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Cerebrovascular Reactivity andSubcortical Infarctions

Letizia M. Cupini, MD; Marina Diomedi, MD; Fabio Placidi, MD;Mauro Silvestrini, MD; Patrizia Giacomini, MD

Objectives: To investigate the association betweendifferent kinds of ischemic lesions and cerebrovascularreactivity (CR) and to evaluate their relationships withthe major risk factors for stroke.

Subjects and Methods: We evaluated CR using thebreath-holding index technique during bilateral

transcranial Doppler monitoring of flow velocity inthe middle cerebral arteries of 41 consecutive pa-tients attending our clinic for a recent, first-ever,ischemic stroke and in 15 control subjects. Based onthe location of the lesion determined by computedtomography, the following 3 types of infarctionswere identified: cortical (or territorial), single sub-cortical, and subcortical with multiple silent subcorti-cal infarctions. Patients with a condition of severecarotid artery stenosis or occlusion, which in itselfcould account for altered CR, were excluded from thisstudy. All physiological and pathologic conditions thatcould possibly cause an impairment in CR wererecorded.

Results: The breath-holding index wassignificantlylowerin the multiple subcortical infarctions group than in thecontrol subjects (P.001), single subcortical infarctionsgroup (P.01), and corticalinfarctionsgroup (P.01). Inall of the groups male sex (P.05) and a history of hyper-tension (P.05), regardless of whether hypertension wastreated, correlated with low CR. The multiple regression

analysis indicated thatthe only significantfactor able to in-fluence the breath-holding index was the type of lesion.

Conclusions: Nonstenoticpatients with first-ever strokewho had a recent symptomatic subcortical infarctionassociated with multiple silent infarctions seem to havean impaired cerebrovascular reserve capacity. The strongassociation of subcortical infarctions with multiple si-lent infarctions with low CR indicates the role of smallvessel vasculopathy and hypoperfusion as possiblepatho-genetic mechanisms of subcortical infarctions with mul-tiple silent infarctions.

Arch Neurol. 2001;58:577-581

THE CORRELATION betweenan impaired functionalblood flow reserve capac-ity and the occurrence ofbrain infarction was previ-

ously reported in patients with severe ca-rotid artery disease.1-4 Patients with lim-itedcerebrovascular reserve capacity haveless adequate perfusion capacity than pa-tients with normal reserves. An impairedcerebrovascular reserve capacity may in-crease the risk of cerebral ischemia in pa-

tients with major cerebral artery occlu-sion.5,6 Patients with severe carotid arterystenosis or occlusion often have a border-zone distribution of brain infarction in thecerebral hemisphere ipsilateral to inter-nal carotid artery disease.7 Border-zone dis-tribution of infarction has traditionallybeen attributed to hypoperfusion relatedto reduced blood flow in zones betweenmajor hemispheric vascular territories.Moreover, cerebrovascular reactivity (CR)

was found to be significantly reduced inlow-flow infarctions compared withthromboembolic infarctions in patientswith ipsilateral carotid stenosis.8 An as-sociation was found between CR andwhitematter lesions. This supports the hypoth-esis that these kinds of lesions may be

associated with hemodynamic ischemicbraininjury.9 In addition, patientswith ma-jor cerebral arterial occlusive diseases andmisery perfusion have a high risk of re-current ischemic stroke.6,10 These find-ings suggest that an impaired cerebrovas-cular reserve capacity is highly related tothe occurrence of ischemic stroke. To ourknowledge, the association between dif-ferent types of ischemic lesions and CRhas not been studied in patients who have

For editorial commentsee page 551

ORIGINAL CONTRIBUTION

From Clinica Neurologica,Ospedale S Eugenio, Universitadi Roma Tor Vergata(Drs Cupini, Diomedi, Placidi,and Silvestrini), Istituto diRicovero e Cura a CarattereScientifico S Lucia(Drs Silvestrini and Placidi),and Clinica delle MalattieNervose e Mentali, Universitadi Roma La Sapienza(Dr Giacomini), Rome, Italy.

