Impact Of Stent-Assisted Recanalization Of Carotid Artery .
JCEI /Journal of Clinical and Experimental Investigations doi:2016; 7 (4): 283-289DOI: 10.5799/jcei.328500RESEARCH ARTICLEImpact of Stent-Assisted Recanalization of Carotid Artery Stenosis onBrain Volume Changes12234Ömer Fatih Nas , Aylin Bican Demir , Mustafa Bakar , Güven Özkaya , Emre Kaçar , Bahattin1Hakyemez1Department of Radiodiagnostics, Uludağ University, School of Medicine, Bursa, Türkiye2Department of Neurology, Uludağ University, School of Medicine, Bursa, Türkiye3Department of Biostatistics, Uludağ University, School of Medicine, Bursa, Türkiye4Department of Radiodiagnostics, Afyon Kocatepe University, School of Medicine, Afyonkarahisar, TürkiyeABSTRACTObjective: The purpose of this study was to investigate the effect of recanalization on stenotic internal carotid arteryon brain volume changes in stent applied patients.Materials and Methods: Carotid stenting was performed in 17 patients with severe carotid artery stenosis betweenJune 2013 and April 2014. High resolution 3D T1 weight images were obtained from each patient 24 hours beforeand 7.2 3.6 months (mean standard deviation) after the procedure on a 3T magnetic resonance imaging scanner.Intracranial total cortical grey matter, total cortical white matter, white matter hypointensity, total intraventricular andsubcortical grey matter volumes were assessed by FreeSurfer version 4.5.0.Results: A significant reduction was found in total cortical white matter and subcortical grey matter volumes (p 0.05).A significant increase was found in white matter hypointensity and total intraventricular volumes after procedure(p 0.05). However, no statistical significant difference was found in total cortical grey matter volume before and afterprocedure (p 0.902).Conclusion: The significant reduction in the postoperative intracranial total cortical white matter and subcortical greymatter volumes and the significant increase in the white matter hypointensity volume were considered to besecondary to neuronal damage. J Clin Exp Invest 2016; 7(4): 283-289Key words: Brain volume changes, carotid stenosis; magnetic resonance imagingINTRODUCTIONPatients with stenosis of internal carotid artery(ICA) have an annual stroke risk of 5-6% whichincreases to 70% if more stenosis occurs.Carotid endarterectomy (CEA) and carotid arterystenting (CAS) are the methods performed toavoid the potential risk of stroke [1].In severe stenosis, cerebral perfusion might bereduced due to decreased blood supply. Todiagnose cerebral microcirculationin patientswith stenosis of ICA, several imaging techniquessuch as cervical and transcranial id xenonium injection and perfusionmagnetic resonance imaging (MRI) are needed.However, post-CAS hemodynamic changes incerebral perfusion are not yet clearly known [2].MR image-guided surface or voxel-based brainanalysis methods help to assess cerebral cortexthickness. FreeSurfer is one of the surfacebased methods, which is most commonly usedand is a frequently referred methodology inclinical trials [3]. It is an easy-to-use brainanalysis software which provides accurate andautomated image analysis [4]. To ourknowledge, there are no published studies thatinvestigated the effect of stent-assistedCorrespondence: Dr. Ömer Fatih Nas, Uludağ Üniversitesi, Tıp Fakültesi, Radyoloji Anabilim Dalı, Bursa, TürkiyeE-mail: omerfatihnas@gmail.comReceived: 25 June 2016, Accepted: 21 December 2016Copyright JCEI / Journal of Clinical and Experimental Investigations 2016, All rights reserved
