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Cerebrovascular Reactivity and Subcortical Infarctions
Letizia M. Cupini, MD;
Marina Diomedi, MD;
Fabio Placidi, MD;
Mauro Silvestrini, MD;
Patrizia Giacomini, MD
Arch Neurol. 2001;58:577-581.
ABSTRACT
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Objectives To investigate the association between different kinds of ischemic lesions
and cerebrovascular reactivity (CR) and to evaluate their relationships with
the major risk factors for stroke.
Subjects and Methods We evaluated CR using the breath-holding index technique during bilateral
transcranial Doppler monitoring of flow velocity in the middle cerebral arteries
of 41 consecutive patients attending our clinic for a recent, first-ever,
ischemic stroke and in 15 control subjects. Based on the location of the lesion
determined by computed tomography, the following 3 types of infarctions were
identified: cortical (or territorial), single subcortical, and subcortical
with multiple silent subcortical infarctions. Patients with a condition of
severe carotid artery stenosis or occlusion, which in itself could account
for altered CR, were excluded from this study. All physiological and pathologic
conditions that could possibly cause an impairment in CR were recorded.
Results The breath-holding index was significantly lower in the multiple subcortical
infarctions group than in the control subjects (P<.001),
single subcortical infarctions group (P<.01),
and cortical infarctions group (P<.01). In all
of the groups male sex (P<.05) and a history of
hypertension (P<.05), regardless of whether hypertension
was treated, correlated with low CR. The multiple regression analysis indicated
that the only significant factor able to influence the breath-holding index
was the type of lesion.
Conclusions Nonstenotic patients with first-ever stroke who had a recent symptomatic
subcortical infarction associated with multiple silent infarctions seem to
have an impaired cerebrovascular reserve capacity. The strong association
of subcortical infarctions with multiple silent infarctions with low CR indicates
the role of small vessel vasculopathy and hypoperfusion as possible pathogenetic
mechanisms of subcortical infarctions with multiple silent infarctions.
INTRODUCTION
THE CORRELATION between an impaired functional blood flow reserve capacity
and the occurrence of brain infarction was previously reported in patients
with severe carotid artery disease.1, 2, 3, 4
Patients with limited cerebrovascular reserve capacity have less adequate
perfusion capacity than patients with normal reserves. An impaired cerebrovascular
reserve capacity may increase the risk of cerebral ischemia in patients with
major cerebral artery occlusion.5, 6
Patients with severe carotid artery stenosis or occlusion often have a borderzone
distribution of brain infarction in the cerebral hemisphere ipsilateral to
internal carotid artery disease.7 Border-zone
distribution of infarction has traditionally been attributed to hypoperfusion
related to reduced blood flow in zones between major hemispheric vascular
territories. Moreover, cerebrovascular reactivity (CR) was found to be significantly
reduced in low-flow infarctions compared with thromboembolic infarctions in
patients with ipsilateral carotid stenosis.8
An association was found between CR and white matter lesions. This supports
the hypothesis that these kinds of lesions may be associated with hemodynamic
ischemic brain injury.9 In addition, patients
with major cerebral arterial occlusive diseases and misery perfusion have
a high risk of recurrent ischemic stroke.6, 10
These findings suggest that an impaired cerebrovascular reserve capacity is
highly related to the occurrence of ischemic stroke. To our knowledge, the
association between different types of ischemic lesions and CR has not been
studied in patients who have had a stroke but who did not have severe carotid
artery disease.
During the past decade, transcranial Doppler ultrasonography (TCD) has
been widely used to assess blood flow velocities in the basal intracranial
arteries and CR to various stimuli, including carbon dioxide (CO2)
reactivity. Many physiological and pathologic conditions such as age, sex,
migraine, smoking, hypertension, and blood flow viscosity could account for
changes in CR CO2.11, 12, 13, 14, 15, 16, 17
These conditions are considered the most common risk factors for stroke. Our
study evaluated the association between different kinds of ischemic lesions
and CR and their relationship to the above-mentioned risk factors for stroke.
Thus, patients with a recognized potential source of CR failure, such as that
observed with carotid artery stenosis or occlusion, were excluded from this
study.
