脑白质疏松症与脑出血患者短期和长期死亡率相关

Leukoaraiosis is Associated with Short-and Long-term Mortality in Patients with Intracerebral Hemorrhage Arnstein Tveiten,MD,*Unn Ljøstad,P h D,* Ase Mygland,P h D,*†xand Halvor Naess,P h D‡Background:There are few recent European studies of mortality after intracerebralhemorrhage(ICH),particularly long-term follow-up studies.No previous Europeanstudies have included information on leukoaraiosis.Methods:We studied all consec-utive patients hospitalized with afirst-ever intracerebral hemorrhage between2005and2009in a well-defined area and assessed the prognostic value of various baselineclinical and radiologic factors.Leukoaraiosis was scored on the baseline computedtomographic(CT)scan as described by van Swieten et al,with an overall score from0to4.Results:One hundred thirty-four patients were followed up for a median of4.7years(interquartile range2.5-6.6).Overall mortality was23%at2days,30%at7days,37%at30days,46%at1year,and53%at2years.Factors independentlyassociated with increased30-day mortality were warfarin use,leukoaraiosisscore,intraventricular hemorrhage,and Glasgow Coma Scale(GCS)score.Factorsindependently associated with long-term mortality in the85patients who survivedthefirst30days were leukoaraiosis score,coronary heart disease,and initial GCSscore.Recurrent ICH occurred in4.5%and was significantly more frequent after lo-bar ICH than after ICH in other locations(11.1%v0%;P5.025).Conclusions:In un-selected patients in Southern Norway withfirst-ever ICH,severe leukoaraiosis isindependently associated with both30-day and long-term mortality in30-day sur-vivors.Warfarin is independently associated with30-day mortality and coronaryheart disease with long-term mortality in30-day survivors.Recurrent ICH is morefrequent after lobar ICH than after ICH in other locations.Key Words:Coronaryheart disease—diabetes mellitus—fatality—hemorrhagic stroke—intracerebralhemorrhage—leukoaraiosis—mortality—prognosis—prognostic factors—stroke—warfarin—white matter changes.Ó2013by National Stroke AssociationTen percent to15%of all strokes are caused by intracere-bral hemorrhage(ICH).1Thirty-day mortality in ICH is higher than in ischemic stroke(40-50%in most studies).2In a recent review,the median30-day mortality was40.4% (range13.1-61.0%)and the median1-year mortality was 54.7%(range46.0-63.6%).3Factors found to be associated with30-day mortality include age,Glasgow Coma Scale (GCS)score,ICH volume,ICH location,the presence of intraventricular hemorrhage(IVH),and oral anticoagula-tion.4-11Studies on factors associated with long-term survival are fewer,particularly follow-up beyond1year. Factors found to be associated with long-term mortality in-clude age,sex,diabetes mellitus,anticoagulation,heart dis-ease,and ICH location and volume.5,8,12,13Demographics and the distribution of risk factors vary between regions and with time.The proportion of warfarin-associated ICH has been increasing,and this has been linked to the in-creased use of warfarin in atrialfibrillation in the elderly.14-16From the*Departments of Neurology;†Habilitation,SørlandetHospital Kristiansand,Kristiansand;‡Department of Neurology,Bergen University Hospital,Bergen;and x Department of ClinicalMedicine,University of Bergen,Bergen,Norway.Received December20,2012;revision received January25,2013;accepted January28,2013.eiten is supported by the Norwegian Health Association.Address correspondence to Arnstein Tveiten,MD,Department ofNeurology,Sørlandet Hospital Kristiansand,4604Kristiansand,Norway E-mail:eiten@sshf.no.1052-3057/$-see front matterÓ2013by National Stroke Association/10.1016/j.jstrokecerebrovasdis.2013.01.017Journal of Stroke and Cerebrovascular Diseases,Vol.-,No.