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219Discussion

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.

showed the presence of a superﬁ cial venous drainage component (Garcin et al 2012). Intracranial hemorrhage is the most common clinical presentation of an AVM and occurs in ~50% of cases. Depending on the site of the lesion and its angioarchitecture, the hemorrhage can be primarily parenchymatous, subarachnoid, ventricular, or any combination of these. The need for treatment strategies is driven by the bleeding risk, which ranges between 2% and 4% per year in patients without previous hemorrhage (Choi and Mohr 2005). Higher annual rates of up to 18% per year have been reported in patients who initially present with a hemorrhage (Arteriovenous Malformation Study Group 1999). The subsequent bleeding risk is highest in the ﬁ rst year after the initial hemorrhage and declines rapidly. Factors that seem to further increase the risk of hemorrhage may be primarily structural (e.g., the presence of a deep venous drainage, a deep periventricular location, an aneurysm), and may also be dynamic (e.g., the presence of a high feeding artery pressure or a slow arterial ﬁ lling) (Duong et al 1998, Fleetwood and Stein- berg 2002, Stapf et al 2006). Dynamic aspects in particular, such as the ﬂ ow velocity of arterial feeders, have been associated with an increased risk of intra- and postoperative neurosurgical treatment complications (Pasqualin et al 1991). Furthermore, a history of hypertension, young age, and male gender has been associated with an increased risk whereas an AVM located in the arterial border zone seems to result in a lower risk of bleeding (Mast et al 1997, Stapf et al 2000). In terms of correlations between lesion size and bleeding risk the results are contradictory, ranging from a positive association to irrelevant. For further reading on AVM and intracranial hemorrhages, see Case 32.

Headache is the presenting symptom in 10–19% of patients with AVM (Hofmeister et al 2000). There are no pathognomonic characteristics of headache associated with intracranial bleeding. In particular, there are no safe criteria to diﬀ erentiate symptomatic from primary headaches such as migraine. However, the incidence of AVMs is not higher within the group of migraine patients (Evans 1996).

Patients may present focal neurologic signs even in the absence of underlying hemorrhage. The reported rates of such deﬁ cits vary widely: 1–40%, depending on the deﬁ ni- tion used. Progressing neurologic deﬁ cits was observed in ~4–8% of patients. As a potential underlying mechanism, a “steal phenomenon” caused by hypoperfusion and subsequent ischemia in the brain tissue surrounding the AVM has been postulated, but this hypothesis is under debate and focal symptoms have been also be explained by mass eﬀ ect of distorted draining veins itself, especially for AVMs in the brainstem (Mast et al 1995a, Mohr et al 2013).

Treatment decisions for patients with AVMs in the brain should include a comparison of the risks of the natural course of the condition with the interventional periprocedural risk of each therapeutic approach (Al -Sha hi a nd Warl ow 200 1). The gra ding s yste m acco rding to the Martin–Spetzler scale is the most frequently used method to classify AVMs and to evaluate the risk of surgical resection (Spetzler and Martin 1986). The scale includes factors such as AVM size: <3 cm (1 point), 3–6 cm (2 points) or >6 cm (3 points), the type of venous drainage: superﬁ cial only (0 points) or deep (1 point),

and the location of the AVM: non-eloquent (0 points) or eloquent (1 point). Increased surgical risk is associated with higher AVM grade which is calculated by points awarded.

Treatment is a growing interdisciplinary challenge and is focused mainly on prevention at least of secondary hemorrhage. The available treatment options are open surgery, radiotherapy, and endovascular therapy, and the last is currently the most frequently used technique. If possible, total elimination of the AVM is the goal. Endovascular embolization, which reduces the size of the malformation, can reduce the risk of hemorrhage before surgery or radiotherapy but frequently fails to completely obliterate the AVM. Stereotactic radiosurgery causes subsequent sclerosis of the blood vessels, obliterating the AVM over a period of 1–2 years. The advantage of the latter method is the opportunity to treat patients with deep-seated AVMs or in eloquent brain regions, which carries a high risk of complications in open surgery. Its major limitation is the treatable size of the AVM. Best results are achieved if the AVM nidus measures <2 cm.