SUBJECTS AND METHODS
The study was prospective and consecutive and included all patients
who have had an acute, first-ever stroke who were admitted to our neurology
ward from January 1, 1998, to October 1, 1999. Patients were enrolled in this
study if they fulfilled the following criteria: (1) their clinical symptoms
correlated with a supratentorial ischemic lesion on computed tomography (CT),
(2) Doppler ultrasonography excluded a hemodynamic stenotic disease of extracranial
carotid and vertebral arteries, and (3) TCD revealed symmetrical middle cerebral
artery (MCA) blood flow velocities and adequate temporal windows permitting
acquisition of continuous bilateral blood flow velocities. Patients with a
history of stroke were excluded from this study. Carotid artery evaluation
was performed using a color-flow B-mode Doppler ultrasonography (model AU5;
Harmonic Esaote Biomedica, Esaote S.p.A., Genoa, Italy), with a 7.5-MHz linear
transducer. Plaque occurrence in the right and left carotid arteries and common
carotid intima media thickness were evaluated. The type of ischemic lesion
was determined by CT performed with a spiral CT scanner (Tomoscan SR 7000;
Philips Medical Systems, Amsterdam, the Netherlands).
Of the 152 patients who had a first-ever ischemic stroke observed during
the study period, 111 were excluded (21 owing to a subtentorial ischemic lesion,
56 owing to the presence of a hemodynamic stenotic disease of the extracranial
carotid and vertebral arteries, and 34 owing to poor insonation of the temporal
bone window or significant asymmetry of MCA blood flow velocities). Forty-one
patients were included in this study. Thirty-two patients underwent brain
magnetic resonance imaging (MRI) scanning (Gyroscan ACS-NT, 1.5 T; Philips
Medical Systems). Twenty-one patients were also studied using MRI angiography.
Basal TCD examination and MRI angiography did not reveal intracranial steno-occlusive
lesions in the included patients. Based on the location of the lesion, 3 types
of infarctions were classified. The first type, a cortical (or territorial)
infarction, was defined as a case of first-attack infarction in which the
CT scan showed a territorial infarction of a main intracerebral artery. The
second type, a single subcortical infarction, was defined as a case of first-attack
infarction in which the CT scan showed a single subcortical hemispheric infarction
compatible with symptoms. According to the classification of Nakano et al,18 the infarctions were restricted to the basal ganglia
and/or white matter on CT, and the overlying cerebral cortex appeared normal.
The maximum diameter of the lesion exceeded 2.0 cm. The third type, a subcortical
infarction with multiple silent subcortical infarctions, was defined as a
case of first-ever stroke in which the CT scan showed multiple subcortical
infarctions. Computed tomographic scans were examined by an expert reader
(M.S.) blinded to the results of the TCD recordings. Evaluation of CR was
performed by 2 operators (M.D. and F.P.) blinded to the CT findings.
The study was carried out in a quiet room with the patients lying in
a comfortable supine position. Bilateral simultaneous flow velocity recording
of MCAs was obtained using a transcranial Doppler instrument (Multi-DopX/TCD;
DWL Elektronische Systeme GmBH, Sipplingen, Germany). Two dual 2-MHz transducers
fitted on a headband and placed on the temporal bone window were used to obtain
a bilateral continuous measurement of mean flow velocity (MFV) in the MCAs.
Examination of vessels of the circle of Willis was performed as described
by Aaslid et al.19 We obtained hypercapnia
with breath holding20 and evaluated CR using
the breath-holding index (BHI) technique in the 41 patients and 15 healthy
volunteers recruited from hospital personnel. The BHI is obtained by dividing
the percent increase in MFV occurring during breath holding by the length
of time (in seconds) the subjects hold their breath after a normal inspiration
[({MFV at the end of breath holding - rest MFV}/rest MFV) x (100/s
of breath holding)]. End-tidal expiratory CO2 level was recorded
using a capnometer (Normocap-oxy; Datex-Ohmeda S.p.A., Segrate, Italy). Mean
blood pressure and heart rate were continuously monitored by means of a blood
pressure monitor (2300 Finapress Ohmeda Medical, Laurel, Md). All subjects
were normocapnic. The MFV at rest was obtained by the continuous recording
of a 1-minute period of normal room air breathing. After a breath-holding
period, the MFV, mean blood pressure, and heart rate were recorded over 4
seconds. Subjects were asked to hold their breath for 30 seconds. The end-tidal
expiratory CO2 level during the first exhalation after apnea was
evaluated. The BHI was calculated when the rise in the level of end-tidal
expiratory CO2 from baseline to the first expiration after breath
holding was more than 8 mm Hg. The efficacy of breath holding was checked
with the respiratory activity monitor. All TCD data were stored on hard disk
for off-line analysis.
