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199Discussion

Valdueza et al., Neurosonology and Neuroimaging of Stroke: A Comprehensive Reference, Second Edition (ISBN 978-3-13-141872-2), copyright © 2017 Thieme Medical Publishers All rights reserved. Usage subject to terms and conditions of license.

ICA-R distal

Fig. B1.5 Extracranial duplex, longitudinal plane. Distal right ICA segment with normal ﬂ ow signal and velocity (109/34 cm/s).

ICA-R ICA-R

Fig. B1.6 Extracranial duplex, harmonic imaging mode. Left: Longitudinal plane. Right: Cross-sectional plane. White lines delineate the vessel borders. Dotted lines delineate the plaque surface. Note the irregular plaque surface and additional contrast traces reaching into the plaque formation, considered to be additional circumscribed plaque ulcerations (arrows).

Fig. B1.7 MRI, diﬀ usion-weighted imaging, axial imaging plane. Fresh right cortical MCA infarction mainly in the left postcentral gyrus.

Discussion

Clinical Aspects

Clinically, our patient had a transient numbness of his left arm suggestive of a TIA. Though the initial CT scan did not show ischemic infarct demarcation, MRI revealed a fresh embolic territorial MCA infarction assumed to be caused by an artery-to-artery embolism from the right-sided high-grade ICA stenosis.

Fig. B1.8 CT angiography, sagittal image plane displaying both c a r o t i d b i f u r c a t i o n s . ( A) Left carotid bifurcation with minor vessel wall irregularities without stenosis. (B) Right carotid bifurcation with marked hypodense plaque formation at the bulb of the ICA (arrow).

tomatic carotid stenosis >70% (NASCET), the annual risk has been calculated to range from 10% to 15% based on 1990s medical therapy (Barnett et al 1998). Surgical revascularization, ﬁ rst performed in the mid-1950s, is recommended if ICA stenosis is 70% or higher based on the results of two large randomized clinical trials—the North American Symptomatic Carotid Endarterectomy Trial (Ba rne tt et al 1998 , NASC ET Col labor ators 1 991 ) and the European Carotid Surgery Trial (ECST Collaborative Group 1991, 1998). These trials compared CEA with medical treatment. Both trials reported similar

Symptomatic ICA Stenosis

Atherosclerosis of the ICA is thought to be responsible for ~8% of all ischemic strokes (Flaherty et al 2013). The risk of ischemic stroke increases proportionally with the grade of carotid stenosis. In patients with a symp-

results after adjusting for the diﬀ erent stenosis grading methods (Rothwell et al 2003a, 2003b) (for further reading see also Chapter 5, “Grading of ICA Stenosis by Digital Subtraction Angiography” under “Extracranial Pathology”). According to these two trials, which included 5,950 patients with symptomatic ICA stenosis, the

200 Case 1 Right Extracranial Internal Carotid Artery Stenosis

Fig. B1.9 CT angiography, enlarged image of the right ICA stenosis. (A) Cross-sectional image of the maximal lumen narrowing, corresponding well with the ultrasound derived cross-sectional image in Fig. B1.2. ICA diameter 9.3 mm, residual lumen 2.57 mm, resulting in a calculated local narrowing of 73% (ECST criteria, local stenosis grade). (B) Cross-sectional image of the distal right ICA. Diameter

5.57 mm, resulting in a calculated NASCET lumen reduction of 54%. (C) Longitudinal plane, rotated 90° counterclockwise to correspond with the ultrasound images in Fig. B1.5 an d Fig. B1.6. Note the small calciﬁ ed spots within the plaque (arrows) and contrast undermining the plaque surface (arrowhead), comparable to the ulceration visualized by ultrasound contrast harmonic imaging in Fig. B1.6.

AB C

Fig. B1.10 CT angiography. (A) Lateral maximal intensity pro- jection (MIP) reconstruction demonstrating the plaque-induced lumen reduction of the right ICA. (B) Color-inversion and digital removal of surrounding tissue signal, leaving a vessel signal similar to what would have been obtained if digital subtraction angiography (DSA) had been performed. The DSA lumen reduction is 70% according to the ECST criteria (referring to the estimated lumen reduction—dotted line), 50–60% according to the NASCET criteria. Note that the real dimensions of the carotid bulb (continuous line) are larger than estimated. (C) 3D reconstruction of the stenosis.

number needed to treat (NNT) for preventing one ipsilateral disabling ischemic stroke or death over 2–6 years follow-up was 15 for the >70% (NASCET) or >80% (ECST) ICA stenosis, and 21 for the 50–69% (NASCET) or 70–79% (ECST) ICA stenosis. Patients with milder stenosis did not beneﬁ t and the NNT to have a postsurgical disabling stroke or death was 45 (Cina et al 2000).

Of note, these ﬁ ndings were only valid if CEA was performed within the ﬁ rst 6 months following stroke or TIA, with the greatest beneﬁ t within the ﬁ rst 2 weeks (Rothwell et al 2004). After 2 years, the risk of stroke in medically treated patients was similar to the low levels observed in surgically treated patients. This result may potentially be explained by spontaneous plaque stabilization or gradual improvement of collateral function over time. Furthermore, patients whose ICAs were nearly occluded did not beneﬁ t from surgery, as (1) the risk of embolic stroke under medical treatment alone is very low and (2) most of the near-occlusion patients had well-developed collaterals impeding hemodynamic stroke (see also Chapter 5, “Intracranial Collateral Pathways in ICA Occlusive Processes” under “Arterial Pathology,” and Case 15).