(REPRINTED) ARCH NEUROL/ VOL 58, APR 2001 WWW.ARCHNEUROL.COM577

2001 American Medical Association. All rights reserved.

wnloaded From: http://archneur.jamanetwork.com/ on 02/12/2014

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had a stroke but who did not have severe carotid artery

disease.During the past decade, transcranial Doppler ultra-

sonography (TCD) has been widely used to assess bloodflow velocities in the basal intracranial arteries and CR tovarious stimuli, including carbon dioxide (CO2) reactiv-ity. Many physiological and pathologic conditions such asage, sex,migraine, smoking, hypertension,and blood flowviscosity could account for changes in CR CO2.

11-17 Theseconditions are considered the most common risk factorsfor stroke. Our study evaluated the association betweendifferent kinds of ischemic lesions and CR and their rela-tionship to the above-mentioned risk factors for stroke.Thus, patients with a recognized potential source of CRfailure, such as that observed with carotid artery stenosis

or occlusion, were excluded from this study.

RESULTS

All patients included in the study performed the re-quired task adequately. The period of apnea ranged from29.1 to 30.6 seconds. Heart rate and mean blood pres-sure showed a slight increase after the end of the apneaperiod 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 stud-

ied. Thirteen patients (group 1) had cortical (or territo-

rial) infarctions (mean [SD] age, 53.911.8 years; agerange, 34-83 years ), 14 patients (group 2) had single sub-cortical infarctions (mean age, 61.4 9.2 years; age range,41-76 years), and 14 patients (group 3) had subcorticalinfarction with multiple silent subcortical infarctions(mean age, 60.5 10.5 years; age range, 44-76 years). Allpatients with subcortical infarction had an additional MRIscan that confirmed the solitary subcortical lesion re-vealed by CT.

Patients characteristics and vascular risk factors arereported in theTable. Mean (SD) age and sex distri-bution for the controls were 57.6612.7 years (age range,37-73 years) for 9 men and 6 women, respectively. Nosignificant difference was noted in age and sex distribu-

tion among the groups. Regarding pharmacological treat-ment of vascular risk factors, no significant difference inthe use of insulin, oral antidiabetes drugs, statins, anddifferent classes of antihypertensive drugs was foundamong the patient groups.

Sincetheside of thestrokewas notstatistically foundto influence CR in the 2 MCAs (ie, group 1, BHI[mean SD] of the symptomatic side: 1.240.51, BHI ofthe asymptomatic side: 1.450.51,P =.09; group 2, BHIof the symptomatic side: 1.330.36, BHI of the asymp-tomaticside: 1.360.39, P=0.6; group 3, BHI of the symp-

SUBJECTS AND METHODS

The study was prospective and consecutive and includedall patients who have had an acute, first-ever stroke whowere admittedto our neurology wardfrom January 1, 1998,to October 1, 1999. Patients were enrolled in this study ifthey fulfilled the following criteria: (1) their clinical symp-toms correlated with a supratentorial ischemic lesion oncomputed tomography (CT), (2) Doppler ultrasonogra-phy excluded a hemodynamic stenotic disease of extracra-nial carotid and vertebral arteries, and (3) TCD revealedsymmetrical middle cerebral artery (MCA) blood flow ve-locitiesand adequate temporal windows permitting acqui-sition of continuous bilateral blood flow velocities. Pa-tients with a history of stroke wereexcluded from this study.Carotid artery evaluation was performed using a color-flow B-mode Doppler ultrasonography (model AU5; Har-monic Esaote Biomedica, Esaote S.p.A., Genoa, Italy), witha 7.5-MHz linear transducer. Plaque occurrence in the rightand left carotid arteries and common carotid intima me-dia thickness were evaluated. The type of ischemic lesionwas determined by CT performed with a spiral CT scan-ner (Tomoscan SR 7000; Philips MedicalSystems,Amster-

dam, the Netherlands).Of the152 patients who hada first-ever ischemic stroke

observed during the study period, 111were excluded (21ow-ing to a subtentorial ischemic lesion, 56 owing to the pres-ence of a hemodynamic stenotic disease of the extracranialcarotid and vertebral arteries, and 34 owing to poor in-sonation of the temporal bone window or significant asym-metry of MCA bloodflow velocities).Forty-one patientswereincluded in this study. Thirty-two patients underwent brainmagnetic resonance imaging (MRI) scanning (Gyroscan