Patients were examined twice, in the acute phase and in a follow-up
visit 1 to 3 months after the acute onset of stroke. Data concerning this
study refer to recordings performed during the follow-up visit since previous
evidence indicates that cerebral hemodynamics can be impaired during the acute
phase of stroke.
All the physiological and pathologic conditions that could account for
the patients' altered CR were recorded. The following known or putative factors
associated with risk were considered: age ( 50, >50, 65, or >65 years);
sex; heavy alcohol consumption ( 300 g/wk), current daily smoking (10
cigarettes per day); hypertension (in treatment with antihypertensive drugs
at the time of admission or hypertension diagnosed during the hospital stay);
an elevated serum cholesterol level (total serum cholesterol level of 6.20
mmol/L [240 mg/dL] at the time of admission); an elevated hematocrit on
admission; and the presence of diabetes mellitus, coagulopathies, and migraine.
As regards statistical analysis, at the first step several analyses
of variance, with patients' characteristics (ie, age groups, sex, and others)
as between-subjects factors and BHI as dependent variable, were used to assess
the relationship between CR and the risk factors. In addition, analysis of
variance with group (4 levels: the 3 groups of patients and the controls)
as between-subjects factor and BHI as dependent variable was used to assess
possible differences in CR among the different groups of patients and controls.
At the second step, to individuate which risk factors were more relevant
on the BHIs, a multiple regression analysis was performed, entering the CR
as a dependent variable and the type of lesion; sex; age; the presence of
hypertension, diabetes mellitus, hypercholesterolemia, coagulopathies, and
migraine; the use of antihypertensive treatment; the patient's tobacco use;
an elevated hematocrit; and excessive alcohol consumption as independent variables.
Each categorical variable was entered as a dummy variable, while age was a
continuous variable. The forward stepwise method was chosen to individuate
recursively the statistically significant factors. The statistical significance
threshold was set at P<.05. All analyses were
performed with StatSoft 5.0 for Windows statistical software (StatSoft Inc,
Tulsa, Okla). The study was approved by the local ethics committee and all
subjects gave their informed consent.
RESULTS
All patients included in the study performed the required task adequately.
The period of apnea ranged from 29.1 to 30.6 seconds. Heart rate and mean
blood pressure showed a slight increase after the end of the apnea period
with respect to the baseline condition: 2% to 3% for heart rate and 3% to
4% for mean blood pressure. Forty-one patients (30 men and 11 women) were
studied. Thirteen patients (group 1) had cortical (or territorial) infarctions
(mean [±SD] age, 53.9 ± 11.8 years; age range, 34-83 years ),
14 patients (group 2) had single subcortical infarctions (mean age, 61.4 ±
9.2 years; age range, 41-76 years), and 14 patients (group 3) had subcortical
infarction with multiple silent subcortical infarctions (mean age, 60.5 ±
10.5 years; age range, 44-76 years). All patients with subcortical infarction
had an additional MRI scan that confirmed the solitary subcortical lesion
revealed by CT.
Patients' characteristics and vascular risk factors are reported in Table 1. Mean (± SD) age and sex
distribution for the controls were 57.66 ± 12.7 years (age range, 37-73
years) for 9 men and 6 women, respectively. No significant difference was
noted in age and sex distribution among the groups. Regarding pharmacological
treatment of vascular risk factors, no significant difference in the use of
insulin, oral antidiabetes drugs, statins, and different classes of antihypertensive
drugs was found among the patient groups.
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Characteristics of Patients Who Have Had an Ischemic Stroke*
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Since the side of the stroke was not statistically found to influence
CR in the 2 MCAs (ie, group 1, BHI [mean ± SD] of the symptomatic side:
1.24 ± 0.51, BHI of the asymptomatic side: 1.45 ± 0.51, P = .09; group 2, BHI of the symptomatic side: 1.33 ±
0.36, BHI of the asymptomatic side: 1.36 ± 0.39, P = 0.6; group 3, BHI of the symptomatic side: 0.97 ± 0.42,
BHI of the asymptomatic side: 0.90 ± 0.36, P
= .32), the mean of the right and left CR was used for further statistical
analysis.
