wenz iD - Proefschrift J.C. Welleweerd by wenz iD

Het verschijnen van dit proefschrift werd mede mogelijk gemaakt met financiële steun van Covidien, ChipSoft, W. L. Gore & Associates, Vascutek en Krijnen Medical Innovations.

ISBN: ISBN/EAN 978-94-6108-969-4 Cover: Janna Catharina Welleweerd & wenz iD Layout and Design: wenz iD | www.wenzid.nl Printed by: Gildeprint Drukkerijen, Enschede

Aneurysms of the extracranial carotid artery Aneurysmata van de extracraniĂŤle arteria carotis (met een samenvatting in het Nederlands)

Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 21 mei 2015 des middags te 2.30 uur

door

Janna Catharina Welleweerd geboren op 27 juli 1981 te Rozenburg

Promotor: Prof dr F.L. Moll Copromotor: Dr G.J. de Borst

Het verschijnen van dit proefschrift werd mede mogelijk gemaakt door de steun van de Nederlandse Hartstichting.

Contents chapter 1

General introduction and thesis outline

chapter 2

Aneurysms of the extracranial carotid artery Oxford Textbook of Vascular Surgery, second edition

chapter 3

Histological analysis of extracranial carotid artery aneurysms PLoS One. 2015 Jan 30;10(1):e0117915

chapter 4

Intra- and inter-observer variability of extracranial carotid artery aneurysm volume measurement Submitted

chapter 5

Management of extracranial carotid artery aneurysm Submitted

chapter 6

Technical options for treatment of extracranial carotid aneurysms Expert Rev Cardiovasc Ther. 2012 Jul;10(7):925-31

chapter 7

Conservative treatment of extracranial carotid artery aneurysms Submitted

chapter 8

Bare metal stents for treatment of extracranial internal carotid artery aneurysms: long-term Results J Endovasc Ther. 2015 Feb;22(1):130-134

chapter 9

Rationale and design of the extracranial Carotid artery Aneurysm Registry J Cardiovasc Surg (Torino). 2015 Feb 6. [Epub ahead of print]

105

chapter 10

Summary, general discussion and future perspectives

119

chapter 11

Nederlandse samenvatting

129

chapter 12

Review Committee Dankwoord - Acknowledgements List of publications Curriculum Vitae

138 139 141 142

chapter

General introduction and thesis outline

chapter 1

The word carotid is derived from the Greek term karotids or karos, meaning to stupefy or plunge into a deep sleep. The term was applied to the arteries of the neck by Rufus of Epheses (circa 100 A.D.) and compression of these arteries was noted to initiated sleep or drowsiness in a person.1 Nowadays, the most common pathology of the carotid artery is stenosis caused by atherosclerotic plaques. This pathology was first described in 1914, and DeBakey, a cardiac surgeon, performed the first successful carotid endarterectomy for stenotic carotid disease in 1953.2 Much earlier, the first operations on the carotid artery were ligation procedures for trauma or haemorrhage. Hebenstreit mentions a patient operated on in 1793, in whom the carotid artery was injured during operative removal of a tumor. The vessel was successfully ligated to stop haemorrhage.3 Sir Astley Cooper, in London, was the first to perform successful ligation of a carotid artery for an extracranial carotid aneurysm (ECAA) on June 22, 1808. The patient, who was 55 years old, had a pulsating tumor in the neck. Cooper applied two surgical ligatures and divided the artery. The patient made a good recovery and lived until 1821.4 Despite knowledge of the existence of ECAAs dating back hundreds of years, not much has been learned regarding natural history and treatment, in particular, compared with stenotic carotid disease and aneurysms in other vascular beds. Obviously, this is because ECAAs are an extremely rare vascular pathology. The exact incidence is unknown because of the lack of structured registration of ECAAs and because many aneurysms probably stay asymptomatic and are only encountered by coincidence. Reported incidences are from single center reports. In these reports, invasive treatment of ECAA occurs in 0.09% to 2.0% of all extracranial carotid interventions and in 0.4% to 2% of all extracranial arterial aneurysm repairs.5-8 ECAAs are most commonly defined as a 150% dilatation of the artery compared with the normal contralateral carotid diameter, or in case of bilateral dilatation compared with the diameter of the non-affected ipsilateral carotid artery.9 Mean diameters of the common carotid artery range from 6 mm in women to 6.5 mm in men and of the internal carotid artery (ICA) from 4.5 mm in women to 5 mm in men.10 The indication â&#x20AC;&#x153;extracranialâ&#x20AC;? in ECAA refers to the location of the aneurysm, in this case all aneurysms between the aortic arch and the base of the skull. Most ECAAs are asymptomatic and are coincidental findings. However, an ECAA can cause serious morbidity. The most feared complication is cerebral ischemia. A stroke, sometimes referred to as a cerebrovascular accident, is the loss of brain function resulting from a disturbance in the blood supply to the brain. This disturbance from either ischemia or hemorrhage and can cause neurological deficits. Hippocrates first described paralysis and loss of speech in a patient (460-370 B.C.)1 Ischemia is caused by blockage of a blood vessel by thrombosis or by arterial embolism. An embolus arises most commonly from the heart, but may also originate from a plaque or aneurysm in the carotid artery. Thrombosis in the aneurysm, probably as a result of the lower blood flow velocity, can cause embolism to the brain. 10

Introduction

Information regarding natural history, indications and best treatment in patients with ECAA is scarce and guidelines are lacking. Medical, surgical, and endovascular treatment of ECAA have all been recommended. For a proper assessment of the benefit and complication risk from the different treatment and revascularization options for ECAA, a better insight in vascular procedural outcome is needed and especially in the natural follow-up. Given the limited number of patients, randomized controlled trials are infeasible in rare diseases such as ECAA. This is why disease registries have become essential for the investigation of diseases, thanks to their potential to describe the natural history of the disease. To collect data on ECAAs we designed the Carotid Aneurysm Registry (CAR).

General aims of this thesis The aim of this thesis was to structurally report the currently available evidence on ECAA etiology, diagnostics, natural history, and treatment outcome. This thesis is intended to form the foundation for future research on ECAA.

Thesis outline This thesis will commence in Chapter 2 by describing the symptoms, classification, etiology, and current diagnostics in ECAA. In Chapter 3, the aneurysm wall composition of ECAA is assessed using histological samples from the aneurysm express. Current aneurysm size and growth are most often determined using the diameter measurement on computed tomography angiography (CTA) imaging. Chapter 4 explores volume measurements of ECAA using a software application. Until today, no consensus on treatment indications exists, and little is known regarding treatment outcome. Short-term and long-term results of conservative, endovascular, and surgical treatment of ECAA are investigated in Chapter 5 using a review of available literature. Chapter 6 explores the technical options of surgical and endovascular treatment of ECAA. The outcome of conservative management in our referral center is described in Chapter 7. Knowledge about the natural history of ECAA is essential in determining treatment indications. Open surgical treatment with restoration of the blood flow is still the current treatment of choice in symptomatic patients. During recent years, endovascular surgery has become an alternative to open surgery. Chapter 8 investigates the technical feasibility and outcome of aneurysm exclusion using a bare-metal stent. To further investigate the natural history and treatment outcome in ECAA, we created the Carotid artery Aneurysm Registry (CAR), and, Chapter 9 describes the rationale and design of this registry. Chapter 10 concludes this thesis by providing a general discussion and future perspectives.

chapter 1

References 1.

Garrison F. History of neurology (revised and enlarged by McHenry LC, jr). Springfield: Thomas; 1969.

DeBakey ME. Successful carotid endarterectomy for cerebrovascular insufficiency. nineteen-year follow-up.

Habenstreit E. Zusatze zu benj. bellsâ&#x20AC;&#x2122;s abhandlung von den geschwuren und deren behandlung. Leipzig:

Cooper A. Account of the first successful operation performed on the common carotid artery for aneurysm

JAMA. 1975;233(10):1083-1085.

Weindmann; 1793.

in the year 1808 with the post-mortem examination in the year 1821. Guys Hosp Rep. 1836(1):53-59. 5.

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712. doi: 10.1067/mva.2000.104101.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200.

Zhou Y, Yang PF, Hong B, et al. Stent placement for the treatment of complex internal carotid bifurcation aneurysms: A review of 16 cases. Turk Neurosurg. 2013;23(2):232-240. doi: 10.5137/1019-5149.JTN.712312.0 [doi].

Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther. 2012;10(7):925-931. doi: 10.1586/erc.12.61 [doi].

De Jong KP, Zondervan PE, Van Urk H. Extracranial carotid artery aneurysms. Eur J Vasc Surg. 1989;3(6):557562.

10. Krejza J, Arkuszewski M, Kasner S, et al. Carotid artery diameter in men and women and the relation to body and neck size. Stroke. 2006(37):1103-1105.

chapter

Gert Jan de Borst MD PhD1, Janna C Welleweerd MD1, Frans L Moll MD PhD1 1

Department of Vascular Surgery, University Medical Center Utrecht, the Netherlands

Aneurysms of the extracranial carotid artery Oxford Textbook of Vascular Surgery, second edition

chapter 2

Introduction Although very rare, aneurysms of the extracranial carotid artery (ECAA) are important to identify and treat. The most common definition is a dilation of the carotid artery greater than 150% of the diameter of normal (uninvolved) internal carotid artery (ICA) or common carotid artery (CCA). ECAAs are most frequently located in the ICA and the dilation may be focal and saccular (Figure 1) or fusiform and extensive. The natural history of ECAA remains unclear (largely because of their rarity and because most are probably treated), but there is an intuitive belief that they rarely remain benign.1 Untreated, ECAA can cause compression in the cervical region causing swelling, pain and cranial nerve palsy. Embolization of thrombus from within the aneurysm can cause cerebral infarction, while the risk of aneurysm rupture is probably very low.2

Figure 1. 3-D CTA of a saccular aneurysm of the ICA in association with marked tortuosity of the vessels. This type of aneurysm can be treated by resection and either primary end-to-end ICA anastomosis, or by anastomosing the distal ICA to the transected ECA main trunk.

Aneurysms of the extracranial carotid artery

Epidemiology Aneurysms of the intracranial arteries are more common (than ECAA) and will not be considered further. Aneurysmal dilatation of the extra-cranial carotid artery was first reported in the late 17th century. A recent meta-analysis has identified 255 published studies describing the management of 1279 patients; ECAAs comprise 0.6-3% of all reported carotid procedures1,3, but they account for only 0.4% of all peripheral aneurysms. However, while there is no evidence that the incidence of ECAA is increasing, it is likely that more ECAAs are now being identified (as opposed to being left undiagnosed) because of the increasing use of Computed Tomographic Angiography (CTA) and Magnetic Resonance Angiography in the investigation of patients presenting with a variety of head and neck pathologies (Figure 2).

Aetiology and pathogenesis In line with aneurysms elsewhere in the body, ECAAs can be true or false. 3-5 The principle causes of true ECAA include; ‘atherosclerosis’ infection (tuberculosis, HIV, Syphilis and Salmonella), arteritis, fibromuscular dysplasia, Marfan’s syndrome and medial degeneration. The commonest causes of false ECAAs include; iatrogenic post carotid endarterectomy, post-trauma and post-dissection (Figure 3). Bilateral ECAAs have been noted in up to 13% of patients 3, while multiple synchronous aneurysms (especially intracranial) have been reported in 15-20% of patients with ECAA. In a small case series, histological examination of ECAAs revealed two distinct categories: dissection (abrupt interruption of the media) and degeneration (general loss of elastin fibers in the media). Degenerative aneurysms showed increased inflammation within the vessel wall compared to ECAAs secondary to dissection.6

Clinical Features ECAA are more common in men than women with a male to female ratio of 2:1. The magnitude of male preponderance is lower than that observed with abdominal aortic aneurysms (10:1), while the mean age of reported cases is around 50 (range 35-68 years.7 The natural history of ECAA is poorly understood. Some have suggested that small asymptomatic ECAAs can be treated conservatively1, however as they enlarge, they rarely remain benign and, if left untreated, will almost inevitably lead to onset of symptoms (stroke prevalence 50%) and mortality (60-70%).8,9 Presentation depends on aetiology, location, and size. The main presentations include; pulsatile mass, TIA/stroke (due to embolism or aneurysm thrombosis), carotid bruit or thrill, cranial nerve palsy (through direct compression), stridor and voice changes (recurrent laryngeal nerve compression, direct laryngeal compression), rupture (rare), Horner’s syndrome (sympathetic nervous system compression) and swallowing problems. 17

chapter 2

Embolization of aneurysm thrombus is more common in patients with true aneurysms as opposed to those with false aneurysms.10

Diagnostic evaluation The purpose of imaging is to; 1) confirm the diagnosis; 2) classify the nature of the ECAA (true/false) and its likely aetiology; and 3) to assess its extent and anatomy in order to plan management.8 Most aneurysms are diagnosed using duplex ultrasound. However, corroborative CTA is essential as it can provide valuable information on extent and whether an intervention might be appropriate. Figure 2 shows a 3D reconstruction CTA of an extensive ECAA in the ICA Limitations of CTA include a relative lack of sensitivity for lesions involving the carotid artery at the skull base or within the contrast-filled cavernous sinuses. In these cases MRA might be preferable.

Figure 2. 3-D CTA of a saccular aneurysm of the ICA. This aneurysm was discovered on CT of the brain performed because of an unexplained collapse.

Aneurysms of the extracranial carotid artery

Figure 3. A, overview of aneurysm due to dissection. Elastin-van Giesson (EvG) stain. Bar = 1.5 mm. B, higher magnification of the same staining as A. Arrow indicates the disrupted internal elastic lamina. Bar = 500μm.

Several ECAA classifications have been based on the anatomic location of the aneurysm. In Bouthillier’s classification, the cervical part is referred to as C1, the petrous part as C2, and the intracranial part as C3-C7.11 The classifications by Attigah and Malikov12,13 use the line of Blaisdell, which is a ‘virtual’ line drawn between the mastoid process and the angle of the mandible. Above this line, the carotid is considered less accessible by a standard surgical approach, and alternative exposure techniques and/or endovascular assistance may be needed.

Indications for surgery In asymptomatic patients with small ECAA, conservative management may have a role. As a rule, patients with a symptomatic ECAA are considered candidates for invasive treatment.14,15 Treatment aims to relieve symptoms and/or to prevent complications such as cranial nerve palsy or pharyngeal compression. The main goal, however, in ECAA management is to prevent thrombo-embolic complications. Naturally, in the case of rupture, there is an acute indication for intervention. Although the aetiology and clinical presentations have remained more or less the same, management strategies for ECAA treatment have changed considerably over the last 50 years. Unfortunately, most of the available evidence is derived from small cases series and an ‘evidence based’ algorithm for ECAA interventions is lacking.

Management In 1805, Sir Astley Cooper performed the first ECAA ligation in a symptomatic patient who died of a post-operative stroke. Contemporary management is based upon mode of presentation, surgeon/interventionist experience, aneurysm location/accessibility and 19

chapter 2

aetiology. Two main management strategies are currently available. The first is conservative management (antiplatelet therapy, statin therapy, antihypertensive therapy). This is appropriate in selected patients (e.g. small asymptomatic aneurysms, truly inoperable cases and patients with severe life-limiting comorbidities). The second is to intervene with either an open surgical approach, a purely endovascular approach or thirdly; a hybrid open/endovascular strategy. At present, open surgical exploration with aneurysm resection with/ without direct repair or an interposition graft remains the gold standard.1,4,8 Endovascular ECAA repair is an attractive and less invasive alternative to open repair, but only small case series have been published.16 However, in selected cases, insertion of a covered stent can be a life-saving intervention (Figure 4).

Figure 4. Endovascular stent placement in extracranial carotid artery aneurysm.

Aneurysms of the extracranial carotid artery

References 1.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone years' experience. Am J Surg. 1979;137(2):196-200.

Chedgy ECP, Ward RD, Lagattolla NF. Synchronous saccular and fusiform extracranial internal carotid artery aneurysms with ipsilateral cerebral embolism. Ann Vasc Surg. 2010;24(7):950.e1; 950.e2.

Welleweerd JC, Borst de GJ, Groot de D, Herwaarden van JA, Lo TH, Moll FL. Bare metal stents for treatment of extracranial internal carotid artery aneurysms; medium and long-term results. <br /> . J Endovasc Ther. 2014;accepted for publication.

Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98.

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712. doi: 10.1067/mva.2000.104101.

Welleweerd JC, Nelissen BGL, Koole D, et al. Histological analysis of extracranial carotid artery aneurysms.

Welleweerd JC, den Ruijter HM, Nelissen BGL, et al. Treatment for extracranial carotid artery aneurysm. A systematic review and meta-analysis. unpublished. 2014.

8. Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x. 9.

Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183. doi: 10.1053/j. semvascsurg.2005.09.002.

10. Radak D, Davidovic L, Vukobratov V, et al. Carotid artery aneurysms: Serbian multicentric study. Ann Vasc Surg. 2007;21(1):23-29. 11. Bouthillier A, van Loveren HR, Keller JT. Segments of the internal carotid artery: A new classification. Neurosurgery. 1996;38(3):425-32; discussion 432-3. 12. Attigah N, Kulkens S, Zausig N, et al. Surgical therapy of extracranial carotid artery aneurysms: Long-term results over a 24-year period. Eur J Vasc Endovasc Surg. 2009;37(2):127-133. doi: 10.1016/j.ejvs.2008.10.020. 13. Malikov S, Thomassin JM, Magnan PE, Keshelava G, Bartoli M, Branchereau A. Open surgical reconstruction of the internal carotid artery aneurysm at the base of the skull. J Vasc Surg. 2010;51(2):323-329. doi: 10.1016/j. jvs.2009.08.084. 14. Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc Surg. 1984;1(3):415-422. 15. Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther. 2012;10(7):925-931. 16. Li Z, Chang G, Yao C, et al. Endovascular stenting of extracranial carotid artery aneurysm: A systematic review. Eur J Vasc Endovasc Surg. 2011;42(4):419-426.

chapter

Janna C. Welleweerd MD*1, Bastiaan G.L. Nelissen MD*1,2, Dave Koole MD PhD1,2, Jean-Paul P.M. de Vries MD PhD3, Frans L. Moll MD PhD1, Gerard Pasterkamp MD PhD2, Aryan Vink MD PhD4, Gert Jan de Borst MD PhD1 * Both authors contributed equally to this work Vascular Surgery, University Medical Center Utrecht, the Netherlands Experimental Cardiology laboratory, University Medical Center Utrecht, the Netherlands 3 Vascular Surgery, St Antonius Hospital, the Netherlands 4 Pathology, University Medical Center Utrecht, the Netherlands 1

Histological analysis of extracranial carotid artery aneurysms PLoS One. 2015 Jan 30;10(1):e0117915

chapter 3

Abstract Introduction Extracranial carotid artery aneurysms (ECAA) are rare but may be accompanied with significant morbidity. Previous studies mostly focused on diagnostic imaging and treatment. In contrast, the pathophysiological mechanisms and natural course of ECAA are largely unknown. Understanding the pathophysiological background may add to prediction of risk for adverse outcome and need for surgical exclusion. The aim of this study was to investigate the histopathological characteristics of ECAA in patients who underwent complete surgical ECAA resection. Material and Methods From March 2004 till June 2013, 13 patients were treated with open ECAA repair. During surgery the aneurysm sac was resected and processed for standardized histological analysis. Sections were stained with routine hematoxylin and eosin and special stains to detect elastin, collagen, different types of inflammatory cells, vascular smooth muscle cells and endothelial cells. Results Histopathological characterization revealed two distinct categories: dissection (abrupt interruption of the media; n=3) and degeneration (general loss of elastin fibers in the media; n=10). In the degenerative samples the elastin fibers in the media were fragmented and were partly absent. Inflammatory cells were observed in the vessel wall of the aneurysms. Conclusion Histological analysis in this small sample size revealed dissection and degeneration as the two distinct underlying mechanisms in ECAA formation.

Histological analysis of ECAA

Introduction Extracranial carotid artery aneurysms (ECAA) are rare with an incidence varying from 0.09 to 2.0% of all carotid surgical procedures.1,2 Aneurysms of the extracranial carotid artery are defined as a dilatation of 50% or more of the diameter of the expected healthy carotid artery.3 Studies on ECAA mostly comprise case reports or small case series focusing on diagnostic imaging and treatment outcome.2,4-6 Although the natural course of ECAA is largely unknown, the clinical presentation of ECAA may be accompanied with significant morbidity. Previous studies reported a stroke prevalence of 50% and a mortality of 60-70% when ECAA is left untreated.7 Some authors suggest that small asymptomatic ECAA could be treated conservatively with strict follow-up, but surgery is generally the accepted treatment for symptomatic ECAA.7-10 The etiology of ECAA is heterogeneous and includes atherosclerosis, postdissection, trauma and infection.2,11 The exact pathophysiological mechanisms however remain unclear, and prognostic factors for clinical outcome are largely unknown. 12 Detailed understanding of the mechanisms of ECAA and general aneurysm formation could be the start of improving diagnostics and treatment. Accordingly, the present study was conducted to investigate the histopathological characteristics of ECAA in patients who underwent complete surgical ECAA resection.

Methods Subjects From March 2004 till June 2013, 38 patients were treated for ECAA in the two participating hospitals (University Medical Center Utrecht, Utrecht, and St Antonius hospital Nieuwegein, the Netherlands). In this study, all patients (n=15) that underwent open ECAA repair with complete aneurysm sac resection (Figure 1) were included. Histological analysis was not possible in two patients due to incomplete preserved samples. Therefore, these two cases were excluded, leaving 13 cases for analysis. Operation indication was decided on after multidisciplinary deliberation and based on presenting symptoms, location, and ECAA size. The medical ethics committees of both participating hospitals (Verenigde Commissies Mensgebonden Onderzoek, St Antonius hospital Nieuwegein and Medisch Ethische Toetsings commissie University Medical Center Utrecht) approved the study and all study participants provided written informed consent. Imaging Morphological characteristics of the aneurysms were assessed by preoperative imaging diagnostics. Computed tomography angiogram (CTA) was used in ten patients, magnetic resonance angiography (MRA) was used in two, and conventional angiography in one patient.

chapter 3

Figure 1. In vivo aneurysm. Aneurysm of a left saccular carotid artery visible between the internal carotid artery (ICA) and the external carotid artery (ECA) and originating from a dorsal loop in the ICA. The common carotid artery is ligatured in red, the ECA is identified with transparent ligatures. A, aneurysm of the ICA; BIF, carotid bifurcation; H, nervus hypoglossus; S, suture; VL, vessel loop.

Sampling During open surgical repair, the complete ECAA sac was collected and subsequently processed for histological analysis. The specimen was fixed in 4% formaldehyde, decalcified for 1 week in ethylenediaminetetraacetic acid and embedded in paraffin. Of the paraffin segments, 4-Âľm-thick sections were cut for histological analyses. Sections were stained for elastin (elastin von Gieson), collagen (Sirius red), macrophages (CD68), T-lymphocytes (CD3), B-lymphocytes (CD 20), plasma cells (CD 138), endothelial cells (CD34) and vascular smooth muscle cells (SMC) (alpha-smooth muscle actin). In addition a routine hematoxylin and eosin staining was performed. Result interpretation Elastin was graded as an estimation of the percentage of media containing elastin fibers. Collagen was graded as an estimation of the percentage present in the vessel wall. The presence of inflammatory cells in aneurysm wall was semi-quantitatively scored as minor or heavy staining. Dissection was defined as an abrupt interruption of the media with signs of organized thrombus in the tear of the vessel wall. Degeneration was defined as decrease of elastin in the media. Histological examination was retrospectively performed collectively by three independent observers (BN, DK and AV) unaware of clinical data. In case of discrepancies in judgment, sections were reanalyzed until consensus was reached. Controls Post-mortem non-aneurysmal carotid specimens from five patients with a median age of 63 (range 51-90) without relevant medical history were used as controls. Two bodies were donated for education and research to University Medical Center Utrecht. Written and witnessed consent for body donation was given prior to death by both controls. 26

Histological analysis of ECAA

Figure 2. Histology of control sample: fibrous cap atheroma. Histology of control sample. Sample taken just distal from the bifurcation. Elastin-van Giesson (EvG) stain. In black the elastic fibers are clearly present and well organized. Atherosclerotic changes, atheroma with a lipid core. E, Elastin; Lip, Lipid core; Lum ext., lumen of the external carotid artery; Lum int., lumen of the internal carotid artery.

Three more specimens were collected in patients for whom the carotid artery was investigated for diagnostic reasons in an autopsy procedure. The use of these specimens is described in the code of proper use of human tissue that is used in the Netherlands.13 Statistical analysis Discrete variables are shown as frequencies and percentages of the total. Continuous variables are shown as median and interquartile range. Categorical variables were investigated using the chi-square test or the Fisherâ&#x20AC;&#x2122;s exact test. Continuous variables were compared using the Studentâ&#x20AC;&#x2122;s t-test. P value < .05 was considered statistically significant.

Results Clinical patientâ&#x20AC;&#x2122;s characteristics Thirteen patients with a median age of 55 years (IQR: 35-75, six males) were included. Baseline characteristics are presented in Table 1. All treated patients were symptomatic and the most common symptom was cerebral ischemia (N=6) (see Table 2). All but one of these patients had ischemia due to (temporary) occlusion of the ipsilateral medial cerebral artery. One patient presented with ischemia of the contralateral medial cerebral artery and a controlateral Horner syndrome. Imaging findings ECAAs were mostly located in the Internal carotid artery (ICA) (n=12) and one ECAA was located in the common carotid artery (CCA). Eight aneurysms were located on the left side. Seven aneurysms were fusiform and six were saccular. The aneurysms varied in 27

chapter 3

size; the median length was 30mm (range: 10-100) and the mean outer diameter 13mm (range: 4-46). There were no radiological signs of dissection pre-operative in any of the aneurysms. Thrombus was present in two aneurysms and six aneurysms had calcifications in the vascular wall. Presence of thrombus or calcifications was not significantly different in degenerative aneurysms or aneurysms after dissection (p= .164 and p= .577).

Table 1. Patient characteristics Total (n=13) Gender male

6 (46%)

Age, years

55 (35-75)

PAD

1 (8%)

Hypertension

7 (54%)

1 (8%)

COPD

1 (8%)

Hypercholesterolemia

2 (15%)

Connective tissue disorder

0 (0%)

Smoking

4 (33%)

0 (0%)

Statin use

6 (46%)

Controls Data are presented as No. (%) unless otherwise indicated. a Median and interquartile range Our five control ICA samples showed no (IQR). Abbreviations. PAD, peripheral artery media degeneration or dissection. In all disease; MI, myocardial infarction; COPD, chronic obstructive pulmonary disease; DM, samples the elastin, smooth muscle cells, and diabetes mellitus. collagen fibers were present and well organized (see Table 3). Inflammatory cells were absent in all but one control specimens. Two samples did show atherosclerotic lesions (sample 3 and 5) that could be classified as a fibrous cap atheroma and pathological intimal thickening (Modified American Heart Association Classification) (Figure 2).14 The atheroma was surrounded by CD68 positive macrophages.