More recently, catheter angioplasty and stenting (CAS), introduced in the 1980s, have been shown to yield both comparable outcomes and procedure-associated complications (see below). Apart from the patient’s views and preferences, a variety of factors have to be considered which might inﬂ uence the decision to intervene or not—and if yes, to choose between CEA and CAS. CAS is preferentially performed when CEA is technically diﬃ - cult, such as in patients with challenging cervical anatomy, restenosis after CEA, or radiation in the cervical area.

Fig. B1.11 (A) Intraoperative ﬁ ndings of the right carotid bifur- cation before opening of the vessel. (B) Opened bifurcation with visualization of the large soft plaque in situ. (C) Removed plaque formation, the original position illustrated by schematic drawing of the carotid bifurcation. Note the largely irregular plaque surface of the specimen. (D) Final operative ﬁ ndings after patching and ves- sel closure. (Intra- and postoperative images with kind permission from Dr. Kasper, Department of Vascular Surgery, Charité—Universitätsmedizin Berlin, Germany.)

Lesions that are either high (above the level of the mandible) or low (below the clavicle) are more accessible to CAS than CEA. CAS may also be used in arterial dissection and ﬁ bromuscular dysplasia which are not managed by surgery. Advanced age favors CEA, despite the increased risk of general anesthesia, because of the lower number of emboli which are generated by the device-related

201Discussion

displacement of large atheromas in the upstream vessels (Touzé et al 2009). Costs of treatment by CAS and CEA are comparable (Ecker et al 2004).

Asymptomatic ICA Stenosis

Controversy persists regarding the appropriate management of asymptomatic ICA stenosis. A recently published analysis of four longitudinal studies including 23,706 individuals (mean age 61 ± 12 years) reported a 2% prevalence of moderate ultrasound-determined 50–69% asymptomatic ICA stenosis and a 0.5% prevalence for stenoses >70%. The prevalence was highest for men >80 years of age (de Weerd 2014).

The overall annual risk of stroke in asymptomatic patients is 1–3%, based on 1990s medical therapy (ECST 1998, Halliday et al 2010), i.e., far lower than in those with recent stroke or TIA of up to 15% within the ﬁ rst year. Any therapeutic strategy therefore requires a very low i n t e r v e n t i o n a l r i s k f o r p a t i e n t s t o b e n e ﬁ t statistically and, more importantly, clinically from the procedure. Two older multicenter studies, the CASANOVA Study (CASANOVA Study Group 1991) and the VA-Asymptomatic Carotid Stenosis Study (Hobson et al 1993), showed negative results. A third study, the Asymptomatic Carotid Surgery Tri al (AC ST) , w hic h i nclud ed 3 ,12 0 p ati ent s, showed a modest but signiﬁ cant absolute risk reduction of 5.4% at 5 years (Halliday et al 2004). Accordingly, 50 patients must be treated to prevent one stroke within 3 years. However, patients will beneﬁ t if the interventional risk of stroke or death due to CEA is not higher than 3%. A 2005 Cochrane Review of 5,223 patients reported a 29% relative risk reduction within 3 years. The absolute risk reduction was ~1% per year (Chambers and Donnan 2005). The assumption that a longer follow-up would result in a more pronounced risk reduction was conﬁ rmed by the 10-year results of the ACST trial. The combined stroke rate (perioperative events and any stroke) after 5 years was 6.9% in the operated group and 10.9% in medically treated patients, and reached 13.4% and 17.9% after 10 years (Halliday et al

2010). These data showed for the ﬁ rst time that CEA may also signiﬁ cantly reduce the stroke risk over a long period, and CEA may be oﬀ er to young asymptomatic patients.

Risk stratiﬁ cation and the identiﬁ cation of asympto- matic patients at a high risk of future stroke will also be a major topic in the near future. Using ultrasound, several predictors of stroke risk have been reported—e.g., microemboli detected using transcranial Doppler (TCD), identiﬁ cation of unstable carotid plaques, plaque ulceration, reduced vasomotor reactivity, and stenosis severity progression.

Patients with microemboli detected using TCD were more likely to have a stroke during the ﬁ rst year of fol- low-up (15.6% versus 1%) (Spence et al 2005). Another study showed that patients with microembolic signals had a 2-year stroke and TIA risk that was >2.5-fold higher than patients without (hazard ratio [HR] 2.54). For ipsilateral stroke alone, the HR was 5.57. The absolute annual ipsilateral stroke and TIA risk was 7.13% in patients with and 3.04% in patients without microembolic signals (Markus et al 2010).

Unstable carotid plaques characterized by plaque echolucency were observed in 37.7% of patients with plaques and associated with an increased risk of ipsilateral stroke (HR 6.43)—an association which increased (HR 10.61) if the unstable plaques were identiﬁ ed in com- bination with microembolic signals (Topakian et al 2011). Data pooled from seven studies (7,557 patients) show that patients with carotid artery plaques across all stenosis grades (0–99%) have an elevated stroke risk (HR 2.31) (Gupta et al 2015b). Patients with more than three plaque ulcerations on 3D ultrasound had a 2-year stroke risk of

18.2% versus a 2-year stroke risk of 1.7% for patients with less than three plaque ulcerations (Madani et al 2011).

Reduced or exhausted vasomotor reactivity correlated with increased risk of stroke/TIA (OR 3.96) (Gupta et al 2012).