ACS-NT,1.5T;PhilipsMedicalSystems).Twenty-onepatientswerealso studiedusingMRI angiography. Basal TCDexami-nation andMRI angiographydidnot revealintracranialsteno-occlusivelesionsin theincluded patients. Based on the loca-tion of the lesion, 3 types of infarctions were classified. Thefirst type, a cortical (or territorial) infarction, was defined asa case of first-attackinfarctionin whichthe CT scan showeda territorialinfarctionof a mainintracerebral artery.The sec-ondtype,asinglesubcorticalinfarction,wasdefinedasacaseoffirst-attack infarctionin whichthe CT scan showeda singlesubcorticalhemisphericinfarctioncompatiblewithsymptoms.According to the classification of Nakano et al,18 the infarc-tions were restricted to the basal ganglia and/or white mat-ter on CT, and the overlying cerebral cortex appeared nor-mal. Themaximum diameter of thelesion exceeded 2.0cm.The third type, a subcortical infarction with multiple silentsubcorticalinfarctions,was definedas a caseof first-everstrokeinwhichtheCT scanshowedmultiple subcortical infarctions.Computed tomographic scans were examined by an expertreader (M.S.) blinded to the results of the TCD recordings.Evaluation of CR was performed by 2 operators (M.D. andF.P.) blinded to the CT findings.

The study was carried out in a quiet room with thepatients lying in a comfortable supine position.Bilateral si-

multaneous flow velocity recording of MCAs was ob-tained using a transcranial Doppler instrument (Multi-D op X/TCD ; D WL Elek tronische Systeme GmBH,Sipplingen, Germany). Two dual 2-MHz transducersfitted on a headband and placed on the temporal bonewindow were used to obtain a bilateral continuous mea-surement of mean flow velocity (MFV) in the MCAs.Examination of vessels of the circle of Willis was per-formed as described by Aaslid et al.19We obtained hyper-capnia with breath holding20 and evaluated CR using the




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tomatic side: 0.970.42, BHI of the asymptomatic side:

0.900.36, P=.32), the mean of the right and left CR wasused for further statistical analysis.

Smoking, diabetes mellitus, elevated serum choles-terol levels, hematocrit, coagulopathies, and use of al-cohol 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 lowCR. However, a history of migraine was significantly re-lated to a high CR (F1,39=8.21,P =.007).

Regarding the comparison of the BHIs among the 3groups of patients and controls, the group effect was sig-nificant (F3,52=6.6, P.001). In particular, the Tukey posthoc analysis showed that BHIs of the subcortical infarc-

tion with multiple silent infarctions group (Figure) wassignificantly lower than that of the controls (P.001) andof both singular subcortical (P.01) and cortical (or ter-ritorial) infarction groups (P.01). No statistical differ-ence of mean BHIs was observed for the controls and theterritorial and singular subcortical infarction groups.

The multiple regression analysis indicated that theonly significant factor able to influence the BHI was thetype of lesion (r=0.46, F1,39 =10.2, P =.003). No othervariable could be entered for a better accounting of BHIvariability. This result does not indicate that the type of

lesion is an independent predictor of CR, since higher

percentages of multiple infarction lesions were observedin patients with hypertension (P =.04, 2 test) and inpatients who smoked (P =.04, 2 test). However, theresult of multiple regression analysis suggests that, atthe evaluation time, the strongest and unique factorable to explain BHI was the type of lesion. In particular,the patients in the subcortical infarction with multiplesilent subcortical infarctions group were characterizedby a significantly lower BHI than the other 2 groups(mean difference=0.41), as confirmed by the aboveanalysis of variance.