Table 2. Aneurysm characteristics Gender/age

Location

Size(mm)

Morphology

Symptoms

Pathology

M/76

LICA

Fusiform

Stroke

Degenerative

F/65

RICA

Fusiform

Pain, mass

Degenerative

F/41

LICA

Saccular

TIA/Stroke

Dissection

M/53

RICA

Saccular

Pulsatile mass

Degenerative

M/46

RCCA

Fusiform

Pain, mass

Degenerative

M/55

LICA

Fusiform

TIA

Dissection

M/50

LICA

Fusiform

TIA

Degenerative

M/26

LICA

Fusiform

Pain, mass

Degenerative

M/47

RICA

Saccular

TIA

Dissection

F/66

RICA

Saccular

Pain

Degenerative

F/75

LICA

Fusiform

CL TIA, Horner

Degenerative

F/62

LICA

Saccular

Hoarseness

Degenerative

F/67

LICA

Saccular

Mass

Degenerative

M male; F female; LICA left internal carotid artery; RICA right internal carotid artery; RCCA right common carotid artery; NR not reported; TIA transient ischemic attack; CL contralateral.

Histological analysis of ECAA

Samples Histological examination was retrospectively performed, four sections were reanalyzed because of discrepancies in judgment between the independent observers, in all sections consensus was reached. Histological examination revealed two distinct categories of ECAA (Table 3). The majority (n=10; 77%) of the samples showed a distinct degenerative pattern of the vessel wall without signs of a dissection (Figure 3). In the degenerative samples the elastin fibers of the media were fragmented and were partly absent (Figure 3E - 3F). Inflammatory cells were present in each sample. In most degenerative samples inflammatory cells were clearly present, both lymphocytes and macrophages were seen; only three samples scored ‘minor’ for all observed types of inflammatory cells. The remaining three samples (23%) showed a dissection with an abrupt interruption of the medial layer (Figure 3A - 3D). The gap in the arterial wall was filled with an organized thrombus with groups of myofibroblasts. All dissective samples showed marks of degeneration in the media and scored ‘minor’ for the different inflammatory cells in the vessel wall. There were no significant differences in any type of inflammatory cell between samples with dissection or samples with degeneration (Table 3). We did find significant differences in SMC and collagen. SMC was higher in the dissection group and collagen was higher in the degenerative samples.

Table 3. Histology characteristics Control (n=5)

Dissection (n=3)

Degeneration (n=10)

P value

Elastin a

95% (30-100%)

25% (2-50%)

30% (0-95%)

.063

Smooth muscle a

88% (15-100%)

95% (60-100%)

65% (5-95%)

.004

Vasa vasorum

minor heavy

4 (80%) 1 (20%)

1 (33%) 2 (67%)

3 (30%) 7 (70%)

1.000

Collagen

minor heavy

3 (60%) 2 (40%)

2 (100%) 0 (0%)

1 (10%) 9 (90%)

.014

Lymphocytes

minor heavy

5 (100%) 0 (0%)

3 (100%) 0 (0%)

6 (60%) 4 (40%)

.497

Plasma cells

minor heavy

5 (100%) 0 (0%)

3 (100%) 0 (0%)

10 (100%) 0 (0%)

B-Lymphocyte

minor heavy

5 (100%) 0 (0%)

3 (100%) 0 (0%)

9 (90%) 1 (10%)

1.000

T-lymphocytes

minor heavy

5 (100%) 0 (0%)

3 (100%) 0 (0%)

6 (60%) 4 (40%)

.497

Macrophages

minor heavy

4 (80%) 1 (20%)

3 (100%) 0 (0%)

4 (40%) 6 (60%)

.192

Continuous data are presented as median (range). Categoric data are presented as number (%) of heavy staining as opposed to minor staining unless otherwise indicated. a Percentage of fibers present in a non-diseased vessel wall.

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Figure 3. Histology of carotid aneurysms. Histology of carotid aneurysms. A-D, dissection; E and F, degeneration. A, overview of aneurysm due to dissection. Elastin-van Giesson (EvG) stain. Bar = 1.5 mm. B, higher magnification of the same staining as A. Arrow indicates the disrupted internal elastic lamina. Bar = 500 μm. C, Hematoxylin and eosin staining of the same panel as B. m, media; t, organized thrombus that replaces the absent media. Bar = 500 μm. D, CD34 immunostain showing endothelial coverage of the thrombus (in brown). Bar = 250 μm. E, overview of an aneurysm due to degeneration. Elastin-van Giesson (EvG) stain. Bar = 4 mm. F, higher magnification of the same staining as E. In black remnants of the elastic fibers of the media. Bar = 1 mm.

Histological analysis of ECAA

Discussion In the current study, histological examination of ECAA showed two distinctive categories: aneurysms after dissection versus degenerative aneurysms. Retrospectively, there were no radiological signs of dissection pre-operative in any of the aneurysms. Clinically and radiological diagnosed aneurysmal formation after previous dissection has been described in literature.15 In the aorta and its branches, degeneration is a wellrecognized cause for aneurysm formation.16,17 Non-dissective causes of peripheral aneurysms, such as carotid or popliteal aneurysms, are believed to exist but had not been histologically confirmed yet.18 We found degenerative aneurysms in 10/13 (73%) patients. The fact that we observed inflammatory cells in the aneurysms suggest that inflammation might also play a role. It must be pointed out that the possibility exists that these two distinctive categories could be different stages of the same disease. Although decrease of SMC was higher in the degenerative samples, degeneration of the medial layer was also observed in all dissection cases and could eventually weaken the vascular wall and facilitate dissection of the intimal and medial layer. Increase of collagen in aneurysms has been demonstrated in analysis of other aneurysmal vessels.19 Theoretically, while collagen is load-bearing at large dimensions and elastin being load-bearing at small dimensions the collagen-elastin ratio changes in aneurysms.20 The result of this study could be the start of understanding the mechanism or mechanisms of ECAA development. This could eventually lead to improved treatment strategies. For example, in most cases of dissecting aneurysms invasive treatment is not indicated, as a major part of these aneurysms remains asymptomatic and does not increase in size while some even spontaneously resolve.21 On the contrary, atherosclerotic origin of ECAA may need more aggressive intervention, although there is a clear need for further natural follow-up in patients with ECAA in general.12 There are some study limitations. Most important, it must be noticed that this study was performed on a small group of patients, consequently our findings have little power and definitive conclusions are difficult to draw. This might also explain why we did not find any aneurysms with another etiology, for example mycotic aneurysms, in our analysis. However, ECAA is a rare disease and only around 1000 cases have been reported in the international literature so far.12 Furthermore, only a selected subgroup of patients presenting with ECAA will undergo surgical resection of the aneurysm. As a consequence, also in our tertiary referral center, the number of patients operated on is limited and therefore it is hard to study larger patient groups. Second, in this study patients were selected based on intervention. The result of this study and the conclusions drawn from them only apply to patients that underwent surgical repair for their ECAA. In conclusion, this is the first histological study of samples taken from ECAA. Histopathological ECAA characterization in this study revealed two distinct categories: dissection and degeneration. The result of this study could be used as a basis for understanding the mechanism of ECAA development. Further study in resected ECAA is needed to explore the clinical relevance of this mechanism. 31

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References 1.

Radak D, Davidovic L, Vukobratov V, et al. Carotid artery aneurysms: Serbian multicentric study. Ann Vasc Surg. 2007;21(1):23-29.

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712.

De Jong KP, Zondervan PE, Van Urk H. Extracranial carotid artery aneurysms. Eur J Vasc Surg. 1989;3(6):557562.

4. Hanabusa K, Nonoyama Y, Taki W. Giant internal carotid artery aneurysm manifesting as difficulty in swallowing. Neurol Med -Chir. 2010;50(10):917-920. 5.

Chedgy ECP, Ward RD, Lagattolla NF. Synchronous saccular and fusiform extracranial internal carotid artery aneurysms with ipsilateral cerebral embolism. Ann Vasc Surg. 2010;24(7):950.e1; 950.e2.

Troisi N, Dorigo W, Pulli R, Pratesi C. A case of traumatic internal carotid artery aneurysm secondary to carotid shunting. J Vasc Surg. 2010;51(1):225-227.

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc Surg. 1984;1(3):415-422.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone years' experience. Am J Surg. 1979;137(2):196-200.

Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183.

10. Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther. 2012;10(7):925-931. 11. Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98. 12. Welleweerd JC, den Ruijter HM, Nelissen BGL, et al. Treatment for extracranial carotid artery aneurysm. A systematic review and meta-analysis. submitted 2015. 13. Burdorf A, Hollema H, van Leeuwen E, et al. Human tissue and medical research: Code of conduct for responsible use (2011). Rotterdam: Stichting FMWV; 2011. 14. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: A comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20(5):1262-1275. 15. James AL, O'Malley S, Milford CA. Extracranial internal carotid artery aneurysm in a child: A diagnostic and surgical challenge. J Laryngol Otol. 1999;113(4):373-375. 16. Nordon IM, Hinchliffe RJ, Loftus IM, Thompson MM. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol. 2010;8:92-102. 17. Sakalihasan N, Limet R, Defawe OD. Abdominal aortic aneurysm. Lancet. 2005;365(9470):1577-1589. 18. Dawson I, Sie RB, van Bockel JH. Atherosclerotic popliteal aneurysm. Br J Surg. 1997;84(3):293-299. 19. Sakalihasan N, Heyeres A, Nusgens BV, Limet R, Lapiere CM. Modifications of the extracellular matrix of aneurysmal abdominal aortas as a function of their size. Eur J Vasc Surg. 1993;7(6):633-637. 20. Dobrin PB. Elastin, collagen, and the pathophysiology of arterial aneurysms. In: Keen RR, Dobrin PB, eds. Development of aneurysms. Georgetown, Texas.: Landis Bioscience; 2000:42-73. 21. Guillon B, Brunereau L, Biousse V, Djouhri H, Levy C, Bousser M-. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology. 1999;53(1):117-122.

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J.C. Welleweerd MD1, C.E.V.B. Hazenberg MD PhD1, J. Hendrikse MD PhD2, F.L. Moll MD PhD1, G.J. de Borst MD PhD1 1 2

Department of Vascular surgery, UMCU, Utrecht, the Netherlands Department of Radiology, UMCU, Utrecht, the Netherlands

Intra- and inter-observer variability of extracranial carotid artery aneurysm volume measurement Submitted

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Abstract Introduction In general, aneurysm size can be assessed through measurement of the maximum aneurysm diameter or volume. In this study we explore the feasibility and reliability of volume measurement in extracranial aneurysms of the internal carotid artery (ECAA). Method Six patients (six men, mean age 49 years) undergoing evaluation for ECAA in our tertiary referral center from August 2012 to June 2014 were included. Aneurysms were saccular in half of the patients, the other half were aneurysms with signs of dissection. The mean diameter reported in the patients’ records was 8.6 mm (SD 4.3 mm). Diameter and volume measurements were performed on Computed Tomographic Angiographic datasets using 3mensio Vascular™ medical imaging software (64 or 256-slice CT scanner, slice thickness 0.57mm). All measurements were performed by two independent investigators (one inexperienced and one experienced with 3mensio software). The intra- and inter-observer variability for all diameter and volume measurements were analyzed using Bland and Altman’s difference against the mean and the repeatability coefficient (RC) was calculated. Results The intra-observer RC of the diameter measurement was 0.83 mm (7.2 %) and the interobserver RC was 1.85 mm (16.0%). The intra-observer RC of the first volume measurement method was 0.16 mL (18.9%); the inter-observer RC was 0.59 mL (68.2%). The intraobserver RC in the second method was 0.29 mL (16.0%), while the inter-observer RC was 0.60 mL (33.3%). Conclusion Volume measurements in ECAA with a semi-automatic method are feasible but at the cost of high repeatability coefficients. In this small explorative study, diameter measurements had a superior inter- and intra-observer reliability compared to volume measurements.

Volume measurements in ECAA

Introduction Extracranial carotid artery aneurysms (ECAAs) are rare, but exact data on the incidence are lacking.1 ECAAs are mostly located at het carotid bifurcation or the proximal part of the internal carotid artery (ICA).2 Based on anatomical location ECAA can be classified as type I-V (Table 1).3,4 ECAA can be categorized, depending on shape, as saccular or fusiform. Although most ECAA are identified by Duplex Ultrasound, Computed tomography angiography (CTA) is the most commonly used modality for detailed diagnostics and follow-up in ECAA.5 (Figure 1) At all stages, the purpose of (additional) imaging in ECAA is to 1) confirm diagnosis; 2) to assess the anatomy for classification and planning of surgical or endovascular treatment; and 3) follow-up of aneurysm growth over time in patients treated conservatively. Aneurysm size or growth can be assessed through measurement of the maximum aneurysm diameter or the aneurysm volume. In abdominal aortic aneurysm (AAA), addition of volumetric measurements to diameter measurement is more sensitive than maximum aneurysm diameter alone when assessing aneurysm growth.6 In ECAA literature no studies exist on optimal imaging approach or on the differential influence of imaging technique applied. In this study we explore the feasibility and reliability of diameter measurements and volume measurement based on CTA images in patients with ECAA.

Figure 1. 3D CTA reconstruction. 3D CTA reconstruction of a dissecting aneurysm in the distal left internal carotid artery.

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Table 1. Classification by Attigah Type I

Isolated and short aneurysms of the ICA above the carotid bulb

Type II

Long aneurysms of the ICA, ranging from the carotid bulb up to the line of Blaisdell

Type III

Aneurysms of the proximal ICA and the carotid bifurcation

Type IV

Aneurysms involving the CCA and ICA as type III, but extending far more distally and proximally

Type V

Isolated aneurysms of the CCA

Methods Patients In this study, volume and diameter measurements were performed on six consecutive ECAA CTA datasets. These datasets belonged to six patients undergoing evaluation or treatment for ECAA in our center from August 2012 to June 2014 (6 men; mean age 49 years (SD 15.9), Table 2). Aneurysms were saccular in half of the patients, the other half were aneurysms with signs of dissection. The mean diameter reported in the patientsÂ´ records was 8.6 mm (SD 4.3 mm). In- and exclusion criteria All CTA datasets of patients with an aneurysm in the ICA were included in this study. Fusiform aneurysms were defined as 150% dilatation of the normal vessel diameter. Saccular aneurysms were defined as a distended sac of any size affecting only part of the arterial circumference. Only CTA datasets conducted in our center and retrieved from a 64- of 356- slice CT scanner were included. Only CTA scans performed after August 2012 were included to guarantee good slice thickness for reconstruction. Imaging Datasets were retrieved after scanning patients in a 64 or 256-slice CT scanner (Philips Brilliance; Philips Medical Systems, Best, The Netherlands). The entire carotid artery, from the aortic arch to the intracranial vessels was scanned. Slice thickness was 0.57mm, increment 0.33, collimation 128x0.625 and pitch 0.3. Field of view was adjusted to patient

Table 2. Patient and aneurysm characteristics Patient

sex

age

Affected side

Aneurysm shape

Reported diameter

Male

Left

Saccular

16 mm

Male

Left

Saccular

4 mm

Male

Left

Dissection

10 mm

Male

Right

Dissection

9 mm

Male

Left

Saccular

5 mm

Male

Left

Dissection

8 mm

Volume measurements in ECAA

size. Radiation exposure parameters were 120 kVp and 150 mA. Intravascular contrast (65 ml Iopromide, Schering, Berlin, Germany) was followed by a saline bolus (40 ml), injected at a flow rate of 6 mL/s. Method of volume measurement The volume of ECAA was measured using two methods, based on methods of aneurysm volume measurement described in literature. (Figure 2) In method 1 the volume of the aneurysm is measured between the points where parallelism of the vessel walls is lost and regained.7,8 In method 2 the volume is measured between two points with a pre-set distance, 20 mm, to the maximum cross section of the aneurysm.9 Measurements The CTA datasets were imported in a workstation and 3mensio VascularTM medical imaging software (3Mensio Medical Imaging B.V., Bilthoven, The Netherlands) was used to perform all measurements. Due to technical limitations of the 3Mensio approach patients with extensive coiling in the carotid artery could not be measured, while no central luminal line (CLL) could be reconstructed in these arteries. The orthogonal Maximum Diameter (OMD) (perpendicular to the carotid center lumen line) was measured by a previously described process.10,11 First, a CLL was semiautomatically constructed, if necessary small corrections were made manually. All diameter measurements were then performed manually. Diameters were measured between the outer walls of the aneurysm. Volume measurements in fusiform and saccular aneurysms were performed using both proposed methods of aneurysm volume. A stretch view of the carotid artery was generated (Figure 3). Outer walls of the aneurysm sac were drawn for four different angles, all perpendicular to the CLL. Aneurysm borders were corrected if necessary and connected by spline interpolation. Finally, the total volume was computed automatically.

Figure 2. Methods of volume measurement. In method 1 the volume of the aneurysm is measured between the points where parallelism of the vessel walls is lost and regained. In method 2 the volume of the aneurysms is measured between two points with a pre-set distance, 20 mm, to the maximum cross section of the aneurysm.

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Figure 3. 3Mensio volume measurement. After semi-automatically constructing a central luminal line a stretch view of the carotid artery was generated. In this example, volume measurement was performed using method 2. The total volume was computed automatically.

Statistical analysis Two investigators (JW (PhD student, with no previous experience in 3mensio CTA measurements) and CH (vascular surgeon and experienced 3mensio user) performed all measurements independently. One Investigator (JW) performed two sets of measurements with an interval of two weeks. To determine inter-observer variability the first measurements of both investigators were compared. The intra- and inter-observer variability for both proposed definitions was calculated using Bland and Altmanâ&#x20AC;&#x2122;s difference against the mean analysis, in which the difference in measurement is plotted against the mean. The standard deviation (SD) of the mean difference was calculated and thereafter, the repeatability coefficients (RC) were calculated. A repeatability coefficient indicates the possible difference in measurements on a subject on 95% of occasions.12

Results Diameter measurement Mean diameter of ECAA was 11.5 mm (range 7.8 to 16.0 mm) for the first measurement of observer 1, 11.6 mm (range 8.3 to 16.7 mm) for the second measurement of observer 1, and 11.0 mm (range 7.4 to 16.8 mm) for observer 2. The intra-observer mean difference in the diameter measurement was 0.22 mm (1.9%), 40

Volume measurements in ECAA

with a RC of 0.83 mm (7.2 %); the inter-observer mean difference was 0.47 mm (4.1%), with a RC of 1.85 mm (16.0%). (Table 3) Volume measurement Method 1 Mean ECAA volume measured with the first method was 0.87 mL (range 0.0 to 2.1 mL) for the first measurement of observer 1, 0.92 mL (range 0.0 to 2.1 mL) for the second measurement of observer 1, and 1.02 ml (range 0.2 to 2.8 mL) for observer 2. The intra-observer mean difference in the first volume measurement method was 0.05 mL (5.8%), with a RC of 0.16 mL (18.9%); the inter-observer mean difference was 0.15 mL (17.3%), with a RC of 0.59 mL (68.2%). (Table 3) . In Figure 4, differences were plotted against the means for the intra- and inter-observer variability. Method 2 With the second method, the mean aneurysm volume was 1.80 mL (range 1.1 to 3.0 mL) for the first measurement of observer 1, 1.82 mL (range 1.1 to 3.2 mL) for the second measurement of observer 1, and 1.75 mL (range 1.1 to 2.6 mL) for observer 2. The intra-observer mean difference in the second method was 0.02 mL (0.93%), with a RC of 0.29 mL (16.0%), while the inter-observer difference was 0.08 mL (4.6%), with a RC of 0.60 mL (33.3%). (Table 3). In Figure 5, differences were plotted against the means for the intra- and inter-observer variability. Between the methods The outcome of method one and two were significantly different, therefore no Bland Altmanâ&#x20AC;&#x2122;s plot could be made for the variability between the two methods.

Table 3. Repeatability Coefficients and Variability of Measurements Difference Variability

Mean

Diameter Intra-observer

0.22 mm (1.9%)

0.42 mm (3.7%)

0.83 mm (7.2%)

Inter-observer

0.47 mm (4.1%)

0.94 mm (8.2%)

1.85 mm (16.0%)

Volume Method 1 Intra-observer

0.05 ml (5.8%)

0.08 ml (9.7%)

0.16 ml (18.9%)

Inter-observer

0.15 ml (17.3%)

0.31 ml (34.8%)

0.59 ml (68.2%)

Volume Method 2 Intra-observer

0.02 ml (0.93%)

0.15 ml (8.2%)

0.29 ml (16.0%)

Inter-observer

0.08 ml (4.6%)

0.31 ml (17.0%)

0.60 ml (33.3%)

Observer 1

0.90 ml (103.8%)

0.30 ml (35.0%)

0.59 ml (68.6%)

Observer 2

0.73 ml (84.6%)

0.50 ml (58.2%)

0.99 ml (114.1%)

Between the methods

Data in parentheses reflect the percentage of the first measurement.

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intraobserver variability method 1

Interobserver variability method 1

,30

,50

,10

difference (ml)

,20

,00

-,10

,00

-,50 -,20

-,30

-1,00 ,00

,50

1,00

1,50

2,00

2,50

,00

mean (ml)

,50

1,00

1,50

2,00

2,50

mean (ml)

Figure 4. Bland and Altman plot method 1

Intraobserver variability method 2

interobserver variability method 2

,70

,40

difference (ml)

,20

,00

,10

-,20

Page 1

-,20

Page 1

-,50 -,40 -,80 1,00

1,50

2,00

2,50

3,00

3,50

1,00

mean (ml)

1,50

2,00

2,50

3,00

mean (ml)

Figure 5. Bland and Altman plot method 2

Page 1

Volume measurements in ECAA

Discussion This explorative study demonstrated volume measurement in ECAA is feasible with a semi-automatic method, however the repeatability coefficients were high for both methods of volume measurement. Diameter measurements had a much better inter and intra-observer reliability compared to volume measurements in ECAA. Theoretically, volumetric measurements better assess aneurysm morphology than diameter measurements and are more sensitive for detection of aneurysm growth.11 Especially in aneurysms with a stable maximum diameter but progression of dilatation along the vessel course might be better be evaluated with volume measurement. Volume measurements in AAA have good intra- and inter-observer reliability, with an intraobserver RC was 4.1% and the inter-observer reliability RC was 5.7%.10,11 The high RCâ&#x20AC;&#x2122;s in this pilot study of ECAA volume measurements could be explained by different factors. First of all, a steep learning curve is expected in performing volume measurements. However, with the low number of available patients there was not enough repetition to get experienced. Secondly, the mean diameter and volume in the included aneurysms were relatively small. Determining the boundaries of the aneurysms is more difficult in these small aneurysms. Future research should investigate the repeatability coefficients of volume measurements in larger sized ECAA and in a larger study population. One of the other main difficulties in ECAA volume measurements is the definition of the volume. In fusiform aneurysms, dilatation affects the entire circumference of the vessel and they are most commonly defined as 150% dilatation of the normal vessel diameter. Saccular aneurysms are a distended sac of any size affecting only part of the arterial circumference. Aneurysm volume definition and measurement techniques are most commonly described in studies on intracranial (saccular) and abdominal aortic aneurysms (fusiform).7-9,13-16 However, also for these aneurysms literature is scarce and contains only case series and (animal) model studies. The most commonly used definition of AAA, described in the SVS standards, defines total aneurysm volume in AAA as the volume within the native aortic wall, measured from the level of the lowest renal artery to a distinctive landmark distal of this point.17 Using landmarks, is in our opinion not applicable to ECAA. When the carotid bifurcation (in ICA aneurysms) and the base of the skull would be chosen as landmarks, vessel tortuosity would serious influence the measurement and result in unreliable volume measurement. Method 2, wherein volume was measured between two points with a pre-set distance of 20mm to the maximum cross section of the aneurysm, had a superior inter-observer reliability. However, it must be considered this method also includes a significant part of the unaffected carotid artery in the volume measurement. When assessing growth based on percentage of volume increase, this might cause underestimation of the actual growth, especially in small aneurysms. Therefore, we recommend assessing aneurysm size in ECAA by diameter and an additional volume measurement of the aneurysm using method 1. In this method the aneurysm volume is measured between the point where the parallelism of the vascular wall is lost and regained. 43

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Furthermore, based on the repeatability coefficients we found in our study, a 20% cutoff for intra-observer analysis should be respected to determine aneurysm growth in both methods. This 20% cut off value to determine growth is much higher compared to other aneurysms, a cut off value of 5% is used and in AAA and intracranial aneurysm.11, 18 The low number of patients in this study could cause this higher percentage. Disagreement between investigators on one measurement has a large effect on the overall repeatability coefficient. In diameter measurement a cut off value of 5% can be used for intra-observer analysis, based on our analysis.

Conclusion Volume measurements in ECAA with a semi-automatic method are feasible but at the cost of high repeatability coefficients. In this small explorative study, diameter measurements had a superior inter- and intra-observer reliability compared to volume measurements. Theoretically, volumetric measurements better assess aneurysm morphology than diameter measurements and are more sensitive for detection of aneurysm growth and therefore they should be added to diameter measurements in assessing aneurysm growth. Future research should investigate the repeatability coefficients of volume measurements in ECAA in a larger study population.

Volume measurements in ECAA

References 1.

Welleweerd JC, den Ruijter HM, Nelissen BGL, et al. Treatment for extracranial carotid artery aneurysm. A systematic review and meta-analysis. Submitted.2015

Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98.

Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther. 2012;10(7):925-931.

Attigah N, Kulkens S, Zausig N, et al. Surgical therapy of extracranial carotid artery aneurysms: Long-term results over a 24-year period. Eur J Vasc Endovasc Surg. 2009;37(2):127-133.

Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial

van Keulen JW, van Prehn J, Prokop M, Moll FL, van Herwaarden JA. Potential value of aneurysm sac volume

carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x.

measurements in addition to diameter measurements after endovascular aneurysm repair. J Endovasc Ther. 2009;16(4):506-513. doi: 10.1583/09-2690.1 [doi]. 7.

Arsicot M, Lathelize H, Martinez R, Marchand E, Picquet J, Enon B. Follow-up of aortic stent grafts: Comparison of the volumetric analysis of the aneurysm sac by ultrasound and CT. Ann Vasc Surg. 2014;28(7):1618-1628. doi: 10.1016/j.avsg.2014.03.034 [doi].

Piazza M, Menegolo M, Ferrari A, et al. Long-term outcomes and sac volume shrinkage after endovascular popliteal artery aneurysm repair. European Journal of Vascular and Endovascular Surgery. 2014;48(2):161168. doi: http://dx.doi.org/10.1016/j.ejvs.2014.04.011.

Bredahl K, Long A, Taudorf M, et al. Volume estimation of the aortic sac after EVAR using 3-D ultrasound - a novel, accurate and promising technique. Eur J Vasc Endovasc Surg. 2013;45(5):450-5; discussin 456. doi: 10.1016/j.ejvs.2012.12.018 [doi].