There is scarce, objective information about the efﬁ cacy and outcome of treatment, reﬂ ecting a lack of long-term follow-up and inconsistencies in treatment evaluation. The reported rate of obliteration of AVMs after surgery conﬁ rmed by angiography is up to 97% (Castel and Kantor 2001). Endovascular embolization of the AVM alone is estimated to be successful in 13–40% of patients (Hartmann et al 2002). Total obliteration by stereotactic radiosurgery is successful in up to 24% of cases (Maruyama et al 2005). Therefore, a multimodal treatment strategy combining the above approaches has evolved within the past three decades.

However, there is also growing awareness that treatment to prevent intracranial bleeding itself carries risks of disabling or fatal outcome, and untreated AVMs may have a better prognosis than previously expected (van Beijnum et al 2011). There is quite a lively debate about the treatment of unruptured AVMs, ranging from immediately interventional therapy (Cockroft 2007) to conservative regiments (Stapf and Mohr 2007). Results of the ARUBA study (A Randomized trial of Unruptured Brain Arteriovenous malformations), published in 2014, have reignited the discussion of the best therapeutic strategy in unruptured AVMs. In this trial, started in 2007, patients were randomized either to conventional medical therapy or to interventional therapy which could, according to the decision of the treating doctors, be microsurgery, embolization, stereotactic radiation, or a combination of these. However, an interim analysis of 223 patients after 33 months showed results clearly favoring the noninterventional group, which led to a subsequent early termination of the trial. At that point 10.1% of the conventionally treated and 30.7% of the interventionally treated patients suﬀ ered from stroke or had died. This diﬀ erence was also observed for the secondary endpoint of death and focal neurologic deﬁ cit after 30 months, which was 15.1% and

46.2%, respectively (Mohr et al 2014). These seemingly clear results were, however, in part severely criticized. In particular, the study protocol was discussed, as more than 87% of reported patients were not included into the trial. Any intervention, even without complete occlusion,

220 Case 4 Left Temporal Arteriovenous Malformation

was considered as a treatment. In the majority of the 116 treated patients, the AVM was in fact not completely occluded, so the risk of bleeding probably remained at least similar to the status prior to the intervention. In addition, an observation time of 3 years might be too short, especially considering the relatively benign character of the disease in young adults (Bervini et al 2014, Potts et al

2015). Therefore, the data from the continuing 5–10-year follow-up has to be awaited.

The advantages of conservative treatment in unruptured AVMs have been shown in a prospective study including 204 patients. Conservative management compared with intervention was associated with better clinical outcomes for up to 12 years (Al-Shahi et al 2014). However, as with any disease, whenever intervention is contemplated the risk and beneﬁ ts of treatment must always be carefully weighed against those of observation alone.

In the case presented here, surgical resection was considered to have a high risk because of the eloquent localization of the AVM (1 point), a size of ~3 cm (2 points), and the deep venous drainage (1 point), resulting in a Martin–Spetzler grade IV. Radiosurgery was not indicated because of the large size of the AVM. Partial endovascular embolization was considered to be a viable treatment option, but our patient decided against therapy. The clinical course over 12 years so far and the eﬀ ective anticon- vulsive management seems to support the use of purely symptomatic treatment in this case.

Angiologic and Anatomic Aspects

AVMs are thought to be caused by errors during the embryonic or fetal stage of vessel formation. The low prevalence in infants suggests that the development of AVM s may ext end over d ecad es. T he bas ic p ath olog y o f an AVM is the direct connection of arteries and veins bypassing the capillary bed, subsequently leading to dilatation and a tortuous course of the aﬀ ected veins. The histopathologic diﬀ erentiation of the arterial and venous proportion of the AVM is diﬃ cult, as the aﬀ ected vessels frequently demonstrate a thin or deﬁ cient tunica media and internal elastic lamina. AVMs are more frequently found in a supratentorial location. The typical AVM angioarchitecture is wedge shaped, with the base toward the cerebral cortex and the apex extending into the brain. Other variants completely lie within the white matter. AVM s t hat ext end in to d eep br ain st ructur es ar e ge nerally fed by the lenticulostriatal, choroidal, or thalamostriatal arteries and their veins frequently drain into the deep venous system. The latter AVM variant corresponds to the lesion found in our patient with blood supply via the anterior and posterior choroidal artery and drainage through the left basal vein of Rosenthal.