Smoking, diabetes mellitus, elevated serum cholesterol levels, hematocrit,
coagulopathies, and use of alcohol were not found to affect CR significantly.
Male sex (F1,39 = 4.93, P = .03) and the
presence of hypertension (whether treated or not) (F1,39 = 4.1, P = .049] were found, regardless of group, to be significantly
related to a low CR. However, a history of migraine was significantly related
to a high CR (F1,39 = 8.21, P = .007).
Regarding the comparison of the BHIs among the 3 groups of patients
and controls, the group effect was significant (F3,52 = 6.6, P<.001). In particular, the Tukey post hoc analysis
showed that BHIs of the subcortical infarction with multiple silent infarctions
group (Figure 1) was significantly
lower than that of the controls (P<.001) and of
both singular subcortical (P<.01) and cortical
(or territorial) infarction groups (P<.01). No
statistical difference of mean BHIs was observed for the controls and the
territorial and singular subcortical infarction groups.
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The mean breath-holding index (BHI) in the 3 groups of patients and
the control subjects. Group 1 indicates those patients with cortical (or territorial)
infarctions (n = 13); group 2, those patients with a single subcortical infarction
(n = 14); group 3, those patients with subcortical infarctions with multiple
silent subcortical infarctions (n = 14); and the controls (n = 15). For further
explanation of the 3 infarction groups see the "Subjects and Methods" section.
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The multiple regression analysis indicated that the only significant
factor able to influence the BHI was the type of lesion (r = 0.46, F1,39 = 10.2, P = .003).
No other variable could be entered for a better accounting of BHI variability.
This result does not indicate that the type of lesion is an independent predictor
of CR, since higher percentages of multiple infarction lesions were observed
in patients with hypertension (P = .04,  2 test) and in patients who smoked (P = .04, 2 test). However, the result of multiple regression analysis suggests
that, at the evaluation time, the strongest and unique factor able to explain
BHI was the type of lesion. In particular, the patients in the subcortical
infarction with multiple silent subcortical infarctions group were characterized
by a significantly lower BHI than the other 2 groups (mean difference = 0.41),
as confirmed by the above analysis of variance.
COMMENT
The primary purpose of this study was to assess the relationship between
hemodynamic reserve capacity and distributions of ischemic lesions in patients
who have had a stroke but who did not have carotid stenosis. Available data
strongly link hypoperfusion with the occurrence of brain ischemia and infarction.21 Hypoperfusion is the proximate cause of all ischemic
stroke; however, the extent of its role as the primary causative factor in
stroke remains unclear.5, 22 The
correlation between an impaired cerebrovascular reserve capacity and the occurrence
of stroke in patients with severe internal carotid artery occlusive disease
has been widely recognized.1, 2, 3, 4, 6
However, the pathogenetic role of an impaired hemodynamic reserve capacity
in stroke patients who did not have carotid stenosis has not been clarified.
The main finding of our study on patients without stenosis first-ever
stroke is that subjects with lower CR were found to have subcortical infarction
with multiple silent subcortical infarctions. We did not observe statistical
differences in CR among the controls, the single subcortical infarction group,
or the cortical (or territorial) infarction group. Previously, a reduction
in CR was reported in low-flow infarction compared with that found in patients
with cortical (or territorial) infarction.8
However, all of the patients included in that study had internal carotid artery
occlusion and, as the authors23, 24, 25, 26
suggested, a restricted collateral blood supply contributed to their finding
of low CR in low-flow infarction. Previous studies23, 24, 25, 26
also suggested that white matter infarctions in terminal distribution vessels
may be a more common consequence of hypoperfusion. An association was previously
shown between decreased CR and periventricular lesions using MRI in asymptomatic
individuals27 and hypertensive patients with
leukoaraiosis.28 An association was also reported
between decreased CR and the size, location, and number of white matter lesions
in elderly persons.9 However, all of these
studies were conducted on both patients with and without stenosis, thus the
effect of carotid stenosis on CR cannot be excluded.