10. van Prehn J, van der Wal MB, Vincken K, Bartels LW, Moll FL, van Herwaarden JA. Intra- and interobserver variability of aortic aneurysm volume measurement with fast CTA postprocessing software. J Endovasc Ther. 2008;15(5):504-510. doi: 10.1583/08-2478.1 [doi]. 11. van Keulen JW, van Prehn J, Prokop M, Moll FL, van Herwaarden JA. Potential value of aneurysm sac volume measurements in addition to diameter measurements after endovascular aneurysm repair. J Endovasc Ther. 2009;16(4):506-513. doi: 10.1583/09-2690.1 [doi]. 12. Bartlett JW, Frost C. Reliability, repeatability and reproducibility: Analysis of measurement errors in continuous variables. Ultrasound Obstet Gynecol. 2008;31(4):466-475. doi: 10.1002/uog.5256 [doi]. 13. Bescos JO, Slob MJ, Slump CH, Sluzewski M, van Rooij WJ. Volume measurement of intracranial aneurysms from 3D rotational angiography: Improvement of accuracy by gradient edge detection. AJNR Am J Neuroradiol. 2005;26(10):2569-2572. doi: 26/10/2569 [pii]. 14. Costalat V, Maldonado IL, Strauss O, Bonafe A. Toward accurate volumetry of brain aneurysms: Combination of an algorithm for automatic thresholding with a 3D eraser tool. J Neurosci Methods. 2011;198(2):294-300. doi: 10.1016/j.jneumeth.2011.04.008 [doi]. 15. Takao H, Ishibashi T, Saguchi T, et al. Validation and initial application of a semiautomatic aneurysm measurement software: A tool for assessing volumetric packing attenuation. AJNR Am J Neuroradiol. 2014;35(4):721-726. doi: 10.3174/ajnr.A3777 [doi].

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16. Yasumoto T, Osuga K, Yamamoto H, et al. Long-term outcomes of coil packing for visceral aneurysms: Correlation between packing density and incidence of coil compaction or recanalization. Journal of Vascular and Interventional Radiology. 2013;24(12):1798-1807. doi: http://dx.doi.org/10.1016/j.jvir.2013.04.030. 17. Chaikof EL, Blankensteijn JD, Harris PL, et al. Reporting standards for endovascular aortic aneurysm repair. Journal of Vascular Surgery. 2002;35(5):1048-1060. doi: http://dx.doi.org/10.1067/mva.2002.123763. 18. Villablanca JP, Duckwiler GR, Jahan R, et al. Natural history of asymptomatic unruptured cerebral aneurysms evaluated at CT angiography: Growth and rupture incidence and correlation with epidemiologic risk factors. Radiology. 2013;269(1):258-265. doi: 10.1148/radiol.13121188 [doi].

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JC Welleweerd MD1, HM den Ruijter PhD2,4, BGL Nelissen MD1, ML Bots MD PhD2, LJ Kappelle MD PhD3, GJE Rinkel MD3, FL Moll MD PhD1, GJ de Borst MD PhD1 1 Department of Vascular Surgery, University Medical Center Utrecht 2 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht 3 Department of Neurology and Neurosurgery, University Medical Center Utrecht 4 Department of Experimental Cardiology, University Medical Center Utrecht

Management of extracranial carotid artery aneurysms Submitted

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Abstract Introduction Aneurysms of the extracranial carotid artery (ECAA) are rare. Several treatments have been developed over the last 20 years, yet the preferred method to treat ECAA is still unknown. This paper is a review of all available literature on the risk of complications and long-term outcome after conservative or invasive treatment of patients with ECAA. Methods Reports on ECAA treatment until July 2014 were searched in PubMed and Embase using the key words: Aneurysm, carotid, extracranial and therapy. Results We identified 281 articles. Selected articles were case reports (n=179) or case series (n=102). Exclusion of papers on less than 10 patients, resulted in the final selection of 39 articles on a total of 1239 patients. Treatment consisted of either conservative treatment in 11% of the cases or invasive treatment in 89% of the cases. Invasive treatment comprised surgery in 94%, endovascular approach in 5%, and a hybrid approach in 1% of the patients. The most common complication described after invasive therapy was cranial nerve damage, which occurred in 11.8% of patients after surgery. The 30-day mortality rate and stroke rate in conservative treated patients was 5.1% and 7.7%, after surgery 2.4% and 4.7%, after endovascular treatment or a combined approach 0.0% and 0.0%. Long term follow up stroke rate was 8.1% in patient treated conservatively, 1.8% after surgery and 0.0% after endovascular or combined approach. Information on confounders in the present study was incomplete. Therefore, adjustments to correct for confounding by indication could not be done. Conclusions This review summarizes the largest available series in literature on ECAA management. The number of ECAA reported in current literature is scarce. The early and long-term outcome of invasive treatment in ECAA is favorable, however cranial nerve damage after surgery occurs frequently. Unfortunately, due to limitations in reporting of results and confounding by indication in the available literature, it was not possible to determine optimal treatment strategy. There is a need for a multicenter international registry to reveal the optimal treatment for ECAA.

Review of literature on ECAA management

Introduction Invasive treatment for extracranial carotid artery aneurysms (ECAA) pertains only 0.6-3.8% of all extracranial carotid interventions1-13, 0.6-2% of all carotid endarterectomies3,5,7,10, and 0.4-2% of all extracranial arterial aneurysm repairs.14-16 A substantial portion of the ECAA probably will clinically remain silent. However, ECAA may lead to neurologic symptoms including transient ischemic attacks (TIA) or ischemic stroke.17-19 Other symptoms include pulsating mass and related cranial nerve dysfunction (CND). Information regarding the natural history, indications and the best treatment in patients with ECAA is scarce and guidelines are lacking. Both medical,15 surgical and endovascular treatment of the aneurysm have been recommended.18,20,21 Best medical treatment comprises antithrombotic treatment and regular follow-up and may have a place in treatment of asymptomatic patients. Traditional surgical treatment, which is the current treatment of choice of symptomatic or growing ECAA, consists of open resection of the entire aneurysm with or without arterial replacement with an interposition graft.14,21-23 However, this approach has been associated with the risk of stroke and cranial nerve damage.24 Endovascular ECAA repair has only been described in small case series.24 For a proper assessment what treatment should be preferred, a better insight in natural history and risk of complications of the different treatments is needed. This paper is a review of all available literature on the risk of complications and long-term outcome after conservative or invasive treatment of patients with ECAA.

Methods Search strategy In July 2014 a search was performed for all literature since 1900 in Medline (with Pubmed as interface) and Embase combining the following search terms: Aneurysm, carotid, extracranial, therapy (and all synonyms for all treatment options). The search was performed according to the search strategy and data collection guidelines of The Metaanalysis Of Observational Studies in Epidemiology (MOOSE) Group.25 Definition of ECAA Because no generally accepted definition of ECAA exists, all aneurysms defined as such by the authors of the parent paper, regardless of the definitions used, located in the internal carotid artery (ICA) or in the common carotid artery (CCA) were included. Only aneurysms located between the CCA origin at the aortic arch and base of the skull were included. Selection of studies Retrieved records were independently screened by two authors (J.W., G.B.) on title, abstract, and full-text. All discrepancies (3%) were discussed until final agreement was reached. If necessary, a third opinion could be obtained, but agreement between authors 51

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was reached in all papers. Inclusion criteria were: 1) Adult patients with an ECAA 2) description of the type of intervention (conservative treatment; surgery; endovascular treatment or any combination); 3) report of data on outcome during follow-up (case fatality, fatal or non-fatal stroke, or local cervical symptoms); and 4) series describing 10 patients or more. Language of publications was restricted to Dutch and English. Studies regarding aneurysms located on the level of skull base or above, aneurysms located in the external carotid artery (ECA), non-human data, and unavailable full-text papers were excluded. Studies presenting data on a group level containing ECA were included because of the low number of ECA in these series and the relevance to present these large series.12,19,26-28 The reference list of all selected articles was hand searched to retrieve additional studies. Selected studies were critically appraised based on study design, study quality, consistency and directness using the GRADE system.29 Subsequently, the level of evidence of the studies was graded by one author (J.W.). The level was graded high, moderate, low or very low. Data extraction Three authors (J.W., B.N., G.B.) independently extracted data by means of predefined parameters. Individual patient data were obtained when available. The following data were retrieved: publication year, country of origin, number of patients, study design, patient characteristics (age, gender, history of smoking, diabetes, hypertension, and hyperlipidemia), aneurysm characteristics (affected vessel, exact location, aneurysm shape, affected side, and aneurysm size), etiology, and detailed method of treatment. Outcome measurements included case fatality, stroke and local cervical symptoms. Local cervical symptoms are defined as any symptom, most likely related to the aneurysm, in the cervical region on the ipsilateral side of the aneurysm. Local cervical symptoms were scored as reported by authors. Furthermore, any neurological deficit with an acute onset persisting for at least 24 hours for which no other cause could be found was considered a stroke. Early complications included all events that occurred within 30 days after intervention, or after detection of the ECAA in patients who received conservative treatment. Late outcome consisted of death from any cause and any stroke that occurred after at least 30 days.

Results After removing duplicates, our search identified 3711 articles (Figure 1). Following screening of title, abstract and full text 278 articles were selected. Hand searching the reference lists of selected articles revealed three more articles, resulting in final selection of 281 articles. Selected articles were case reports (n=179) or case series (n=102). Exclusion of papers on less than 10 patients, resulted in the final selection of 39 articles on a total of 1239 patients (a complete list of all included articles can be found in the APPENDIX).1-4,6,7,7,8,11,12,14-16,18,19,26-28,30-51 The level of evidence of 23 studies was graded low and 16 records very low. 52

Review of literature on ECAA management

Synonyms for “carotid artery” AND “aneurysm” AND “therapy”

Total articles n = 6030

Embase n = 3333

PubMed n = 2697 Duplicates excluded (n = 2319)

Screened on title and abstract n = 3711

Full text assessment n = 476 Included after reference list search n=3 Final inclusion n = 281

Case series >10 patients n = 39

Case series <10 patients n = 63

Case reports n = 179

Figure 1. Literature search flow chart

Patient and aneurysm characteristics At presentation, 1150 aneurysms (87%) were symptomatic, 476 (36%) presented with cerebral ischemia (120 strokes, 291 TIAs, and in 56 patients cerebral ischemia was not further specified), other symptoms at presentation were a cervical mass, a hematoma or rupture, pain or CND (Table 1, Figure 2). 53

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Aneurysm size was defined, by only two reports, as a localized increase of the caliber in the carotid artery of more than 50% compared to reference values or to the expected vessel diameter. 2,8 The main cause of the ECAA was atherosclerotic disease, followed by trauma, but for 275 aneurysms (21%) no specific cause was given (Table 1, Figure 2). Most aneurysms, 608 (46%), were located in the ICA (Table 1, Figure 2). Since information on aneurysm shape was missing in over 50% of cases this item was not reported in this paper.

Treatment A minority of aneurysms, 145 (11%), was treated without an invasive intervention (Table 2). Invasive treatment consisted of surgery in 1102 (94%) aneurysms, endovascular treatment in 57 (5%) aneurysms, or a combined approach in 18 (1%) aneurysms. (Table 2)

Table 1. Aneurysm characteristics Variables

Reports included

Patients Aneurysms

(% )

21%

trauma4c

1322

25%

Atherosclerosis

509

Traumatic

144

Mycotic

Other

329

Not reported

275

5% 11%

Cerebral ischemia

476

Mass

442

Asymptomatic

172

Compression

119

Local pain

Other

185

Location

13%

Bifurcation

261

CCA

108

Not reported

336

ICA internal carotid artery, CCA common carotid artery, ECA external carotid artery.

51%

36%

local symptoms cerebral ischemia asymptoma4c

25% 1%

608

other missing

Symptoms

ECA

atherosclerosic myco4c

Etiology

ICA

38%

1239

46%

ICA Bifurca4on CCA

20%

ECA missing

Figure 2. Symptoms at presentation, etiology and location of the ECAA. ICA internal carotid artery, CCA common carotid artery, ECA external carotid artery.

Review of literature on ECAA management

Table 2. Treatment details

Conservative therapy

Endovascular treatment

Surgery

Combined approach

Intervention

Anticoagulant therapy

No therapy

Medical management n.s.

Antiplatelet therapy

Conservative therapy n.s.

112

Stent placement

Balloon exclusion

Stent placement with coil embolization

Embolization

Endovascular n.s.

Resection with interposition graft

376

Resection with direct anastomosis

264

Partial resection with reconstruction

107

Ligation

Aneurysmorraphy

ECA to ICA transposition

Bypass

Surgery n.s.

210

Combined approach n.s.

ECIC bypass with balloon occlusion

n.s. not specified.

Early outcome In total 24 (2.4%) patients deceased, of which13 patients had a fatal stroke (1.3%), and 34 (3.4%) patients had a non-fatal stroke within 30 days.(Table 3) Conservative treatment had a case fatality rate of 5% (n=2), surgical treatment 2% (n=22) and in the endovascular treated patients (including the endovascular treated patients in which the procedure was combined with an open procedure) no deaths occurred within 30 days (Table 3). CND occurred in 110 (12%) patients after surgery and was never reported after endovascular treatment or combined surgical and endovascular treatment. Long term outcome Follow-up duration was most often presented as a mean follow-up of the study population and patients lost to follow-up was not reported in the majority of studies. Therefore, it is not possible to present the number of patients available for follow-up or the exact duration. During follow-up 81 patients deceased, of which eight had a fatal stroke, and 11 patients had a non-fatal stroke (Table 3). In the patients who received conservative treatment five died, compared to 76 in the surgically treated patients. Most deaths (n=68, 83%) were reported as not aneurysm related. Long term survival and stroke free survival was the highest in the endovascular treated patients. 55

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30-day Mortality n (%)

30-day stroke n (%)

30-day fatal stroke n (%)

30-day non-fatal stroke n (%)

CND (n)

Long-term Mortality n (%)

Long-term stroke n (%)

Long-term fatal stroke n (%)

Long-term Non-fatal stroke n (%)

Table 3. Treatment outcome

Conservative

2 (5.1)

3 (7.7)

2 (5.1)

1 (2.5)

Surgery

22 (2.4) 44 (4.7) 11 (1.2)

33 (3.5) 110 (11.8) 76

Endovascular

0 (0)

Surgery + Endovascular

0 (0)

CND cranial nerve deficit, NA not applicable. The data of the following articles was not included in this analysis because the data could not be split for the different interventions: Higashida 19861, Aleksic 20052, De Jong 19893, McCollum 19794, Padayachy 20125, Frankhauser 20136.

Confounding by indication An important issue we considered in the evaluation of which treatment option is superior using observational data is confounding by indication. Patients with certain characteristics receive a certain treatment, but these specific characteristics could be associated with a worse or beneficial outcome. For correcting confounding by indication completeness of potential confounders is needed. However, information on confounders in the present study is far from complete and could not be retrieved from the papers. Therefore, adjustments could not be made and therefore, no valid comparison of outcome for the four different treatments was possible.

Discussion ECAA are rare, leading to retrieval of only 39 case series containing 10 or more patients. Early mortality and number of strokes is low in surgical and endovascular treatment. Furthermore, the long-term follow-up demonstrates low stroke numbers in both intervention groups which supports the assumption invasive treatment could prevent stroke. These findings are in line with other publications.20,52,53 The high CND in surgically treated patients is probably related to distal location of aneurysms in the ICA and to the extensive dissection needed to perform complete aneurysm resection. The available information on ECAA treatment in literature heavily suffers, due to its rarity, from small case series, missing data, publication bias and confounding by indication. Furthermore, the level of evidence of the available literature is low to very low; therefore any estimate of effect based on these records is very uncertain. Therefore, no evidence-based recommendation can be given for an individual patient with an ECAA. 56

Review of literature on ECAA management

The natural course of ECAA is still hardly understood. Since knowledge on natural course is required to balance the benefit of any type of intervention, thus far, no treatment guideline or expert consensus for the management of ECAA has been developed. Probably, the main goal in the management of ECAA is to prevent thrombo-embolic complications of the aneurysm. In aneurysms in other vascular territories size is often used as an indication to intervene. Aneurysm size may probably be most related to aneurysm rupture. However, rupture is considered very unusual in ECAA, and most surgeons may only intervene in patients with thrombo-embolic symptoms or proven progressive ECAA growth. Medical therapy in ECAA, including medication choice, has been unexplored and needs to be further investigated. However, ECAA can occur after dissection in the carotid artery or in patients with generalized atherosclerotic disease. In these diseases medical therapy has been long used and scientifically substantiated. We would recommend following medical treatment guidelines of the most probable underlying disease until more evidence is available regarding medical treatment in ECAA patients. Operative therapy has been advocated for any ECAA because of the high mortality risk in non-operated cases.15,18,21,23 Nowadays, small case series advocating an endovascular approach to treat ECAA reported favourable procedural results but with limited number of cases and no mid or long-term follow-up.52,54 Endovascular treatment with a stent may be the most favourable option of the invasive treatments, mainly because of a high prevalence of CND associated with surgical treatment. Although the approach of this study allowed us to present early and late outcomes of ECAA treatment, the present study has several limitations. First of all, no randomized controlled trials have been published on ECAA treatment and data for the present analysis were obtained from case series only. Inherently, our assessment was limited to information provided in these articles resulting in a high rate of missing data. The reported rates for neurological complications may be biased because none of the studies performed independent and structural confirmation of these events. Furthermore, publication bias may have occurred while case series regularly present only striking and/ or invasively treated cases. Another disadvantage is that physicians may be tended to publish successful rather than unsuccessful cases. Although, by excluding small case series the risk of publication bias was reduced. Because of this publication bias the results of this study may not be generalizable to the ECAA population. In addition, since this was an observational study, the baseline characteristics of the patients undergoing different treatment were not completely identical. In this study there was confounding by indication because treatment choice was based on patient and aneurysm characteristics. Some of these characteristics may give rise to a different prognosis. Unfortunately, due to incomplete data and low patient numbers this confounding by indication could not be corrected and comparison between treatment outcome for the different treatment groups was not possible. Because in 31 out of 39 studies the data was presented on a group level, performing any sub analyses was not possible. The present study does represent the largest evaluation of treatment in patients with ECAA. 57

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This review for the first time clearly shows the lack of knowledge on the natural course of ECAA, and the fact that population based reporting makes it impossible to perform an individualized patient data analysis. To gain more accurate information regarding the prognosis and results of both conservatively and invasively treated ECAA more research is needed. Initiating a randomized controlled trial is infeasible because of the low incidence of ECAA and the low case fatality rates, but more knowledge regarding natural history and treatment indications might clearly be obtained from a well-designed prospective study. Consequently, we designed a prospective web-based international registry to collect data on ECAA (www.carotidaneurysmregistry.com).55

Conclusion This review summarizes the largest available series in literature on ECAA treatment. The scarce data consist of a mix of conservative, open surgical and a growing number of endovascular interventions. There is no consensus on indications in ECAA treatment. The early and long-term outcome of invasive treatment in ECAA is favorable, however cranial nerve damage after surgery occurs frequently. This review supports the need for an international multicenter registry to reveal the optimal treatment for ECAA.

Review of literature on ECAA management

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10. Dehn TC, Taylor GW. Extracranial carotid artery aneurysms. Ann R Coll Surg Engl 1984; 66:247-50. 11. Busuttil RW, Davidson RK, Foley KT, Livesay JT, Barker WF. Selective management of extracranial carotid arterial aneurysms. Am J Surg 1980; 140:85-91. 12. Pratschke E, Schafer K, Reimer J, Stiegler H, Stelter WJ, Becker HM. Extracranial aneurysms of the carotid artery. Thorac Cardiovasc Surg 1980; 28:354-8. 13. Taylor SM, Langan III EM, Snyder BA, Cull DL, Crane MM. Nonendarterectomy procedures of the carotid artery: A five-year review. Am Surg 1999; 65:323-7. 14. El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas Heart Institute experience. J Vasc Surg 2000; 31:702-12. 15. McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. Twentyone years' experience. Am J Surg 1979; 137:196-200. 16. Zhou W, Lin PH, Bush RL, Peden E, Guerrero MA, Terramani T, Lubbe DF, Nguyen L, Lumsden AB. Carotid artery aneurysm: Evolution of management over two decades. J Vasc Surg 2006; 43:493-6. 17. Mishaly D, Pasik S, Barzilai N, Mashiah A. Repair of internal carotid aneurysm under local anaesthesia. Case report. J Cardiovasc Surg 1992; 33:380-2. 18. Zwolak RM, Whitehouse WM,Jr, Knake JE, Bernfeld BD, Zelenock GB, Cronenwett JL, Erlandson EE, Kazmers A, Graham LM, Lindenauer SM. Atherosclerotic extracranial carotid artery aneurysms. J Vasc Surg 1984; 1:415-22. 19. Radak D, Davidovic L, Vukobratov V, Ilijevski N, Kostic D, Maksimovic Z, Vucurevic G, Cvetkovic S, Avramov S. Carotid Artery Aneurysms: Serbian Multicentric Study. Ann Vasc Surg 2007; 21:23-9. 20. El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas Heart Institute experience. J Vasc Surg 2000; 31:702-12.

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21. Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther 2012; 10:925-31. 22. Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg 2009; 79:281-7. 23. Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg 2005; 18:178-83. 24. Li Z, Chang G, Yao C, Guo L, Liu Y, Wang M, Liu D, Wang S. Endovascular stenting of extracranial carotid artery aneurysm: a systematic review. Eur J Vasc Endovasc Surg 2011; 42:419-26. 25. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008-12. 26. Rhodes EL, Stanley JC, Hoffman GL, Cronenwett JL, Fry WJ. Aneurysms of extracranial carotid arteries. Arch Surg 1976; 111:339-43. 27. Zhang Q, Duan ZQ, Xin SJ, Wang XW, Dong YT. Management of extracranial carotid artery aneurysms: 17 years' experience. Eur J Vasc Endovasc Surg 1999; 18:162-5. 28. Fankhauser GT, Stone WM, Fowl RJ, O'Donnell ME, Bower TC, Meyer FB, Money SR. Surgical and medical management of extracranial carotid artery aneurysms. J Vasc Surg 2013; 57:291. 29. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328:1490. 30. Aleksic M, Heckenkamp J, Gawenda M, Brunkwall J. Differentiated treatment of aneurysms of the extracranial carotid artery. J Cardiovasc Surg 2005; 46:19-23. 31. Bower TC, Pairolero PC, Hallett JW,Jr, Toomey BJ, Gloviczki P, Cherry KJ,Jr. Brachiocephalic aneurysm: the case for early recognition and repair. Ann Vasc Surg 1991; 5:125-32. 32. Coffin O, Maiza D, Galateau-Salle F, Martel B, Vignon C, Neri E, Derlon J-. Results of surgical management of internal carotid artery aneurysm by the cervical approach. Ann Vasc Surg 1997; 11:482-90. 33. Coldwell DM, Novak Z, Ryu RK, Brega KE, Biffl WL, Offner PJ, Franciose RJ, Burch JM, Moore EE. Treatment of posttraumatic internal carotid arterial pseudoaneurysms with endovascular stents. J Trauma 2000; 48:470-2. 34. Davidovic L, Kostic D, Maksimovic Z, Markovic D, Vasic D, Markovic M, Duvnjak S, Jakovljevic N. Carotid artery aneurysms. Vascular 2004; 12:166-70. 35. De Jong KP, Zondervan PE, Van Urk H. Extracranial carotid artery aneurysms. Eur J Vasc Surg 1989; 3:557-62. 36. Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg 2009; 49:93-8. 37. Garg K, Rockman CB, Lee V, Maldonado TS, Jacobowitz GR, Adelman MA, Mussa FF. Presentation and management of carotid artery aneurysms and pseudoaneurysms. J Vasc Surg 2012; 55:1618-22. 38. Higashida RT, Hieshima GB, Halbach VV, Goto K. Cervical carotid artery aneurysms and pseudoaneurysms. Treatment by balloon embolization therapy. Acta Radiol Suppl 1986; 369:591-3. 39. Krupski WC, Effeney DJ, Ehrenfeld WK, Stoney RJ. Aneurysms of the carotid arteries. Aust N Z J Surg 1983; 53:521-5. 40. Nair R, Robbs JV, Naidoo NG. Spontaneous carotid artery aneurysms. Br J Surg 2000; 87:186-90. 41. Padayachy V, Robbs JV. Carotid artery aneurysms in patients with human immunodeficiency virus. J Vasc Surg 2012; 55:331-7. 42. Angiletta D, Pulli R, Marinazzo D, Frotino P, Maiellaro L, Regina G. Surgical and endovascular treatment of extracranial carotid artery aneurysms: Early and long-term results of a single center. Ann Vasc Surg 2014; 28:659-64.

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43. Guillon B, Brunereau L, Biousse V, Djouhri H, Levy C, Bousser M-. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology 1999; 53:117-22. 44. Pulli R, Gatti M, Credi G, Narcetti S, Capaccioli L, Pratesi C. Extracranial carotid artery aneurysms. J Cardiovasc Surg (Torino) 1997; 38:339-46. 45. Sayed A, Elwan H, Fouad F, Taha A, Elhindawi K, Khairy H, Gad A, Kamal Eldin H. Behcet Extracranial Carotid Aneurysms: Is There Still a Role for Ligation? Eur J Vasc Endovasc Surg 2010; 39:17-22. 46. Schievink WI, Piepgras DG, McCaffrey TV, Mokri B, Day AL, Batjer HH. Surgical treatment of extracranial internal carotid artery dissecting aneurysms. Neurosurgery 1994; 35:809-16. 47. Szopinski P, Ciostek P, Kielar M, Myrcha P, Pleban E, Noszczyk W. A series of 15 patients with extracranial carotid artery aneurysms: Surgical and endovascular treatment. Eur J Vasc Endovasc Surg 2005; 29:256-61. 48. Radak D, Davidovic L, Tanaskovic S, Banzic I, Matic P, Babic S, Kostic D, Isenovic ER. A tailored approach to operative repair of extracranial carotid aneurysms based on anatomic types and kinks. Am J Surg 2014. 49. Friedman WA, Day AL, Quisling RG, Sypert GW, Rhoton AL,Jr. Cervical carotid dissecting aneurysms. Neurosurgery 1980; 7:207-14. 50. Nordanstig J, Gelin J, Jensen N, Osterberg K, Stromberg S. National experience with extracranial carotid artery aneurysms: Epidemiology, surgical treatment strategy, and treatment outcome. Ann Vasc Surg 2014; 28:882-6. 51. Pulli R, Dorigo W, Alessi Innocenti A, Pratesi G, Fargion A, Pratesi C. A 20-year experience with surgical management of true and false internal carotid artery aneurysms. Eur J Vasc Endovasc Surg 2013; 45:1-6. 52. Li Z, Chang G, Yao C, Guo L, Liu Y, Wang M, Liu D, Wang S. Endovascular stenting of extracranial carotid artery aneurysm: A systematic review. Eur J Vasc Endovasc Surg 2011; 42:419-26. 53. Attigah N, Kulkens S, Zausig N, Hansmann J, Ringleb P, Hakimi M, Eckstein HH, Allenberg JR, Bockler D. Surgical therapy of extracranial carotid artery aneurysms: long-term results over a 24-year period. Eur J Vasc Endovasc Surg 2009; 37:127-33. 54. Welleweerd JC, Borst de GJ, Groot de D, Herwaarden van JA, Lo TH, Moll FL. Bare metal stents for treatment of extracranial internal carotid artery aneurysms; medium and long-term results.Â J Endovasc Ther 2014; accepted for publication. 55. Welleweerd JC, de Borst GJ. Extracranial Carotid Artery Aneurysm: Optimal Treatment Approach. eur j vasc endovasc 2014:http://dx.doi.org/10.1016/j.ejvs.2014.11.007.