CT and MRI have a substantial role in the diagnosis of AVM s. Locat ion , si ze, a nd re lat ion t o surro und ing in trac ranial structures can be identiﬁ ed with MR techniques. Furthermore, the presence of hemosiderin indicates previous hemorrhage. DSA remains the gold standard for assessing the often complex AVM angioarchitecture. The predominance of various feeding vessels and the different vascular territories involved, potentially present aneurysms, and the venous drainage pattern are all eval-

uated by this technique and indispensable for treatment planning. New developments in dynamic CT and MRI techniques increasingly enable the analysis of not only morphologic but also functional aspects of cerebral perfusion in AVM patients (for further details, see Case 27, Case 32, and Case 40).

Ultrasound is a noninvasive screening tool for both detection and follow-up evaluation of brain AVMs. While transcranial Doppler (TCD) only allows assessment of hemodynamic parameters like high ﬂ ow velocities and low pulsatility, transcranial color-coded sonography (TCCS) may additionally depict the AVM nidus itself, the hemodynamic features of the feeders, and the draining vessels, which makes TCCS more sensitive than TCD. Success rates in AVM nidus visualization depend more on location than on size. In an analysis of 54 patients with proven AVM on DSA, a nidus was identiﬁ ed in 72% of cases. Three further AVMs were found by detection of feeder ﬂ ow signals only. The calculated sensitivity reached 88.9% for the detection of AVMs located in the basal aspects of the frontal, parietal, and temporal lobes, i.e., the regions that can be well accessed by TCCS if the common examination planes are used. The smallest detectable nidus diameter reported was 1.5 cm (Bartels 2005). AVMs near the cortical–subcortical junction of the parietal, frontal, and occipital lobes as well as the cerebellum are more diﬃ cult to de- tect with TCCS, even the larger ones. Contrast-enhanced TCCS increased the detection of AVM nidus in 30 patients signiﬁ cantly compared with native TCCS (96.7% versus 70%). Moreover, contrast-enhanced sonography was signiﬁ cantly superior to unenhanced sonography for detec- tion of feeding arteries (83.7% versus 59.5%) (L.S. Wang et al 2014). In good insonation conditions, the contralateral hemisphere may be insonated up to the cortical areas (see also Case 32).

Using the systolic ﬂ ow velocity as the diagnostic crite- rion alone, a prospective study in 114 patients revealed a sensitivity of 97% in detecting AVMs >5 cm and a sensitivity of 84% in detecting AVMs between 2.6 cm and 5 cm. Among the small AVMs (<2.5 cm), the AVM was missed in 61%. Flow velocity correlated with the AVM size, probably reﬂ ecting its volume ﬂ ow. Lower sensitivities were found if the PI was used as the diagnostic criterion (Mast et al 1995b). The diagnostic accuracy may be increased by using echo-contrast agents, as shown in a small TCD study in 12 AVM patients, which reported a sensitivity of 92% (Uggowitzer et al 1999). Furthermore, a diminished carbon dioxide cerebrovascular reactivity (CVR) can be detected by TCD, which may be even more sensitive than increased ﬂ ow velocities (Diehl et al 1994).

An additional ultrasonographic parameter is the global cerebral circulation time (gCCT). Shortening of blood transit via arteriovenous shunting in untreated patients is well known from catheter angiography and dynamic CT studies (Bartolini et al 1992, Gilroy et al 1963). Global cerebral circulation time measures the time diﬀ erence between the arrival of a bolus of contrast between the extracranial ICA and the IJV, using Doppler or duplex ultrasound. Patients with a high-ﬂ ow AVM were shown to have a signiﬁ cantly shorter gCCT (3 ± 1. 3 seconds) than healthy controls (7 ± 1.3 seconds) (Schreiber et al 2002a, 2003b). Global cerebral circulation time did not