It is generally accepted that among the pathogenetic causes of subcortical
hemispheric infarctions are small vessel disease, thromboembolic occlusions
of small arteries, and hemodynamic impairment in low-flow conditions.8, 9, 18, 23 Our
finding that an impaired hemodynamic reserve capacity in patients without
stenosis is associated with multiple subcortical ischemic lesions supports
the hypothesis that some subcortical ischemic lesions may be associated with
hemodynamic ischemic injury to the brain. Hypoperfusion could account for
the finding of silent infarction in patients with first-ever, subcortical,
symptomatic stroke. In our study, among the risk factors that could account
for impaired CR, hypertension, and male sex were found to be significantly
and independently from groups associated with low CR. The effect of hypertension
and its treatment on CR were previously outlined.15
Hypertension is considered the most important single risk factor for ischemic
stroke29, 30 and is considered
one of the main risk factors for stroke recurrence.31
However, not all studies have shown that when blood pressure is controlled,32 the risk of stroke recurrence is reduced. We observed
that despite whether they were being treated, the patients with hypertension
had the lowest CR. This finding raises the critical issue of the efficacy
of antihypertensive treatment for patients who have had a stroke.29, 33 Among risk factors for stroke, age,
hypertension, and diabetes mellitus were not found to be significantly different
in cortical and subcortical stroke.34 However,
hypertension was shown to be strongly and independently correlated with silent
cerebral infarctions.35, 36, 37, 38
Silent cerebral infarctions are frequently shown by CT and MRI in the subcortical
white matter or the basal ganglia in patients who have had a stroke and in
elderly subjects.35, 36, 37
Recently, it was suggested that silent cerebral infarctions appear first in
the white matter in association with aging and hypertension and that the appearence
of silent cerebral infarctions in the basal ganglia predicts a progression
of generalized atherosclerosis.39 Genetic risk
factors for silent brain infarction have also been suggested.40
The effect of hypertension on small vessels is well known. A vascular "remodeling"
occurs in cerebral blood vessels during chronic hypertension.41
It has been suggested that this structural alteration impairs autoregulation,
exposing the deep white matter to fluctuations in blood pressure.
We observed a significant increased CR in patients with a history of
migraine. The study of interictal CR in migraineurs has provided contradictory
results.13 Since in our study only 3 patients
were migrainous, we cannot draw definitive conclusions concerning this issue.
CONCLUSIONS
Our study outlines the strong link between impaired CR and the finding
of silent subcortical infarctions among patients who did not have carotid
stenosis with a recent first-ever, symptomatic, subcortical stroke. The clinical
relevance of hemodynamic factors in the pathogenesis of subcortical infarctions
requires further investigation. Future studies on a larger number of patients
are also needed to establish whether TCD evaluation of CR could be a convenient
bedside test to differentiate subcortical stroke due to small vessel vasculopathy
from that of other causes, especially emboli.
AUTHOR INFORMATION
Accepted for publication July 13, 2000.
We thank P. Pasqualetti, PhD, for critically reading the manuscript
and for his expert assistance with the statistical analysis.
From Clinica Neurologica, Ospedale S Eugenio, Universita' di Roma "Tor
Vergata" (Drs Cupini, Diomedi, Placidi, and Silvestrini), Istituto di Ricovero
e Cura a Carattere Scientifico "S Lucia" (Drs Silvestrini and Placidi), and
Clinica delle Malattie Nervose e Mentali, Universita' di Roma La Sapienza
(Dr Giacomini), Rome, Italy.
Corresponding author: Letizia M. Cupini, MD, Clinica Neurologica,
Universita' di Roma "Tor Vergata," Ospedale S Eugenio, P. le Umanesimo 10,
00144 Rome, Italy (e-mail lecupini{at}tin.it).
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Neurological findings in late-onset depressive disorder: comparison of individuals with and without depression
BALDWIN et al.
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Altered cerebral vasoregulation in hypertension and stroke
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L-Arginine Improves Diminished Cerebral CO2 Reactivity in Patients
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Stroke 2003;34:643-647.
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Two Types of Lacunar Infarcts: Further Arguments From a Study on Prognosis
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Stroke 2002;33:2072-2076.
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Subcortical Infarctions, Transcranial Doppler, and Cerebral Vasomotor Reactivity
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Arch Neurol 2001;58:551-552.
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