A Prospective Multicenter Study Of The Distribution Of Cerebral Small Vessel Disease In Intracerebral Hemorrhage Patients And Efficiency Of Modified Small Vessel Disease Score In Prognosis

Objective: Cerebral small vessel disease(CSVD)is a clinical,imaging,and pathology syndrome.The distribution and prognosis of CSVD in spontaneous intracerebral hemorrhage(s ICH)patients is unclear.Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation(MISTIE Ⅲ)trial recorded a decent quality data of s ICH patients.This study aimed to describe the distribution of CSVD markers in severe s ICH patients and investigating its effect on prognosis via the MISTIE Ⅲ cohort.Based on the result,a score system would be builded to describe the total burden of CSVD individually and for prognosis.First part: Selected the s ICH cohort via prospective multicenter study,observe the distribution of CSVD and determind standard of further research.Second part: Copmare the difference between outcome groups and investigate the risk factor.Identify the effect of CSVD markers with outcome and differential standards.Third part: Study the prognosis strength of CSVD markers,CSVD score and CAA score.Invited the m CSVD score through results and test its ability of prognosis in s ICH patients.Method: The MSITIE Ⅲ is an international multicenter,randomized,single-blind clinical trial focused on severe s ICH patients.It investigated the efficacy and safety of minimally invasive surgery compared to standard medical treatment.The primary outcome is the modified Rankin scale(m RS)365 days after stroke onset.m RS more than 3 was defined as an unfavorable outcome and m RS less or equal than 3 was defined as a favorable outcome.The target of the trial is to decrease the ICH volume to less than 15 m L at end of treatment(EOT).Our study was using the MISTIE Ⅲ cohort.During the design of the MISTIE Ⅲ study,we set several timepoints for collecting MRI including onset,7 days after stroke,and 30 days after stroke.In this study,we observed the first available MRI.There are various CSVD markers.We included lacunar infarct,cerebral microbleed(CMB),enlarged perivascular spaces(EPVS),white matter hyperintensity(WMH),and cortical superficial siderosis(c SS).The record of markers is based on the standard for reporting vascular changes on neuroimaging(STRIVE).According to two previous reported scores,cerebral small vessel disease score(CSVD score),and cerebral amyloid angiopathy score(CAA score)to report the total burden of CSVD.Based on the result and clinical experience,come up with a new modified score and compare their prognosis strength.First part: Supratentorial s ICH patients from 78 international centers through 2015-2017 was enrolled.The samples with qualified imaging was selected with available outcome data.We used the first MRI from onset to investigate the distribution of CSVD markers including Lacune,CMBs,EPVS,WMHs,and c SS.The CSVD score and CAA score was calculated at same time.Meanwhile,we randomly chosed 10% of imaging for cross check the difference between image reviewers.Second part: The outcome is 365 days m RS from onset.0-3 was defined as favorable outcome while 4-6 was defiened as unfavorable outcome.The baseline data and CSVD markers was tested between outcome groups.The standard of marker was setted.Also,CSVD score and CAA score was tested between outcome groups.Third part: Based on multivariant regression models,we calculated the prognosis effect of each markers and scores.The m CSVD score included lacune,CMBs more or equal than 5,severe EPVS,severe WMHs,and c SS.The m CSVD score was compared with original scores.Result: MISTIE Ⅲ trial included 506 patients from 78 centers and randomized into treatment groups from Dec.2013 to Aug 2017.The MISTIE Ⅲ study published at Lancet in 2019.288 patients had available neuroimaging and included in this study.139 are from the medical group and 149 are from the surgical group.127(44%)patients had 365 days favorable outcome while 161(56%)had an unfavorable outcome.93 patients reached EOT less than 15 m L goal,49 had a favorable outcome and 44 have an unfavorable outcome.CSVD markers are common in s ICH patients.Between two outcome groups(favorable vs.unfavorable),lacunar infarct is 8 vs.18(6% vs.11%,p=0.21);CMBs more than 5 is 19 vs.42(15% vs.26%,p=0.03);severe basal ganglia EPVS(more than 10)is 63 vs.103(50% vs.64%,p=0.02);severe WMHs(Fazekas score more or equal than 3 or deep fazekas score more or equal than 2)is 38 vs.109(30% vs.68%,p<0.001);c SS is 9 vs.27(7% vs.17%,p=0.02).In the multivariant analysis,the adjusted OR of CSVD score is 1.72(95% CI1.29-2.33,AUC=0.673,p=0.0003),the