221Discussion

c o r r e l a t e w i t h A V M s i z e . A s a n i n d i r e c t a p p r o a c h t h e technique may even be more sensitive in detecting an AVM tha n th e as sessme nt o f ﬂ ow velocity and PI, as it will also work in AVMs in cortical/subcortical locations that are not directly accessible by TCCS. The test proved to be even more sensitive if applied to occipital dural ﬁ stulas, revealing a mean gCCT of 1.1 ± 0.9 seconds (Schreiber et al 2004). Apart from its diagnostic implication, this test has the potential to be used as an additional monitoring tool for treatment procedures such as stepwise embolization or surgical occlusion. Its clinical

relevance has yet to be evaluated (for further reading on multimodal ultrasound, see also Chapter 3, “Cerebral Circulation Time” under “Parameters of Cerebral Hemodynamics,” and Case 27).

Improved surgical and endovascular treatment options have drawn increasing attention toward the cerebral hemodynamic status of patients with AVMs, particularly aiming to assess the subsequent risk of bleeding. TCCS and TCD are useful in analyzing ﬂ ow velocity, pulsatility, CVR, and the gCCT. However, none of these parameters seem to directly correlate with the risk of bleeding.

222

Case 5

Left M1 Middle Cerebral Artery Stenosis

Clinical Presentation

A 29-year-old woman was admitted to a district general hospital. Four weeks prior, she had developed a ﬁ rst-time mild aphasia and right-sided sensory hemisyndrome but had not paid attention to her symptoms. She was a heavy smoker (15 cigarettes/day) and took an oral contraceptive but no other drugs or vasoactive medication. She reported no headaches during the time until presentation and there was no history of migraine. Her mother had suﬀ ered from stroke aged 24 years. On admission, her National Institute of Health Stroke Scale (NIHSS) score was 2.

Initial Neuroradiologic Findings

MRI of the brain revealed a fragmented left frontoparietal ischemic lesion in the middle cerebral artery (MCA) territory. There was gadolinium enhancement in the infarcted areas, consistent with a partial subacute territorial MCA infarction. Intracranial 3D time-of-ﬂ ight MR angiography (TOF-MRA) showed an isolated left proximal high-grade M1-MCA segment stenosis with reduced or absent M2-MCA signals and a mild right M1-MCA and A1-segment anterior cerebral artery (ACA) stenosis. A prominent left posterior cerebral artery (PCA) signal was considered as an indirect sign of collateral PCA ﬂ ow activation (Fig. B5.1 and Fig. B5.2).

Suspected Diagnosis

Subacute left MCA territory ischemia caused by a r t e r y - t o - a r t e r y e m b o l i s m i n h i g h - g r a d e l e f t p r o x i m a l M1-MCA stenosis and suspected contralateral M1-MCA and A1-ACA stenoses.

showed mild leptomeningeal collateralization via the ACA. The right M1-MCA appeared mildly narrowed. The posterior circulations showed no abnormalities (Fig. B5.3 and Fig. B5.4).

Clinical Course

During the patient’s hospital stay the clinical symptoms improved. Thrombophilia, vasculitis, Fabry’s disease, and an autoimmune etiology were excluded. A normal transesophageal echocardiogram and a 24-hour electrocardiogram (ECG) made a cardiac cause unlikely. Dual antiplatelet treatment with aspirin and clopidogrel was started and after 6 months switched to aspirin alone. After a clinical uneventful time of 2 years she presented for follow-up control. She was still smoking but no longer took the contraceptive pill. Clinically, a mild sensory aphasia and memory deﬁ cits remained. On MRI, no acute ischemic lesions were detected but a mild, parietal accentuated left-sided hemiatrophy had developed. TOFMRA revealed no progress of reported vessel abnormalities (not shown).

Questions to Answer by Ultrasound Techniques

• Were there vessel wall changes in the extracranial brain-supplying arteries?

• Were the grades of stenoses still comparable to the initial DSA results?

• If yes, what was the grade of the left proximal M1-MCA stenosis?

• Where there signs of collateral ﬂ ow activation?

• Could the mild contralateral M1-MCA and A1-ACA stenoses be conﬁ rmed?