Level of evidence

Low

Very low

Low

Very low

First Author

Nordanstig 20141

Radak 20142

Angiletta 20143

Pulli 20134

Frankhauser 20135

Garg 20126

Padayachy 20127

Malikov 20108

132

Patients (N)

141

Aneurysms (n)

Table 1. Summary of all studies included in the review.

Online supplement

66 and 73

64 and 67

Age (mean/range)

53/ 87

56/ 58

Male (%)

Symptoms (N)

4 atherosclerotic 2 traumatic 7 other

22 mycotic

4 atherosclerotic 5 traumatic 5 other

49 other

1 traumatic 49 other

1 asx 6 CNS 4 local

1 asx 1 CNS 20 local

13 asx 1 CNS 2 local

69 asx 18 CNS 54 local

13 CNS 6 local

18 atherosclerotic 13 asx 4 traumatic 10 CNS 1 mycotic 2 local 3 other

77 atherosclerotic 16 asx 3 other 32 CNS

34 atherosclerotic 18 asx 2 mycotic 10 CNS 12 other 32 local

Etiology (N)

13 ICA

6 CCA 3 bifurcation 5 ICA

11 CCA 15 bifurcation 114 ICA 1 ECA

50 ICA

3 CCA 23 bifurcation

22 CCA 4 bifurcation 54 ICA

5 CCA 12 bifurcation 31 ICA

Location (N)

1 death 14 CND

3 deaths 1 stroke 3 CND

1 death 1 CND

1 death 1 stroke

19 deaths 3 strokes CND 10.5%, 13%

1 stroke 2 CND

2 deaths 4 strokes 2 CND

5 Deaths 4 strokes 2 Ipsilateral stroke CND 12.5 %

Outcome

Retrospective study reporting on technique and results of a lateral skull base approach with cervical-to-petrous carotid artery bypass in ECAA.

Single center retrospective review on all patients with HIV carotid aneurysms.

Single center retrospective review of ECAA.

Single center retrospective review of patients with true (group 1) and false ECAA (group 2).

Retrospective analysis of surgical management in true (group 1) and false ECAA (group 2).

Single center retrospective study of surgical and endovascular treated ECAA.

Retrospective analysis of an operative approach for ECAA in two major vascular surgery university clinics.

Review of all ECAA patients registered in the Swedish National Registry for Vascular Surgery (Swedvasc).

Study Details

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Low

Very low

Low

Very low

Low

Srivastava 20109

Sayed 201010

Attigah 200911

Donas 200912

Radak 200713

Zhou 200614

Aleksic 200515

Szopinski 200516

Davidovic 200417

El-Sabrout 200018

Rosset 200019

12 local

8 CNS 7 local

12 CNS 10 local

9 atherosclerotic 3 traumatic 13 other

6 asx 18 CNS 3 local

23 atherosclerotic 28 CNS 6 traumatic 48 local 38 other

17 atherosclerotic 10 CNS 7 local

5 atherosclerotic 6 traumatic 1 mycotic 3 other

10 atherosclerotic 3 asx 1 traumatic 11 local 3 mycotic

22 atherosclerotic 7 asx 5 traumatic 5 CNS 15 other 40 local

73 atherosclerotic 5 asx 6 traumatic 44 CNS 12 other 47 local

29 atherosclerotic 4 asx 32 other 29 CNS 20 local

42 atherosclerotic 3 asx 1 mycotic 29 CNS 14 other 15 local

12 other

7 atherosclerotic 7 mycotic

Retrospective review of ECAA patients in three hospitals. Patients were divided in two groups : I (1985-1994) and II (1995-2004).

Single center retrospective review of ECA treated surgically and endoluminally. Single center retrospective review of ECAA treatment. Retrospective review of surgically treated ECAA in two hospitals. Single center retrospective review of surgically treated ECAA.

2 deaths 4 strokes 6 CND 5 deaths 5 strokes 2 CND 19 deaths 1 stroke 4 CND

1 death 2 strokes 3 CND 4 deaths 2 stroke 1 CND 2 deaths 3 strokes 2 CND 23 deaths 5 strokes 4 CND 2 deaths 2 ipsilateral strokes 11 CND

9 CCA 26 bifurcation 26 ICA 29 bifurcation 61 ICA 1 ECA NR

10 bifurcation 4 ICA 1 CCA 3 bifurcation 11 ICA

2 CCA 15 ICA

Retrospective, multicenter review of treatment of ECAA.

11 deaths 3 stroke 17 CND

6 CCA 25 bifurcation 33 ICA

Retrospective review of ECAA.

Single center retrospective review of surgically treated ECAA.

Retrospective review of surgically treated ECAA.

Single center retrospective review of Behcet ECAAs.

2 deaths 1 stroke 1 CND

2 CCA 3 bifurcation 7 ICA

Single center retrospective review of ECAA treatment.

2 strokes 1 CND

1 CCA 10 bifurcation 8 ICA

Review of literature on ECAA management

Low

Very low

Low

Very low

Very Low

Very low

Nair 200020

Coldwell 200021

Zhang 199922

Guillon 199923

Coffin 199724

Pulli 199725

Faggioli 199626

Moreau 199427

Schievink 199428

Bower 199129

De Jong 198930

Higashida 198631

36 to 69

6 to 73

4 asx 1 CNS 49 local

9 CNS 3 local

8 CNS 10 local

7 CNS 19 local

5 traumatic 5 other

3 atherosclerotic 8 traumatic 2 mycotic 9 other

11 traumatic 11 other

1 asx 1 CNS 1 local

11 CNS 2 local

17 CNS 23 local

10 asx 4 CNS

12 atherosclerotic 26 CNS 6 traumatic 12 local 1 mycotic 19 other

9 atherosclerotic 1 traumatic 14 other

10 atherosclerotic 7 asx 11 other 10 CNS 5 local

3 atherosclerotic 3 traumatic 9 other

7 traumatic 1 mycotic 8 other

28 atherosclerotic 16 CNS 22 traumatic 55 local 7 mycotic 9 other

16 traumatic

3 atherosclerotic 10 mycotic 10 other

2 CCA 12 ICA

22 ICA

24 ICA

1 CCA 8 bifurcation 12 ICA

15 ICA

20 ICA

10 CCA 41 bifurcation 13 ICA 2 ECA

13 CCA 12 bifurcation 7 ICA

2 strokes

1 death 1 CND

1 death 1 stroke 7 CND

2 strokes 17 CND

4 death 1 stroke 29 CND

1 death 2 stroke 5 CND

3 strokes 2 CND

2 Deaths 4 CND

1 death

4 deaths 4 strokes

none

2 deaths 1 stroke

Single center retrospective review of ECAA.

Single center retrospective review of surgically treated brachiocephalic aneurysms.

Single center retrospective review of surgically treated dissecting aneurysms.

Single center retrospective review of surgically treated ECAA.

Single center retrospective review of ECAA treatment.

Retrospective review of surgically treated ECAA.

Single center retrospective review of surgically treated ECAA.

Single center retrospective review of ECAA after dissection.

Single center retrospective review of management of ECAA.

Single center retrospective review of posttraumatic ECAA treated with endovascular stent.

Single center retrospective review of spontaneous ECAA.

chapter 5

Low

Very low

Low

Very low

Low

Very low

Low

Zwolak 198433

Krupski 198334

Pratschke 198035

Friedman 198036

Busuttil 198037

McCollum 197938

Rhodes 197639

18 to 78

14 CNS 5 local

7 CNS 27 local

5 CNS

2 asx 12 CNS 5 local

2 asx 13 CNS 3 local

16 atherosclerotic 13 CNS 4 traumatic 20 local 3 other

6 atherosclerotic

1 traumatic 12 other

13 atherosclerotic 12 CNS 9 traumatic 30 local 2 mycotic 4 other

8 atherosclerotic 5 traumatic 5 mycotic 3 other

24 atherosclerotic 15 CNS 13 local

7 traumatic 1 mycotic 11 other

Single center retrospective review of cervical carotid dissecting aneurysm. Single center retrospective review of surgically treated ECAA. Single center retrospective review of ECAA.

10 deaths

1 death 1 stroke 3 deaths 2 stroke 13 deaths 3 strokes 4deaths 2 strokes 3 CND

9 CCA 4 bifurcation 10 ICA 5 ECA

NR 2 CCA 13 bifurcation 8 ECA

Single center retrosprective review of ECAA.

2 death 3 stroke 6 CND

1 CCA 8 bifurcation 3 ICA

Single center retrospective review of ECAA.

Retrospective review of atherosclerotic ECAA encountered in three affiliated hospitals.

7 deaths 4 stroke 6 CND

2 CCA 12 bifurcation 10 ICA

Single center retrospective review of surgically treated ECAA.

1 stroke 6 CND

20 ICA

CNS central neurological symptoms, ICA internal carotid artery, CCA common carotid artery, ECA external carotid artery, CND cranial nerve dysfunction, ECAA extracranial carotid artery aneurysm(s), NR not reported.

Very low

Sundt 198632

Review of literature on ECAA management

chapter 5

References 1.

Nordanstig J, Gelin J, Jensen N, Osterberg K, Stromberg S. National experience with extracranial carotid artery aneurysms: Epidemiology, surgical treatment strategy, and treatment outcome. Ann Vasc Surg. 2014;28(4):882-886.

Radak D, Davidovic L, Tanaskovic S, et al. A tailored approach to operative repair of extracranial carotid aneurysms based on anatomic types and kinks. Am J Surg. 2014.

Angiletta D, Pulli R, Marinazzo D, Frotino P, Maiellaro L, Regina G. Surgical and endovascular treatment of extracranial carotid artery aneurysms: Early and long-term results of a single center. Ann Vasc Surg. 2014;28(3):659-664.

Pulli R, Dorigo W, Alessi Innocenti A, Pratesi G, Fargion A, Pratesi C. A 20-year experience with surgical management of true and false internal carotid artery aneurysms. Eur J Vasc Endovasc Surg. 2013;45(1):1-6. doi: 10.1016/j.ejvs.2012.10.011 [doi].

Fankhauser GT, Stone WM, Fowl RJ, et al. Surgical and medical management of extracranial carotid artery aneurysms. J Vasc Surg. 2013;57(1):291.

6. Garg K, Rockman CB, Lee V, et al. Presentation and management of carotid artery aneurysms and pseudoaneurysms. J Vasc Surg. 2012;55(6):1618-1622. 7.

Padayachy V, Robbs JV. Carotid artery aneurysms in patients with human immunodeficiency virus. J Vasc Surg. 2012;55(2):331-337.

Malikov S, Thomassin JM, Magnan PE, Keshelava G, Bartoli M, Branchereau A. Open surgical reconstruction of the internal carotid artery aneurysm at the base of the skull. J Vasc Surg. 2010;51(2):323-329. doi: 10.1016/j. jvs.2009.08.084.

Srivastava SD, Eagleton MJ, Oâ&#x20AC;&#x2122;Hara P, Kashyap VS, Sarac T, Clair D. Surgical repair of carotid artery aneurysms: A 10-year, single-center experience. Ann Vasc Surg. 2010;24(1):100-105.

10. Sayed A, Elwan H, Fouad F, et al. Behcet extracranial carotid aneurysms: Is there still a role for ligation? Eur J Vasc Endovasc Surg. 2010;39(1):17-22. 11. Attigah N, Kulkens S, Zausig N, et al. Surgical therapy of extracranial carotid artery aneurysms: Long-term results over a 24-year period. Eur J Vasc Endovasc Surg. 2009;37(2):127-133. 12. Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98. 13. Radak D, Davidovic L, Vukobratov V, et al. Carotid artery aneurysms: Serbian multicentric study. Ann Vasc Surg. 2007;21(1):23-29. 14. Zhou W, Lin PH, Bush RL, et al. Carotid artery aneurysm: Evolution of management over two decades. J Vasc Surg. 2006;43(3):493-496. 15. Aleksic M, Heckenkamp J, Gawenda M, Brunkwall J. Differentiated treatment of aneurysms of the extracranial carotid artery. J Cardiovasc Surg. 2005;46(1):19-23. 16. Szopinski P, Ciostek P, Kielar M, Myrcha P, Pleban E, Noszczyk W. A series of 15 patients with extracranial carotid artery aneurysms: Surgical and endovascular treatment. Eur J Vasc Endovasc Surg. 2005;29(3):256261. 17.

Davidovic L, Kostic D, Maksimovic Z, et al. Carotid artery aneurysms. Vascular. 2004;12(3):166-170.

18. El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712.

Review of literature on ECAA management

19. Rosset E, Albertini JN, Magnan PE, Ede B, Thomassin JM, Branchereau A. Surgical treatment of extracranial internal carotid artery aneurysms. J Vasc Surg. 2000;31(4):713-723. doi: 10.1067/mva.2000.104102. 20. Nair R, Robbs JV, Naidoo NG. Spontaneous carotid artery aneurysms. Br J Surg. 2000;87(2):186-190. 21. Coldwell DM, Novak Z, Ryu RK, et al. Treatment of posttraumatic internal carotid arterial pseudoaneurysms with endovascular stents. J Trauma. 2000;48(3):470-472. 22. Zhang Q, Duan ZQ, Xin SJ, Wang XW, Dong YT. Management of extracranial carotid artery aneurysms: 17 yearsâ&#x20AC;&#x2122; experience. Eur J Vasc Endovasc Surg. 1999;18(2):162-165. 23. Guillon B, Brunereau L, Biousse V, Djouhri H, Levy C, Bousser M-. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology. 1999;53(1):117-122. 24. Coffin O, Maiza D, Galateau-Salle F, et al. Results of surgical management of internal carotid artery aneurysm by the cervical approach. Ann Vasc Surg. 1997;11(5):482-490. 25. Pulli R, Gatti M, Credi G, Narcetti S, Capaccioli L, Pratesi C. Extracranial carotid artery aneurysms. J Cardiovasc Surg (Torino). 1997;38(4):339-346. 26. Faggioli G, Freyrie A, Stella A, et al. Extracranial internal carotid artery aneurysms: Results of a surgical series with long-term follow-up. J Vasc Surg. 1996;23(4):587-595. 27. Moreau P, Albat B, Thevenet A. Surgical treatment of extracranial internal carotid artery aneurysm. Ann Vasc Surg. 1994;8(5):409-416. 28. Schievink WI, Piepgras DG, McCaffrey TV, Mokri B, Day AL, Batjer HH. Surgical treatment of extracranial internal carotid artery dissecting aneurysms. Neurosurgery. 1994;35(5):809-816. 29. Bower TC, Pairolero PC, Hallett JW,Jr, Toomey BJ, Gloviczki P, Cherry KJ,Jr. Brachiocephalic aneurysm: The case for early recognition and repair. Ann Vasc Surg. 1991;5(2):125-132. 30. De Jong KP, Zondervan PE, Van Urk H. Extracranial carotid artery aneurysms. Eur J Vasc Surg. 1989;3(6):557562. 31. Higashida RT, Hieshima GB, Halbach VV, Goto K. Cervical carotid artery aneurysms and pseudoaneurysms. treatment by balloon embolization therapy. Acta Radiol Suppl. 1986;369:591-593. 32. Sundt Jr. TM, Pearson BW, Piepgras DG. Surgical management of aneurysms of the distal extracranial internal carotid artery. J Neurosurg. 1986;64(2):169-182. 33. Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc Surg. 1984;1(3):415-422. 34. Krupski WC, Effeney DJ, Ehrenfeld WK, Stoney RJ. Aneurysms of the carotid arteries. Aust N Z J Surg. 1983;53(6):521-525. 35. Pratschke E, Schafer K, Reimer J, Stiegler H, Stelter WJ, Becker HM. Extracranial aneurysms of the carotid artery. Thorac Cardiovasc Surg. 1980;28(5):354-358. doi: 10.1055/s-2007-1022108. 36. Friedman WA, Day AL, Quisling RG, Sypert GW, Rhoton AL,Jr. Cervical carotid dissecting aneurysms. Neurosurgery. 1980;7(3):207-214. 37. Busuttil RW, Davidson RK, Foley KT, Livesay JT, Barker WF. Selective management of extracranial carotid arterial aneurysms. Am J Surg. 1980;140(1):85-91. 38. McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200. 39. Rhodes EL, Stanley JC, Hoffman GL, Cronenwett JL, Fry WJ. Aneurysms of extracranial carotid arteries. Arch Surg. 1976;111(4):339-343.

chapter

Janna C Welleweerd Bsc1, Frans L Moll MD PhD1, Gert Jan de Borst MD PhD1 1

Vascular Surgery, University Medical Center Utrecht, the Netherlands

Technical options for treatment of extracranial carotid aneurysms Expert Rev Cardiovasc Ther. 2012 Jul;10(7):925-31

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Abstract Extracranial carotid artery aneurysm (ECAA) is an uncommon but serious condition. The morbidity and mortality of ECAA are assumed to be high when untreated. ECAA treatment presents a challenge because of accessibility of the carotid artery and lack of evidencebased guidelines. When exclusion of the aneurysm is considered, surgical resection of the aneurysm with reconstruction of blood flow is still considered the gold standard. Several alternative and endovascular approaches are discussed.

Introduction Extracranial carotid artery aneurysm (ECAA) is a rare condition with a reported incidence of 0.09â&#x20AC;&#x201C;2.0% of all carotid surgical procedures.1-4 The etiology of ECAA is diverse and ranges from atherosclerosis to infection and trauma 5,6. An ECAA may present most commonly with central neurologic symptoms due to cerebral embolism but might also present with local compression causing cranial nerve function loss or dysphagia. However, ECAA are usually detected by coincidence and are believed to remain asymptomatic. 7 Most aneurysms are diagnosed using echo/ duplex ultrasound imaging, but computed tomography angiography is more accurate, and 3D computed tomography angiography reconstructions contribute to the diagnostic and therapeutic work-up.8 Symptomatic patients with ECAA usually receive invasive treatment because of the assumed high morbidity and mortality rate when untreated.9 In asymptomatic ECAA, conservative treatment still has an important place. A clear algorithm or specific indications for treatment are lacking. Most available evidence is from small case series or case reports, making it difficult to propose a balanced format to indicate intervention. Sir Astley Cooper performed the first ECAA ligation in a symptomatic patient in 1805. The patient died of postoperative stroke, but this surgical approach was the first step to the surgical interventions applied today.10 Several different techniques for ECAA treatment have been developed since then. Currently, complete aneurysm resection with arterial reconstruction is considered the gold standard. However, there is great variety in techniques performed, and no evidence-based guidelines on ECAA treatment have been defined. Personal experience, aneurysm location and etiology are important in balancing and choosing the optimal treatment strategy. Accessibility of the internal carotid artery (ICA) is considered the most important issue in planning ECAA revascularization. Several ECAA classifications based on the anatomic location of the aneurysm relative to the common carotid artery (CCA) and ICA have been suggested. Classification based on anatomic location Most authors refer to the cervical vertebrae to concretize ECAA location. This indirect approach may create confusion with the classification by Bouthillier for the entire carotid artery. In Bouthillierâ&#x20AC;&#x2122;s classification, the cervical part is referred to as C1, the petrous part as C2 and the intracranial part as C3â&#x20AC;&#x201C;C7.11 The classifications by Attigah et al.12 and 70

Technical options of ECAA treatment

Malikov et al.13 (Tables 1 and 2) use the line of Blaisdell, which is a virtual line between the mastoid process and the angle of the mandible. Above this line, the carotid is considered less accessible by the standard surgical approach, and alternative techniques with endovascular assistance may be needed.

Table 1 Type I

Table 2 Isolated and short aneurysms of the ICA above the carotid bulb

Type II

Long aneurysms of the ICA, ranging from the carotid bulb up to the line of Blaisdell

Type III

Aneurysms of the proximal ICA and the carotid bifurcation

Type IV

Aneurysms involving the CCA and ICA as type III, but extending far more distally and proximally

Type V

Isolated aneurysms of the CCA

Segment 1

The bicarotid region

Segment 2

The retrostyloid region (above Blaisdell)

Segment 3

The infratemporal fossa below the penetration into the base of the skull

CCA: Common carotid artery; ICA: Internal carotid artery. Table adapted from Bouthillier.11

Treatment options Surgical treatment Preparation Preoperative planning is essential in ECAA reconstruction. Accessibility is of critical essence, and if necessary, other specialists, such as the ear, nose and throat team, will need to be consulted. Most surgeons prefer general anesthesia during carotid aneurysm surgery, but local anesthesia has been applied successfully.5 The patientâ&#x20AC;&#x2122;s neck should be slightly extended and the head turned opposite to the affected side without compressing the contralateral carotid artery.13 The standard approach to the carotid artery is anterior to the sternocleidomastoid muscle.5 The carotid bifurcation, jugular vein and ICA can then be dissected with special attention to the vagal and the hypoglossal nerve.13 Proximal and distal carotid control can be obtained by clamp positioning, and in case of distal extension of the aneurysm, a Fogarty catheter might be helpful.5 Before the artery is clamped, intravenous unfractionated heparin should be provided to prevent thrombotic occlusion.14 Shunt use and intraoperative cerebral monitoring Brain perfusion might be seriously hampered during clamping of the carotid artery because of the temporary interruption of ipsilateral blood flow.15 To reduce the associated risk for intraoperative stroke, many surgeons place an intraluminal shunt over the clamped section. In standard endarterectomy in the UK, 73.6% of surgeons use a shunt routinely, 22.2% selectively and 4.2% never.15 The most frequently used types of shunt are the Javid 71

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shunt and the Pruitt-Inahara shunt. The Javid shunt is a 32-cm- long tapered shunt, 17F gauge proximally and 10F distally. It has fusiform swellings at each end and is held in place by external clamps. The Pruitt-lnahara shunt has a constant diameter of 10F and is held in place by incorporated inflatable balloons at each end.16 When applied selectively, the need for a shunt can be based on different cerebral monitoring techniques. These include indirect assessment of cerebral blood flow during the operation by monitoring electroencephalographic activity, carotid stump back pressure, somatosensory evoked potentials or direct flow assessment by transcranial Doppler. When the patient is operated on under local anesthetics, changes in cognitive and neurologic functions can be used to determine the indication for a shunt.15 Aneurysms located in the CCA, the carotid bifurcation and the proximal ICA. Surgical treatment of ECAA can be technically demanding due to the complexity of the region and the relation between the carotid artery and several cranial nerves. The surgical options for ECAA treatment include: proximal and distal ligation of the ICA, bypass without resection, and resection of the aneurysm with direct or indirect reconstruction of blood flow. As stated, ligation of the carotid artery was first executed by Sir Astley Cooper and is still used today in selected and mostly urgent cases such as in patients with ruptured or mycotic extracranial aneurysms.10 Although clearly associated with an increased risk for stroke, some believe that ligation can be safely performed when the back pressure exceeds 70mm Hg, which suggests an intact contralateral blood flow and patent circle of Willis.8 Relatively rarely used techniques are bypass of the aneurysm without resection and the extracranialâ&#x20AC;&#x201C;intracranial (EC-IC) bypass.5 When the aneurysm is not excluded from the circulation, even when there is preferential flow through the EC-IC bypass, the aneurysm still might cause central neurologic symptoms due to embolization.5 For this reason, the EC-IC bypass should always be combined with a ligation of the aneurysmcontaining part of the carotid artery.17 However, when anatomically possible, resection of the ECAA with complete reconstruction of the carotid blood flow is still considered by many surgeons as the treatment of choice.5,8,17 When the aneurysm can be resected completely, the carotid artery can be reconstructed in several ways. In case of an elongated or redundant carotid artery, a primary end-to-end reconstruction can be made with a single anastomosis (Figure 1).17 Otherwise, an autogenous saphenous vein is the graft of choice to create an interposition bypass of the resected artery.5,8 When no suitable vein is available, a polytetrafluoroethylene or Dacron interposition graft can be used, by definition needing two anastomoses (Figure 2).17 The anastomoses between native artery and interposition graft can be made end-to-end or end-to-side. In case the aneurysmal dilatation is confined to the ICA, the external carotid artery (ECA) can be used as a proximal transposition site (Figure 3). The proximal ICA in this technique is ligated after resection of the aneurysm, followed by splicing of the ECA. An anastomosis can then be made between the proximal part of the ECA and the distal part of the ICA.8 Sometimes, the aneurysm cannot be resected completely due to large size or adherence to surrounding structures. As a last resort, if complete bypass or other technique cannot be used, a partial resection can be performed with direct closure or patch placement (Figure 4).8 72

Technical options of ECAA treatment

Figure 1. Primary end-to-end reconstruction with a single running anastomosis. (A) ECAA located in the ICA. (B) Resection of the aneurysm. (C) End-to-end anastomosis. ECAA: Extracranial carotid artery aneurysm; ICA: Internal carotid artery.

Figure 2. End-to-end reconstruction with interposition graft. (A) ECAA located in the ICA. (B) Resection of the aneurysm. (C) End-to-end reconstruction with interposition graft. ECAA: Extracranial carotid artery aneurysm; ICA: Internal carotid artery.

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Figure 3. Aneurysm resection with transposition ECA to ICA. (A) ECAA located in the ICA. (B) Resection of the aneurysm and ligation of the distal ECA. (C) Transposition of the proximal ECA to the distal ICA and ligation of the proximal ICA. ECAA: Extracranial carotid artery aneurysm; ECA: External carotid artery; ICA: Internal carotid artery.

Figure 4. Partial aneurysm resection with patch placement. (A) ECAA located at the level of the carotid bifurcation. (B) Partial excision of the aneurysm. (C) Closure with patch placement. ECAA: Extracranial carotid artery aneurysm.