COMMENT

The primary purpose of this study was to assess the rela-tionship between hemodynamic reserve capacity and dis-tributions of ischemic lesions in patients who have had astroke butwhodidnothave carotid stenosis. Availabledatastrongly link hypoperfusion with the occurrence of brainischemia and infarction.21 Hypoperfusion is the proxi-mate cause of all ischemic stroke; however, the extent ofits role as the primary causative factor in stroke remainsunclear.5,22 The correlation between an impaired cerebro-vascular reserve capacity and the occurrence of stroke inpatients with severe internal carotid artery occlusive dis-

breath-holding index (BHI) technique in the 41 patientsand 15 healthy volunteers recruited from hospital person-nel. The BHI is obtained by dividing the percent increasein MFV occurring during breath holding by the length oftime (in seconds) the subjects hold their breath after a nor-mal inspiration [({MFV at the end of breath holding restMFV}/rest MFV)(100/s of breath holding)]. End-tidal ex-piratoryCO2 level was recordedusing a capnometer (Nor-mocap-oxy; Datex-Ohmeda S.p.A., Segrate, Italy). Meanblood pressure and heart rate were continuously moni-tored by means of a blood pressure monitor (2300 Fina-press Ohmeda Medical, Laurel, Md). All subjects were nor-mocapnic.The MFVat rest wasobtainedby the continuousrecording of a 1-minute period of normal room air breath-ing. After a breath-holding period, the MFV, mean bloodpressure, andheartrate were recorded over 4 seconds. Sub-

jects were asked to hold their breath for 30 seconds. Theend-tidal expiratory CO2level during the first exhalationafter apnea was evaluated. The BHI was calculated whenthe rise in the level of end-tidal expiratory CO 2from base-line to the first expiration after breath holding was morethan 8 mm Hg. The efficacy of breath holding was checkedwith the respiratory activity monitor. All TCD data werestored on hard disk for off-line analysis.

Patients were examined twice, in the acute phase andin a follow-up visit 1 to 3 months after the acute onset ofstroke. Data concerning this study refer to recordings per-formed during the follow-up visit since previous evidenceindicates that cerebral hemodynamics can be impaired dur-ing the acute phase of stroke.

All the physiological and pathologic conditions thatcould account for the patients altered CR were recorded.The following known or putative factors associated withrisk were considered: age (50,50,65, or65 years);

sex;heavy alcohol consumption(300 g/wk), current dailysmoking (10 cigarettes per day); hypertension (in treat-ment with antihypertensive drugs at the time of admissionor hypertension diagnosed during the hospital stay); an el-evated serum cholesterol level (total serum cholesterol levelof6.20 mmol/L [240 mg/dL] at the time of admission);an elevated hematocrit on admission; and the presence ofdiabetes mellitus, coagulopathies, and migraine.

As regards statistical analysis, at the first step severalanalyses of variance, with patients characteristics (ie, agegroups, sex,and others)as between-subjectsfactors andBHIas dependent variable, were used to assess the relationshipbetween CR andthe riskfactors. In addition, analysis of vari-ance with group (4 levels: the 3 groups of patients and thecontrols) as between-subjects factor and BHI as dependentvariable was used to assesspossible differences in CR amongthe different groups of patients and controls.

At the second step, to individuate which risk factorswere morerelevant on the BHIs, a multiple regression analy-sis was performed, entering the CR as a dependent vari-able and the type of lesion; sex; age; the presence of hy-pertension, diabetes mellitus, hypercholesterolemia,coagulopathies, and migraine; the use of antihypertensivetreatment; the patients tobacco use; an elevated hemato-

crit;and excessive alcohol consumption as independent vari-ables. Each categorical variable was entered as a dummyvariable, while age was a continuous variable. The for-ward stepwise method was chosen to individuate recur-sively the statistically significant factors. The statistical sig-nificance threshold was set at P.05. All analyses wereperformed with StatSoft 5.0 for Windows statistical soft-ware (StatSoft Inc, Tulsa, Okla). The study was approvedby the local ethics committee and all subjects gave theirinformed consent.




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ease has been widely recognized.1-4,6 However, the patho-genetic role of an impaired hemodynamic reserve capac-ity in stroke patients who did not have carotid stenosishas not been clarified.