284Nas OF, et al, Stent-assisted Recanalization of Carotid Artery Stenosisrecanalization on brain volume changes byusing the software FreeSurfer.In this study, we investigated the effect ofrecanalization on stenotic ICA on brain volumechanges in stents applied patients by evaluatingT1-weighted 3D MR images before and after theprocedure.METHODSPatientsCarotid stenting was performed in 17 patients (9on the left, 4 on the right side and 4 on bothsides, 21 total stents) with severe ICA stenosisbetween June 2013 and April 2014. Severestenosis is defined by the North AmericanSymptomatic Carotid Endarterectomy Trial(NASCET) as more 70% narrowing of thevessel [5]. Inclusion criteria were as follow; ahistory of carotid stenting with severe (more than70%) carotid stenosis, a T1-weighted 3D MRIsbefore and after the procedure and cerebralischemic risk. Patients not meeting these criteriawere excluded. Fourteen males (82.4%) and 3female were enrolled (17.6%). The mean degreeof stenosis was 89.4 7.8% on the right side and86.5 7.5 % on left side. The patients’ mean agewas 65.8 5.7 years (age range 56-77 years).Table 1 shows the co-morbidities of all patientsi.e. 88% of the patients had hypertension (n 15),47% had coronary artery disease (n 8), 41%had smoking history (n 7), 18% had diabetes(n 3), 18% had a history of cerebrovascularevent (n 3), and 12% hyperlipidemia (n 2). Highresolution 3D T1-weighted images wereacquired on a 3T MRI scanner using 32-channelhead coil 24 hours before and an average of7.18 3.6 months after the procedure (rangingfrom 2 to 12 months). Intracranial total corticalgrey matter, total cortical white matter, whitematter hypointensity, total intraventricular andsubcortical grey matter volumes were assessedby using the software FreeSurfer version 4.5.0.Approval was obtained from the ethicscommittee before the study.Interventional TechniqueInformed consent was obtained from all patientsthat were scheduled for endovascular stentplacement. Acetylsalicylic acid (Aspirin ; Bayer)100-300 mg/day and clopidogrel (Plavix ;J Clin Exp InvestSanofi-Synthalebo) 75 mg/day p.o. wasadministered at least 72 hours prior to theprocedure. Stenting was performed under sterileconditions and local anesthesia (2% prilocaine;Citanest, AstraZeneca) using a biplane, flatpanel angiography unit (AXIOM Artis FD BiplaneAngiosuite; Siemens Medical Solutions). An 8Fintroducer was inserted into the right commonfemoral artery using the single-wall puncturetechnique. During the procedure, 5000-7000units of heparin were administered intraarterially.Either right or left common carotid artery (CCA)was reached by using a guidewire (Roadrunner;Cook) and an 8F guiding catheter (Envoy;Cordis) depending on the stenosis site. Right orleft ICA stenosis was determined on theangiographic images. The stenosis was crossed6with a filter device (Emboshield NAV ; Abbottvascular). The filter was opened in the petrousportion of the ICA. After opening the filter, a3x20 mm balloon (Empira; Cordis) was used forpre-dilatation. Then, a self-expanding nitinolcarotid stent [Protege stent (n 9); Covidien, Xactstent (n 7); Abbott vascular and Precise stent(n 5); Cordis] was placed into the ocludedsegment. ICA reconstruction was obtained with5x20 mm balloons (Viatrac 14 Plus; Abbottvascular and Aviator Plus; Cordis) after thestenting. The filter was removed from thepetrous portion of the ICA and the femoral arteryaccess site was closed with a vascular y after the procedure, 1000 U/hourintravenous heparin was administrated for 8hours, followed by enoxaparine (Clexane ,Aventis) 0.6 ml/day s.c. for three days. Noclinical deficit occurred in the patients followingthe successful endovascular treatment. Stablepatients were discharged one day afteroperation and prescribed acetylsalicylic acid100-300 mg/day for lifelong and clopidogrel 75mg/day for 3-6 months.Magnetic Resonance ImagingConventional axial, sagittal and coronal T1 andT2-weighted images were acquired on a 3Tscanner (Achieva 3.0T Tx; Philips) using a 32channel head coil. High resolution T1-weighted3D images were acquired using 3D-FFE (threedimensional fast field echo) sequence with scantime of approximately 5.5 minutes. Theparameters were as followed: repetition time(TR)/echo time (TE): 8.2/3.8, inversion time (TI):www.jceionline.orgVol 7, No 4, December 2016