-(---),2013:pp1-71Leukoaraiosis is a commonfinding in neurologic im-ages of stroke patients.It is a feature of cerebral small ves-sel pathologies,including hypertensive arteriopathy, amyloid angiopathy,and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephal-opathy.There is increasing evidence of an association between severe leukoaraiosis and outcome in ischemic stroke.17-19For ICH,we have found only2studies reporting an association between leukoaraiosis and outcome,both from South Korea.20,21There are no European studies including leukoaraiosis in the prediction of outcome in ICH.Recurrent ICH has been estimated to be4%to7%per year.Data on the distribution of ischemic strokes com-pared to recurrent ICHs are scarce and inconsistent.In a review,only69classifiable recurrent strokes were avail-able for assessment.The authors concluded that the re-view revealed the limitations of the available data and implied the need for more research.22The aim of this study was to assess the factors associ-ated with both30-day and long-term mortality in unse-lected patients hospitalized withfirst-ever ICH in Southern Norway.We hypothesized that leukoaraiosis was associated with increased mortality.An additional aim of the study was to assess the rate of ICH recurrence. MethodsPatientsThe study includes all consecutive patients hospital-ized with afirst-ever ICH between2005and2009at Sørlandet Hospital Kristiansand in Kristiansand,Norway. The hospital serves a well-defined catchment area with 152,000inhabitants.There is a low-threshold policy of admitting all patients with suspected stroke to the neuro-logic department regardless of age and stroke severity. There is no neurosurgical department.All patients with suspected stroke are examined in the emergency room by the neurology staff.In select cases when neurosurgical treatment is considered,the patient is transferred to a neurosurgical department in Oslo.The cohort has been presented in detail elsewhere.16We excluded trau-matic ICH,ICH related to intracranial malignant tumors, ruptured aneurysms,or thrombolytic treatment,and cases with isolated intraventricular hemorrhage without visible affection of the cerebral parenchyma.Clinical and Radiologic DataRisk factors and clinical and radiologic data were recorded in a stroke registry from September2007and retrieved from patientfiles in cases before that time.We recorded smoking(ever),hypertension(a known diagnosis),diabetes mellitus(a known diagnosis,either insulin-dependent or-independent),atrialfibrillation (AF;documented before or during the hospital stay),and coronary heart disease(CHD;defined as having had an acute myocardial infarct,coronary bypass surgery, or percutaneous coronary intervention),and the use of platelet inhibitors and warfarin.We categorized patients by GCS score into3groups(3-4,5-12,and14-15)as sug-gested by Hemphill et al.4All patients had a noncontrast computed tomographic(CT)scan at baseline.One of the authors(A.T.)assessed all CT images.Hematoma location was classified as lobar(predominantly cortical or subcor-tical white matter),deep cerebral,brainstem,or cerebel-lum.Thalamic hemorrhages were allocated to the deep cerebral category.The brainstem category included pon-tine and mesencephalic hemorrhages.Hematoma volume was calculated with the A3B3C/2formula.23The pres-ence of intraventricular blood was registered.Leukoar-aiosis was scored on the baseline CT scan.We used the leukoaraiosis grading described by van Swieten et al.24 The anterior and posterior regions were examined sepa-rately.Leukoaraiosis was distinguished from infarction by its poorly defined borders.The severity of hypoden-sity,if present,was expressed in one of two degrees for each of the2regions.In grade1,the abnormality was re-stricted to the region adjoining the ventricles.In grade2, the increased hypodensity involved the entire region from lateral ventricle to the cortex.The scores of the2re-gions were added giving an overall score from0to4.24 OutcomesDeath was automatically updated monthly through a link to the National Population Register.25The follow-up period was closed on December31,2011.Patients not registered as dead by this date were considered alive. Causes of death,updated to December31,2011were obtained from the cause of death registry/Statistics Nor-way.26In addition,patientfiles were reviewed for clinical and radiologic information on cause of death.In all pa-tients who were discharged alive,we checked for recur-rence of ICH by combining information from the cause of death registry and from the review of patientfiles for information on readmission,neuroimaging,or outpatient contact.Statistical AnalysisDescriptive statistics were used to summarize the num-ber of