Finally, progression in the severity of asymptomatic stenosis was also related to stroke. The 8-year cumulative ipsilateral cerebral ischemic stroke rate was 16% for p a t i e n t s w i t h p r o g r e s s i o n , 9 % i n u n c h a n g e d s t e n o s i s , a n d 0% in patients with regression (Kakkos et al 2014).

MRI and CT additionally allow for the assessment of intraplaque hemorrhage and silent embolic infarcts. MRI-identiﬁ ed intraplaque hemorrhage associated with a 2–3.5-fold higher risk of cerebrovascular events (Hellings et al 2010, Singh et al 2009). Silent embolic infarcts, during an average follow-up of 4.1 years were associated with a >8.5-fold higher risk for cerebral ischemia (Miwa et al 2010).

Surgery Versus Interventional Treatment (Stenting and/or Angioplasty)

Further risk–beneﬁ t assessment is necessary for percuta- neous carotid angioplasty and CAS interventions, which are increasingly being used and may potentially oﬀ er a therapeutic alternative to CEA, particularly in patients with a high risk of developing postsurgical complications. CAS has a lower number of complications—e.g., local wound infections, local bleeding, cranial nerve palsy—and has been shown to decrease both the length of hospital stay and short-term treatment costs. However, stenting does not remove atheromatous plaque and the rate of restenosis is greater after stenting than following carotid surgery. Early studies reported that complication rates were much higher after stenting than after open surgery. However, the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS investigators

2001), which compared endovascular treatment with CEA found no diﬀ erence between the two procedures in the number of strokes or deaths. This was, however, because the CEA group had a 9.9% complication rate— i.e., 2 times higher than in the NASCET and ECST trials. The 5-year follow-up data of the CAVATAS study showed that ipsilateral, nonperioperative strokes and TIAs occurred in 19.3% of the patients with endovascular treatment compared with 17.2% in the operated patients. The rate of any nonperioperative stroke was 21.1% and 15.4%. Overall, more strokes occurred in the endovascular treatment group. However, the diﬀ erence between ipsilateral nonperioperative stroke rates was not statistically signiﬁ - cant ( Ederle et al 2009).

202 Case 1 Right Extracranial Internal Carotid Artery Stenosis

The Stent-Protected Angioplasty versus Carotid E n d a r t e r e c t o m y ( S P A C E ) s t u d y f a i l e d t o s h o w n o n i n f e r i ority of CAS compared with CEA in 1,200 patients with symptomatic ICA stenosis. The 30-day incidence of ipsilateral ischemic stroke or death was 6.84% in the stenting group and 6.34% in patients after CEA (Ringleb et al

2006). The French Endarterectomy Versus Angioplasty-3S (EVA3S) study, in contrast, was stopped prematurely after inclusion of 527 patients with symptomatic ICA stenosis ≥60% because of an obvious inferiority of the stenting treatment. The 30-day incidence of any stroke or death was 3.9% after CEA and 9.6% after stenting. However, in this study, the skill requirements for the treating physicians were remarkably diﬀ erent. Surgeons were allowed to participate if they had performed at least 25 CEAs in the year before the study began, whereas interventional physicians could participate if they had performed a total number of 12 ICA or 35 supra-aortic artery stenting procedures, including 5 in the ICA (Mas et al 2006).

The data from SPACE, EVA3S, and the Interna tional C a r o t i d S t e n t i n g S t u d y ( I C S S ) , p u b l i s h e d i n 2 0 1 0 , w e r e pooled and reanalyzed. Together, the three studies i n c l u d e d 3 , 4 3 3 p a t i e n t s w i t h a ≥50% symptomatic ICA s t e n o s i s . S i g n i ﬁ cant advantages for the CEA group com- pared with CAS were calculated for the primary endpoint (any stroke or death, 5.8% versus 8.9%) as well as for the endpoint any stroke alone (4.9% versus 8.2%). In addition, the above risk in patients aged ≥70 years was roughly twice as high in the CAS group (12%) compared with the CEA group (5.9%) (Bonati et al 2010). On the other hand, the recently published long-term follow-up data from the ICSS trial reported no signiﬁ cant diﬀ erence in function- al outcome or risk of fatal strokes for either treatment of symptomatic ICA stenoses after an average observational period of 4.2 years. In 1,713 patients included, the number of severe strokes did not diﬀ er between CAS and CEA (6.4% versus 6.5%). The total number of strokes was higher in the stent group (15.2% versus 9.4%), but these were predominantly non-disabling stroke events (Bonati et al 2015).

Another important study comparing CAS and CEA in symptomatic as well as asymptomatic ICA stenoses is the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) study, published in 2010. Here, 2,505 patients with either symptomatic (1,321) or asymptomatic (1,181) ICA stenosis were included and randomized for CAS or CEA. Patients with symptomatic stenosis had an ultrasounddetermined grade of stenosis ≥70% or an angiographically determined grade of stenosis ≥50%. Patients with asympto- matic stenosis were included from ≥60% stenosis onwards. Study endpoints were stroke, death, or myocardial infarction within 30 days or ipsilateral stroke beyond 30 days. Considering the primary endpoints, no signiﬁ cant diﬀ er- ence was seen between CEA and CAS after 4 years (6.8% versus 7.2%). Patients in the CEA group showed a lower periprocedural stroke risk (2.3% versus 4.1%), but a higher risk of suﬀ ering a periprocedural myocardial infarction (2.3% versus 1.1%). The results did not diﬀ er between men and women or between symptomatic and asymptomatic stenoses (Brott et al 2010). Compared with earlier trials, this study was distinguished by an extended preparation period and strict monitoring. In particular, it was ensured that the CEA quality criteria were followed.

