Altinbas, A

Blackham, KA

Bonati, LH

Brown, MM

de Borst, GJ

Engelter, ST

Hendrikse, J

Jongen, LM

Jäger, R

Kappelle, LJ

Lyrer, PA

Macdonald, S

Müller, MD

Nederkoorn, PJ

Richards, T

van der Worp, HB

Werring, DJ

Wetzel, SG

Wolff, T

UCL Discovery

Copyright © 2019  Korean Stroke SocietyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.pISSN: 2287-6391 • eISSN: 2287-6405Letter to the EditorJournal of Stroke 2019;21(1):116-119https://doi.org/10.5853/jos.2018.02838116 http://j-stroke.orgDear Sir:Carotid artery stenting (CAS) is a less invasive alternative to ca-rotid endarterectomy (CEA) for treatment of symptomatic carotid stenosis. The risk of peri-procedural cerebral ischemia is greater with CAS than with CEA.1 However, evidence on the occurrence of new hemorrhagic brain lesions after CAS or CEA is sparse. We aimed to assess the frequency of clinically silent brain hemor-rhage on magnetic resonance imaging (MRI) after CAS and CEA in the MRI substudy of the International Carotid Stenting Study (ICSS), a registered clinical trial (RCTN25337470).In ICSS, patients with symptomatic carotid stenosis were ran-domized in a 1:1 ratio to CAS or CEA.2 In the ICSS-MRI substudy, patients were scanned with multi-modal MRI 1 to 7 days be-fore, 1 to 3 days after and 30±3 days after revascularization, in-cluding gradient-recalled echo (GRE) T2*-weighted MRI. The primary outcome of the present study was the presence of at least one new hemorrhagic brain lesion on the 30-day scan, de-fined by any new signal hypointensity within the brain paren-chyma on GRE T2* which was not present before treatment. Small, rounded hypointense lesions measuring ≤10 mm in diam-eter were classified as cerebral microbleeds (CMBs).3 New hem-orrhagic lesions on the 1-month follow-up scan occurring at the site of ischemic brain lesions seen on fluid-attenuated in-version recovery sequences before treatment, or at the site of new diffusion-weighted imaging lesions in the scan done 1 to 3 days after treatment, were classified as hemorrhagic transfor-mations of ischemic infarcts, and were not counted as part of the primary outcome.Details on the CAS and CEA procedures have been described Silent Intracerebral Hemorrhage in Patients Randomized to Stenting or Endarterectomy for Symptomatic Carotid StenosisMandy D. Müller,a Lisa M. Jongen,b Aysun Altinbas,c Kristine A. Blackham,d Paul J. Nederkoorn,e Sumaira Macdonald,f Rolf Jäger,g Thomas Wolff,h Philippe A. Lyrer,a L. Jaap Kappelle,i  Stephan G. Wetzel,j Toby Richards,k Jeroen Hendrikse,b Gert J. de Borst,l H. Bart van der Worp,i  Stefan T. Engelter,a,m David J. Werring,n Martin M. Brown,n Leo H. Bonati,a,n on behalf of the ICSS-MRI Study InvestigatorsaDepartment of Neurology and Stroke Center, University Hospital Basel, University of Basel, Basel, SwitzerlandbDepartment of Radiology, University Medical Center Utrecht, University The Netherlands, Utrecht, the NetherlandscDepartment of Pediatric Neurology, Leiden University Medical Center, Leiden University, Leiden, the NetherlandsdDepartment of Diagnostic and Interventional Neuroradiology, University Hospital Basel, University of Basel, Basel, Switzerland eDepartment of Neurology, Academic Medical Center, Amsterdam, the Netherlands fDepartment of Radiology, Freeman Hospital, Newcastle upon Tyne, UKgAcademic Neuroradiological Unit, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, UKhDepartment of Vascular Surgery, University Hospital Basel, University of Basel, Basel, SwitzerlandiDepartment of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, the NetherlandsjInstitute of Neuroradiology, Clinic Hirslanden, Zurich, SwitzerlandkDivision of Surgery and Interventional Sciences, University College London, London, UKlDepartment of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the NetherlandsmNeurorehabilitation Unit, University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, University of Basel, Basel, SwitzerlandnDepartment of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, UKVol. 