patients and baseline characteristics using the Pear-son Chi-square or Fisher exact tests as appropriate for comparisons of categorical data,the t test for continuous parametric variables,and the Mann–Whitney U test for nonparametric variables.Correlations were tested using the Pearson correlation.We used logistic regression to assess associations between various baseline factors and 30-day mortality.For long-term mortality,we used Cox proportional hazard regression and included only patients who had survived30days.Both short-and long-term mortality factors werefirst entered one byEITEN ET AL.2one in univariate analyses.We checked for collinearity. We then performed multivariate analyses using the for-ward stepwise method,including age,sex,and factors with P values,.15in univariate analyses.The leukoaraio-sis score was used as a continuous variable.P,.05was considered statistically significant.Statistical analyses were performed with SPSS software(version18;SPSS Inc.,Chicago,IL).Ethics ApprovalThe study was approved by the regional committee of medical research ethics.ResultsIn total,134patients with afirst-ever ICH were fol-lowed up for a median of4.7years(interquartile range 2.5-6.6years),for a total of630patient-years.No patients were lost to follow-up.Baseline characteristics are shown in total and for each sex in Table1.There were some sex differences in baseline characteristics.Men were signifi-cantly younger,were more often smokers,and had some-what larger hematomas than women.White patients accounted for131of134(97.8%)cases.Five patients (3.8%)were treated surgically.Twenty-one(15.6%)pa-tients had a reversal of anticoagulant treatment with co-agulation factor concentrate(15patients)or fresh frozen plasma(6patients).Thirty patients had intravenous blood pressure–lowering treatment.Overall mortality at2days was23.1%,at7days29.9%, at30days36.6%,at1year46.3%,and at2years53.0%.At the end of follow-up,84of134(63%)patients were dead. In Table2,the30-day mortality is presented listed by ICH location and ICH volumes.30mL or,30mL.30-day MortalityAll baseline factors listed in Table1were tested in uni-variate analysis for association with30-day mortality.The following factors met the criteria for additional analysis in multivariate analysis(P values):age(.118),sex(.290), diabetes mellitus(.025),coronary heart disease(.069), warfarin(.001),atrialfibrillation(.013),GCS score(.001), ICH volume(.001),brainstem location(.049),intraventric-ular hemorrhage(.001),and leukoaraiosis score(.008). The results of the multivariate analysis are shown in Table3.Significant independent factors were:warfarin, GCS score,intraventricular hemorrhage,and leukoaraio-sis score.For leukoaraiosis,the odds ratio for30-day mortality was1.6for each increasing point in the leukoar-aiosis score.The2independent variables that had the highest corre-lation were ICH volume and GCS score(Pearson correla-tion0.569;P,.001).We also ran the multivariate analysis without inclusion of the GCS score.ICH volume and brainstem location were then significant factors in addi-tion to the otherwise unaltered warfarin,intraventricular hemorrhage,and leukoaraiosis score.In16cases,all of which were fatal within30days,the baseline CT scan was uninterpretable with respect to the leukoaraiosis score.Therefore,these cases were excluded in the multivariate analysis of30-day mortality shown in Table3.We performed the same multivariate analysis without inclusion of leukoaraiosis score as a variable, including133of134patients.The remaining significant factors(warfarin,GCS score,and intraventricular hemor-rhage)were unaltered;the16patients with uninterpret-able leukoaraiosis scores had significantly greater ICH volumes than the118with interpretable scores(median 125v15mL;P,.001).There was no difference in age (75.9v75.1years;P5.794).For warfarin users,the median international ratio(INR) was 2.6(interquartile range 2.2-2.9).Only2patients (5.6%)had an INR of.4.Therefore,most cases of warfarin-associated ICH occurred with therapeutic INR levels.Long-term Mortality in30-day SurvivorsThere were8530-day survivors,35of whom died during the follow-up period.Twenty of44(45.5%)men and15of41(36.6%)women died(P5.509).All baseline