The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study, like the CREST study, included patients with asymptomatic carotid stenosis for CAS; however, unlike CREST, they used a distal embolus protection device. In this study 70% of the 334 patients included had a stenosis ≥80%. The combined endpoint (stroke, death, myocardial infarction) after 30 days was 5.4% for the CAS and 10.2% for the CEA group, which increased to 9.9% and 21.5% after 1 year (Yadav et al 2004). However, long-term follow-up data revealed no signiﬁ cant diﬀ erences between the aforementioned endpoints (Gurm et al 2008).

In general, high-quality data regarding CAS treatment for asymptomatic ICA stenosis is scarce. Choi and coworkers compared CAS and CEA complication rates from 186 clinics outside study conditions. Of the identiﬁ ed patients with asymptomatic carotid stenosis, 17,716 had been treated with CEA and 3,962 had received CAS. Postoperative strokes and death within the hospital occurred more frequently in the CAS group (4% versus 1.5%) (Choi et al 2015).

To s umma ri ze t he cu rr ent d ata , C AS i s a n alt er nate option for treatment of symptomatic carotid stenoses if the periprocedural risk is <6%. Patients aged <70 years seem to proﬁ t more from CAS, whereas pa- tients ≥70 years beneﬁ t more from CEA. The goal for periprocedural risk when treating asymptomatic ICA stenosis should therefore be <3%.

As discussed above, the beneﬁ ts of CEA and CAS are well documented by randomized trials for symptomatic ICA stenosis as well as for selected patients with asymptomatic stenosis. However, these results are all based on comparison with standard medical therapy from the 1990s. Since then, conservative treatment options have substantially improved and have become increasingly tailored for both primary and secondary atherosclerosis prevention. New treatment evaluations regarding extracranial carotid stenosis are therefore needed. More speciﬁ cally, it currently remains unclear if newer opti- mized conservative medical treatments are more eﬃ ca- cious than interventional treatment in patients with low stroke recurrence risk proﬁ les. Our current treatment guidelines are based on studies initiated in the 1980s, where treatment of hypertension, other vascular risk factors, and lifestyle modiﬁ cations were not optimal. For example, the mean systolic blood pressure in the NASCET study was 147 mm Hg after a 2-year treatment period (Chaturvedi 2013). Another important component of today’s secondary stroke prevention is the use of statins, as documented by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study (Sillesen et al 2008). A recent study that included 2,770 TIA patients, of whom 387 were found to have a ≥50% carotid stenosis, reported that the risk of manifest stroke within 7 days following TIA was 3.8% in patients pretreated with a statin and 13.2% in those without pretreatment (Merwick et al 2013).

Dual antiplatelet therapy is another option that is increasingly used. In the Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) study 5,170 patients were included within 24 hours after minor stroke or TIA and either

203Discussion

treated with aspirin (75 mg/day) alone or with a combination of aspirin and clopidogrel (300 mg loading dose followed by 75 mg/day). The stroke rate after 90 days was

8.2% in the dual antiplatelet therapy group compared with 11.7% in the aspirin group (Y. Wang et al 2013). Unfortunately, the number of patients with extracranial ICA stenosis was not reported. There are, however, surrogate marker studies available that support the beneﬁ t of dual antiplatelet therapy in patients with symptomatic ICA stenosis. Detection rates of TCD-determined microemboli are known to correlate with stroke and TIA occurrence. The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) study, which analyzed 109 patients using TCD, revealed that a combined application of aspirin and clopidogrel reduces the rate of microembolic signals by 40% compared with treatment with aspirin alone (Markus et al

2005) (for further reading on TCD embolus detection, see Chapter 4, “Microembolic Signals”).

Together, experiences over the past years suggest that an optimal medical treatment (OMT) for macroangiopathy requires a multimodal conceptual basis. This becomes particularly evident if the data of the Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study, published in 2011, are analyzed. There, all patients with a symptomatic intracranial stenosis 70–99% received vigorous medical treatment. After 1 year in this group, the primary endpoint had occurred in only 12% of cases, which was 50% lower than the predicted event rate calculated from previous studies. These results then were superior to the additional intracranial stent placement (Chimowitz et al 2011) (for more details see also Case 5).

The potential of optimized medical treatment was also demonstrated by a recent study that included patients with symptomatic extracranial ICA stenosis (stroke or TIA) who were referred to a vascular surgical clinic. Until a decision regarding CEA was made, patients received multimodal OMT with double antiplatelet therapy (aspirin + clopidogrel) in combination with a statin following a standardized protocol. The stroke and TIA rate before OMT introduction had been 29%, which dropped to 2.5% after the initiation of the treatment protocol. Within the OMT group, only TIAs (no strokes) occurred (Shahidi et al 2013). Historic data report a 10–20% stroke rate within 90 days after TIA if an underlying macroangiopathy is present.

Recent studies also indicate that OMT reduces stroke rates in patients with asymptomatic extracranial stenoses as well and leads to annual stroke rates of <1% in these patients (Abbott 2009, den Hartog et al 2013, Marquardt et al 2010). This means that any interventional therapy for asymptomatic ICA stenosis will have to be compared to these data. Advances in medical therapy as well as improvements in CEA and CAS have led to the initiation of a new generation of trials for the treatment of carotid stenosis. The currently recruiting CREST 2 and SPACE 2 studies compare OMT alone with OMT + CEA or OMT + CAS (Pahigiannis et al 2014, Reiﬀ et al 2014). The ongoing ECST 2 trial includes patients with symptomatic carotid stenosis and an estimated annual stroke risk <3% and

compares OMT alone with a combination of OMT and revascularization. However, results and potential therapeutic consequences remain unclear.