Technical options of ECAA treatment

Although a positive aspect of this technique is the reduced risk of cranial nerve injury, it must not be considered an accepted alternative to conventional repair because it leaves diseased aneurysmal wall that is prone to further dilatation.5 Aneurysms at the base of the skull Aneurysms of the carotid artery above the line of Blaisdell, respectively type IV and segment 2–3, as classified by Attigah et al.12 and Malikov et al.13, often can be exposed but distal control may be relatively hard to obtain.8,18 To obtain distal control and good exposure, an extension of a standard lateral incision and division of the posterior belly of the digastric muscle is usually not sufficient.19 The operating field may be narrow in the distal end of the neck, and several cranial nerves are at risk. To create further exposure, the mandible may be subluxated using an anterior–contralateral pull. In experienced hands, this is relatively easy, requires little preoperative time and has a low morbidity rate.20 This approach creates 1–2cm of additional exposure of the distal ICA. Alternatively, a resection of part of the mandible is an option. Dividing the sternocleidomastoid muscle at its insertion into the mastoid process, possibly followed by removal of part of the mastoid process and vaginal process of the temporal bone, has also been suggested to improve exposure. The styloid process can also be resected with retraction or removal of the styloid muscles and ligaments.8,12,18 Disadvantages of these approaches are the relatively high risk of permanent cranial nerve damage, contamination with oral flora, inappropriate bone healing and delay in oral intake.8,13,18

Endovascular treatment Preparation Endovascular treatment is mostly performed under local anesthetics, with percutaneous access obtained through a common femoral artery puncture. If the lesion is localized in the proximal CCA, a retrograde approach can be used, puncturing the distal CCA after surgical exploration. Patients are generally loaded with clopidogrel preoperatively, and systemic heparinization is administered during the procedure to obtain an activated clotting time of 250–300 s. To prevent embolization from the lesion, a cerebral protection device could be deployed in the distal ICA.21,22 Endovascular stent placement Primary stent placement instead of surgical treatment can be considered in patients with a hostile neck due to cervical radiation or previous surgery or when the location of the aneurysm is inaccessible (above Blaisdell type IV, segment 2 and 3) or the CCA is low (low type V).12,13 The stent must be placed overlapping the entire aneurysm, and both the landing zones must be disease-free vascular walls to obtain a ‘healthy-to-healthy’ bridge. Stent choice depends primarily on the arterial anatomy and specific characteristics of the lesion. A wide variety of carotid stents are available, including balloon-expandable and self-expanding stents, metal and bare-metal stents as well as tapered versus non-tapered 75

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stents. In stenotic carotid artery lesions, self-expanding stents are most widely applied.23 Bare-metal stents are often the stent of choice for ECAA treatment. They alter the arterial inflow, which usually results in thrombosis of the aneurysm but preserves vessel patency at the same time. If complete aneurysm thrombosis does not occur, bare-metal stents can be combined with coil mobilization. The detachable coils are inserted into the aneurysm by placing a micro catheter through interstices of the uncovered stent. The coils alter the blood flow within the aneurysm and induce thrombus formation.8,18 Covered stents with an internal or external lining, which promote thrombosis in the aneurysm better, can be used as an alternative in non-branching arteries and widenecked aneurysms or pseudoaneurysms.8 The stent can be lined with different materials, for example, a vein or polytetrafluoroethylene. Some stents have a heparinized surface to reduce the risk of vessel thrombosis and intimal hyperplasia.24 The risk of embolization during stent placement might be reduced using a covered stent because of trapping of debris in the aneurysm that otherwise could protrude through the interstices of the bare- metal stent.25 A disadvantage of the covered stent is the need for a larger delivery system compared with those for uncovered stents and thus is a more technically challenging procedure.8 Passing and deployment of a stent graft with long sheath and large diameter through a tortuous carotid artery, especially in older patients, remain technically difficult.26 If the aneurysm is located at the bifurcation or involves both the CCA and the ICA (type III, IV or segment 1) 12,13, a mismatch in vessel diameter could occur. This mismatch occurs in only 10â&#x20AC;&#x201C;15% of patients and can be overcome with a bare tapered stent. These relatively new stents have a different proximal and distal diameter to provide a smooth transition between the CCA and ICA. The tapering can be conical or a more anatomic adapted shouldered shape containing a short transition zone in the midsegment.23 Endovascular embolization Coil embolization is seldom used as a sole treatment for peripheral aneurysms because it is technically challenging, requires passing the micro catheter through the neck of the aneurysm and has a risk of distal migration of the coils.18,24,25 (merged) Loffroy described a packing technique in pseudoaneurysms using detachable microcoils placed in a concentric fashion. This technique can be used in pseudoaneurysms with a maximum diameter size of 50mm. Packing of the aneurysm with these coils, sometimes combined with an injection of ethylene vinyl alcohol copolymer, results in aneurysm exclusion in 80â&#x20AC;&#x201C;90%.27 Coils are mainly used in combination with bare-metal stents. Embolization of the aneurysm may also be obtained by percutaneous injection of thrombin. This method has good results in the treatment of pseudoaneurysms of the femoral artery but is still considered technically difficult or too risky in ECAA. The risk of propagation of the clot out of the aneurysm into the intracranial system is considered unacceptable.27 Cases have been reported in which thrombin embolization, using angiography- or ultrasound-guided localization of the aneurysm, followed by percutaneous thrombin injection, has been applied successfully, but no larger series are published.28 76

Technical options of ECAA treatment

New developments Hybrid approach Because of arterial kinking or redundant arterial loops, stent placement to promote thrombosis in a more distally located ECAA is not always possible. These common anatomic variations in the proximal carotid artery can be easily removed during open surgery. Resection of the loop, followed by a single direct arterial anastomosis, facilitates the possibilities of an endovascular approach of a more distally located ECAA. Mainly, type I and type V aneurysms are suitable for stent placement.12 Multiple authors have described a hybrid approach for high aneurysms with proximal loops or kinks (Figure 5) in which the anatomic variation is removed in an open procedure, followed by direct puncture of the carotid artery for stent placement. Some straighten the carotid artery manually after dissection, place the stent and shorten the artery afterward.18,29

Figure 5. Hybrid approach. (A) Aneurysm located in the distal ICA. (B) Resection of a loop in the ICA. (C) Primary end-to-end anastomosis of the ICA. (D) Endovascular stent placement over the ECAA. ECAA: Extracranial carotid artery aneurysm; ICA: Internal carotid artery.

Flow-diverting stent New developments in stent design and cerebral protection devices clearly promote an endovascular approach for ECAAs. One of the most recent stent designs is the flowdiverting stent, which is designed to alter blood flow in the vessel in favor of the longitudinal axis.12,30,31 In this way, it changes the inflow and outflow of blood in the aneurysm and promotes thrombosis theoretically better than by a bare-metal stent. Flow-diverting stents are laser-cut metallic structures premounted on a stainless steel wire and attached distally to a capture coil. Exact measurement of the vessel diameter is essential in this type of stent because oversizing will result in decreased hemodynamic effects. Multiple stents may have to be placed to achieve a significant hemodynamic effect.30 77

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Expert Commentary and 5-year view ECAA are rare but may cause serious morbidity when not treated on time. The lack of evidence-based treatment guidelines may offer a dilemma to the treating physician. When treatment is indicated, accessibility of the ECAA is the key issue. Resection of the aneurysm with complete reconstruction of blood flow is still considered the gold standard for treatment, but less invasive but possibly equally effective techniques need to be evaluated. As there are no evidence-based guidelines, practitioners will have to depend on gained experience and indication based on the location and etiology described in the available literature.

Technical options of ECAA treatment

References 1.

Bower TC, Pairolero PC, Hallett JW,Jr, Toomey BJ, Gloviczki P, Cherry KJ,Jr. Brachiocephalic aneurysm: The

Knight GC, Hallman GL, Reul GJ, Ott DA, Cooley DA. Surgical management of extracranial carotid artery

case for early recognition and repair. Ann Vasc Surg. 1991;5(2):125-132.

aneurysms. report of 17 cases. Tex Heart Inst J. 1988;15(2):91-97. 3.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200.

Sundt Jr. TM, Pearson BW, Piepgras DG. Surgical management of aneurysms of the distal extracranial internal carotid artery. J Neurosurg. 1986;64(2):169-182.

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712. doi: 10.1067/mva.2000.104101.

6. Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98. 7.

Kaupp HA, Haid SP, Jurayj MN, Bergan JJ, Trippel OH. Aneurysms of the extracranial carotid artery. Surgery. 1972;72(6):946-952.

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc Surg. 1984;1(3):415-422.

10. Kirsner AB, Sheon RP. Medico-chirurgical transactions. A cardiovascular cluster. Circulation. 1970;42(4):751757. 11. Bouthillier A, van Loveren HR, Keller JT. Segments of the internal carotid artery: A new classification. Neurosurgery. 1996;38(3):425-32; discussion 432-3. 12. Attigah N, Kulkens S, Zausig N, et al. Surgical therapy of extracranial carotid artery aneurysms: Long-term results over a 24-year period. Eur J Vasc Endovasc Surg. 2009;37(2):127-133. doi: 10.1016/j.ejvs.2008.10.020. 13. Malikov S, Thomassin JM, Magnan PE, Keshelava G, Bartoli M, Branchereau A. Open surgical reconstruction of the internal carotid artery aneurysm at the base of the skull. J Vasc Surg. 2010;51(2):323-329. doi: 10.1016/j. jvs.2009.08.084. 14. Norgren L, Swedish EnoxaVasc Study Group. Can low molecular weight heparin replace unfractionated heparin during peripheral arterial reconstruction? an open label prospective randomized controlled trial. J Vasc Surg. 2004;39(5):977-984. doi: 10.1016/j.jvs.2004.01.033. 15. Rerkasem K, Rothwell PM. Routine or selective carotid artery shunting for carotid endarterectomy (and different methods of monitoring in selective shunting). Cochrane Database Syst Rev. 2009;(4)(4):CD000190. doi: 10.1002/14651858.CD000190.pub2. 16. Wilkinson JM, Rochester JR, Sivaguru A, Cameron IC, Fisher R, Beard JD. Middle cerebral artery blood velocity, embolisation, and neurological outcome during carotid endarterectomy: A prospective comparison of the javid and the pruitt-inahara shunts. Eur J Vasc Endovasc Surg. 1997;14(5):399-402. 17.

Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183. doi: 10.1053/j. semvascsurg.2005.09.002.

18. Trinidad-Hernandez M, Introcaso JH, White JV. Combined open and endovascular treatment of a saccular aneurysm and redundant loop of the internal carotid artery. J Vasc Surg. 2006;44(3):642-646. doi: 10.1016/j. jvs.2006.05.015.

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19. Vikatmaa P, Makitie AA, Railo M, Tornwall J, Alback A, Lepantalo M. Midline mandibulotomy and interposition grafting for lesions involving the internal carotid artery below the skull base. J Vasc Surg. 2009;49(1):86-92. doi: 10.1016/j.jvs.2008.08.047. 20. Frim DM, Padwa B, Buckley D, Crowell RM, Ogilvy CS. Mandibular subluxation as an adjunct to exposure of the distal internal carotid artery in endarterectomy surgery. technical note. J Neurosurg. 1995;83(5):926-928. doi: 10.3171/jns.1995.83.5.0926. 21. Eskandari MK, Longo GM, Matsumura JS, et al. Carotid stenting done exclusively by vascular surgeons: First 175 cases. Ann Surg. 2005;242(3):431-6; discussion 436-8. 22. Brown KE, Usman A, Kibbe MR, et al. Carotid stenting using tapered and nontapered stents: Associated neurological complications and restenosis rates. Ann Vasc Surg. 2009;23(4):439-445. doi: 10.1016/j. avsg.2008.11.007. 23. Bosiers M, Deloose K, Verbist J, Peeters P. Carotid artery stenting: Which stent for which lesion? Vascular. 2005;13(4):205-210. 24. Elpiniki T, Salviato E, Rocca T, Braccini L, Galeotti R, Mascoli F. Heparin surface stent-graft for the treatment of a carotid pseudoaneurysm. Ann Vasc Surg. 2010;24(7):952.e9-952.e12. doi: 10.1016/j.avsg.2010.02.046. 25. Taha MM, Nakahara I, Higashi T, Iwamuro Y, Watanabe Y, Taki W. Interventional neuroradiological techniques for the treatment of aneurysms of the supra-aortic extracranial arteries. Neurol Med Chir (Tokyo). 2010;50(4):275-280. 26. Ghazi P, Haji-Zeinali AM, Zarghampour M. Staged endovascular treatment of left common carotid artery large aneurysm with gore-hemobahn stent-graft after right common carotid artery stenosis angioplasty. J Invasive Cardiol. 2010;22(7):E129-31. 27. Loffroy R, Rao P, Ota S, et al. Packing technique for endovascular coil embolisation of peripheral arterial pseudo-aneurysms with preservation of the parent artery: Safety, efficacy and outcomes. Eur J Vasc Endovasc Surg. 2010;40(2):209-215. doi: 10.1016/j.ejvs.2010.03.009. 28. Holder R, Hilton D, Martin J, Harris PL, Rowlands PC, McWilliams RG. Percutaneous thrombin injection of carotid artery pseudoaneurysm. J Endovasc Ther. 2002;9(1):25-28. 29. Groot de D, Herwaarden van JA, Borst de GJ, Lo R, Moll FL. Extra-cranial carotid aneurysm exclusion by bare metal stent. Charing cross symposium oral presentation. 2009. 30. Fischer S, Vajda Z, Aguilar Perez M, et al. Pipeline embolization device (PED) for neurovascular reconstruction: Initial experience in the treatment of 101 intracranial aneurysms and dissections. Neuroradiology. 2011. doi: 10.1007/s00234-011-0948-x. 31. Lylyk P, Miranda C, Ceratto R, et al. Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: The buenos aires experience. Neurosurgery. 2009;64(4):632-42; discussion 642-3; quiz N6. doi: 10.1227/01.NEU.0000339109.98070.65.

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J.C. Welleweerd MD1, V.E.C. Pourier MD1, L.J. Kappelle MD PhD2, G.J.E. Rinkel MD2 Y.M. Ruigrok MD PhD2, H.B. van der Worp MD PhD2, T.H. Lo, MD3, F.L. Moll MD PhD1, G.J. de Borst MD PhD1 ascular Surgery, University Medical Center Utrecht, The Netherlands V Neurology, University Medical Center Utrecht, The Netherlands 3 Department of Radiology, University Medical Center Utrecht The Netherlands 1

Conservative treatment of extracranial carotid artery aneurysms Submitted

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Abstract Objective Extracranial carotid artery aneurysms (ECAA) are rare but can potentially cause major thromboembolic neurologic events. No evidence-based treatment guidelines are available, but in asymptomatic and non-growing aneurysms a conservative strategy may be warranted. Limited data exist on long-term outcome of conservative treatment in these patients. This study reports our single center experience with conservative management in patients with an ECAA. Methods In our tertiary referral center from 1999 to 2014, a consecutive series of 28 patients, with a mean age of 51 years, were retrospectively analyzed. Three patients had bilateral aneurysms, resulting in a total of 31 aneurysms in the present analysis. Treatment decisions were made by the individual specialist. Conservative treatment consisted of follow-up alone in 9 patients (11 aneurysms) and 19 patients (20 aneurysms) received anticoagulant or antiplatelet medication. Primary study endpoint was ipsilateral stroke and secondary endpoint was any symptom related to the aneurysm. Results In this cohort, all patients with no symptoms related to the aneurysm at presentation remained asymptomatic during follow-up. One patient, who refused invasive treatment for an asymptomatic but growing ECAA, had a fatal ipsilateral ischemic stroke 13 months after the aneurysm was discovered. Furthermore, one patient, who initially presented with local symptoms experienced TIA like sensation. There were three, not aneurysm related, deaths during follow-up. Conclusion During short-term follow-up the risk of cerebral infarction in the territory of the affected carotid artery seems small, but large data describing long-term follow-up are needed. In patients with small asymptomatic ECAA it seems justified to consider a conservative approach.

Conservative treatment of ECAA

Introduction Aneurysms of the extracranial carotid artery (ECAA) are rare, with reports on treatment of only around 1000 cases in world literature.1 The etiology is divers and ranges from atherosclerosis, infection, granulomatous disease, to (traumatic) dissection.2 Most ECAA are asymptomatic and coincidental findings. However ECAA can result in a pulsatile mass, cranial nerve compression or major thromboembolic neurological sequelae.3-5 No evidence based guidelines or indications to guide therapy are available. Available literature consists of (mostly retrospective) case series.1 To determine treatment indications knowledge especially on the natural course of ECAA is needed. In current literature, some consider the natural course to be poor because of reported stroke and mortality rates of more than 50%.6-8 However, these figures might be outdated. Based on a small series reporting stable follow-up and even shrinkage of these aneurysms, a conservative approach seems also warranted in asymptomatic post-dissection ECAA.9 To date, a conservative strategy is considered appropriate for asymptomatic and nongrowing extracranial carotid aneurysms but this recommendation is based on level 3 evidence without data from prospective studies.1,4 Therefore, in this single center series, we reviewed the midterm outcome of patients with ECAA receiving conservative treatment.

Methods Patients This retrospective study analyzed a consecutive series of 28 patients (19 men). All patients were referred, in the last 15 years, for an ECAA to our tertiary vascular referral and stroke center. Data on patient characteristics, aneurysm characteristics, intervention, and short and long-term outcomes were collected using a prespecified form. Mean age of the patients was 51 years (SD 13.6). Patient characteristics and risk factors are presented in Table 1.

Table 1. Patient characteristics n=27 Male

19 (67.9%)

Mean age (mean, SD)

51.4 (13.6)

Hypertension

12 (42.9%)

COPD Hyperlipidemia

2 (7.1%) 8 (28.6%)

Smoking Current smoker

5 (17.9%)

Previous smoker

7 (25.0%)

nonsmoker

9 (32.1%)

3 (10.7%)

Coronary heart disease

4 (14.3%)

Peripheral arterial disease Other aneurysms

2 (7.1%) 3 (10.7%)

DM diabetes mellitus; n number of patients; SD standard deviation.

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ECAA Table 2. Aneurysm characteristics ECAA were defined as a 150% fusiform n (%) dilatation of the normal vessel diameter or Side a saccular aneurysm of any size. To be Left 14 (45.2%) included, aneurysms had to be located in Right 17 (54.8%) the common carotid artery, the external Location carotid artery or in the extracranial part of Distal ICA 13 (41.9%) the internal carotid artery (ICA). Extracranial Prox. ICA 3 (9.7%) was defined as any location between the CCA 1 (3.2%) CCA origin at the aortic arch and the carotid ECA 0 (0.0%) siphon at the skull base. NR 13 (41.9%) Aneurysms were bilateral in three patients, Size (median, range) resulting in a total of 31 aneurysms in this 10.6 mm (4-48) study (Table 2). The diagnosis was Shape established by computed tomography Saccular 23 (74.2%) angiography in 14 aneurysms, magnetic Fusiform 7 (22.6%) resonance imaging in 15 cases, digital NR 1 (3.2%) subtraction angiography in one aneurysm n number of aneurysms; Prox. ICA proximal and in one aneurysm the imaging method internal carotid artery; CCA common carotid artery; ECA external carotid artery; NR not was not reported. The median ECAA reported. diameter was 11 mm (range 4-48 mm) and aneurysms were more frequently located on the right side (n=17). The majority of aneurysms were saccular (n=23) and localized in the distal ICA (n=13). A total of 15 aneurysms arose after dissection, two aneurysms were caused by connective tissue diseases, and one aneurysm was qualified as atherosclerotic. Clinical presentation Most patients were asymptomatic at presentation (n=21). Two patients had experienced events (transient ischemic attack (TIA), n=2), but were asymptomatic for three and nine months at the time of presentation in our hospital. (Table 3) Symptoms were present in 10 patients at presentation. A neurologic event was the presenting symptom in two cases (stroke n=1, TIA n=1). Eight patients had local symptoms of the aneurysm of which two patients presented with a pulsatile mass in the neck. Treatment Treatment consisted of follow-up alone in 11 aneurysms and in 20 aneurysms follow-up was combined with anticoagulant or antiplatelet medication (acetylsalicylic acid n=10, acetylsalicylic acid and dipyridamole n=5, acetylsalicylic acid and clopidogrel n=1, fenprocoumon n=2, acenocoumarol and clopidogrel n=1, ascal and prasugrel n=1). In most patients the indication for conservative treatment was an asymptomatic aneurysms (n=21).

Conservative treatment of ECAA

Outcome Table 3. Presenting symptoms Primary outcome measurement was ipsilateral ischemic stroke. Stroke was Asymptomatic defined as any central neurological deficit Asymptomatic, with a history of neurologic event in the vascular territory of the aneurysmatic CND vessel, with an acute onset persisting for at Mass least 24 hours for which no other cause Headache could be found. Stroke The secondary outcome was all aneurysm TIA related symptoms reported by the patient Tinnitus during follow-up. Symptoms considered to Total be aneurysm related were a mass in the CND cranial nerve dysfunction; neck, cranial nerve dysfunction (including ischemic attack. hoarseness and dysphagia), TIA in the vascular territory of the aneurysmatic vessel, aneurysm rupture, local pain or sensory sensations and headache.

n (%) 19 (61.3%) 2 (6.5%) 3 (9.7%) 2 (6.5%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 31 (100%) TIA transient

Statistical analysis For continuous variables, means and standard deviations (SD) or medians and ranges were calculated, and for categorical variables, absolute numbers and/or percentages were calculated.

Results All patients were available for follow-up, with a mean follow-up duration of with a mean follow-up duration of 2.5 years (SD 2.8) years. Asymptomatic ECAA All patients with asymptomatic and non-growing ECAA had a favorable outcome. (Table 4) There were no central neurological symptoms during follow-up, with a mean duration of 30 months (SD 35 months). Two patients died during follow-up from other causes (one of lung carcinoma and one patient died after four months of an unknown cause, though at autopsy there were no indications of carotid aneurysm rupture). Asymptomatic, growing ECAA During follow-up repeated imaging demonstrated aneurysm growth in one patient. This asymptomatic patient, with an 22 mm aneurysm of the left ICA, was advised to undergo surgical resection, which she refused. This patient was admitted to our hospital because of a stroke in the posterior circulation 13 months after diagnosis. (Table 4) During this admission this patient also had a major stroke in the vascular territory of the middle cerebral artery, which was eventually fatal. CTA showed thrombosis of the entire MCA and ICA distal of the aneurysm. 87

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FU Time (months) mean (SD)

FU fatal stroke

FU non-fatal stroke

FU TIA

FU mortality NAR

Table 4. Treatment outcome

Asymptomatic

29.9 (35.0)

0 (0.0%)

2 (10.0%)

Asymptomatic, growing

13.0 (-)

1 (100%)

0 (0.0%)

Local symptoms, non-growing

33.9 (34.8)

0 (0.0%)

1 (12.5%)

Central neurological symptoms, non-growing

31.5 (44.6)

0 (0.0%)

n number of patients; TIA transient ischemic attack; NAR Not Aneurysm Related; FU follow-up.

Symptomatic ECAA with local symptoms During follow-up, with a mean duration of 34 months (SD 35 months), One patient, who initially presented with local symptoms of the ECAA, experienced a single TIA like sensation in her eye and left arm. (Table 4) A mass was visible one patient, this patient also had a tingling sensation in the neck. One patient died during follow-up due to myocardial infarction. Symptomatic ECAA with central neurologic event A conservative strategy was also adopted in four patients with a single central neurologic event (minor stroke, TIA or amarousis fugax). During follow-up, with a mean duration of 32 months (SD 45 months) all patients remained asymptomatic. (Table 4)

Discussion This study shows that risk of cerebral infarction in the territory of the affected carotid artery is low during short-term follow-up in asymptomatic and stable ECAA. Therefore, in these stable and asymptomatic aneurysms a conservative strategy might be justified, consisting of follow-up and antiplatelet or anticoagulation medication.4 However, this report shows postponing treatment in growing aneurysms can be fatal. This study reports on one of the largest experiences with conservative management in ECAA.1 The low stroke and mortality rate we found for conservative management of ECAA is in agreement with the one other publication on conservative management in ECAA, which described a series of patients with dissecting aneurysms.9 The major part of the aneurysms in this study remained asymptomatic and did not increase in size while some even spontaneously resolved.9 The earlier reported stroke rate of 50% is derived from literature from the beginning of the 20th century.6,7 On the basis of this rate, many aneurysms of the extracranial carotid artery have been treated invasively. It must be noted this rate includes all ECAAs, including 88

Conservative treatment of ECAA

mycotic, symptomatic and growing aneurysms. Furthermore, these patients were not treated with anticoagulant or antiplatelet medication, which is currently a well-accepted preventive therapy for cardiovascular events.10 Medical therapy choice in ECAA has been unexplored and needs to be further investigated. However, ECAA can occur after dissection in the carotid artery or in patients with generalized atherosclerotic disease. In these diseases medical therapy has been long used and scientifically substantiated. This study has limitations, first of all, because the retrospective character there is missing data regarding aneurysm and patient characteristics. Some patients have been lost to follow-up or the physician ceased follow-up for unknown reasons. Secondly, there is selection bias, the sample in this study consist of patient in whom the treating physician selected a treatment strategy based on the patientâ&#x20AC;&#x2122;s clinical presentation and aneurysm characteristics. Furthermore, although this study is one of the largest reports on conservative management in ECAA a larger population is needed to substantiate treatment guidelines.11

Conclusion In conclusion, during short-term follow-up the risk of cerebral infarction in the territory of the affected carotid artery seems small, but large data describing long-term follow-up are needed. In patients with small asymptomatic ECAA it seems justified to consider a conservative approach.

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References 1.

Welleweerd JC, den Ruijter HM, Nelissen BGL, et al. Treatment for extracranial carotid artery aneurysm. A systematic review and meta-analysis. submitted. 2014.

Welleweerd JC, Nelissen BGL, Koole D, et al. Histological analysis of extracranial carotid artery aneurysms.

De Jong KP, Zondervan PE, Van Urk H. Extracranial carotid artery aneurysms. Eur J Vasc Surg. 1989;3(6):557562.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200.

Radak D, Davidovic L, Vukobratov V, et al. Carotid artery aneurysms: Serbian multicentric study. Ann Vasc

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg.

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc

Surg. 2007;21(1):23-29.

2000;31(4):702-712. doi: 10.1067/mva.2000.104101.

Surg. 1984;1(3):415-422. 8.

Nathan Winslow M. Extracranial aneurysm of the internal carotid artery: history and analysis of the cases registered. Arch Surg. 1926;13(5):689-729.

Guillon B, Brunereau L, Biousse V, Djouhri H, Levy C, Bousser M-. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology. 1999;53(1):117-122.

10. Antithrombotic Trialistsâ&#x20AC;&#x2122; Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. 11. Welleweerd JC, Bots ML, Kappelle LJ, et al. Rationale and design of the extracranial carotid artery aneurysm registry (CAR). J Cardiovasc Surg (Torino). 2015 Feb 6. [Epub ahead of print]

chapter

Janna C. Welleweerd MD1, Gert Jan de Borst MD, PhD1, Daphne de Groot MD, PhD2, Joost A. van Herwaarden MD, PhD1, Rob T.H. Lo, MD2, Frans L. Moll MD, PhD1 1 2

ascular Surgery, University Medical Center Utrecht, the Netherlands V Radiology, University Medical Center Utrecht, the Netherlands

Bare metal stents for treatment of extracranial internal carotid artery aneurysms: long-term results J Endovasc Ther. 2015 Feb;22(1):130-134

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Abstract Purpose To examine the long-term outcomes of bare metal stent placement for exclusion of extracranial internal carotid artery (ICA) aneurysms. Methods From 2006 to 2011, 7 consecutive symptomatic patients (4 men; mean age 52 years) with surgically inaccessible extracranial ICA aneurysms were treated with a bare stent at a single center. Patients received clopidogrel and aspirin for 3 months after the procedure and aspirin thereafter for life. Clinical follow-up with duplex ultrasound and/or computed tomographic angiography was performed at 3, 6, and 12 months and yearly thereafter. Results All procedures were technically successful; no neurological complications occurred. After 6 months, there was complete thrombosis of the aneurysm in all except one case. In this asymptomatic patient, the residual active flow was successfully obliterated by additional coil embolization. Over a mean follow-up of 57Âą22 months, all patients were alive and free of local or central neurological symptoms. All stents were patent, and thrombosis of the aneurysms was complete. Conclusion In this small series, treatment of extracranial ICA aneurysms with a bare stent seems technically feasible and safe. All treated extracranial ICA aneurysms were excluded by primary intervention or secondary coil embolization.