factors listed in Table1were tested in univariate analysis for association with mortality.The following factors met the criteria for additional multivariate analysis(P values): age(.001),sex(.454),coronary heart disease(,.001), GCS score(.074),ICH volume(.056),and leukoaraiosis score(.004).The results of multivariate analysis are shown in Table4.The following factors were significantly associ-ated with mortality after30days in multivariate analysis: CHD,GCS score,and leukoaraiosis score.For leukoaraio-sis,the odds ratio for long-term mortality was1.6for each increasing point in the leukoaraiosis score.Only1patient with an initial GCS score of3to4survived30days.We therefore merged the groups GCS3to4and GCS5to12. RecurrenceFour of88(4.5%)patients who were discharged alive after the index ICH had an imaging-confirmed recurrent ICH during follow-up.One was fatal.Recurrent ICH was more frequent after lobar index ICH(4/36[11.1%]) than after index ICH in other locations(0/52[0%];P5 .025).Five patients(5.7%)had confirmed ischemic stroke after the index ICH,none of which were fatal.The index ICH was lobar in2,deep cerebral in1,and cerebellar in1. Cause of DeathCauses of death are shown in Table5and are listed by in-or out-of-hospital deaths.In the11out-of-hospital deaths with unspecified stroke as the reported cause,LEUKOARAIOSIS AND ICH3none had imaging confirmation,and it is unclear whether the reported cause refers to a clinically diagnosed recur-rent stroke or the index ICH.The 6cases of malignancies were:colon cancer (n 51),malignant melanoma (n 51),bronchial cancer (n 51),glottis cancer (n 51),and myelo-matosis (n 51).The causes merged as ‘‘other’’were:Alzheimer disease (n 51)paralytic ileus (n 51),urinary tract infection (n 51),depressive episode (n 51),hema-temesis (n 51),chronic obstructive pulmonary disease(n 52),ruptured aortic aneurysm (n 51),systemic lupus erythematosus (n 51),and type 2diabetes mellitus (n 51).DiscussionThis study shows that leukoaraiosis is associated with both 30-day and long-term mortality in patients with first-ever ICH.It also shows that CHD is associated with increased long-term mortality.Table 1.Baseline characteristics in 134patients with first-ever intracerebral hemorrhageTotalMen Women P value *N (%)134(100)74(55)60(45)Risk factorsAge (y),mean (SD)75.3(12)72.9(12)78.2(12).010Hypertension,n (%)72(55)41(57)31(52).532Diabetes mellitus,n (%)18(13)12(16)6(10).294Coronary heart disease,n (%)20(15)15(20)5(8).054Atrial fibrillation,n (%)35(26)20(27)15(25).791Previous stroke/TIA,n (%)28(21)16(22)12(20).818Warfarin,n (%)36(27)23(31)13(22).221Platelet inhibitor,n (%)48(36)28(38)20(33).598Smoking ever,n (%)51(41)38(56)13(23),.001Glasgow Coma Scale score,n (%).42513-1582(62)44(60)38(64)5-1229(22)15(20)14(24)3-422(17)15(20)7(12)ICH volume (mL),median (IQR)17.5(5-44)21(9-60)15(4-37).046Location,n (%).170Lobar 49(37)23(31)26(43)Deep61(46)39(53)22(37)Brain stem 11(8)7(10)4(7)Cerebellum13(10)5(7)8(13)Intraventricular hemorrhage,n (%)50(37)31(42)19(32).224Leukoaraiosis score,n (%)015(13)9(15)6(11)125(21)15(24)10(18)222(19)9(15)13(23)37(6)4(7)3(5)449(42)25(40)24(43)Total score,median (IQR)2(1-4)2(1-4)2(1-4).500Abbreviations:IQR,interquartile range;SD,standard deviation;TIA,transient ischemic attack.Missing data (no.of cases):Hypertension (2),smoking (10),GCS score (1),leukoaraiosis score (16).*Men versus women.Table 2.Thirty-day mortality in relation to intracerebral hemorrhage location and volumeLocation All volumes,30mL .30mL P value *n/dead %n/dead (%)n/dead (%)Lobar 49/153125/31224/1250.005Deep 61/243940/71821/1781,.001Brainstem 11/7668/4503/3100.236Cerebellum 13/32311/192/2100.038All locations134/493784/151850/3468,.001*Volumes ,30mL versus .30mL.EITEN ET AL.4The overall mortality at standardized time points is in general agreement with previous reports.5,8,13,27-29With volumes exceeding30mL,all hematoma locations other than lobar carried a high30-day mortality rate(Table2). Smaller cerebellar hematomas had the lowest mortality rates.This is in line with other studies.5,8,9The mean age of75years is relatively high,and the proportion of patients using warfarin(26.9%)is higher than in most reports.30-day MortalityTo our knowledge,our study is