285Nas OF, et al, Stent-assisted Recanalization of Carotid Artery Stenosis1018 ms, number of signal averages (NSA): 1,flip angle: 8 , field of view (FOV): 240 240 mm,matrix: 240 240, slice voxel size: isovolumetric1 mm, and 170 slices.Morphometric Analysesgrey matter volumes (p 0.05). The mean totalcortical white matter and subcortical grey matter3volumes were 428110 75521 mm and 15733333 18077 mm before and 412200 73801 mm3and 155154 17297 mmafter CAS,respectively.Images acquired by the high resolution MRIwere transferred into a DICOM format forMacintosh-based computer. FreeSurfer4.5.0software was used for morphometric analyses.First, distortions on the images caused by thepatient movements and variations of brightnesscaused by the changes in the B1 field werecorrected. Second, images were placed on theTalairach coordinate system which allowed forpre-labeling by using manually created standardbrain templates. This led to the increasedsuccess of segmentation. Also errors caused bypathologies were reduced this way. Tabula wasautomatically deleted, and the rest was used asa brain mask for labeling and ation were reviewed. If necessary;corrected and volume measurements wererepeated by a specialist radiologist. Postprocessing took approximately 8 hours in eachpatient. This way, measurements of total corticalgrey matter, total cortical white matter, whitematter hypointensity, total intraventricular andsubcortical grey matter volumes were obtainedand used in statistical analysis.Statistical analysesAll statistical analyses were performed withSPSS 22.0 statistical program. Whether datademonstrated a normal distribution or not wasdetermined using Shapiro-Wilk test. Descriptivevalues of variables were expressed as means,standard deviations, medians, minimums andmaximums. Wilcoxon signed rank test andmatched pairs t-test were used for groupcomparison. The level of significance wasdetermined as 0.05.Figure 1. Graphical analyses of pre and post-CAScerebral volumes: Total cortical grey matter volume.A significant increase was observed in the totalintraventricular and white matter hypointensityvolumes(p 0.05).Themediantotalintraventricular and white matter hypointensity3volumes were (min-max) 30945 mm (15944357931) and 4591 mm (1980-20464) before and3334967 mm (19333-76057) and 6491 mm(2571-22526) after CAS, respectively (Figures 15, Table 2).RESULTSAfter CAS, no statistical significant differencewas observed in the total cortical grey mattervolumes (p 0.902). The mean total cortical grey3matter volume was 381875 41334 mm before3and 381496 41757 mm after CAS. On theother hand, a significant reduction was observedin the total cortical white matter and subcorticalJ Clin Exp Investwww.jceionline.orgVol 7, No 4, December 2016
286Nas OF, et al, Stent-assisted Recanalization of Carotid Artery StenosisFigure 2. Graphical analyses of pre and post-CAScerebral volumes: Total cortical white matter volume.Figure 4: Graphical analyses of pre and post-CAScerebral volumes: Total intraventricular volume.Figure 3. Graphical analyses of pre and post-CAScerebral volumes: Subcortical grey matter volume.Table 1. Demographic data of 17 patients.Patients’ Sex/Carotid stenosis (side and degree HT CADHistory ofHistory of DM HLnumberage(%))smokingCVE1M/69L: 95 2F/65R:95, L:75 3M/63L: 90 4M/71L: 90 5M/56R:75, L: 80 6M/63L: 90 7M/64R:95 8M/64R:95, L: 75 9M/60R:95 10M/61R:90 11F/74R:90, L: 95 12M/64L:80 13M/69R:80 14F/77L: 90 15M/61L: 95 16M/74L: 90 17M/63L:80 M: Male, F: Female, R: Rıght, L: Left, HT: Hypertension, CAD: Coronary Artery Disease, CVE: CerebrovascularEvents, DM: Diabetes Mellitus, HL: HyperlipidemiaTable 2. Statistical analyses of pre and post-CAS cerebral volumesParametersBefore CAS*3Total cortical grey matter (mm ) mean sd381875 413343Total cortical white matter (mm ) mean sd428110 755213Subcortical grey matter (mm ) mean sd157333 180773Total intraventricular (mm ) Median (min 30945 (15944 - 57931)max)3White matter hypointensity (mm ) Median4591 (1980 - 20464)(min - max)*CAS indicates carotid artery stentingJ Clin Exp Investwww.jceionline.orgAfter CAS*381496 41757412200 73801155154 1729734967 (19333 - 76057)p0.9020.0050.0160.0096491 (2571 - 22526)0.017Vol 7, No 4, December 2016