Introduction Surgical treatment of an extracranial internal carotid artery (ICA) aneurysm is a rare intervention, compromising <2% of all arterial aneurysm repairs.1 If left untreated, ICA aneurysm may lead to significant morbidity2 and remain as a potential source of emboli to the brain.3 A carotid aneurysm may also present as a pulsating cervical mass or cranial nerve dysfunction due to local compression. In symptomatic patients, complete aneurysm resection with arterial reconstruction is currently considered the treatment of choice.4-6 However, no evidence-based guidelines exist for extracranial carotid aneurysm treatment, and numerous techniques for exclusion have been reported in literature.4 Extracranial ICA aneurysm at the base of the skull often can be approached surgically, but distal exposure and control may be hard to obtain.6-9 Therefore, stent placement has been proposed as an alternative in these situations. The stent needs to bridge healthy to healthy arterial tissue and subsequently promote thrombosis in the excluded aneurysm with continuation of blood flow to the brain. In the scarce available literature, mostly covered stents have been applied in the treatment of extracranial ICA aneurysm.10 94

Outcome of bare metal stent placement in ECAA

Some investigators have shown that pressure reduction and exclusion of intracranial aneurysms is feasible using bare metal stents alone or combined with coil placement.11,12 We report our preliminary experience with bare stent placement in patients with surgically difficult-to-access true extracranial ICA aneurysms.

Methods Patients Between 2006 and 2011, 38 patients with 43 extracranial ICA aneurysms were seen at our tertiary referral center. Of these, 24 aneurysms were treated conservatively, 11 patients underwent surgery, and 8 patients were treated with an endovascular intervention. In the endovascular subgroup, one aneurysm was excluded by coil embolization; the other 7 consecutive patients (4 men; mean age 52 years) with true ICA aneurysms were treated with a bare stent (Table 1) after providing informed consent. Etiology was dissection or trauma in 4 patients, Ehlers Danlos type IV in one, and unknown in the other two, with no signs of dissection on imaging. Five patients were symptomatic; the other two had proven aneurysm growth. All patients underwent computed tomographic angiography (CTA). Indications for treatment were discussed within a multidisciplinary vascular panel.

Table 1. Patient Data and Treatment Outcomes Sex/ Age, y

Presenting Symptoms

Tx Year

Type of Stent

Outcome at 30 Days

FU, mo

Long-term Patency

Long-term Follow-up

1. M/55

Horner syndrome, headache

2006

Precise

Hematoma

Good*

Asymptomatic

2. F/33

Asymptomatic, 2006 ED type 4

Neuroform (×2)

Asymptomatic

Good*

Transient weakness right arm interpreted as epilepsy

3. M/56

Mass

2006

Precise

Asymptomatic

Good*

Asymptomatic

4. F/43

Tinnitus left ear

2007

Protégé

Asymptomatic

Good*

Asymptomatic

5. F/73

Pulsating sensation

2007

Precise

Hematoma; temporary hypoglossal nerve dysfunction

Persistent sac flow (CE)

Asymptomatic

6. M/50

Stroke

2009

Precise

Hematoma; temporary facial nerve dysfunction

Good*

Asymptomatic

7. M/54

Asymptomatic

2011

Solitaire

Asymptomatic

Good*

Asymptomatic

Tx: treatment, FU: Follow-up ED: Ehlers Danlos, CE: coil embolization. *Good: no stenosis, aneurysm excluded.

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All aneurysms were located in the distal ICA and therefore not suitable for surgical resection. Patients were started on dual antiplatelet treatment (clopidogrel 75 mg/d and aspirin 100 mg/d) before treatment. Stent Placement Access to the ICA was obtained through a femoral approach in 2 (Figure 1A) or via a direct common carotid artery (CCA) puncture after standard surgical exposure in 5 patients who had significant kinking in the ICA. In 3 of these patients, the carotid artery was manually straightened; in the other 2, the severely elongated ICA required surgical shortening to facilitate access of guidewires and positioning of a stent in the distal ICA (Figure 1B). When stent placement was combined with a surgical procedure, patients were operated on under general anesthesia with perioperative transcranial Doppler (TCD) and electroencephalographic (EEG) monitoring according to standard hospital protocol for carotid surgical procedures.13,14 The percutaneous transfemoral procedures were performed under local anesthesia and sometimes light sedation. After ICA access was obtained, a 0.014-inch guidewire (Choice PT; Boston Scientific, Natick, MA, USA) was introduced. After carefully maneuvering the guidewire cranially past the aneurysm, a self-expanding bare stent [Precise (Cordis, Bridgewater, NJ, USA),

Figure 1. (A) An aneurysm located in the ICA treated with stent placement over the extracranial carotid artery. The stent is deployed overlapping at least several millimeters of the disease-free artery. (B) Aneurysm located in the distal ICA. First the loop in the artery is resected followed by primary end-to-end anastomosis. The stent is deployed over the aneurysm as in A.

Outcome of bare metal stent placement in ECAA

Protégé (Covidien, Mansfield, MA, USA), Solitaire (Covidien), or Neuroform (Boston Scientific)] was selected based on aneurysm characteristics, vascular anatomy, and diameter of the vessel. In aneurysms with difficult-to-access aneurysms because of loops or kinking, the Neuroform or Solitaire stent was chosen because of superior maneuverability. In one patient, the stent within a stent technique was used to increase the overall metal surface coverage and redirect blood flow.15 ICAs with a >5-mm diameter were treated with a Protégé or Solitaire stent. All stents were deployed overlapping at least several millimeters of the proximal and distal disease-free carotid artery (Figure 1). Technical success, defined as correct stent position overlapping sufficient proximal and distal disease-free artery without compromising the vessel lumen, was assessed by control angiography immediately following stent placement. Follow-up Clinical surveillance was routinely performed with CTA or duplex ultrasound at 3, 6, and 12 months after the procedure and yearly thereafter. All patients continued to receive aspirin lifelong; clopidogrel was stopped 3 months after the procedure.

Results The stent was deployed at the predetermined position in all patients. Completion angiography showed reduced filling of the aneurysm sac in all patients (Figure 2). No emboli were registered by TCD during the combined surgical and endovascular procedures, and EEG did not indicate perioperative cerebral ischemia. No deaths or strokes occurred within 30 days of intervention. Two patients (numbers 5 and 6, Table 1) experienced temporary nerve palsy due to wound traction, with stretching of the auricular branch of the facial nerve; they fully recovered during follow-up. Clinical follow-up was available for all patients with a mean duration of 57±22 months (range 26–84). All patients were alive and without any local or central neurological symptoms during follow-up, which included 17 CTAs and 18 duplex examinations in total. After 6 months, all aneurysms were thrombosed except one (Table 1). In this asymptomatic patient (number 5), scheduled CTA revealed active flow in the aneurysm sac. In addition to clopidogrel, the patient had also been using acenocoumarol for several years after a myocardial infarction. This leakage of contrast through the stent struts was successfully treated by placing coils through the meshwork of the stent until total exclusion of the sac was achieved (Figure 3). Duplex at 3 months after the coil procedure showed no evidence of residual flow in the aneurysm, which had reduced in size. None of the other 6 patients underwent any additional vascular procedure during follow-up. At the most recent examination, the stent was fully patent and thrombosis of the aneurysm sac was complete in all 7 patients.

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Figure 2. (A) An aneurysm located in the distal ICA before stent placement. (B) Reduced filling of the aneurysm sac after stent placement.

Figure 3. (A) Residual flow in the ICA aneurysm after plicature of the carotid artery and subsequent stent placement. (B, C) Coil placement in the aneurysm sac with total exclusion.

Outcome of bare metal stent placement in ECAA

Discussion Accessing an extracranial carotid artery aneurysm can be difficult when it is located distal in the ICA or there is proximal vessel elongation. In our limited series, we showed successful exclusion of the sac using bare stents with the option to place coils at a later stage in case of incomplete thrombosis. The procedure has provided good clinical and technical results in all patients, the majority followed for >5 years. When we began this study, we anticipated that additional interventions, such as coil placement, would be necessary in perhaps half of the patients. Heretofore, exclusion of aneurysms with bare stents had been demonstrated primarily in intracranial aneurysms with coronary stents (15% metal surface coverage). Angiographic follow-up after 1 year showed over three quarters of the patients had complete aneurysm occlusion after initial stent placement.16 A complete obliteration rate of 66% was also demonstrated after placement of the Neuroform stent (6.5%â&#x20AC;&#x201C;9.5% metal coverage) in intracranial aneurysms.11 The 86% complete initial obliteration rate in our series was higher than expected. If stent placement is not sufficient to achieve complete thrombosis of the aneurysm, several additional treatments are available. When there are no clinical symptoms and no aneurysm growth, a wait and see policy can be applied. Carotid aneurysms are considered to have a low risk for rupture, and thrombosis of the aneurysm induced by stent placement will probably prevent thromboembolic events.17 If continued aneurysm perfusion produces symptoms or induces aneurysm growth, coil embolization through the stent meshwork is possible, as demonstrated in our patient.18-21 The mechanism of aneurysm treatment by uncovered stents is probably multifactorial. First of all, it is based on the hemodynamics in the aneurysm sac. For an aneurysm without collaterals, blood flowing into the sac generates vortices. The turbulence becomes stronger until they reach the aneurysm outlet. These continuous movements induce stress in the arterial wall.22 A postulated mechanism of aneurysm exclusion by an uncovered stent is inflow alteration by the stent skeleton. The stent redirects the blood flow from a vortex into laminar flow, leading to stasis of blood in the sac that promotes thrombosis.23-26 Although theoretically every stent will have a certain effect on the inflow of the aneurysm, unfortunately there is no scientific evidence regarding the degree of blood flow redirection of the different stents. Furthermore, stent placement will change (straighten) the geometry of the vessel, which influences inflow and promotes stasis and thrombosis within the aneurysm. Another factor adding to aneurysm exclusion could be endothelialization and fibroblastic infiltration of the stent from the adjacent vascular wall or circulating myofibroblasts.23,24,26 It must be noted we used these stents in a non-branching artery and probably dissecting aneurysms. In arterial branching, a monolayer stent will decrease the vortex but it will persist, while a multilayer stent will laminate the flow.22 The superior flexibility of bare stents compared to covered stents is very useful in guiding through the often tortuous carotid arteries.27 The superior flexibility of the bare stents compared to the covered stent might also result in less stent-induced kinking because the bare stent is more prone to adjust to the shape of the vessel. Besides flexibility, bare 99

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stents have another advantage: covered stents are more prone to in-stent stenosis and thrombosis at short and long-term follow-up.28,29 In 2006, when we started using bare stents in ICA aneurysms, flow-diverting stents (FDS; 30%â&#x20AC;&#x201C;35% metal coverage) were just coming to market. They had been developed after promising outcomes of bare stent monotherapy in intracranial aneurysms (obliteration rates of 86% to 93%30,31). In our study, we demonstrated an obliteration rate of 86%; even taking into account the additional intervention in one patient, this method would still have been less expensive than if we had used an FDS. Even today, with the wide availability of FDS, bare stent placement in extracranial ICA aneurysms could be more economical. Limitations The single center experience and small number of patients in our study as a result of the low incidence of ICA aneurysm are shortcomings of this study. Due to different morphology of the aneurysms and anomalies of surrounding anatomy, different type of stents and access modes had to be used. Nonetheless, we were able to achieve durable aneurysm exclusion with only one reintervention in our cohort. Conclusion Bare stent treatment is technically feasible and safe in a non-branching aneurysm of the extracranial ICA. Our limited experience in this small series has produced excellent medium and even long-term outcomes.

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References 1.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200.

Radak D, Davidovic L, Vukobratov V, et al. Carotid artery aneurysms: Serbian multicentric study. Ann Vasc Surg. 2007;21(1):23-29.

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc

Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms.

Surg. 1984;1(3):415-422.

Expert Rev Cardiovasc Ther. 2012;10(7):925-931. 5. 6.

Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183. Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x.

Attigah N, Kulkens S, Zausig N, et al. Surgical therapy of extracranial carotid artery aneurysms: Long-term results over a 24-year period. Eur J Vasc Endovasc Surg. 2009;37(2):127-133. doi: 10.1016/j.ejvs.2008.10.020.

Trinidad-Hernandez M, Introcaso JH, White JV. Combined open and endovascular treatment of a saccular aneurysm and redundant loop of the internal carotid artery. J Vasc Surg. 2006;44(3):642-646. doi: 10.1016/j. jvs.2006.05.015.

10. Li Z, Chang G, Yao C, et al. Endovascular stenting of extracranial carotid artery aneurysm: A systematic review. Eur J Vasc Endovasc Surg. 2011;42(4):419-426. 11. Gross BA, Frerichs KU. Stent usage in the treatment of intracranial aneurysms: Past, present and future. J Neurol Neurosurg Psychiatry. 2013;84(3):244-253. doi: 10.1136/jnnp-2011-302007 [doi]. 12. Saatci I, Yavuz K, Ozer C, Geyik S, Cekirge HS. Treatment of intracranial aneurysms using the pipeline flowdiverter embolization device: A single-center experience with long-term follow-up results. AJNR Am J Neuroradiol. 2012;33(8):1436-1446. doi: 10.3174/ajnr.A3246 [doi]. 13. Ballotta E, Saladini M, Gruppo M, Mazzalai F, Da Giau G, Baracchini C. Predictors of electroencephalographic changes needing shunting during carotid endarterectomy. Ann Vasc Surg. 2010;24(8):1045-1052. doi: 10.1016/j.avsg.2010.06.005 [doi]. 14. Pennekamp CW, Moll FL, de Borst GJ. The potential benefits and the role of cerebral monitoring in carotid endarterectomy. Curr Opin Anaesthesiol. 2011;24(6):693-697. doi: 10.1097/ACO.0b013e32834c7aa1 [doi]. 15. Mehta B, Burke T, Kole M, Bydon A, Seyfried D, Malik G. Stent-within-a-stent technique for the treatment of dissecting vertebral artery aneurysms. AJNR Am J Neuroradiol. 2003;24(9):1814-1818. 16. Zenteno MA, Santos-Franco JA, Freitas-Modenesi JM, et al. Use of the sole stenting technique for the management of aneurysms in the posterior circulation in a prospective series of 20 patients. J Neurosurg. 2008;108(6):1104-1118. doi: 10.3171/JNS/2008/108/6/1104 [doi]. 17. Dawson J, Fitridge R. Update on aneurysm disease: Current insights and controversies. peripheral aneurysms: When to intervene - is rupture really a danger? Prog Cardiovasc Dis. 2013;56(1):26-35. 18. Bush RL, Lin PH, Dodson TF, Dion JE, Lumsden AB. Endoluminal stent placement and coil embolization for the management of carotid artery pseudoaneurysms. J Endovasc Ther. 2001;8(1):53-61. doi: 2.

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19. Fessler RD, Ringer AJ, Qureshi AI, Guterman LR, Hopkins LN. Intracranial stent placement to trap an extruded coil during endovascular aneurysm treatment: Technical note. Neurosurgery. 2000;46(1):248-51; discussion 251-3. 20. Klein GE, Szolar DH, Raith J, Fruhwirth H, Pascher O, Hausegger KA. Posttraumatic extracranial aneurysm of the internal carotid artery: Combined endovascular treatment with coils and stents. AJNR Am J Neuroradiol. 1997;18(7):1261-1264. 21. Phatouros CC, Sasaki TY, Higashida RT, et al. Stent-supported coil embolization: The treatment of fusiform and wide-neck aneurysms and pseudoaneurysms. Neurosurgery. 2000;47(1):107-13; discussion 113-5. 22. Henry M, Plydorou A, Frid N, et al. Treatment of renal artery aneurysm with the multilayer stent. J Endovasc Ther. 2008;15(2):231-236. 23.

Ruiz CE, Zhang HP, Butt AI, Whittaker P. Percutaneous treatment of abdominal aortic aneurysm in a swine model: Understanding the behavior of aortic aneurysm closure through a serial histopathological analysis. Circulation. 1997;96(7):2438-2448.

24. Ruiz CE, Zhang HP, Douglas JT, Zuppan CW, Kean CJ. A novel method for treatment of abdominal aortic aneurysms using percutaneous implantation of a newly designed endovascular device. Circulation. 1995;91(9):2470-2477. 25. Sim SY, Shin YS, Cho KG, et al. Blood blister-like aneurysms at nonbranching sites of the internal carotid artery. J Neurosurg. 2006;105(3):400-405. doi: 10.3171/jns.2006.105.3.400. 26. Villareal RP, Kar B, Howell MH, Strickman N, Krajcer Z. Bare metal stents with or without coil embolization for abdominal aortic aneurysm exclusion in high-risk patients. Catheter Cardiovasc Interv. 2001;54(1):12-18. 27. Del Corso L, Moruzzo D, Conte B, et al. Tortuosity, kinking, and coiling of the carotid artery: Expression of atherosclerosis or aging? Angiology. 1998;49(5):361-371. 28. Liu AY, Paulsen RD, Marcellus ML, Steinberg GK, Marks MP. Long-term outcomes after carotid stent placement treatment of carotid artery dissection. Neurosurgery. 1999;45(6):1368-73; discussion 1373-4. 29. Schillinger M, Dick P, Wiest G, et al. Covered versus bare self-expanding stents for endovascular treatment of carotid artery stenosis: A stopped randomized trial. J Endovasc Ther. 2006;13(3):312-319. doi: 10.1583/061819.1. 30. Lylyk P, Miranda C, Ceratto R, et al. Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: The buenos aires experience. Neurosurgery. 2009;64(4):632-42; discussion 642-3; quiz N6. doi: 10.1227/01.NEU.0000339109.98070.65 [doi]. 31. Klisch J, Eger C, Sychra V, Strasilla C, Basche S, Weber J. Stent-assisted coil embolization of posterior circulation aneurysms using solitaire ab: Preliminary experience. Neurosurgery. 2009;65(2):258-66; discussion 266. doi: 10.1227/01.NEU.0000348295.44970.C8 [doi].

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J.C. Welleweerd MD1, M.L. Bots MD PhD2, L.J. Kappelle MD PhD3, G.J.E. Rinkel MD3, Y.M. Ruigrok MD PhD3, A.F. Baas MD PhD4, H.B. van der Worp MD PhD3, M.D.I. Vergouwen MD PhD3, R.L.A.W. Bleys MD PhD5, J. Hendrikse MD PhD6, T.H. Lo MD6, F.L. Moll MD PhD1, G.J. de Borst MD PhD1 Department of Vascular surgery, UMCU, Utrecht, The Netherlands Julius Center for Health Sciences and Primary Care, UMCU, Utrecht, The Netherlands 3 Department of Neurology and Neurosurgery, UMCU, Utrecht, The Netherlands 4 Department of Medical genetics, UMCU, Utrecht, The Netherlands 5 Department of Anatomy, UMCU, Utrecht, The Netherlands 6 Department of Radiology, UMCU, Utrecht, The Netherlands 1

Rationale and design of the extracranial Carotid artery Aneurysm Registry J Cardiovasc Surg (Torino). 2015 Feb 6. [Epub ahead of print]

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Abstract Objectives Aneurysms of the extracranial carotid artery (ECAA) are rare. Although most ECAA are identified in asymptomatic patients, serious neurological complications may occur. Current literature on treatment outcome contains mainly case reports and small case series with incomplete data and lack of long-term follow-up. There is clear lack on natural follow-up data, and there is no clear treatment algorithm. An international webbased registry to collect data on patients with ECAA is designed to provide clinical guidance on this scarce pathology. Methods The Carotid Aneurysm Registry (CAR) is open for inclusion of all patients with a fusiform or saccular ECAA. Patients with primary or secondary ECAA can be enrolled in CAR independent of the type of treatment (conservative or invasive). CAR participation does not interfere with the local physicianâ&#x20AC;&#x2122;s treatment policy. Follow-up and imaging can also be scheduled according to local clinical practice. The primary endpoint of the CAR in conservative patients is occurrence of symptoms related to the aneurysm at 30 days, one, three, and five years. The primary endpoint in invasively treated patients is freedom from symptoms of the aneurysm at 30 days, one, three, and five years. Analyses will relate outcome to etiology, imaging characteristics, ECAA growth patterns, and (if applicable) revascularization technique applied. Discussion The aim of the registry is to prospectively collect follow-up data on patients with an ECAA, being either treated conservatively or by invasive aneurysm exclusion strategies. The CAR database will be used to address diagnostic and therapeutic research questions. Collecting and analyzing the data gained from the registry could be the first step towards development of treatment guidelines and expert consensus for the management of ECAA.

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Rationale and design of the CAR

Introduction Extracranial carotid artery aneurysms (ECAA) are very rare. Due to limitations in the literature consisting of only case reports and small case series, data on the incidence is lacking.1 Most ECAA are asymptomatic and found by coincidence. When patients are symptomatic, most frequent they experience a local problem such as a pulsatile mass or have local compression of the pharynx or peripheral nerves. The most feared complications are ischemic stroke due to embolism from the aneurysm and rupture. However, rupture occurs infrequently.2,3 Etiology is diverse and ranges from atherosclerosis, infection, fibromuscular dysplasia, and connective tissue disease, to traumatic or â&#x20AC;&#x2DC;spontaneousâ&#x20AC;&#x2122; dissection.4-6 The natural course is probably poor, with a reported stroke rate of up to 50%.2,7,8 Asymptomatic ECAA could be treated with a wait-and-see policy or best medical treatment, as suggested by some authors.4 These suggestions are mainly expert opinions based on clinical experience while scientific data is lacking. Surgical resection of the aneurysm, with arterial reconstruction, is considered by many to be the gold standard for symptomatic ECAA.2,8-10 For ECAA due to a traumatic etiology, endovascular stenting has been advocated in the past decade. Although success rates of endovascular therapy are high, no long-term follow-up is available.11,12 For proper assessment of what treatment should be preferred, a better insight into the natural history and risk of complications of the different treatments is needed. To collect data on ECAA we designed the Carotid Aneurysm Registry (CAR), a prospective webbased international registry assessing follow-up in patients with an ECAA. For detailed objectives of the CAR see Table 1. The primary aim of this registry is to collect data on ECAA to assess the natural history of ECAA and the safety and durability of different treatment strategies.

Methods CAR is a prospective web-based international observational registry collecting data on patients with an ECAA. The initiative for CAR was started by the Department of Vascular Surgery at the University Medical Centre of Utrecht (UMCU), being a large vascular tertiary referral center in The Netherlands. The registry will be conducted according to the principles of the Declaration of Helsinki (as last amended at the 64th WMA General Assembly, Fortaleza, Brazil, October 2013).13 The medical ethics committee of the UMCU has approved the study and all patients must give written informed consent before enrollment. We intend to include as many patients as possible in this registry, the inclusion will be ongoing.

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Enrollment criteria Participation in the CAR is intended for all patients diagnosed with an ECAA, either primary or secondary, and fusiform or saccular (Table 2). Fusiform aneurysms are defined as 150% dilatation of the normal vessel diameter, saccular aneurysm as a distended sac of any size affecting only part of the arterial circumference. To be included, aneurysms must be located in the common carotid artery (CCA), the external carotid artery or in the extracranial part of the internal carotid artery (ICA). Extracranial is defined as any location between the CCA origin at the aortic arch and the carotid siphon at the skull base. To be included in the registry, patients need to be 18 years or older. All patients must give written informed consent before enrollment. There are no additional exclusion criteria. Treatment and follow-up Data registration within CAR does not interfere with the physicianâ&#x20AC;&#x2122;s treatment decision. Furthermore, patients who only receive medication or are followed in time can also be

Table 1. Carotid Aneurysm Registry Objectives International Objective 1

To provide data on the natural course of ECAA.

The registry collects detailed information on patient- and aneurysm characteristics in patients who are followed in time and did not receive treatment. Outcome is collected at 30 days after diagnosis and during follow-up.

Objective 2

To provide data on existing and evolving practice patterns.

The registry collects detailed information on patient characteristics, aneurysm characteristics and type of intervention.

Objective 3

To identify risk factors for thrombo-embolic complications related to the aneurysm.

The registry collects detailed information on patient characteristics, aneurysm characteristics and thrombo-embolic complications.

Objective 4

To document the safety of invasive ECAA treatment.

The registry collects detailed information on type of intervention and peri- and postoperative complications.

Objective 5

To document freedom of symptoms of the aneurysm after invasive treatment at short and mid- and long-term follow-up.

The registry collects detailed information on treatment outcome. Outcome is collected at 30 days and during follow-up.

Objective 6

To identify optimal imaging techniques in diagnostics, pre-interventional planning and follow-up in ECAA patients.

A local prospective study to identify optimal imaging techniques is underway.

Objective 7

To identify genetic causes or familial patterns in ECAA.

Patients will be evaluated for signs of connective tissue disease. If indicated, diagnostic gene analysis will be performed. Single blood withdrawal is performed, after specific informed consent, in patients from our hospital who are included in the registry for future genetic research.

Objective 8

To identify histological characteristics of ECAA.

Tissue from patients undergoing aneurysm resection in our hospital, after specific informed consent, will be used to further study the histology of ECAA.

Local

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Table 2. Inclusion criteria Inclusion criteria CAR 1

Individual has a single or bilateral aneurysm(s) of the extracranial carotid artery. Defined as 150% dilatation of the normal vessel diameter, or any saccular aneurysm. The aneurysm is located between the CCA origin at the aortic arch and the carotid siphon at the skull base.

Individual is â&#x2030;Ľ18 years of age.