thefirst from Europe to show an association between leukoaraiosis and mortality after ICH,and thefirst based on an unselected cohort re-garding age and severity.We have only found2studies before ours that explored this association,both from South Korea.In one single-center study,there was an in-creased90-day poor outcome(dependency or death,mor-tality not specified).In a nationwide multicenter study of 1321patients,leukoaraiosis was associated with in-creased early and long-term mortality.Both study popu-lations differed substantially from ours,with a low mean age of60years in both studies,compared to75years in our study,and a large proportion were treated surgically(32%and35%,respectively)compared to 3.8%in our study.In thefirst study,patients with antico-agulant treatment were excluded;in the other,there was no information on anticoagulation.20,21In previous studies,leukoaraiosis has been shown to be an independent risk factor for warfarin-associated ICH and for ICH after thrombolytic treatment for acute ischemic stroke.30,31A recent study of79patients in the United States revealed an association between leukoaraiosis and greater ICH volumes and a trend toward more hematoma growth.32Ourfindings regarding warfarin and30-day mortality are in agreement with previous studies.Warfarin was a significant independent factor,as seen in several stud-ies,15,33-35and most cases of warfarin-associated ICH oc-curred with therapeutic INR levels,which has also been shown by others.14The increasing proportion of warfarin-associated ICH linked to increasing use of warfarin in AF14-16and the poor outcome are highly relevant issues in the current ongoing shift toward the increased use of new oral anticoagulants.Three new oral anticoagulants have shown a reduced risk of ICH in head to head comparison with warfarin in patients with nonvalvular AF.36-38GCS score,ICH volume,and the presence of intraven-tricular hemorrhage have been identified as predictors of a high early mortality in several studies.11,39-41In our study,ICH volume was not a significant independent factor in multivariate analysis when the GCS score was in the model,but was highly significant when the GCS score was removed from the model.This probably reflects an underlying impact of ICH volume on the GCS score.We view ICH volume as the more causative of the two.In our study,increasing ICH volume correlated significantly with a lower GCS score.In a community-based study in Texas,increased ICH volume was identified as an independent predictor of a lower GCS score.42Table3.Multivariate analysis of factors associated with30-day mortality*Factors OR(95%CI)P value Warfarin 4.4(1.2-15.5).022Leukoaraiosis score 1.6(1.06-2.5).026GCS score13-151—5-129.6(2.8-33.3),.0013-4102.6(8.9-1183.2),.001Intraventricular hemorrhage 5.7(1.5-20.4).008 Abbreviations:CI,confidence interval;GCS,Glasgow Coma Scale;OR,odds ratio.No.of cases included:117of134(87.3%).*Using forward stepwise logistic regression.Table4.Multivariate analysis of factors associated with long-term mortality in30-day survivors*Factors HR(95%CI)P value Coronary heart disease 5.7(2.5-13.2),.001GCS score13-15——3-12y 3.5(1.4-8.8).008Leukoaraiosis score 1.6(1.2-2.1).001 Abbreviations:CI,confidence interval;HR,hazard ratio.No.of cases included:85of85(100%).*Cox regression,forward stepwise.y GCS scores3to4and5-12were merged because there was only 1case in the GCS3to4group.Table5.Causes of death for in-hospital and out-of-hospitaldeathsCause,n(%)In-hospital(N559)Out-of-hospital(N525) Index ICH37(63)3(12) Recurrent ICH1(2)0(0) Cerebral infarct0(0)0(0) Unspecified stroke0(0)12(48) Cardiac disease9(15)3(12) Pneumonia2(3)1(4) Malignancy5(9)1(4) Other causes5(9)5(20) Abbreviation:ICH,intracerebral hemorrhage.LEUKOARAIOSIS AND ICH5Long-term Mortality in30-day Survivors Leukoaraiosis was independently associated with in-creased long-term mortality in multivariate analysis. This is in agreement with the only existing previous study,which was conducted with nonwhite patients.21 CHD was not significantly associated with30-day mortal-ity,but it was independently associated with increased long-term mortality.Two Swedish studies found that CHD was associated with increased30-day and