287Nas OF, et al, Stent-assisted Recanalization of Carotid Artery Stenosishemodynamic failure’, and is the most severestage of hemodynamic impairment [8,10].Cerebral vascularization and the brain mayadapt to the chronic reduction in CBF in areas ofthe brain with no cerebral infarction throughseveral potential mechanisms. While CBF mayincrease with the development of collateralways, CBF can decrease in order to provide thebalance of CMRO2. It is suggested that reducedCMRO2 in normal brain areas can causeselective ischemic neuronal loss [8]. Based onthis study, we believe that the chronic hypoxia inpatients with stenotic ICA leads to ischemicneuronal loss.Figure 5. Graphical analyses of pre and post-CAScerebral volumes: Total intraventricular volume, (e)White matter hypointensity volume.DISCUSSIONMagnetic resonance angiography (MRA) andtranscranial doppler demonstrated that collateralcirculation in patients with ICA stenosis did notplayed a role in assessment of the brainperfusion. Digital subtraction angiography (DSA)also provided significant information about y (PET) and single photon emissioncomputed tomography (SPECT) are invasivemethods, whereas arterial spin-labeling (ASL)MRI is a non-invasive method for theassessment of regional cerebral blood flow(CBF) [6]. Van Laar et al [6] observed a 15%increase in post-CAS regional CBF levels in theipsilateral hemisphere whereas and Ko et al [7]observed a 21% increase when using ASL-MRIand SPECT.Distal perfusion pressure and CBF are normalwhen the collateral pathways are sufficient insevere carotid stenosis [8,9]. If the collateralpathways are insufficient and the perfusionpressure distal to the stenosis is reduced, thenautoregulatory dilation can keep the CBF atnormal levels. When autoregulatory dilationcapacity is exceeded, the CBF will be reducedrelative to the cerebral rate of oxygenmetabolism (CMRO2). In addition, oxygenextraction fraction (OEF) will be increased tomaintain the normal CMRO2. This condition iscalled ‘misery perfusion’ or ‘stage IIJ Clin Exp InvestAdult human brain accounts for 2% of the totalbody weight, receives 15% of the total cardiacoutput and consumes 20% of the inhaledoxygen. The blood flow delivers oxygen andglucose to neurons needed for transmembraneion transport, electrical activities, cellular transport and cytoskeletal integrity.A normal CBF rate is 50–60 mL/100 g/min inprimates and 100 mL/100 g/min in rats andgerbils. A 50% reduction in CBF can betolerated. However, a reduction between 2550% in CBF can lead to ischemic injury due toinhibition of protein synthesis, prevention of theflow of transient potassium and calcium ions,cytotoxic edema and acidosis. This injury maybe followed by neuronal apoptosis. A CBF lessthan 25% leads to rapidly loss of neuronfunctions whereas a CBF less than 15-20% ofnormal values leads to irreversible neuronaldamage. The brain is quite susceptible to bothfocal and global ischemia. Unless ischemia isreversed, reperfusion increases the ischemicinjury. Excitotoxicity, impaired calcium ionhomeostasis, nitric oxide, free radicals,inflammation and apoptosis can be responsiblefor cerebral ischemia and reperfusion injury.Nitric oxide and free radicals may either dodirect damage or cause indirect damage bymeans of inflammation and apoptosis [11].Atherosclerotic risk factors like hyperlipidemia,diabetes, hypertension, smoking and aging mayinduce release of reactive oxygen species fromendothelium, vascular smooth muscle cells andadventitial cells which can lead to impaircerebral autoregulation. Hypoxia caused bywww.jceionline.orgVol 7, No 3, September 2016