21 / No. 1 / January 2019https://doi.org/10.5853/jos.2018.02838 http://j-stroke.org 117Table 1. Baseline characteristics, radiological, and clinical outcome eventsCharacteristic CAS (n=84) CEA (n=78) Total (n=162)Age (yr) 70.4±8.9 69.4±8.5 69.9±8.7Male sex 65 (77.4) 53 (67.9) 118 (72.8)Vascular risk factorsHistory of hypertension 57 (68.0) 56 (72.0) 113 (70.0)History of diabetes 18 (21.0) 19 (24.0) 37 (23.0)History of hypercholesterolemia 54 (64.0) 54 (69.0) 108 (67.0)Smoking (past or present) 66 (79.0) 54 (69.0) 120 (74.0)Coronary heart disease 15 (18.0) 20 (26.0) 35 (22.0)Peripheral artery disease 11 (13.0) 10 (13.0) 21 (13.0)Blood pressure at randomization (mm Hg)Systolic 158.6±28.3 158.2±25.1 158.4±26.8Diastolic 81.9±14.0 81.9±11.9 81∙9±13.0Mean 107.5±17.2 107.4±14.9 107.4±16.1Blood pressure at hospital discharge (mm Hg)Systolic 135.1±19.8 134.7±17.1 134.9±18.4Diastolic 71.6±12.8 72.5±10.8 72.1±11.8Mean 92.8±13.0 93.3±11.3 93.0±12.1Blood pressure at 1 month follow-up (mm Hg)Systolic 157.9±21.7 152.4±23.5 155.2±22.7Diastolic 83.6±11.8 81.5±10.8 82.6±11.4Mean 108.4±13.5 105.1±13.5 106.8±13.5Most recent ipsilateral event*Amaurosis fugax 21 (25.0) 14 (18.0) 35 (22.0)Retinal stroke 5 (6.0) 1 (1.0) 6 (4.0)Transient ischemic attack 24 (29.0) 30 (40.0) 54 (34.0)Hemispheric stroke 34 (41.0) 31 (41.0) 65 (41.0)Score on modified Rankin Scale at randomization0 38 (45.0) 28 (36.0) 66 (41.0)1 19 (23.0) 19 (24.0) 38 (24.0)2 23 (27.0) 21 (27.0) 44 (27.0)3 4 (5.0) 8 (10.0) 12 (7.0)4 0 (0.0) 2 (3.0) 2 (1.0)Degree of ipsilateral carotid stenosis at randomization†Moderate (50%–69%) 13 (16.0) 7 (9.0) 20 (13.0)Severe (70%–99%) 71 (85.0) 71 (91.0) 142 (88.0)Contralateral severe carotid stenosis or occlusion 4 (5.0) 3 (4.0) 7 (4.0)Baseline MRI characteristics‡Presence of ischemic lesion on DWI before treatment 32 (38.0) 29 (37.0) 61 (38.0)Presence of CMB on GRE T2* before treatment 16 (19.0) 12 (15.0) 28 (17.0)Total ARWMC score 4 (2–7) 4 (2–8) 4 (2–7)Radiological outcome events on 1-month MRI New hemorrhagic brain lesions 5 (6.0) 5 (6.4) 10 (6.2)Ipsilateral carotid territory 4 ( 4 ( 8 (Contralateral carotid or vertebrobasilar territory 1 ( 1 ( 1 (Müller et al.  Cerebral Microbleeds after Carotid Revascularizationhttps://doi.org/10.5853/jos.2018.02838118 http://j-stroke.orgin detail before.2 In short, premedication for CAS was discre-tionary, although the combination of aspirin and clopidogrel was recommended. Use of heparin during the procedure was mandatory. All CEA patients received antiplatelet therapy be-fore and after the procedure. Assessment of MRI scans was done through consensus reading by two experienced readers who were blinded to the allocated treatment and clinical out-come. In case of disagreement between the two, a third re-viewer made the final decision. We analyzed all patients who received the randomly allocat-ed treatment (CAS or CEA) and both the pre-treatment and 30-day MRI scans including GRE T2* sequences in sufficient quality. We compared the proportion of patients with the pri-mary outcome between the CAS and the CEA group using Fisher’s exact test. Binary logistic regression analysis was per-formed to study the association between each of the clinical and radiological baseline variables (Table 1) and the primary outcome in both treatment groups combined. From 2005 to 2009, 260 patients were randomized at five ICSS-MRI substudy centers (CAS, n=129; CEA, n=131). Our Characteristic CAS (n=84) CEA (n=78) Total (n=162)Clinical outcome eventsDeath 0 ( 0 ( 0 (Any stroke 7 (8.3) 3 (3.8) 10 (6.2)Ischemic 7 ( 3 ( 10 (Hemorrhagic 0 ( 0 ( 0 (Values are presented as mean± standard deviation, number (%), or median (interquartile range).CAS, carotid artery stenting; CEA, carotid endarterectomy; MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging; CMB, cerebral microbleed; GRE, gradient-recalled echo; ARWMC, age-related white matter changes.*Type of qualifying event was not available in two patients in the CEA arm; †Degree of stenosis according to North American Symptomatic Carotid Endarter-ectomy Trial (NASCET) method; ‡On pre-treatment scan done within International Carotid Stenting Study (ICSS)-MRI Study.Table 1. ContinuedFigure 1. Study flow chart. Inclusion and reasons for exclusion of patients from analysis. CAS, carotid artery stenting; CEA, carotid endarterectomy; BMT, best medical therapy; MRI, magnetic resonance imaging; GRE, gradient-recalled echo; MI, myocardial infarction.1 Received BMT only129 Allocated CAS 131 Allocated CEA84 Included in primary analysis78 Included in primary analysis97 CAS initiated 87 CEA initiated94 CAS completed 87 CEA completed260 Patients randomised3 GRE not done3 CAS aborted (1 received CEA, 2 received BMT only)7 MRI contraindicated1 No consent to MRI substudy20 MRI scanner unavailable before treatment1 Fatal peri-procedural MI1 Fatal procedural stroke1 Sudden cardiac death2 In rehab or nursing home at 1 month2 Withdrew consent for follow-up scan3 MRI scanner unavailable at follow-up100 Underwent pre-treatment scan92 Underwent pre-treatment scan84 Underwent follow-up scan79 Underwent follow-up scan4 GRE not done1 Patient withdrew consent for treatment and received BMT only1 Fatal peri-procedural stroke1 No follow-up scan for medical reasons6 MRI scanner unavailable at follow-up1 Received CAS5 Received BMT only9 MRI contraindicated2 No consent to MRI substudy1 No pre-treatment scan for medical reasons21 MRI scanner unavailable before treatment1 GRE not doneVol. 