Angiologic and Anatomic Aspects

The detection and quantiﬁ cation of extracranial carotid stenosis is one of the most important indications for diagnostic ultrasound, as the degree of stenosis has been shown to strongly correlate with stroke risk.

Careful application of the following criteria leads to a reliable ultrasound-based carotid stenosis assessment, not only matching the gold standard results but also providing additional hemodynamic parameters which cannot be derived by any of the competing methods. Grading of ICA stenosis by means of color-coded duplex sonography is based on two principles:

• A <50% ICA diameter reduction is assessed by ge-

ometric vessel lumen analysis, i.e., by measuring area and diameter in the cross-sectional and longitudinal image using the B- and color-mode of the ultrasound system.

• A ≥50% ICA diameter redu ction is assessed on the ba-

sis of hemodynamic parameters derived from pre-, intra-, and poststenotic Doppler spectrum analysis (see Chapter 5, “Grading of ICA Stenosis by Duplex Ultrasonography” under “Extracranial Pathology”).

Area measurements in high-grade stenosis can be performed for orientation, but should not be used for exact graduation as the color-mode within a stenosis often suffers aliasing or color oversteering eﬀ ects which may lead to an underestimation of the real lumen reduction. In our case, the Doppler spectrum analysis showed only an increased intrastenotic ﬂ ow velocity matching well with a stenosis of 70% (ECST criteria) and 50% (NASCET criteria) and also correlating well with the CTA evaluation. In contrast, if a poststenotic ﬂ ow pattern distal to the stenosis, e.g., in the distal extracranial ICA or proximal intracranial ICA (C6 segment), as well as recruitment of intracranial collateral vessels are present, a stenosis of >80% (ECST criteria) and >70% (NASCET criteria) would be diagnosed.

The carotid bifurcation is particularly susceptible to the development of atherosclerotic lesions. This is mainly caused by a vessel widening of the carotid bulb, a frequently present anatomic characteristic. This leads to turbulent blood ﬂ ow causing altered mural tensile stress and changes in compliance, composition, and metabolism of the arterial vessel wall. The true initiating event for early plaque induction is still not entirely clear; however, the above ﬁ ndings indicate that ﬂ ow-associated mechanical factors might particularly predispose to plaque formation.

Duplex ultrasound not only allows for grading carotid stenosis but also for analyzing plaque morphology. High-resolution ultrasound enables the description of atherosclerotic plaque by examining its echogenicity (anechoic or echolucent to echogenic), texture (homogeneous to heterogeneous), surface contour (smooth to rough), surface motion (uniform to

204 Case 1 Right Extracranial Internal Carotid Artery Stenosis

discrepant), and progression or regression in echogenicity. Histologic investigations have shown that soft lipid-rich plaques present a higher embolic risk than hard calcium- containing plaques (Bock et al 1993). Carotid artery plaque inﬂ ammation is a further parameter indicating vulnerability of a vessel lesion. A recent study including 36 patients with ≥70% ICA stenosis showed that 2-deoxy-2-[

F] ﬂ uoro-D glucose (18F-FDG) uptakes on positron emission tomography/CT (PET) correlated with histological assessments of inﬂ ammation and was higher in symptomatic patients compared with asymptomatic carotid artery plaques (Skagen et al 2015). Ultrasound may also analyze plaque vulnerability and vessel inﬂ am- mation by assessing neovascularization seen as plaque enhancement after echo-contrast administration (Kunte et al 2012, Partovi et al 2012, Vicenzini et al 2007). Carotid contrast ultrasound imaging appears to be an emerging technique for identifying plaque angiogenesis. A study of 147 subjects showed that marked intraplaque neovascularization was associated with cerebrovascular events (OR 4.0) (Staub et al 2010). MRI also allows the visualization of plaque angiogenesis and inﬂ ammation by the use of gadolinium (J. Wang et al 2014).

Ultrasound has to compete with digital subtraction angiography (DSA), CTA, and contrast-enhanced ( c e ) - M R A . M a n y r e p o r t s a n d s t u d i e s h a v e p u b l i s h e d indices, parameters, and grading methods and have g e n e r a l l y c o n c l u d e d t h a t n o c u r r e n t s i n g l e m e t h o d c a n precisely quantify the degree of carotid stenosis. Despite these methodologic disputes, some authors exclusively favor duplex sonography whereas others consider DSA as an absolute necessity despite the reported 1% interventional morbidity, which is probably even higher in symptomatic vascular patients (see also Case 24). Up to now DSA remains the gold standard method as the NASCET and ECST studies are based on it. However, even the DSA technique has limitations leading to imprecise grading of stenosis. The underlying reason is that carotid stenoses are almost never circular in shape. A single conventional DSA projection therefore risks over- or underestimating stenosis, as has been shown if compared with the “true” degree of stenosis in surgically removed specimens, whereas ultrasound and CTA are less prone to this potential source of artifact (Alexandrov et al 1993). New 3D-computed rotational DSA techniques might help overcome this problem; however, other noninvasive or less invasive techniques are progressing and will proba-

bly replace DSA at least for the purpose of stenosis evaluation. A meta-analysis that included 41 studies, 2,541 patients, and 4,876 arteries comparing noninvasive imaging of symptomatic ICA stenosis with DSA underscores this prediction (Wardlaw et al 2006a). Stenoses assessed by the ECST grading system or by the common carotid artery method (CC) were converted into NASCET grades (conversion formula: NASCET = (ECST or CC-40)/0.6). For stenoses between 70% and 99% the sensitivity/speciﬁ city values for ce-MRA, TOF-MRA, CTA, and duplex ultrasound were 0.94/0.93, 0.88/0.84, 0.76/0.94, and