288Nas OF, et al, Stent-assisted Recanalization of Carotid Artery Stenosiscerebral ischemia may affect a number ofneurons at different levels. Several factors suchas hypoxia and cerebral ischemia are known toinduce neuronal apoptosis in the nervoussystem [12]. Chen et al [13] demonstratednuclear DNA damage after middle cerebralartery stenosis and reperfusion in rats, whichwas indicative of neuronal apoptosis. Pulsinelliet al [14] investigated ischemic neuronaldamage following transient bilateral forebrainischemia in a Wistar rat model of four-vesselstenosis. They occluded vertebral arteriespermanently and 24 hours later common carotidarteries transiently for 10, 20 and 30 minutes.After 10 minutes of stenosis, ischemic cellchanges were observed in cerebral hemispheresof the rats, and after 30 minutes of stenosisearly neuronal damage occurred. The authorsconcluded that neuronal damage progressivelyadvanced with time.MR image-guided cerebral cortex thicknessestimation methods can be categorized into twogroups: surface and voxel-based brain ion of grey matter, white matter andcerebrospinal fluid. Laplacian and Registrationare voxel-based methods whereas theFreeSurfer is a surface-based method. Surfacebased methods are more widely used comparedto voxel-based ones due to accessible softwarepackages such as BrainSuite, BrainVISA andFreeSurfer. The FreeSurfer is the most commonmethod employed in clinical trials beyond allsurface-based methods [3], because it is easy touse and rapidly developing brain analysissoftware for the assessment of functional andstructural features and connections in the brain.FreeSurfer is a freeware and can be improvedwith hardware and software platforms. It allowscross-modal intra-subject registration, combinedvolume and surface cross-subject registration,probabilistic estimation of cytoarchitectonicboundaries, automated tractography andlongitudinal analysis. Furthermore, the softwarecan also be used for the assessment ofneurologicalandgeneticbasisofneuroanatomical disorders, healthy developmentand aging [4]. Liem et al [15] reported thatsurface-based metric parameters (corticalthickness, surface area and volume) of theFreeSurfer have high reliability in theassessment of age-related structural alterationsJ Clin Exp Investin brain regions of healthy elderly individuals. Inour study, we preferred the FreeSurfer softwaresince its easy-to-use nature and the accurateand automate image analysis properties.This study had some limitations. First, thenumber of patients included in the study waslimited. Second, no CEA control group wasanalyzed. Third, only the FreeSurfer surfacebased method was used. Forth, no clinicalexamination was performed after CAS. Last, thiswas a retrospective study without a controlgroup.In conclusions, intracranial neuronal loss inpatients treated with CAS for severe ICAstenosis might be due to neuronal damage asdetermined by FreeSurfer surface-basedvolumetric measurements. Furthermore, thesignificant increase in the total intraventricularvolume might be related to the reduction in thetotal white matter volume. Evaluation of thisstudy together with postmortem studies andother brain analysis softwares will be useful.Declaration of conflicting interests: Theauthors declared no conflicts of interest withrespect to the authorship and/or authorship ofthis article.Funding: The authors received no financialsupport for the research and/or authorship ofthis article.REFERENCES1. Yun TJ, Sohn CH, Han MH, et al. Effect of carotidartery stenting on cerebral blood flow: evaluationof hemodynamic changes using arterial spinlabeling. Neuroradiology 2013;55:271-81.2. Tavares A, Caldas JG, Castro CC, et al. Changesin perfusion-weighted magnetic resonanceimaging after carotid angioplasty with stent. IntervNeuroradiol 2010;16:161-69.3. Clarkson MJ, Cardoso MJ, Ridgway GR, et al. Acomparison of voxel and surface based corticalthickness Estimation methods. Neuroimage2011;57:856-65.4. Fischl B. FreeSurfer. Neuroimage. 2012;62:774-81.5. Fox AJ. How to measure carotid stenosis.Radiology 1993;186:316-18.www.jceionline.orgVol 7, No 4, December 2016