Individual has signed informed consent

included in our registry. Treatment and follow-up visits, including imaging studies, are performed and scheduled as usual in the treating physicianâ&#x20AC;&#x2122;s clinical practice, as this study does also not interfere with or influence the follow-up regimen. Conservative management and invasive treatment can be performed according to standard practice at the local clinical site. The first visit after any initial intervention will be considered the 30-day visit and the timing of this visit may vary according to local follow-up regimen. When follow-up is discontinued by the treating physician, the patient will be sent a short questionnaire after one and five years. The local physician can at all time consult the UMCU multidisciplinary expert team, or refer the patient for a clinical advice. Study endpoints 1) Conservative management. The primary endpoint is occurrence of aneurysm related symptoms at one, three and five years. Occurrence of symptoms is defined as any new or worsening of existing aneurysm related symptoms. Aneurysm related symptoms include ischemic stroke or transient ischemic attack (TIA) in the territory of the relevant carotid artery, all symptoms due to compression (dysphagia, nerve dysfunction, etc.), cervical mass, local pain or headache, tingling sensations, hematoma and local bleeding due to aneurysm rupture. TIA is defined as any central neurological deficit with an acute onset persisting for less than 24 hours for which no other cause could be found. Stroke is defined as any central neurological deficit with an acute onset persisting for at least 24 hours for which no other cause could be found. Disability will be assessed with the modified Rankin scale.14 2) Invasive treatment. The primary endpoint is freedom from aneurysm related symptoms (defined as described above) at 30 days and at one, three and five years. Freedom from aneurysm related symptoms is defined as absence of new or worsening aneurysm related symptoms. The secondary endpoint in invasively treated patients comprises treatment safety. Assessment of treatment safety includes scoring of peri- and postoperative complications and registration of re-interventions due to complications performed within 30 days after initial treatment. Complications may include peripheral nerve dysfunction (sensory and motor dysfunction), local hematoma or infection, local pain or headache, TIA, ischemic stroke, local bleeding or aneurysm rupture, and all-cause mortality. All deaths within 30 days after procedure are defined as procedure related. 109

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Endpoint monitoring An endpoint adjudication committee, consisting of clinical experts, is set up to harmonize and standardize endpoint assessment and to determine whether the endpoints meet described criteria (Figure 1). This committee will review important subjective endpoints reported by trial investigators. The members of this committee are blinded to the treatment regimen. Data collection and monitoring Data will be collected on an individual patient basis, and will be recorded through a web-based case report form (CRF) on the study website (www.carotidaneurysmregistry. com). Items scored on the CRF include patient and aneurysm characteristics, imaging, intervention and primary and secondary endpoints (all items are listed in APPENDIX I). Data will be collected at baseline, at the moment of intervention, at the 30-day (or first postoperative) visit and during the follow-up phase, with no predefined end date. Data will be stored anonymously and will remain at the UMCU in a secure environment, as approved by the local ethical committee. CAR is an international multicenter registry. Within each hospital a number of physicians may be involved in the treatment of patients with ECAA. In each contributing hospital one physician can act as a representative for that hospital. The steering committee will meet with these representatives on annual basis to discuss progress (Figure 1).

Caro0d Aneurysm Registry Steering commi:ee

Project management team UMCU

Data entry Adjudica0on commi:ee

Endpoints

Repor0ng Figure 1. flowchart of study organization.

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Annual progress mee0ng

Principle inves0gators par0cipa0ng hospitals

Rationale and design of the CAR

Statistical analysis The data entered in the registry through the web-based CRF will be checked regularly for consistency and completeness. This will be done manually and through statistical monitoring in SPSS. Physicians will be contacted in order to recover incomplete, inconsistent, or missing data. Statistical analyses will take place yearly with reporting after one, three, and five years. Statistical analyses will be performed using SPSS software.

Discussion The natural course of ECAA is still hardly understood. Some authors suggest that an asymptomatic carotid aneurysm could be treated conservatively with either antiplatelet therapy or anticoagulation.4 However, publications on conservative management of ECAA or on the natural history of ECAA are scarce, and treatment decisions based on size, form and etiology need to be further assessed.1 Since knowledge on natural course is required to balance the benefit of any type of intervention, thus far, no treatment guideline or expert consensus for the management of ECAA has been developed (Objective 1, Table 1). Personal experience, aneurysm location and etiology are nowadays important in balancing and choosing the optimal treatment strategy (Objective 2, Table 1). We believe that the main goal in the management of ECAA is 1) to protect patients from unnecessary interventions with their potential hazards; and 2) to be able to identify those patients with a high risk of (thrombo-embolic) complications related to the aneurysm (Objective 3, Table 1). To gain more accurate information regarding the prognosis and results of both conservatively and invasively treated ECAA more research is needed. Initiating a randomized controlled trial is not feasible because of the low incidence of ECAA and the low event rates, but more knowledge regarding natural history and treatment indications might be obtained from a prospective multicenter study or the establishment of an international registry. Therefore, the CAR (Carotid Aneurysm Registry) is designed to prospectively register data on ECAA patients and the treatment outcomes and its risks (Objective 4 and 5, Table 1). Furthermore, the CAR will also comprehend local research initiatives on genetics, imaging and histology in ECAA15 (Objective 6-8, Table 1). Collecting and analyzing the data gained from the registry could be the first step towards treatment guideline or expert consensus for the management of ECAA.

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References 1.

Welleweerd JC, den Ruijter HM, Nelissen BGL, et al. Treatment for extracranial carotid artery aneurysm. A systematic review and meta-analysis. Submitted. 2015.

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712. doi: 10.1067/mva.2000.104101.

Dawson J, Fitridge R. Update on aneurysm disease: Current insights and controversies: Peripheral aneurysms: When to intervene - is rupture really a danger? Prog Cardiovasc Dis. 2013;56(1):26-35. doi: 10.1016/j. pcad.2013.05.002 [doi].

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200.

5. Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98. 6.

Rodrigues VJ, Elsayed S, Loeys BL, Dietz HC, Yousem DM. Neuroradiologic manifestations of loeys-dietz

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc

Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms.

Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183. doi: 10.1053/j.

syndrome type 1. AJNR Am J Neuroradiol. 2009;30(8):1614-1619. doi: 10.3174/ajnr.A1651 [doi].

Surg. 1984;1(3):415-422.

Expert Rev Cardiovasc Ther. 2012;10(7):925-931.

semvascsurg.2005.09.002. 10. Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x. 11. Coldwell DM, Novak Z, Ryu RK, et al. Treatment of posttraumatic internal carotid arterial pseudoaneurysms with endovascular stents. J Trauma. 2000;48(3):470-472. 12. Li Z, Chang G, Yao C, et al. Endovascular stenting of extracranial carotid artery aneurysm: A systematic review. Eur J Vasc Endovasc Surg. 2011;42(4):419-426. 13. World Medical Association. World medical association declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [doi]. 14. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-607. 15. Welleweerd JC, Nelissen BGL, Koole D, et al. Histological analysis of extracranial carotid artery aneurysms. PLoS One. 2015 Jan 30;10(1):e0117915.

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APPENDIX I Intake Patient details Date of birth Sex Male/Female Nationality Race Arabic; Asian; Caucasian; Black; Indian; Other Medical history Vascular medical history None; Unknown; Hypertension; Peripheral arterial occlusive disease; Carotid artery stenosis; Aneurysm elsewhere; Aortic aneurysm; Intracranial aneurysm; Other (vascular) Cardiac medical history None; Unknown; Angina pectoris; Myocardial infarction; PTCA; CAGB; Heart valve disease; Heart valve replacement; Atrial fibrillation; Heart arrhythmia; Cardiac decompensation; Cardiomyopathy; Heart transplantation; Other (cardiac) Diabetes None; Unknown; Non-insulin dependent; Insulin dependent; Diabetes with organ failure; Other (diabetes) Pulmonary medical history None; Unknown; COPD/asthma/ emphysema/chronic bronchitis; Pulmonary fibrosis; Pulmonary transplant/resection; Other (pulmonary) Neurologic medical history None; Unknown; TIA; Stroke (ischemic); Stroke (hemorrhagic); Stroke (subarachnoid hemorrhage); Stroke (not further specified); Muscle disease; Hemiplegia/spinal cord injury; Parkinson disease/dementia; schizophrenia/severe depression/psychosis; Other (neurologic) Other comorbidity Connective tissue disease None; Unknown; Marfan disease; Fibromuscular dysplasia; Ehlers-Danlos syndrome; Loeys-Dietz syndrome Neck None; Unknown; Previous neck surgery; Ipsilateral carotid artery surgery; Ipsilateral central venous catheter; Trauma to the neck 113

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region; Radiation neck Current medication None; Aspirin; Clopidogrel; Prasugrel; Acenocoumarol; Heparin; Statin; Other Patient fitness Modified Rankin Scale No symptoms.; No significant disability: Able to carry out all usual activities, despite some symptoms.; Slight disability: Able to look after own affairs without assistance, but unable to carry out all previous activities.; Moderate disability: Requires some help, but able to walk unassisted.; Moderately severe disability: Unable to attend to own bodily needs without assistance, and unable to walk unassisted.; Severe disability: Requires constant nursing care and attention, bedridden, incontinent.; Dead Family history Family history of aneurysm No; Unknown; AAA;TAAD (thoracic aortic aneurysm/dissection); Visceral aneurysm; Popliteal aneurysm; Intracranial artery aneurysm; Extracranial carotid artery aneurysm Cardiovascular family history No; Yes; Unknown Family history of connective tissue disease Fibromuscular dysplasia; Ehlers-Danlos syndrome; Loeys-Dietz syndrome Risk factors Length (in cm) Weight (in kg) Smoking No; Unknown; Quit smoking; Yes Alcohol (units per week) Hyperlipidemia No; Yes; Unknown Homocysteinemia No; Yes; Unknown Carotid artery aneurysm Affected side Left; Right; Bilateral; Unknown Location Common carotid artery; Proximal internal carotid artery (close to the bifurcation); Distal internal carotid artery (close to the base of the skull); Internal carotid artery (not further specified); External carotid artery; Unknown Shape Saccular; Fusiform; Unknown Measurements (in mm) 114

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Main symptom Asymptomatic; Mass; Peripheral nerve dysfunction; Horner syndrome; TIA in the catchment area (for instance: ipsilateral MCA); Stroke (ischemic) in the catchment area (for instance: ipsilateral MCA); Hematoma; Rupture; Pain local; Headache; Difficulty swallowing; Hoarseness; Unknown; Other Other symptoms Asymptomatic; Mass; Peripheral nerve dysfunction; TIA in the catchment area (for instance: ipsilateral MCA); Stroke (ischemic) in the catchment area (for instance: ipsilateral MCA); Hematoma; Rupture; Pain local; Headache; Difficulty swallowing; Hoarseness; Unknown; Other Presentation Coincidental finding; Symptomatic, referred through the GP; Symptomatic, through the emergency department; During follow-up from vascular or neurosurgery. Presumed etiology Trauma; Dissection; Atherosclerosis; Infection; Connective tissue disease; After carotid surgery; Iatrogenic; Unknown; Other Imaging Available imaging Duplex carotid arteries; CTA carotid arteries; CT brain; MRA carotid arteries; MRA brain Interpretation of duplex Interpretation of CTA carotid arteries Interpretation of CT brain Interpretation of MRA carotid arteries Interpretation of MRA brain Intervention Intervention side Left; Right Did a multidisciplinary team Discuss the case before treatment? Yes; No; Unknown Intervention date Urgency of the intervention Elective: with no urgency; Urgent: subacute, planned >12 hours in advance; Rush: acute, planned <12 hours in advance; Unknown.

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Type of intervention No treatment for ECAA; Medication (any medication started or continued based on an ECAA diagnosis); Endovascular treatment; Surgery; Combined surgery and endovascular treatment; Other. Follow-up <30 days Intervention side Did any complications occur during intervention? Did any radiologic or Surgical re-intervention take place?

Left; Right No; Yes; Unknown

No; Yes; Unknown

Type of re-intervention Re-intubation; Transfusion; Surgery; Endovascular treatment; Other Main reason for re-intervention Bleeding; Infection; Unknown; Other Early complications postoperative None; Mass; Peripheral nerve dysfunction; Stroke (ischemic) in the catchment area (for instance: ipsilateral MCA); TIA in the catchment area (for instance: ipsilateral MCA); Hematoma; Rupture; Pain local; Headache; Difficulty swallowing; Hoarseness; Death; Unknown; Other. Date of hospital discharge Readmission in the hospital No; Yes; Unknown Modified Rankin Scale No symptoms.; No significant disability: Able to carry out all usual activities, despite some symptoms.; Slight disability: Able to look after own affairs without assistance, but unable to carry out all previous activities.; Moderate disability: Requires some help, but able to walk unassisted.; Moderately severe disability: Unable to attend to own bodily needs without assistance and unable to walk unassisted.; Severe disability: Requires constant nursing care and attention, bedridden, incontinent.; Dead.

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Follow-up >30 days Intervention side Left; Right Date of follow up visit Did any symptoms of the (excluded) ECAA occur since the last follow-up visit? None; Mass; Peripheral nerve dysfunction; TIA in the catchment area (for instance: ipsilateral MCA); Stroke (ischemic) in the catchment area (for instance: ipsilateral MCA); Hematoma; Rupture; Pain local; Headache; Difficulty swallowing; Hoarseness; Unknown; Other. Is the patient deceased? No; Yes What was the cause of death? Death as a result of the ECAA; Death with another cause (for example, myocardial infarction); Unknown Date of death Modified Rankin Scale No symptoms.; No significant disability: Able to carry out all usual activities, despite some symptoms.; Slight disability: Able to look after own affairs without assistance, but unable to carry out all previous activities.; Moderate disability: Requires some help, but able to walk unassisted.; Moderately severe disability: Unable to attend to own bodily needs without assistance, and unable to walk unassisted.;Severe disability: Requires constant nursing care and attention, bedridden, incontinent.; Dead. Have there been any changes in treatment of the ECAA since the last follow-up visit? No; Medication stopped; Medication started; New intervention; Unknown; Other Current antithrombotic medication Aspirin; Clopidogrel; Prasugrel; Heparin; Acenocoumarol; Phenprocoumon; Unknown; Other.

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Summary, general discussion and future perspectives

chapter 10

Summary and Discussion (Part of this summary is adopted from the editorial: Extracranial Carotid Artery Aneurysm: Optimal Treatment Approach.) Extracranial aneurysms of the carotid artery (ECAA) are rare, but the exact incidence is unclear. ECAA comprise 0.6% to 3% of all carotid procedures but account for only 0.4% of all peripheral aneurysms.1-3 These numbers are derived from single-center experiences and are therefore probably unreliable. Furthermore, a substantial portion of ECAAs probably will remain clinically silent. ECAAs are more common in men than in woman, and the mean age of reported cases is approximately 50 years. ECAAs appear to be mostly coincidental findings but can lead to significant morbidity. Cerebral ischemia due to embolism from the aneurysm is the most feared symptom.4,5 (Chapter 2) A number of important questions regarding ECAAs need to be addressed. The main ambiguities in ECAAs will be discussed, and recommendations will be given. These issues are related to the etiology of ECAAs, the role of imaging in ECAAs, treatment indications, and treatment outcome. ECAA etiology Although many authors report atherosclerotic ECAAs, the etiology is diverse. 6,7 In Chapter 3, histological analysis in a small sample of 13 patients with ECAA is described. The aneurysm sac was resected during surgery and processed for histological analysis. Elastin, collagen, different types of inflammatory cells, vascular smooth muscle cells, and endothelial cells were analyzed. The study revealed dissection (abrupt interruption of the media) and degeneration (general loss of elastin fibers in the media) as two distinct underlying mechanisms in ECAA formation. This finding could eventually lead to improved treatment strategies. For example, invasive treatment might not be indicated in most dissecting aneurysms because most of these aneurysms remain asymptomatic and do not increase in size, and some even spontaneously resolve, whereas an ECAA with an atherosclerotic origin may need more aggressive intervention.8 However, we can currently only speculate about this while no evidence-based guidelines or indications for invasive therapy are available. Imaging in ECAA Computed tomography angiography (CTA) is the most commonly used modality for diagnostics and follow-up in ECAA, though duplex ultrasound, magnetic resonance angiography (MRA), and digital subtraction angiography can also be used.9 One limitation of CTA is a lack of sensitivity for lesions involving the carotid artery at the skull base, which is a frequent location of ECAAs.10 MRA could be the modality of choice in these distal lesions. Imaging in ECAA can be used to confirm diagnosis, classify ECAA, or monitor aneurysm growth during follow-up. Measurement of aneurysm size can also be an indicator of successful endovascular stent treatment, with shrinkage or arrested growth during follow-up indicating adequate 120

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exclusion of the aneurysm from the circulation.11,12 Aneurysm size or growth can be assessed through measurement of the maximum aneurysm diameter or the aneurysm volume. In abdominal aortic aneurysm (AAA), addition of volumetric measurements to diameter measurements is more sensitive than using maximum aneurysm diameter alone when assessing aneurysm size.11,12 In Chapter 4 we demonstrate volume measurement is also feasible in ECAA. Inter-observer and intra-observer reliability were used to compare diameter measurement and two methods of volume measurements. The intra-observer and inter-observer reliability of diameter measurements was superior, with a repeatability coefficient of 0.83 mm (7.2%). The repeatability coefficients were high for both methods of volume measurement. Theoretically, volumetric measurements better assess aneurysm morphology than diameter measurements and are more sensitive for detection of aneurysm growth and therefore they should be added to diameter measurements in assessing aneurysm growth. Future research should investigate the repeatability coefficients of volume measurements in ECAA in a larger study population. ECAA treatment indications and outcome No evidence-based guidelines or indications for invasive therapy in ECAA are available. Chapter 5 reports the results of a systematic review that was performed to summarize the outcomes of ECAA treatment. This review showed a clear lack of evidence on ECAA treatment. Only 39 series describing 10 ECAA patients or more with a total number of patients of 1239 were retrieved. Furthermore, because the data in most series are reported only by group level, the confounding by indication was impossible to correct and no statistical comparison could be made between different treatment regimens. Chapter 6 provides an overview of the (technical) options of ECAA treatment, including conservative, surgical, and endovascular management. Conservative management Presumably, the natural course of ECAAs is poor, with a reported stroke rate of up to 50%.4,13,14 However, some have suggested that asymptomatic ECAAs could be treated conservatively with regular follow-up sometimes combined with anticoagulant or antiplatelet medication.1 A case series of ECAAs treated conservative management, consisting of two patients with 31 aneurysms, is described in Chapter 7. The stroke and mortality rate was 5% in conservative management of ECAA, and all patients with small, stable and asymptomatic ECAA had a favorable outcome. This is in agreement with the only other publication reporting conservative management in ECAA, which described a series of patients with dissecting aneurysms. Most of the aneurysms in that study remained asymptomatic and did not increase in size, and some even spontaneously resolved.8 In our series, however, postponing invasive treatment in a patient with an aneurysm that was asymptomatic but growing resulted in a fatal stroke. The earlier reported stroke rate of 50% is derived from literature from the beginning of the 20th century. On the basis of this rate, many aneurysms of the extracranial carotid artery have been treated invasively. It must be noted this rate includes all ECAAs, including 121

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symptomatic and growing aneurysms. Furthermore, these patients were not treated with anticoagulant or antiplatelet medication, which is currently a well-accepted preventive therapy for cardiovascular events.15 In conclusion, it seems justified to consider a conservative approach in ECAAs that are stable, small, and asymptomatic. Surgical management Traditional surgical treatment, which is the current treatment of choice of a symptomatic or growing ECAA, consists of open resection of the entire aneurysm, with or without arterial replacement with an interposition graft.6,9,16 The carotid artery can be reconstructed in several ways. In case of an elongated or redundant carotid artery, a primary end-toend reconstruction can be made with a single anastomosis.16 Otherwise, an autogenous saphenous vein is the graft of choice to create an interposition bypass of the resected artery.6,9 When no suitable vein is available, a polytetrafluoroethylene or Dacron interposition graft can be used. Early mortality and the number of strokes is low in surgical treatment, and the long-term follow-up also demonstrates low stroke numbers, which supports the assumption that invasive treatment can prevent stroke (Chapter 5). However, this surgical approach has been associated with the risk of stroke and cranial nerve injury.17,18 Cranial nerve injury occurs in 10% to 15% of patients and is probably related to the distal location of aneurysms in the ICA and to the extensive dissection needed to perform complete aneurysm resection.18 (Chapter 5) Endovascular management Although the long-term outcome of endovascular therapy is still unknown, the periprocedural and short-term results reported in the literature are promising.17 Compared with stenting in carotid stenotic disease, stenting in aneurysmatic carotid arteries theoretically has a low risk of embolism as long as the guidewire does not need to pass a plaque or stenosis.17,18 Endovascular stenting in ECAA patients thus far has been mainly applied in patients with traumatic ECAA, with a high success rate of 92.8%.17 An endovascular approach can also be considered in ECAAs located distal in the ICA or in patients unfit for surgery. Stents covered with an internal or external lining are predominantly applied to exclude the aneurysm from the circulation.17 Exclusion of an aneurysm is also possible with a bare-metal stent.19,20 The mechanism of aneurysm exclusion with a bare-metal stent is multifactorial but is probably mainly based on hemodynamics. The stent redirects the blood flow from a vortex to a laminar flow, leading to stasis of blood and thrombosis in the aneurysm.21-24 Chapter 8 describes the midterm outcomes of treatment of ICA aneurysms with a bare-metal stent. This small series showed this technique is also technically feasible and safe in ECAAs. In only one of seven patients was there was residual flow in the aneurysm, which was successfully treated with additional coil embolization. The advantage of a bare-metal stent is the superior flexibility, which is very useful in the often-tortuous carotid arteries.25 In addition to this flexibility, bare-metal stents are also 122

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less prone to in-stent stenosis and thrombosis.26,27 Endovascular stent placement seems a good alternative for ECAA treatment, especially because of the reported high incidence of cranial nerve injury after surgery.18 (Chapter 5) However, more research is needed regarding the long-term outcomes of stent placement in ECAAs. For a proper assessment of the benefit and complication risk from the different treatment and revascularization options for ECAA, a better insight in vascular procedural outcome is needed and especially in the natural follow-up. Given the limited number of patients, randomized controlled trials are infeasible in rare diseases such as ECAA. This is why disease registries have become essential for the investigation of diseases, thanks to their potential to describe the natural history of the disease. To collect data on ECAAs we designed the Carotid Aneurysm Registry (CAR), a prospective Web-based international registry assessing natural course, results of intervention, and follow-up data in patients with an ECAA. The rationale and objectives of the CAR are described in Chapter 9. The aim of the registry is to prospectively collect follow-up data on patients with an ECAA. All patients treated either conservatively or by invasive strategies can be included. Data from the registry will be used to address diagnostic and therapeutic research questions.

Future perspectives There is, also after this thesis, a clear lack of knowledge on ECAA. First, greater clarity is needed regarding the natural history of ECAAs. Hopefully, the results from this prospective international registry, the results of which will be analyzed at 1 and 5 years, will provide this information. Furthermore, future research should especially focus on predicting which ECAAs will become symptomatic. Predictors to be considered could be etiology, aneurysm diameter or volume, the amount of thrombus in the aneurysm, and previous symptoms. That there are some distinct etiologies in ECAA, with probably a different natural course, seems plausible. Current literature suggests, for example, that ECAAs arising after dissection in the carotid artery have a favorable outcome and might even resolve spontaneously.8 Therefore, more effort is needed to determine the etiology in patients, such as by extensive exploration of the patientâ&#x20AC;&#x2122;s history and, for example, with MRA imaging of the vessel wall, before invasive treatment is performed. Matrix metalloproteinase (MMP) has a role in the formation and expansion of AAAs. MMPtargeted vessel wall imaging can, for instance, demonstrate vessel wall inflammation, and its ability to predict growth in murine aneurysms has been demonstrated.28 Future research should also further investigate whether volume measurement should be an addition to diameter measurement in determining ECAA aneurysm growth, as has already been proven in AAA.11,12 Volume measurement might be a better method of evaluation, especially in ECAAs with a stable maximum diameter but progression of dilatation along the vessel course. Whether size or growth is just as important in ECAAs as in aneurysms in other vascular beds might be questionable. Size and growth are most 123

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of all predictors of aneurysm rupture, for instance, in AAAs. Rupture is very rare in ECAAs, however, and the most feared symptom is cerebral ischemia. Risk factors for the occurrence of emboli could be the amount of thrombus in the aneurysm or blood flow dynamics, where low velocity might induce clot formation. The prediction of cerebral infarction by detecting microemboli (using transcranial Doppler or MRI) could also be explored. In atherosclerotic disease, studies have shown the recurrence probability of cerebral infarction is increased in microembolus-positive patients.29-31 Open surgical repair is presently the gold standard in ECAA treatment.6,9,16 Most ECAAs are located in the distal ICA, and an endovascular approach could be considered in these patients to prevent cranial nerve injury. Endovascular repair is promising, but solid longterm follow-up data are missing, and outcomes should be investigated further. In addition, there could be specific subgroups of patients, such as those with extensive comorbidities, who would benefit most from endovascular repair. Because multidisciplinary cooperation is very important in many diseases, patients with ECAAs can be referred from the general practitioner to different specialists (vascular surgeon, neurologist, ear nose and throat specialist) according to the patientâ&#x20AC;&#x2122;s symptoms. Treatment of ECAA also requires a multidisciplinary approach in considering and combining imaging with medical therapy and invasive treatment options. Therefore, more effort needs to be put in multidisciplinary cooperation in ECAA diagnosis and treatment.

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References 1.

McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200.

Moreau P, Albat B, Thevenet A. Surgical treatment of extracranial internal carotid artery aneurysm. Ann Vasc Surg. 1994;8(5):409-416.

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc Surg. 1984;1(3):415-422.

Radak D, Davidovic L, Tanaskovic S, et al. A tailored approach to operative repair of extracranial carotid

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg.

aneurysms based on anatomic types and kinks. Am J Surg. 2014.

2000;31(4):702-712. doi: 10.1067/mva.2000.104101. 7.

Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98.

8. Guillon B, Brunereau L, Biousse V, Djouhri H, Levy C, Bousser M-. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology. 1999;53(1):117-122. 9.

Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x.

10. Hacein-Bey L, Provenzale JM. Current imaging assessment and treatment of intracranial aneurysms. AJR Am J Roentgenol. 2011;196(1):32-44. doi: 10.2214/AJR.10.5329 [doi]. 11.

van Keulen JW, van Prehn J, Prokop M, Moll FL, van Herwaarden JA. Potential value of aneurysm sac volume measurements in addition to diameter measurements after endovascular aneurysm repair. J Endovasc Ther. 2009;16(4):506-513. doi: 10.1583/09-2690.1 [doi].

12. van Prehn J, van der Wal MB, Vincken K, Bartels LW, Moll FL, van Herwaarden JA. Intra- and interobserver variability of aortic aneurysm volume measurement with fast CTA postprocessing software. J Endovasc Ther. 2008;15(5):504-510. doi: 10.1583/08-2478.1 [doi]. 13. El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712. 14. Nathan Winslow M. Extracranial aneurysm of the internal carotid artery: history and analysis of the cases registered. Arch Surg. 1926;13(5):689-729. 15. Antithrombotic Trialistsâ&#x20AC;&#x2122; Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. 16. Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183. doi: 10.1053/j. semvascsurg.2005.09.002. 17. Li Z, Chang G, Yao C, et al. Endovascular stenting of extracranial carotid artery aneurysm: A systematic review. Eur J Vasc Endovasc Surg. 2011;42(4):419-426. 18. Nordanstig J, Gelin J, Jensen N, Osterberg K, Stromberg S. National experience with extracranial carotid artery aneurysms: Epidemiology, surgical treatment strategy, and treatment outcome. Ann Vasc Surg. 2014;28(4):882-886.