0.89/0.84. For 50–69% stenoses the corresponding values were 0.77/0.97, 0.37/0.91, 0.67/0.79, and 0.36/0.91. The data demonstrate that high-grade stenoses may be almost equally well detected by either of the above methods, whereas all methods are less accurate for assessing less severe stenoses. Future clinical stroke trials in patients with high-grade stenoses or study setups requiring a repeated follow-up investigation might therefore rather make use one of the noninvasive diagnostic methods which will in time gradually further reduce the importance of DSA.

The current question therefore remains: which of the above techniques will be the future method of choice? In our opinion, ultrasound use will increase and become the ﬁ rst-line investigation in routine clinical practice and follow-up examination because of its widespread availability, low costs, and avoidance of patient discomfort. Except in acute stroke, ce-MRA might become the most relevant conﬁ rmatory technique in ambulatory pa- tients. However, CTA, which, like the duplex ultrasound technique, allows measurement of the real carotid bulb diameter and the residual intrastenotic vessel lumen, has made tremendous progress and will be the preferable method in acute stroke patients. Dual-source techniques, which use two X-ray sources and two detectors simultaneously, facilitate the evaluation of densely calciﬁ ed ICA stenosis (Lv et al 2014). Plaque calciﬁ cation and subsequent inadequate visualization of the vascular wall is a major limitation in B-mode and color-mode imaging of carotid stenosis. Large and concentric calciﬁ ed plaques may completely obscure ﬂ ow in a vessel over several centimeters, impeding the evaluation of a stenosis. In such conditions ce-MRA seems to be the method of choice. Future studies will show which of the methods described here, either alone or in combination, will serve as the future gold standard.

Case 2

Free-ﬂ oating Thrombus of the Left Internal Carotid Artery

205

Clinical Presentation

A 54-year-old woman was admitted to the emergency department with right-sided weakness and aphasia that had started 50 minutes prior to her presentation. She had a history of non-Hodgkin’s lymphoma, diagnosed 4 years ago. She had stopped taking methotrexate 2 days p rior to admission because of the following hematologic abnormalities: thrombocytosis (750/nL; normal range 150–400/nL), leukopenia (3.86/nL; normal range 4.5–11.0/nL), and anemia (93 g/L; normal range 120–157 g/L). She was also taking oral steroids on a long-term basis for coexisting Sjögren’s syndrome. The neurologic examination on admission revealed incomplete motor aphasia, a mild right-sided hemiparesis, and a right facial paresis (National Institute of Health Stroke Scale [NIHSS] score of 7).

Initial Neuroradiologic Findings

Admission cranial CT showed no signs of acute cerebral ischemia. Cerebral MRI the following day revealed multiple small cortical and subcortical ischemic lesions in the left anterior cerebral artery (ACA) and middle cerebral artery (MCA) territories. A contrast-enhanced MR angiogram (MRA) of the extracranial brain-supplying vessels was initially reported to show right distal vertebral artery narrowing as an anatomic variant but otherwise normal ﬁ ndings especially with regard to the left internal carotid artery (ICA) (Fig. B2.1, Fig. B2.2, Fig. B2.3).

Diagnosis

Multiple small, embolic cerebral infarctions in the left ACA and MCA territory of unknown origin.

Question to Answer by Ultrasound Techniques

• To ﬁ nd or exclude an embolic source in the left com- mon carotid artery (CCA) or ICA.

Initial Neurosonologic Findings (Day 1)

Extracranial Duplex Sonography

B-mode imaging of the left ICA distal to the carotid bifurcation displayed a lumen reduction of 50%

caused by a mildly hyperechoic f loating structure (12.5 × 5 mm) that was partially adherent to the lateral vessel wall (Fig. B2.4). Doppler spectra and blood flow velocities were regular even at the maximum of stenosis. There were no pathologic f indings in the right CCA and ICA (see Videos

B2.1 and B2.2).

Transcranial Duplex Sonography

All detectable intracranial vessels revealed normal and symmetric ﬂ ow signals. However, several microembolic signals were recorded during insonation of the left MCA (Fig. B2.5; see also Video

A4.1).

Conclusion

Partially ﬂ oating, unstable, continuously microemboli emitting thrombus in the left proximal ICA causing a lumen reduction of ~50%.

Clinical Course

Because of the patient’s complex hematologic history, rt-PA treatment was contraindicated according to current guidelines. Instead, she was given intravenous partial thromboplastin time (PT T)-guided heparin. The pattern of multiple small infarctions in the left ACA and MCA territory indicated an artery-to-artery embolic etiology, caused by the ﬂ oating thrombus within the left ICA. On re-evaluation of the MR angiograms, a circumscribed signal of reduced intensity was observed in the left ICA directly above the carotid bifurcation, in accordance with the initial duplex results (Fig. B2.6). Carotid endarterectomy (CEA) was consid- ered to be the best treatment. The patient had surgery on the same day (Fig. B2.7). Postoperative follow-up was uneventful.