long-term mortality(1year in1study and3years in the other). However,for long-term mortality,CHD was not an inde-pendent factor in multivariate analysis in either of the studies.8,13In a study from Finland,CHD was an independent predictor of3-month mortality.43Our study adds to the existing knowledge by showing an indepen-dent association between CHD and long-term mortality in30-day survivors.Some previous studies of predictors of long-term mortality included all patients,5,8while others included only30-day survivors.12Warfarin was not associated with long-term mortality.A similarfinding was reported in a1-year follow-up study in Finland,where Kaplan–Meier survival curves for warfarin users and nonusers diverged over thefirst days but appeared to parallel each other thereafter.15In a large study from the United States,anticoagulant ther-apy was an independent predictor of long-term mortality, but in this analysis,all cases were included,not just30-day survivors,and therefore excess early mortality in warfarin users may have influenced thefindings.5In our study,as in several others,sex was not associated with long-term mortality.5,6,10Some studies have shown higher long-term mortality in men versus women.8,12In Sweden,one study reached the opposite conclusion.13 RecurrenceOurfinding of recurrent ICH in4.5%of the population during the follow-up period may be low compared with previous estimates of4%to7%per year,22,44,45but overall numbers are small.Recurrent ICH was more frequent after lobar ICH than ICH in other locations. This is in agreement withfindings in a review and in a cohort study in the United States,where both reported a higher risk of recurrent ICH after lobar ICH.22,45In Southern Sweden,no difference in recurrence risk was found between lobar and deep cerebral hemorrhage.8 Wefind it reasonable to speculate that ourfindings may be linked to underlying amyloid angiopathy.Published data on the proportional distribution of ischemic and hemorrhagic recurrent events are scarce and inconsistent. In a review,there was an overweight of recurrent ICH in7 hospital-based studies but not clear in3population-based studies.22In Southern Sweden,similar numbers of hem-orrhagic and ischemic recurrences were found.8In our study,numbers were very small,but we found a similar distribution.Strengths and LimitationsIn our opinion,the major strength of this study is the un-selected cohort.By using all identified cases offirst-ever ICHs within a defined area,we believe the cohort is repre-sentative of current demographic and risk factor distribu-tion in Southern Norway.The study also has some limitations.Overall,the numbers are relatively small,espe-cially in some subgroups.This must be kept in mind and the results interpreted with caution.For leukoaraiosis,CT im-ages were uninterpretable in some cases.However,we be-lieve that other researchers assessing leukoaraiosis in acute ICH will be confronted with the same limitation in some cases—particularly in patients with large hematomas.A possible limitation is the use of the forward stepwise method,which creates models by statistical selection of var-iables.It is,however,among the most widely used methods in multivariate analysis.In the current study,the candidate factors were all chosen as clinically relevant and commonly used in similar studies.We got the same results with the backward stepwise method,and when we removed the leu-koaraiosis score from the model,the remaining significant factors were the same.Although the national death register was used,uncertainty remains about the cause of some out-of-hospital deaths.It has been argued in both Denmark and Norway that the quality of the cause of death registers is poor for research purposes.46,47In conclusion,this study shows that in unselected pa-tients in Southern Norway withfirst-ever ICH,leukoar-aiosis is independently associated with both30-day and long-term mortality in those who survive30days.CHD is independently associated with long-term mortality. This study shows that long-term mortality strongly re-lates to the burden of vascular disease.Recurrent ICH is more frequent after lobar than deep cerebral hemorrhage. 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