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19. Gross BA, Frerichs KU. Stent usage in the treatment of intracranial aneurysms: Past, present and future. J Neurol Neurosurg Psychiatry. 2013;84(3):244-253. doi: 10.1136/jnnp-2011-302007 [doi]. 20. Saatci I, Yavuz K, Ozer C, Geyik S, Cekirge HS. Treatment of intracranial aneurysms using the pipeline flowdiverter embolization device: A single-center experience with long-term follow-up results. AJNR Am J Neuroradiol. 2012;33(8):1436-1446. doi: 10.3174/ajnr.A3246 [doi]. 21. Ruiz CE, Zhang HP, Butt AI, Whittaker P. Percutaneous treatment of abdominal aortic aneurysm in a swine model: Understanding the behavior of aortic aneurysm closure through a serial histopathological analysis. Circulation. 1997;96(7):2438-2448. 22. Ruiz CE, Zhang HP, Douglas JT, Zuppan CW, Kean CJ. A novel method for treatment of abdominal aortic aneurysms using percutaneous implantation of a newly designed endovascular device. Circulation. 1995;91(9):2470-2477. 23. Sim SY, Shin YS, Cho KG, et al. Blood blister-like aneurysms at nonbranching sites of the internal carotid artery. J Neurosurg. 2006;105(3):400-405. doi: 10.3171/jns.2006.105.3.400. 24. Villareal RP, Kar B, Howell MH, Strickman N, Krajcer Z. Bare metal stents with or without coil embolization for abdominal aortic aneurysm exclusion in high-risk patients. Catheter Cardiovasc Interv. 2001;54(1):12-18. 25. Del Corso L, Moruzzo D, Conte B, et al. Tortuosity, kinking, and coiling of the carotid artery: Expression of atherosclerosis or aging? Angiology. 1998;49(5):361-371. 26. Liu AY, Paulsen RD, Marcellus ML, Steinberg GK, Marks MP. Long-term outcomes after carotid stent placement treatment of carotid artery dissection. Neurosurgery. 1999;45(6):1368-73; discussion 1373-4. 27. Schillinger M, Dick P, Wiest G, et al. Covered versus bare self-expanding stents for endovascular treatment of carotid artery stenosis: A stopped randomized trial. J Endovasc Ther. 2006;13(3):312-319. doi: 10.1583/061819.1. 28. Golestani R, Razavian M, Nie L, et al. Imaging vessel wall biology to predict outcome in abdominal aortic aneurysm. Circ Cardiovasc Imaging. 2014;8(1):10.1161/CIRCIMAGING.114.002471. Print 2015 Jan 30. doi: 10.1161/CIRCIMAGING.114.002471 [doi]. 29. Valton L, Larrue V, le Traon AP, Massabuau P, Geraud G. Microembolic signals and risk of early recurrence in patients with stroke or transient ischemic attack. Stroke. 1998;29(10):2125-2128. 30. Nakajima M, Kimura K, Shimode A, et al. Microembolic signals within 24 hours of stroke onset and diffusionweighted MRI abnormalities. Cerebrovasc Dis. 2007;23(4):282-288. doi: 000098328 [pii]. 31. Iguchi Y, Kimura K, Kobayashi K, Ueno Y, Shibazaki K, Inoue T. Microembolic signals at 48 hours after stroke onset contribute to new ischaemia within a week. J Neurol Neurosurg Psychiatry. 2008;79(3):253-259. doi: jnnp.2007.123414 [pii].

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Het extracraniële aneurysma van de arteria carotis (ECAA) is een zeldzame aandoening.1-4 Een ECAA wordt doorgaans gedefinieerd als een fusiforme verwijding van >150 procent ten opzichte van de verwachte diameter van de arteria carotis of een sacculair aneurysma van elke grootte. Hoewel de meeste ECAA waarschijnlijk asymptomatisch zijn en bij toeval worden ontdekt, kunnen patiënten cerebrale embolieën ontwikkelen die leiden tot ernstige neurologisch uitval (TIA of beroerte). ECAA komen vaker bij mannen voor dan bij vrouwen en de gemiddelde leeftijd van patiënten is rond de 50 jaar.5,6 (Hoofdstuk 2) ECAA etiologie Vaak wordt atherosclerose als belangrijkste oorzaak van ECAA beschreven, de etiologie kan echter zeer divers zijn.7,8 In Hoofdstuk 3 wordt een histopathologische analyse van ECAA beschreven. In deze serie ondergingen 13 patiënten een chirurgische resectie van het complete carotis aneurysma. Histologische bewerking betrof voor elke coupe een overzichtskleuring middels hematoxyline en eosine. Verder werden de coupes gekleurd voor elastine vezels, collageen, gladde spiercellen, endotheel, macrofagen en lymphocyten. Histopathologisch waren de aneurysmata in te delen in twee groepen. Eén groep was te herkennen door de aanwezigheid van een dissectie met een abrupte onderbreking van de media. De andere groep was te herkennen aan een degeneratief beeld met een duidelijke afname van elastine vezels in de media. Deze indeling kan nuttig zijn voor de interpretatie van beeldvormend onderzoek en voor behandelindicaties. Mogelijk is de prognose van een ECAA afhankelijk van de etiologie. Echter, harde uitspraken hierover kunnen niet worden gedaan in verband met het ontbreken van gefundeerd onderzoek. Beeldvorming in ECAA Computed tomography angiography (CTA) wordt het meest gebruikt in de diagnostiek en follow-up van ECAA’s. Het is echter ook mogelijk het aneurysma in beeld te brengen middels duplex, magnetic resonance angiogram (MRA) of digitale substractie angiografie.9 Aneurysmata gelokaliseerd hoog in de arteria carotis interna en dicht bij de schedelbasis kunnen waarschijnlijk beter in beeld worden gebracht middels MRA omdat de sensitiviteit van CTA in dit gebied verlaagd is. Het doel van beeldvorming bij ECAA is het stellen van de diagnose, het classificeren van het aneurysma en het beoordelen van groei gedurende follow-up. Het bepalen van de grootte van het aneurysma middels beeldvormende technieken kan ook gebruikt worden als uitkomstmaat van endovasculaire behandeling. Wanneer het aneurysma krimpt of gelijk blijft in grootte is dit een indicatie van succesvolle uitschakeling.10,11 De grootte of groei kan worden bepaald op basis van de diameter of het volume van het aneurysma. In aneurysmata van de abdominale aorta bleek uit eerder onderzoek de toevoeging van volumemetingen aan diametermeting meer sensitief dan alleen maximale diametermetingen.10,11

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In hoofdstuk 4 laten we zien dat volumemetingen ook mogelijk zijn in ECAA. De intra- en interbeoordelaar betrouwbaarheid van diametermetingen en twee volumemeting methoden werden vergeleken. Maximale diameter metingen bleken het meest betrouwbaar met een repeatability coefficient (RC) van 0.83mm (7.2%). Voor beide volumemeting methoden was de RC hoog. In theorie kan een volumemeting de groei en morfologie van een aneurysma beter vervolgen en daarom zouden ze moeten worden toegevoegd aan diameter metingen. Toekomstig onderzoek zal moeten uitwijzen of de RC van volumemetingen beter is wanneer deze wordt onderzocht in een grotere studiepopulatie. Behandelindicaties en resultaten in ECAA De optimale behandeling van asymptomatische carotis aneurysmata is vooralsnog onbekend, met name omdat gegevens over het natuurlijk beloop ontbreken.1 Symptomatische aneurysmata worden over het algemeen chirurgisch behandeld.12,13 Endovasculaire behandeling is een techniek in ontwikkeling maar ondanks acceptabele procedurele resultaten in kleine case series ontbreekt de langere termijn follow-up.13,14 Een wetenschappelijke onderbouwing voor indicatie stelling of optimale behandeling is op dit moment niet voor handen.4 In hoofdstuk 5 wordt een overzicht van de literatuur over de behandeling van ECAA gegeven. Deze review bevestigde het gebrek aan wetenschappelijk bewijs rondom de behandeling van ECAA. Er werden slechts 39 studies gevonden die de behandeling van meer dan tien patiënten met ECAA beschreven. Bij het vergelijken van het resultaat van verschillende behandelopties moest worden gecorrigeerd voor confounding by indication. Echter, door te veel missende informatie kon deze correctie niet worden uitgevoerd en daarom kon geen betrouwbare vergelijking tussen de verschillende behandelopties worden gemaakt. Hoofdstuk 6 geeft een overzicht over alle mogelijke behandeltechnieken bij patiënten met een ECAA. In dit hoofdstuk worden de conservatieve, chirurgische en endovasculaire behandelmogelijkheden beschreven. Conservatieve behandeling Aangenomen wordt dat het natuurlijk beloop van ECAA slecht is, met een beschreven beroerte cijfer van 50%.7,13 Asymptomatische en stabiele aneurysmata worden tegenwoordig meestal conservatief behandeld met follow-up die eventueel gecombineerd kan worden met medicatie omdat gedacht wordt dat de prognose van deze groep relatief gunstig is. In de caseserie die wordt beschreven in hoofdstuk 7 werden patiënten die conservatief werden behandeld retrospectief geanalyseerd. Tijdens de follow-up, met een mediane duur van 24 maanden (range 1-72 maanden) overleed één patiënte, 13 maanden na het stellen van de diagnose ECAA, aan een fatale beroerte in het stroomgebied van het aneurysma. Concluderend werd in deze studie een geruststellend laag jaarlijks beroerte risico gevonden. Het lijkt gerechtvaardigd, op basis van deze studie, om een conservatieve strategie te kiezen in patiënten met een asymptomatisch ECAA. Het aantal patiënten in deze serie, veroorzaakt door de zeldzaamheid van de aandoening, is echter laag en het effect beschreven in deze studie van lage wetenschappelijke waarde. 131

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Chirurgische behandeling De huidige gouden standaard voor de behandeling van symptomatische of groeiende ECAA is chirurgische resectie met herstel van de continuïteit van de slagader.7,12,15 Er zijn verscheidene reconstructie mogelijkheden; Wanneer de arteria carotis een lang en gekronkeld verloop heeft is het mogelijk een primaire anastomose te maken.12 Indien een overbrugging nodig is wordt in eerste instantie gekozen voor een veneuze interpositie graft en indien deze niet beschikbaar is kan een polytetrafluorethyleen of dacron interpositie graft worden gebruikt.7,15 De uitkomsten van chirurgische behandeling zijn gunstig, de mortaliteit en het risico op een per- of postoperatieve beroerte is laag (hoofdstuk 5). De chirurgische benadering heeft echter ook nadelen. In 10-15% van de patiënten die chirurgie ondergaan is er postoperatief (tijdelijke) uitval van zenuwen in het operatiegebied.16,17 Mogelijk wordt dit hoge risico veroorzaakt door de vaak distale locatie van ECAA in de arteria carotis interna en de uitgebreide dissectie die noodzakelijk is voor complete resectie van het aneurysma. Endovasculaire behandeling De peri-procedurele en korte termijn uitkomsten van endovasculaire behandeling van ECAA’s zijn gunstig en veelbelovend.16 Er is echter nog weinig bekend over de lange termijn follow-up. Endovasculaire stentplaatsing in ECAA’s is theoretisch minder risicovol, wat betreft embolierisico, vergeleken met stentplaatsing in stenoserende carotispathologie omdat de voerdraad geen plak of nauwe stenose hoeft te passeren.16,17 Endovasculaire stentplaatsing werd tot op heden met name toegepast bij patiënten met een ECAA met een traumatische etiologie, waarbij een succespercentage van 93.8% werd bereikt.16 Een endovasculaire benadering kan worden overwogen in ECAA’s in de distale ICA die slecht toegankelijk zijn voor een chirurgische benadering of bij patiënten die een hoog risico hebben op peri-operatieve morbiditeit. Bij endovasculaire behandeling worden de meeste ECAA uitgeschakeld met een gecoate metalen stent.16 Echter, bij intracraniële aneurysmata is aangetoond dat uitschakeling ook met een niet-gecoate metalen stent mogelijk is.18,19 Het belangrijkste voordeel van deze niet-gecoate stents is de grotere flexibiliteit, welke goed van pas komt bij het manoeuvreren door de, vaak tortueuze, ICA. Trombose van het aneurysma, na behandeling met een niet-gecoate stent, wordt waarschijnlijk geïnduceerd door de omzetting van de wervelende bloedstroom in het aneurysma in een laminaire flow door het skelet van de stent.20-23 In de serie, die wordt beschreven in hoofdstuk 8, bleek de behandeling van ECAA met een niet-gecoate metalen stent technisch haalbaar en veilig. Na zes maanden was er complete trombose van alle, behalve één, aneurysmata. Deze (asymptomatische) patiënt had een aanhoudende flow in het aneurysma waarvoor succesvolle coiling plaatsvond. Voor een goede analyse van de voordelen en complicaties van de verschillende behandelmogelijkheden voor ECAA’s is meer kennis van de uitkomsten op korte en lange termijn van de verschillende behandelingen noodzakelijk. Verder is met name meer inzicht nodig in het natuurlijk beloop van de aandoening voor een goede afweging. Gezien het kleine aantal patiënten is een gerandomiseerde studie niet mogelijk in 132

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zeldzame aandoeningen zoals ECAA. Verbetering van kennis en behandeling over zeldzame aandoeningen kan gerealiseerd worden door internationale prospectieve dataregistratie. Met dit doel is de internationale Carotid Aneurysm Registry (CAR) opgezet. De resultaten uit deze cohort studie kunnen een bijdrage leveren aan de optimale behandelstrategie voor de individuele patiĂŤnt met ECAA en de weg vrij maken voor de ontwikkeling van richtlijnen over de behandeling van ECAA. De motivering en doelen de CAR worden in hoofdstuk 9 beschreven.

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References 1. McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. twentyone yearsâ&#x20AC;&#x2122; experience. Am J Surg. 1979;137(2):196-200. 2.

Moreau P, Albat B, Thevenet A. Surgical treatment of extracranial internal carotid artery aneurysm. Ann Vasc Surg. 1994;8(5):409-416.

Welleweerd JC, den Ruijter HM, Nelissen BGL, et al. Treatment for extracranial carotid artery aneurysm. A

Zwolak RM, Whitehouse WM,Jr, Knake JE, et al. Atherosclerotic extracranial carotid artery aneurysms. J Vasc

systematic review and meta-analysis. submitted 2014.

Surg. 1984;1(3):415-422. 6.

Radak D, Davidovic L, Vukobratov V, et al. Carotid artery aneurysms: Serbian multicentric study. Ann Vasc Surg. 2007;21(1):23-29.

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas heart institute experience. J Vasc Surg. 2000;31(4):702-712.

8. Donas KP, Schulte S, Pitoulias GA, Siebertz S, Horsch S. Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms. J Vasc Surg. 2009;49(1):93-98. 9.

Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x.

10. van Prehn J, van der Wal MB, Vincken K, Bartels LW, Moll FL, van Herwaarden JA. Intra- and interobserver variability of aortic aneurysm volume measurement with fast CTA postprocessing software. J Endovasc Ther. 2008;15(5):504-510. doi: 10.1583/08-2478.1 [doi]. 11. van Keulen JW, van Prehn J, Prokop M, Moll FL, van Herwaarden JA. Potential value of aneurysm sac volume measurements in addition to diameter measurements after endovascular aneurysm repair. J Endovasc Ther. 2009;16(4):506-513. doi: 10.1583/09-2690.1 [doi]. 12. Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin Vasc Surg. 2005;18(4):178-183. 13. Welleweerd JC, Moll FL, de Borst GJ. Technical options for the treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther. 2012;10(7):925-931. 14. Zhou W, Lin PH, Bush RL, et al. Carotid artery aneurysm: Evolution of management over two decades. J Vasc Surg. 2006;43(3):493-496. 15. Choudhary AS, Evans RJ, Naik DK, Tripathi RK, Wickremesekera JK. Surgical management of extracranial carotid artery aneurysms. ANZ J Surg. 2009;79(4):281-287. doi: 10.1111/j.1445-2197.2009.04860.x. 16. Li Z, Chang G, Yao C, et al. Endovascular stenting of extracranial carotid artery aneurysm: A systematic review. Eur J Vasc Endovasc Surg. 2011;42(4):419-426. doi: 10.1016/j.ejvs.2011.05.008. 17. Nordanstig J, Gelin J, Jensen N, Osterberg K, Stromberg S. National experience with extracranial carotid artery aneurysms: Epidemiology, surgical treatment strategy, and treatment outcome. Ann Vasc Surg. 2014;28(4):882-886. 18. Gross BA, Frerichs KU. Stent usage in the treatment of intracranial aneurysms: Past, present and future. J Neurol Neurosurg Psychiatry. 2013;84(3):244-253. doi: 10.1136/jnnp-2011-302007 [doi].

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19. Saatci I, Yavuz K, Ozer C, Geyik S, Cekirge HS. Treatment of intracranial aneurysms using the pipeline flowdiverter embolization device: A single-center experience with long-term follow-up results. AJNR Am J Neuroradiol. 2012;33(8):1436-1446. doi: 10.3174/ajnr.A3246 [doi]. 20. Ruiz CE, Zhang HP, Butt AI, Whittaker P. Percutaneous treatment of abdominal aortic aneurysm in a swine model: Understanding the behavior of aortic aneurysm closure through a serial histopathological analysis. Circulation. 1997;96(7):2438-2448. 21. Ruiz CE, Zhang HP, Douglas JT, Zuppan CW, Kean CJ. A novel method for treatment of abdominal aortic aneurysms using percutaneous implantation of a newly designed endovascular device. Circulation. 1995;91(9):2470-2477. 22. Villareal RP, Kar B, Howell MH, Strickman N, Krajcer Z. Bare metal stents with or without coil embolization for abdominal aortic aneurysm exclusion in high-risk patients. Catheter Cardiovasc Interv. 2001;54(1):12-18. 23. Sim SY, Shin YS, Cho KG, et al. Blood blister-like aneurysms at nonbranching sites of the internal carotid artery. J Neurosurg. 2006;105(3):400-405. doi: 10.3171/jns.2006.105.3.400.

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Review Committee Dankwoord List of publications Curriculum vitae

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Review Committee Prof. dr. M.C. Verhaar Department of Nephrology and hypertension University Medical Center Utrecht, Utrecht, The Netherlands Prof. dr. R.L.A.W. Bleys Department of Anatomy University Medical Center Utrecht, Utrecht, The Netherlands Prof. dr. L.J. Kappelle Department of Neurology University Medical Center Utrecht, Utrecht, The Netherlands Prof. dr. J.F. Hamming Department of Vascular Surgery Leiden University Medical Center, Leiden, The Netherlands Dr. J. Hendrikse Department of Radiology University Medical Center Utrecht, Utrecht, The Netherlands

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Dankwoord Graag wil ik een aantal mensen bedanken die hebben geholpen dit proefschrift tot stand te brengen. Professor F.L. Moll, u staat altijd klaar voor uw promovendi. Uw begeleiding op maat en inspirerende ideeĂŤn motiveerden mij bijzonder tijdens mijn promotie. Hartelijk dank voor uw vertrouwen in mij en mijn promotie. Dr. G.J. de Borst, beste Gert Jan, bedankt voor de kans die je me bood om bij je onderzoek te komen doen, ik heb het als een hele leuke tijd ervaren. Je hebt veel energie en tijd gestoken om dit project succesvol te maken. Je geduld en kritische blik waardeer ik bijzonder en ik heb heel veel van je geleerd op wetenschappelijk gebied en ook daar buiten. Leden van de beoordelingscommissie: prof dr. M.C. Verhaar, prof. dr. R.L.A.W. Bleys, prof. dr. L.J. Kappelle, prof. dr. J.F. Hamming en dr. J. Hendrikse. Dank voor het plaatsnemen in mijn commissie en het beoordelen van mijn proefschrift. Dank aan alle vaatchirurgen van het UMCU voor jullie hulp en interesse: Joost van Herwaarden, Raechel Toorop, Stijn Hazenberg, Paul van Schaik en Boudewijn Reichmann. Susan en Cobie van het secretariaat vaatchirurgie. Bedankt voor jullie attentheid en gezellige praatjes tussendoor. Alle chirurgen en arts-assistenten chirurgie in het UMCU, bedankt voor jullie steun en samenwerking. Alle chirurgen en arts-assistenten chirurgie van het Jeroen Bosch Ziekenhuis. Bedankt voor jullie hartelijke welkom. Dank aan alle, nog niet eerder genoemde, coauteurs voor jullie bijdragen en opbouwende kritieken: prof dr G. Pasterkamp, prof dr M.L. Bots, prof G.J.E. Rinkel, dr Y. M. Ruigrok, dr M.D.I. Vergouwen, dr H.B. van der Worp, drs T.H. Lo, dr J.P.P.M. de Vries, dr A. Vink, Annette Baas, Vanessa Pourier (we blijven elkaar zien!), Bas Nelissen (van het begin tot het eind!), Dave Koole, Hester den Ruijter en Daphne de Groot. Alle mede-promovendi met wie ik tijdens mijn promotie heb samengewerkt, in het bijzonder: Joyce Vrijenhoek, Martin Teraa, Peter Paul Wisman, Amy Gunning, Leonie Haverkamp, Amir Basir, Tesse Leunissen, Steffi Rombouts, Stephanie Peeters Weem, Claire Pennekamp en last but not least Wouter Hogendoorn. Jullie allemaal bedankt voor jullie hulp bij het realiseren van dit proefschrift en de gezellige momenten tijdens mijn promotietijd. 139

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Lieve Juliette, Mieke en Ceren. Lieve cootjes, bedankt voor jullie gezelligheid, steun en motiverende woorden tijdens de afgelopen jaren. Ik hoop dat we nog veel heerlijke avonden samen hebben en veel van elkaars diversiteit kunnen leren. Lieve Joslin en Fleur, bedankt voor de mooie (grote en kleine) momenten de afgelopen jaren. Jullie interesse in mijn onderzoek heb ik gewaardeerd, maar het met jullie van het leven genieten nog meer! Lieve Tom, Anne Claire, Duco, Maartje en Teun, wat ben ik bij jullie in een warme familie beland. Jullie staan altijd voor ons klaar en ik voel me welkom om op ieder moment bij jullie binnen te vallen. Bedankt voor de gezelligheid, jullie interesse en steun. Lieve Harm en Ellen, lief broertje. Wat geweldig dat jij mijn broer bent. Ik ben trots op wat je allemaal bereikt hebt en vind het heerlijk dat we nu dicht bij elkaar wonen en regelmatig gezellig afspreken. Dank voor jullie steun (en oppassen op Evelijn) tijdens de afgelopen drukke periode. Lieve Oma, hartelijk dank voor uw steun en interesse tijdens mijn onderzoek. Ik vond het altijd leuk om u met trots op de hoogte te houden van de laatste ontwikkelingen. U vertelde mij eens dat opa ooit begon aan een promotie, nu maak ik het, met hem in gedachten, af. Lieve pap en mam, bedankt dat jullie me altijd zoveel ruimte hebben gegeven om alles te doen wat ik wilde. Hoewel dat voor jullie vaak vanzelfsprekend is realiseer ik me dat ik bijzonder geluk heb met ouders zoals jullie! Zonder jullie steun was ik hier niet gekomen. Lieve Evelijn, je bent een zonnetje in ons leven. Je aanstekelijke lach maakt iedere dag een klein feestje. Lieve Maurits, wat een geweldige tijd maken we met elkaar mee! Bedankt voor je steun en liefde tijdens de afgelopen jaren, je bent mijn alles. We proosten op de toekomst!

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List of publications

List of publications Nizar Moayeri MD PhD, Annelot C Krediet MD, Janna C Welleweerd BSc, Ronald LAW Bleys MD PhD, Gerbrand J Groen MD PhD. Early ultrasonographic detection of low volume intraneural injection. Br J Anaesth. 2012 Sep;109(3):432-8. Janna C Welleweerd BSc, Frans L Moll MD PhD, Gert Jan de Borst MD PhD. Technical options for treatment of extracranial carotid aneurysms. Expert Rev Cardiovasc Ther. 2012 Jul;10(7):925-31. drs. Jantien C. Welleweerd, prof. dr. Frans. L. Moll, dr. Gert Jan de Borst. Database voor extracraniële aneurysmata van de arteria carotis: “CAR“. Ned Tijdschr Geneeskd. 2014;158:A8026. Welleweerd JC, de Borst GJ; the Carotid Aneurysm Registry Project Group. Extracranial Carotid Artery Aneurysm: Optimal Treatment Approach. Editorial. Eur J Vasc Endovasc Surg. 2014 Dec 9. Janna C. Welleweerd MD, Bastiaan G.L. Nelissen MD, Dave Koole MD, Jean-Paul P.M. de Vries MD PhD, Frans L. Moll MD, PhD, Gerard Pasterkamp MD PhD, Aryan Vink MD PhD, Gert Jan de Borst MD PhD. Histological analysis of extracranial carotid artery aneurysms. PLoS One. 2015 Jan 30;10(1):e0117915. J.C. Welleweerd, MD; L.J. Kappelle, MD PhD; G.J.E. Rinkel, MD; Y.M. Ruigrok, MD PhD; A.F. Baas, MD PhD; H.B. van der Worp, MD PhD; J. Hendrikse, MD PhD; M.L. Bots, MD PhD; R.L.A. Bleys, MD PhD; F.L. Moll, MD PhD, G.J. de Borst, MD PhD. Rationale and design of the extracranial carotid artery aneurysm registry. J Cardiovasc Surg (Torino). 2015 Feb 6. [Epub ahead of print] J.C. Welleweerd, MD, D. de Groot, M.D., J.A. van Herwaarden, MD PhD, G.J. de Borst, M.D. PhD, R. Lo, M.D., F.L. Moll, M.D. PhD. Bare metal stents for treatment of extracranial internal carotid artery aneurysms; long-term results. J Endovasc Ther. 2015 Feb;22(1):130-134. GJ de Borst, J.C. Welleweerd, F.L. Moll. Oxford textbook of vascular surgery – Second edition. section 6- “Aneurysms of the extracranial carotid artery” Debette S, Compter A, Labeyrie MA, Uyttenboogaart M, Metso TM, Majersik JJ, GoeggelSimonetti B, Engelter ST, Pezzini A, Bijlenga P, Southerland AM, Naggara O, Béjot Y, Cole JW, Ducros A, Giacalone G, Schilling S, Reiner P, Sarikaya H, Welleweerd JC, Kappelle LJ, de Borst GJ, Bonati LH, Jung S, Thijs V, Martin JJ, Brandt T, Grond-Ginsbach C, Kloss M, Mizutani T, Minematsu K, Meschia JF, Pereira VM, Bersano A, Touzé E, Lyrer PA, Leys D, Chabriat H, Markus HS, Worrall BB, Chabrier S, Baumgartner R, Stapf C, Tatlisumak T, Arnold M, Bousser MG. Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection. Accepted for publication in The Lancet Neurology. 141

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Curriculum vitae Janna Catharina (Jantien) Welleweerd was born on July 27th, 1981 in Rozenburg, The Netherlands. After graduation from secondary school in 1999, she studied to be a physical therapist and specialized in sports- and orthopaedic rehabilitation. After working in a sports medical center and for the field hockey club Kampong she started medical school in 2007 at the University of Utrecht. During her master program she started research on extracranial carotid artery aneurysms under supervision of dr. G.J. de Borst. After finishing medical school in 2013 she worked on her thesis at the UMC Utrecht supervised by prof. dr. F.L. Moll and combined this with teaching medical students and surgical interns. Currently, she is working as a resident in the surgical department at the Jeroen Bosch Ziekenhuis in â&#x20AC;&#x2122;s Hertogenbosch. Jantien is married to Maurits Specken and they have a one-year-old daughter called Evelijn.

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