The etiology of the intravascular thrombus was unclear, but the underlying hematologic disease with severe thrombocytosis was suggestive for a paraneoplastic coagulopathy (anticardiolipin antibody levels were not raised). Blood culture and transesophageal echocardiography excluded an infectious cause. The intravenous heparin was replaced by low-dose subcutaneous heparinization after 10 days, which was continued until a therapeutic decision regarding the lymphoma was made. The neurologic deﬁ cits improved markedly and the pa- tient was discharged with a mild right-sided hemiparesis and amnesic aphasia.

206 Case 2 Free-ﬂ oating Thrombus of the Left Internal Carotid Artery

Fig. B2.1 MR diﬀ usion-weighted image (b = 1,000), axial plane. Is- chemic lesions in the basal ganglia and in the left-sided MCA territory.

Fig. B2.3 Extracranial contrast-enhanced MRA, coronal MIP. Normal aspect in the conventional MIP projection.

Fig. B2.2 MR diﬀ usion-weighted image (b = 1,000), axial plane. Multiple ischemic cortical lesions within the left-sided ACA and MCA territory.

BIF-L

Fig. B2.4 Extracranial duplex, longitudinal plane. B-mode sonography reveals a ﬂ oating thrombus (12.5 × 5 mm) that is partial- ly adherent to the lateral vessel wall in the right proximal ICA, d i r e c t l y a b o v e t h e c a r o t i d b i f u r c a t i o n , r e d u c i n g t h e l u m e n b y a p p r o x i m a t e l y 5 0 % .

Neurosonologic Findings (Day 20)

Follow-up ultrasound examination 2 weeks after dis-

Discussion

Clinical Aspects

charge demonstrated a normal left ICA (Fig. B2.8; see also Video

B2.3).

We have descr ibed a pati ent with multiple emb olic infarctions within the ACA and MCA territory caused by embolic fragments from a free-ﬂ oating thrombus within

Final Diagnosis

the left ICA. The patient had a history of non-Hodgkin’s

lymphoma and developed severe thrombocytosis and Multiple embolic infarcts within the ACA and MCA territories caused by a partially ﬂ oating thrombus in the proximal left ICA. The presumed etiology was a paraneoplastic coagulopathy.

anemia after chemotherapy with methotrexate. Hyper-

coagulability is a well-known paraneoplastic syndrome

associated with several hematologic malignancies. Clin-

ical incidence of thromboembolic disease in cancer

M1-MCA-L

Fig. B2.5 TCCS ( tran stemp oral appro ach) , le ft-s ided inson atio n, upper pontine plane. Normal ﬂ ow signal in the left M1-MCA (ﬂ ow velocity 92/29 cm/s). Note the microembolic signal within the Doppler spectrum (arrow).

207Discussion

Fig. B2.6 Extracranial contrast-enhanced MRA, coronal single-plane

MIP. In accordance with the ultrasound ﬁ ndings, a review of the an- giograms revealed a circumscribed area of reduced signal intensity in the left ICA, directly above the carotid bifurcation (arrowhead).

BIF-L

Fig. B2.7 Intraoperative view. Thrombus in the left proximal ICA.

patients ranges from 1% to 11% but has been reported in up to 50% of cases at autopsy (Frenkel and Bick 1998, Schwarzbach et al 2012). Hypercoagulability is thought to arise from interactions between tumor cells, endothelial cells, macrophages, and platelets as well as from procoagulatory and ﬁ brinolytic factors associated with the tumor cells themselves. The tumor cells may produce specific tissue factors or cancer procoagulants, both of which activate factor X (Falanga and Rickles 1999). An embolic cause was seen in more than one-half of cases in stroke patients with cancer (Cestari et al 2004).

Aside from the underlying hematologic disease, Sjögren’s syndrome was present in our patient and was being managed with steroids. Up to one-third of patients with Sjögren’s syndrome are known to have

BIF-L

Fig. B2.8 Extracranial duplex, longitudinal plane. Left carotid bifurcation with normal intraluminal B-mode echogenicity after surgery.

antiphospholipid antibodies (Fauchais et al 2004), which are a known cause of acquired hypercoagulability. In fact, the antiphospholipid antibody syndrome is more common than any inherited coagulopathy. In this condition, venous and arterial thrombi are equally common (Pasoto et al 2012, Thomas 2001). In our patient, the anticardiolipin antibodies were negative. However, the steroid treatment could still have promoted a prothrombotic constellation.

Finally, our patient presented with anemia and thrombocytosis, which can both be associated with thrombus formation in the carotid arteries in patients without identiﬁ able macrovascular disease (Akins et al 1996). Gener- ally, thrombus formation requires platelet activation and aggregation on an endothelial surface with subsequent

208 Case 2 Free-ﬂ oating Thrombus of the Left Internal Carotid Artery

ﬁ brin deposition. A straightforward hypothesis could be that thrombocytosis leads to thrombus formation, but the correlation between high platelet counts and thrombosis is poor (Kessler et al 1982). Abnormal platelet activation and function are probably more important than the absolute platelet count. Anemia leads to increased ﬂ ow ve- locities and subsequent turbulent blood ﬂ ow which may damage the endothelium and lead to platelet aggregation. This eﬀ ect would be most prominent at vessel bifurca- tions such as at the carotid bulb. Iron deﬁ ciency anemia itself may favor arterial ischemic stroke and blood loss may aggravate ischemic infarction growth (Bösel et al 2005, Munot et al 2011).