The main finding of our study on patients withoutstenosis first-ever stroke is that subjects with lower CRwere found to have subcortical infarction with multiplesilent subcortical infarctions. We did not observe statis-tical differences in CR among the controls, the singlesub-cortical infarction group, or the cortical (or territorial)

infarction group. Previously, a reduction in CR was re-ported in low-flow infarction compared with that foundin patients with cortical (or territorial) infarction.8 How-ever, all of the patients included in that study had inter-nal carotid artery occlusion and, as the authors23-26 sug-gested, a restricted collateral blood supply contributedto their finding of low CR in low-flow infarction. Previ-ous studies23-26 also suggested that white matter infarc-tions in terminal distribution vessels may be a more com-mon consequence of hypoperfusion. An association waspreviously shown between decreased CR and periven-

tricular lesions using MRI in asymptomatic individu-als27 and hypertensive patients with leukoaraiosis.28 Anassociation was also reported between decreased CR andthe size, location, and number of white matter lesions in

elderly persons.9

However, all of these studies were con-ducted on both patients with and without stenosis, thusthe effect of carotid stenosis on CR cannot be excluded.

It is generally accepted that among the pathoge-netic causes of subcortical hemispheric infarctions aresmall vessel disease, thromboembolic occlusions of smallarteries, and hemodynamic impairment in low-flow con-ditions.8,9,18,23 Our finding that an impaired hemody-namic reserve capacity in patients without stenosis is as-sociated with multiple subcortical ischemic lesionssupports the hypothesis that some subcortical ischemiclesions may be associated with hemodynamic ischemicinjury to the brain. Hypoperfusion could account for thefinding of silent infarction in patients with first-ever, sub-

cortical, symptomatic stroke. In our study,among theriskfactors that could account for impaired CR, hyperten-sion, and male sex were found to be significantly and in-dependently from groups associated with low CR. Theeffect of hypertension and its treatment on CR were pre-viously outlined.15 Hypertension is considered the mostimportant single risk factor for ischemic stroke29,30 andis considered one of the main risk factors for stroke re-currence.31 However, notall studies have shown that whenblood pressure is controlled,32 the risk of stroke recur-rence is reduced. We observed that despite whether theywere being treated, the patients with hypertension hadthe lowest CR. This finding raises the critical issue of theefficacy 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 tobe significantly different in cortical and subcorticalstroke.34 However, hypertension was shown to be stronglyand independently correlated with silent cerebral infarc-tions.35-38 Silent cerebral infarctions are frequently shownbyCT and MRI in the subcortical white matter orthe basalganglia in patients who have had a stroke and in elderlysubjects.35-37 Recently, it was suggested that silent cere-bral infarctions appear first in the white matter in asso-ciation with aging and hypertension and that the ap-

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BHI

Group 1 Group 2 Group 3 Control

Subjects

The mean breath-holding index (BHI) in the 3 groups of patients and thecontrol subjects. Group 1 indicates those patients with cortical (or territorial)infarctions (n=13); group 2, those patients with a single subcorticalinfarction (n=14); group 3, those patients with subcortical infarctions withmultiple silent subcortical infarctions (n=14); and the controls (n=15).For further explanation of the 3 infarction groups see the Subjects andMethods section.

Characteristics of Patients Who Have Had an Ischemic Stroke*

Variable

Patients With Cortical(for Territorial) Infarctions

(n = 13)

Patients With SingleSubcortical Infarctions

(n = 14)

Patients With Subcortical InfarctionsWith Multiple Silent Subcortical Infarctions

(n = 14)

Age, mean SD, y 53.9 11.8 61.4 9.2 60.5 10.5

Sex

Male 6 (46) 12 (86) 12 (86)

Female 7 (54) 2 (14) 2 (14)

Hypertension 5 (38) 7 (50) 11 (79)Diabetes mellitus 0 3 (21) 3 (21)

Smoking 3 (23) 7 (50) 10 (71)

Heavy use of alcohol 2 (15) 1 (7) 1 (7)

Hypercholesterolemia 6 (46) 5 (36) 1 (7)

Viscosity 1 (8) 0 0

Migraine headache 2 (15) 1 (7) 0

*Data are given as the number (percentage) of patients unless otherwise indicated.




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