21 / No. 1 / January 2019https://doi.org/10.5853/jos.2018.02838 http://j-stroke.org 119study population included 162 patients (CAS, n=84; CEA, n=78) who underwent treatment as randomly allocated and had complete MRI scans done before and 30 days after treat-ment. Patient flow and reasons for exclusion from the present analysis are detailed in Figure 1. Patients were well matched in baseline characteristics (Table 1). Thirty-one patients were studied in 3 Tesla scanners (CAS, n=15; CEA, n=16) and 131 in 1.5 Tesla scanners (CAS, n=69; CEA, n=62).Seven patients in the CAS group (8.3%) and three patients in the CEA group (3.8%) suffered an ischemic stroke. All pre-ex-isting hemorrhagic brain lesions seen on the pre-treatment scan were still visible on the 1-month follow-up scan. No clini-cally manifest hemorrhagic strokes occurred. Hemorrhagic brain lesions, exclusively in the form of a single CMB, occurred in five patients in the CAS group (6.0%) and in five patients in the CEA group (6.4%, P=0.88). CMBs were located in the terri-tory supplied by the treated carotid artery in eight patients and in the contralateral carotid territory in two patients. In the CAS group, two CMBs were located in deep structures (basal gan-glia), two in the frontal lobe, and one in the temporal lobe. In the CEA group, two CMBs were located in deep structures (ex-ternal capsule and deep/periventricular white matter), two in the frontal lobe, and one in the temporal lobe. None of the pa-tients with CMBs had symptoms attributable to the lesion or cerebral hyperperfusion syndrome (CHS). CMBs were not asso-ciated with any patient baseline characteristics including pres-ence of CMBs before treatment, or baseline severity of white matter changes.Our study has limitations. Due to the small number of pa-tients exhibiting new hemorrhagic brain lesions on MRI after carotid revascularization, we are not able to draw any mean-ingful conclusions on the association between hemorrhagic brain lesions and CHS, nor any of the assessed baseline risk factors including pre-existing CMBs. Second, no information was available on blood pressure values directly after CAS or CEA, or within a few days thereafter. In addition, only about one fifth of our patients were imaged on 3 Tesla scanners, and susceptibility weighted imaging sequences were not done. Therefore, we might have underestimated the true frequency of CMBs to some degree. In conclusion, we found that hemorrhagic brain lesions after carotid revascularization are rare, do not differ between CAS and CEA, and in our study exclusively occurred in the form of a single CMB, predominantly located in the territory supplied by the treated carotid artery. References1. Bonati LH, Jongen LM, Haller S, Flach HZ, Dobson J, Nederkoorn PJ, et al. New ischaemic brain lesions on MRI af-ter stenting or endarterectomy for symptomatic carotid ste-nosis: a substudy of the international carotid stenting study (ICSS). Lancet Neurol 2010;9:353-362. 2. International Carotid Stenting Study investigators, Ederle J, Dobson J, Featherstone RL, Bonati LH, van der Worp HB, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (international carotid stenting study): an interim analysis of a randomised controlled trial. Lancet 2010;375:985-997. 3. Gregoire SM, Chaudhary UJ, Brown MM, Yousry TA, Kallis C, Jäger HR, et al. The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds. Neu-rology 2009;73:1759-1766.Correspondence: Leo H. BonatiDepartment of Neurology and Stroke Center, University Hospital Basel, University of Basel, Petersgraben 4, CH-4031 Basel, Switzerland Tel: +41-61-2652525 Fax: +41-61-2654100E-mail: leo.bonati@usb.chReceived: October 1, 2018Revised: January 15, 2019Accepted: January 15, 2019The authors have no financial conflicts of interest.

Silent Intracerebral Hemorrhage in Patients Randomized to Stenting or Endarterectomy for Symptomatic Carotid Stenosis

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Silent Intracerebral Hemorrhage in Patients Randomized to Stenting or Endarterectomy for Symptomatic Carotid Stenosis

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