A free-ﬂ oating thrombus (FFT) in the carotid artery is a rare condition of currently unknown etiology with serious embolic consequences (Bhatti et al 2007). Since the ﬁ rst description of FFT by Chiari in 1905, several single cases and small series of patients have been reported in the literature, but the true incidence of carotid thrombi is unknown. The lack of a uniﬁ ed deﬁ nition poses diﬃ culty in identiﬁ cation of uniformly comparable clinical trials or even case studies. The recently proposed deﬁ nition of FFT according to the literature is “an elongated thrombus attached to the arterial wall with circumferential blood ﬂ ow at its distal most aspect with cyclical motion relating to cardiac cycles” (Bhatti et al 2007). According to this deﬁ nition, a 0.62% (16/2,572) incidence of FFT in all patients scanned for carotid artery disease has been published (Ferrero et al

2011). Others reported intraluminal thrombi of the carotid artery in 0.4% (9/2,250) of patients undergoing arteriography after cerebral ischemia (Biller et al 1986). Although artery-to-artery emboli from atherosclerotic carotid artery lesions are a common cause of stroke, an angiographic identiﬁ cation of a ﬁ xed or mobile carotid thrombus is un- common. In an analysis of ~2,000 angiograms in patients with cerebral ischemia, thrombi were reported in only 29 subjects (Buchan et al 1988). In cases without atherosclerosis, thrombi have been associated with iron deﬁ - ciency anemia and the use of illicit drugs (Akins et al 1996, Konzen et al 1995). Fur thermore, diﬀ erent types of blood hypercoagulability seem to play a signiﬁ cant role in the pathophysiology of FFT (Bhatti et al 2007). Compared with patients with atherosclerotic wall disorders, patients with FFT are usually younger and men are twice as likely to be aﬀ ected as women (Bhatti et al 2007).

No guidelines have been published regarding the therapeutic management of ﬂ oating carotid plaque material or thrombi, and reported approaches are controversial. In our patient, thrombolytic therapy was contraindicated despite her arrival within the 4.5-hour time window because of her underlying hematologic disease. In addition, thrombolysis of a FFT may increase the risk of further fragmentation, which could lead to embolization. In isolated studies, systemic thrombolysis was reported to be eﬀ ec- tive in resolving acute carotid stent thrombosis (Hamann et al 2002, Steiner-Böker et al 2004). Unfortunately, none of the large intravenous thrombolysis trials have evaluated the presence of vessel occlusion or ﬂ oating thrombus be- fore therapy, although aiming for recanalization of occluded arteries. The second therapeutic approach applied in our patient is the emergency CEA. Our successful intervention is in line with the results of a small case series of ﬁ ve

patients undergoing early carotid surgery after initial anticoagulation (Bösel et al 2010). However, compared with standard carotid surgery this procedure seems to carry a higher perioperative risk and morbidity, particularly in the neurologically unstable patient (Buchan et al 1988, Combe et al 1990). It should therefore only be considered in selected cases. A noninvasive bedside ultrasound evaluation of the brain-supplying arteries may help to decide whether emergency CEA would be appropriate.

Finally, noninvasive medical treatment with anticoagulants (heparin, warfarin, or both) has been reported in single cases or small series of patients with complete disappearance of the thrombus and good clinical outcome. In a small case series of ﬁ ve patients revealing an ICA FFT in nonatherosclerotic stroke, antiplatelet therapy with clopidogrel led in all cases to complete thrombus regression within 6 months. No stroke recurrence was observed during a mean follow-up of 2.4 years (Vassileva et al 2015).

Although overall numbers are too small to allow controlled comparison between the above approaches, all the strategies described seemed reasonable. Which treatment approach to choose remains an individual decision. Endovascular approaches have also been used but appear to have a high embolic risk (Park et al 2012).

Angiologic and Anatomic Aspects

Thrombus formation within the carotid artery classically occurs if severe atherosclerotic disease is present. The majority of carotid thrombi develop on stenotic or ulcerated atherosclerotic lesions (Caplan et al 1984, Pessin et al 1986). They may subsequently lead to vessel occlusion, thromboembolic events, or both.

A carotid FFT seems to be a rare phenomenon, perhaps because it is rarely recognized before embolization. In addition, MRA and computed tomography angiography (CTA)—today often used as ﬁ rst-line diagnostic methods—currently provide only a snapshot image of the thrombus and cannot display its ﬂ oating character, i.e., its changing position over time. As cerebral angiography is no longer a routine ﬁ rst-line diagnostic tech- nique in ischemic stroke, carotid duplex sonography is currently the best method to demonstrate dynamic changes of vessel walls in FFT and their related structures (Arning and Herrmann 1988). The case presented here is an excellent example, clearly demonstrating the ﬂ oating character of the thrombus with its characteristic oscillating movements. Digital subtraction angiography (DSA) was not required as no additional information would have been gained, whereas catheter angiography increases the risk of thrombus dislodgement. This underlines the importance of performing ultrasound in the early, hyperacute phase of stroke.

MRI is currently the optimal method to detect fresh cerebral ischemic lesions. However, its ability to image intravascular thrombi has so far not been well investigated. Our case report illustrates the potential pitfalls using contrast-enhanced (ce)-MRA. For initial calculation of the image the widely used maximum intensity projection (MIP) technique was applied for postprocessing of image data. This method uses only the image points with the maximal intensity along the chosen projection for image

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