRI||=||cerebrovascular resistance index|
|MCA||=||middle cerebral artery|
|NVAF||=||nonvalvular atrial fibrillation|
This study was supported in part by research grant 95/0575 from the Fondo de Investigaciones Sanitarias de la Seguridad Social. The authors would like to dedicate this work to the memory of Dr Thomas K. Tatemichi.
- Received July 21, 1995.
- Revision received November 21, 1995.
- Accepted December 15, 1995.
- Copyright © 1996 by American Heart Association
Chodosh EH, Foulkes MA, Kase C, Wolf PA, Mohr JP, Hier DB, Price TR, Furtado JG. Silent stroke in NINCDS Stroke Data Bank. Neurology. 1988;38:1674-1679.
Boon A, Lodder J, Heuts-van Raan L, Kessels F. Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke: relationship with index-stroke subtype, vascular risk factors, and mortality. Stroke. 1994;25:2384-2390.
Kase C, Wolf PA, Chodosh EH, Zacker HB, Kelly-Hayes M, Kannel WB, D’Agostino RB, Scampini L. Prevalence of silent stroke in patients presenting with initial stroke: the Framingham Study. Stroke. 1989;20:850-852.
Herderschee D, Hijdra A, Algra A, Koudstaal PJ, Kapelle LV, van Gijn J, for the Dutch TIA Trial Study Group. Silent stroke in patients with transient attack or minor ischemic stroke. Stroke. 1992;23:1220-1224.
Hougaku H, Matsumoto M, Kitagawa K, Harada K, Oku N, Itoh T, Maeda H, Handa N, Kamada T. Silent cerebral infarction as a form of hypertensive target organ damage in the brain. Hypertension. 1992;20:816-820.
van Gijn J, Kraaijeveld CL. Blood pressure does not predict lacunar infarction. J Neurol Neurosurg Psychiatry. 1982;45:147-150.
Boiten J, Lodder J, Kessels F. Two clinically distinct lacunar infarct entities? A hypothesis. Stroke. 1993;24:652-656.
Mast H, Thompson JLP, Lee S, Mohr JP, Sacco RL. Hypertension and diabetes mellitus as determinants of multiple lacunar infarcts. Stroke. 1995;26:30-33.
Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke. 1988;19:547-554.
Liu CK, Miller BL, Cummings JL, Mehringer CM, Goldberg MA, Hown SL, Benson DF. A quantitative MRI study of vascular dementia. Neurology. 1992;42:138-143.
Braffman BH, Zimmerman RA, Trojanowski JQ, Gonatas NK, Hichey WF, Schlepfer WW. Brain MR: pathologic correlation with gross and histopathology, I: lacunar infarction and Virchow-Robin spaces. AJNR Am J Neuroradiol. 1988;9:621-628.
Rubba P, Faccenda F, Di Somma S, Gnasso A, Scarpato N, Iannuzzi A, Nappi G, Postiglione A, De Divitiis O, Mancini M. Cerebral blood flow velocity and systemic vascular resistance after reduction of low-density lipoprotein in familial hypercholesterolemia. Stroke. 1993;24:1154-1161.
Chamorro A, Sacco RL, Mohr JP, Foulkes MA, Kase CS, Tatemichi TK, Wolf PA, Price TR, Hier DB. Clinical-computed tomographic correlations of lacunar infarction in the Stroke Data Bank. Stroke. 1991;22:175-181.
Gautier JC. Cerebral ischemia in hypertension. In: Russell RWR, ed. Vascular Disease of the Central Nervous System. New York, NY: Churchill Livingstone; 1983:224-244.
Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T. Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension. 1994;23:565-568.
Baumbach GL, Heistad DD. Cerebral circulation in chronic arterial hypertension. Hypertension. 1988;12:89-95.
Shimada K, Kawamoto A, Matsubayashi K, Ozawa T. Silent cerebrovascular disease in the elderly: correlation with ambulatory pressure. Hypertension. 1990;16:692-699.
Dozono K, Ishii N, Nishihara Y, Horic A. An autopsy study of the incidence of lacunes in relation to age, hypertension, and arteriosclerosis. Stroke. 1991;22:993-996.
Isaka Y, Okamoto M, Ashida K, Imaizumi M. Decreased cerebrovascular dilatory capacity in subjects with asymptomatic periventricular hyperintensities. Stroke. 1994;25:375-381.
Takano T, Nagatsuka K, Ohnishi Y, Takamitsu Y, Matsuo H, Matsumoto M, Kimura K, Kamada T. Vascular response to carbon dioxide in areas with and without diaschisis in patients with small, deep hemispheric infarction. Stroke. 1988;19:840-845.
Kobayashi S, Okada K, Yamashita K. Incidence of silent lacunar lesion in normal adults and its relation to cerebral blood flow and risk factors. Stroke. 1991;22:1379-1383.
Sugimori H, Ibayashi S, Irie K, Ooboshi H, Nagao T, Fujii K, Sadoshima S, Fujishima M. Cerebral hemodynamics in hypertensive patients compared with normotensive volunteers: a transcranial Doppler study. Stroke. 1994;25:1384-1389.
Pappata S, Mazoyer B, Tran Dihn S, Cambon H, Levasseur M, Baron JC. Effects of capsular or thalamic stroke on metabolism in the cortex and cerebellum: a positron tomography study. Stroke. 1990;21:519-524.
Di Renzo M, Grassi G, Pedotti A, Mancia G. Continuous versus intermittent blood pressure measurements in estimating 24-hour average blood pressure. Hypertension. 1983;5:264-269.