289Nas OF, et al, Stent-assisted Recanalization of Carotid Artery Stenosis6. Van Laar PJ, Hendrikse J, Mali WP, et al. Alteredflow territories after carotid stenting and carotidendarterectomy. J Vasc Surg 2007;45:1155-61.7. Ko NU, Achrol AS, Chopra M, et al. Cerebral bloodflow changes after endovascular treatment ofcerebrovascularstenoses.AJNRAmJNeuroradiol 2005;26:538-42.8. Derdeyn CP, Videen TO, Fritsch SM, et al.Compensatory mechanisms for chronic cerebralhypoperfusion in patients with carotid occlusion.Stroke 1999;30:1019-24.9. Norrving B, Nilsson B, Risberg J. rCBF in patientswith carotid occlusion. Resting and hypercapnicflow related to collateral pattern. Stroke1982;13:155-62.10. Baron JC, Bousser MG, Rey A, et al. Reversal offocal "misery-perfusion syndrome" by extraintracranial arterial bypass in hemodynamiccerebral ischemia. A case study with 15O positronemission tomography. Stroke. 1981;12:454-59.11. Cheung RT. The utility of melatonin in reducingcerebral damage resulting from ischemia andreperfusion. J Pineal Res 2003;34:153-60.12. Sastry PS, Rao KS. Apoptosis and the nervoussystem. J Neurochem 2000;74:1-20.13. Chen J, Jin K, Chen M, et al. Early detection ofDNA strand breaks in the brain after transientfocal ischemia:İmplications for the role of DNAdamage in apoptosis and neuronal cell death. JNeurochem 1997;69:232-45.14. Pulsinelli WA, Brierley JB, Plum F. Temporalprofile of neuronal damage in a model of transientforebrain ischemia. Ann Neurol. 1982;11:491-98.15. Liem F, Mérillat S, Bezzola L, et al. Reliability andstatistical power analysis of cortical andsubcortical FreeSurfer metrics in a large sample ofhealthy elderly. Neuroimage 2015;108:95-109.J Clin Exp Investwww.jceionline.orgVol 7, No 4, December 2016
carotid stent [Protege stent (n 9); Covidien, Xact stent (n 7); Abbott vascular and Precise stent (n 5); Cordis] was placed into the ocluded segment. ICA reconstruction was obtained with 5x20 mm balloons (Viatrac 14 Plus; Abbott vascular and Aviator Plus; Cordis) after the stenting. The filter was removed from the
group, with Xact Carotid stent (Abbott Vascular, Santa Clara, California), Nexstent Carotid stent, Carotid Wallstent (Boston Scientific, Natick, Massachusetts) being classified as closed-cell stent and Precise carotid stent, Protégé carotid stent (Cordis, Warren, New Jersey), Acculink carotid stent (Acculink system,
evaluated based on three of the evaluated carotid stent models. Two out of five stent models (Acculink RX 10 mm and Precise 10mm) had the same distal outer stent sheath diameter but a different stent sheath length. Two stent models (Precise 7mm and Precise 10mm) had the same distal outer stent sheath length but a dif-ferent stent sheath diameter.
Stent B was created to represent another closed-cell stent design resembling a XACT stent (XACT Carotid stent system, Abbot Vascular, CA, USA) and Stent C was created for an open-cell design to resemble an ACCULINK stent (RX ACCULINK , Abbot Vascular, CA, USA). Details of the geometric parameters are sum-marised in Appendix B.
The XIENCE Alpine Stent System uses the identical stent and stent contacting balloon materials, and the identical drug coating formulation and drug dose density (100 ug/cm²) as the XIENCE PRIME Everolimus Eluting Coronary Stent System. The XIENCE Alpine Stent System is available in two delivery system configurations: Rapid Exchange (RX) and
The system of self-expanding metal stent contains two el-ements: esophageal stent formed by nitinol and covered by silicone membrane. Besides the two parts, intraluminal radioactive stent is also composed of another nitinol sheath outside of the stent, which can contain
Stent Type Stent Design Free Cell Area (mm2) Wallstent Closed cell 1.08 Xact Closed cell 2.74 Neuroguard Closed cell 3.5 Nexstent Closed cell 4.7 Precise Open cell 5.89 Protégé Open cell 20.71 Acculink Open cell 11.48 Stent Free Cell Area Neuroguard IEP Carotid Stent
Xact Carotid Stent Open cell stent design . Carotid WALLSTENT Endoprosthesis Precise PRO Rx Nitinol Stent System RX Acculink Carotid Stent. Influence of Stent Cell Design on Adverse Events Cell design Total Population Without protection With protection Closed Cell 5.9% (26/437) 5.8% (21/362) 6.7% (5/75) Open Cell 11% (14/127) 12.3%
In recent years, there has been an increasing amount of literature on . A large and growing body of literature has investigated . In recent years, several studies have focused on