adjusted OR of CAA score is 1.63(95% CI 1.26-2.15,AUC=0.675,p=0.0003).In surgical subgroup analysis,the adjusted OR of CSVD score is 2.13(95% CI 1.41-3.36,AUC=0.685,p=0.0005),the adjusted OR of CAA score is 2.21(95% CI 1.47-3.51,AUC=0.701,p=0.0003).In EOT less than 15 m L subgroup analysis,the adjusted OR of CSVD score is 3.91(95% CI 2.06-8.99,AUC=0.742,p=0.0002),the adjusted OR of CAA score is 4.59(95% CI 2.28-11.57,AUC=0.763,p=0.0002).Based on the result and discussion,we gave out a modified cerebral small vessel disease score(m CSVD score).The score has 5 components,each one is 1 point: lacunar infarct,CMBs more or equal than 5,severe EPVS in basal ganglia,severe WMHs,and c SS.The m CSVD score has a significant difference between outcome groups.In full cohort,the OR is 1.91(95% CI 1.43-2.61,AUC=0.697,p<0.0001);in surgical group,the OR is 2.50(95% CI 1.63-4.05,AUC=0.709,p<0.0001);in EOT less than 15 m L group,the OR is 4.53(95% CI 2.28-11.63,AUC=0.791,p=0.0002).First part: MISTIE Ⅲ study included 506 patients from 78 centers.288 of them have qualified imaging.149(52%)are surgical patients while 139(48%)are medical patients.No significant difference was founded between selected patients and unselected patients.All of the 5 markers were obsevered in cohort.56(19%)patients have the CSVD score 0 point,1 point are 80(28%),2 points 87(30%),3 points 57(20%),4 points 8(3%).For CAA scores,0 point are 98(34%),1 point are 82(28%),2 points are 53(18%),3 points are 32(11%),4 points are 21(7%),5 points are 2(2%),6 points is 0.The cross check did not found difference between reviewers.Second part: 127(44%)of 288 patietns reached favorable outcome,161(56%)had unfavorable outcome.EOT volume less than 15 m L,age,diabetes,ICH volume at onset,IVH,deep ICH location,GCS,and SBP at onset had significant difference between outcome groups.In favorable outcome group,8(6%)have lacune while 18(11%)in unfavorable group,p=0.21.CMBs more than 5 is 19(15%)vs.42(26%),p=0.03.Severe EPVS(more than 10)is 63(50%)vs.103(64%),p=0.02.Sever WMHs(Fazekas score more or equal than 3 or deep fazekas score more or equal than 2)is 38(30%)vs.109(68%),p<0.001.c SS is 9(7%)vs.27(17%),p=0.02.For CSVD score,in favorable groups,0 point are 66(52%),1 point are 29(23%),2 points 20(16%),3 points 9(7%),4 points 3(2%);in unfavorable groups,0 point are 17(11%),1 point are 38(24%),2 points 56(37%),3 points 41(25%),4 points 6(3%),p<0.001.For CAA score,in favorable groups,0 point are 39(31%),1 point are 42(33%),2 points 28(22%),3 points 16(13%),4 points 2(1%),5 points is 0,6 points is 0;in unfavorable groups,0 point are 32(20%),1 point are 53(33%),2 points 33(21%),3 points 23(14%),4 points 18(11%),5 points are 2(1%),6 points is 0,p<0.001.Third part: Lacunar infarct,CMBs more or equal than 5,severe EPVS in basal ganglia,severe WMHs,and c SS was included in m CSVD score.In full cohort,OR of CSVD score is 1.72(95% CI=1.29-2.33,p=0.0003),CAA score is 1.63(95% CI=1.26-2.15,p=0.0003),m CSVD score is 1.91(95% CI=1.43-2.61,p<0.0001).In surgical cohort,OR of CSVD score is 2.13(95% CI=1.41-3.36,p=0.0005),CAA score is 2.21(95% CI= 1.47-3.51,p=0.0003),m CSVD score is 2.50(95% CI= 1.63-4.05,p<0.0001).in EOT cohort,OR of CSVD score is 3.91(95% CI=2.06-8.99,p=0.0002),CAA score is 4.59(95% CI=2.28-11.57,p=0.0002),m CSVD score is 4.53(95% CI=2.28-11.63,p=0.0002)Conclusion: First part: CSVD markers are commonly found in s ICH patients.This study describes the distribution of CSVD markers via prospective multicenter study and reported the distribution of c SS in severe s ICH poatients firstly.The score system can concluded the burden of CSVD.Second part: EOT volume less than 15 m L,age,diabetes,ICH volume at onset,IVH,deep ICH location,GCS,and SBP at onset are risk factors of unfavorable outcomes in our cohort.CSVD markers are different between outcome groups.Lacunar infarct,CMBs more or equal than 5,severe EPVS in basal ganglia,severe WMHs,and c SS are the differential cutoff.The CSVD score and CAA score have disadvantages.Third Part: Each CSVD markers have effect on outcome of s ICH.CSVD score and CAA score have good ability of prognosis in full cohort,surgical subgroup and EOT sub group,while m CSVD have better prognosis value and easier for clinical practice.We firstly evaluated the distribution of CSVD markers in a large randomized selected cohort.CSVD markers are different between outcome groups.CSVD score and CAA score can describe the burden of CSVD.The m CSVD score is easier in clinical practice and has a stronger prognosis strength compare to the two other scores,the m CSVD score may have other useage in clinical practice.