Conventional Angiography (Day 2)

Because of the unclear underlying vessel processes digital subtraction angiography (DSA) was performed. Segmental high-grade narrowing of the proximal left M1-MCA segment was conﬁ rmed. The distal course of the vessel was normal. The contrast ﬁ lling of the left-sided distal MCA branches was mildly delayed in comparison with branches of the ipsilateral ACA. Late arterial phase images

Initial Neurosonologic Findings

Extracranial Duplex Sonography

B-mode imaging revealed no atherosclerotic vascular changes. Doppler spectrum analysis showed normal and symmetric ﬂ ow signals in both carotid and vertebral arteries.

223Initial Neurosonologic Findings

Transcranial Duplex Sonography

Doppler spectrum analysis revealed an increased ﬂ ow velocity reaching 328 cm/s peak systolic ﬂ ow in the left proximal M1-MCA segment at a depth of 50 mm. A severe poststenotic ﬂ ow pattern was detected in both vis- ible M2-MCA branches. The right M1-MCA revealed a mild turbulent ﬂ ow signal with increased ﬂ ow velocities (222/106 cm/s). Both A1-ACA had increased ﬂ ow veloci-

Fig. B5.1 MR diﬀ usion-weighted (b=1,000) image (A) and T1-weighted image after gadolinium administration (B), axial plane. Mild signal increase in the left MCA territory in the left frontoparietal cortex and corresponding contrast enhancement, compatible with a subacute t e r r i t o r i a l M C A i s c h e m i a . ( C o u r t e s y o f S . P a r i s , A . H e i n i c h e , a n d A . R e c k e r , Radiologische Praxis am Evangelischen Krankenhaus Herzberge, Berlin, Germany.)

ties (left A1-ACA 157/72 cm/s, right A1-ACA 153/74 cm/s). On the left side the cause could either be stenosis or collateral ﬂ ow activation. Reviewing MRA and DSA ﬁ nally ruled out stenosis. On the right side, the raised A1-ACA ﬂ ow was assumed to indicate a stenosis. The left P2-PCA showed a mild increased ﬂ ow velocity (82/30 cm/s) which was considered to be caused by collateral ﬂ ow activation. The right PCA and the vertebrobasilar arteries showed normal ﬂ ow signals (Figs. B5.5–B5.12).

Fig. B5.2 3D TOF-MRA, coronal maximal intensity projection (MIP). Markedly reduced ﬂ ow signal in the proximal left M1-MCA (arrows) with a short gap at its origin (arrow), suggesting a high-grade stenosis. Note also the irregularities in the mid part of the right M1MCA (large arrowhead) and A1-ACA (short arrowhead). Note also the prominent ﬂ ow signal in the periphery of the left PCA (arrow- heads) indicating leptomeningeal collateral ﬂ ow. (Courtesy of S. Paris, A. Heiniche, and A. Recker, Radiologische Praxis am Evangelischen Krankenhaus Herzberge, Berlin, Germany.)

Fig. B5.3 DSA, left ICA injection, posteroanterior view (A) and left anterior oblique view (B). Severe short-segmental narrowing of the proximal MCA (arrow). The contrast ﬁ lling of the left-sided distal MCA branches is mildly delayed in comparison to the distal branches of the ipsilateral ACA (arrows) indicating a hemodynamic signiﬁ cance of the M1-MCA stenosis. (Courtesy of Dr. Langhoﬀ , Angiologische Abteilung, Evangelischen Krankenhaus Herzberge, Berlin, Germany.)

Fig. B5.4 DSA, right ICA injection, posteroanterior view (A) and right anterior oblique view (B). A mild stenosis is seen in the mid part of the right M1-MC A (arrowhead) as well as in the mid part of the A1-ACA (arrow). (Courtesy of Dr. Langhoff, Angiologische Abteilung, Evangelischen Krankenhaus Herzberge, Berlin, Germany.)

224 Case 5 Left M1 Middle Cerebral Artery Stenosis

M1-MCA-L

Fig. B5.5 TCCS ( tran stemp oral appro ach) , le ft-s ided inson atio n, midbrain plane, color-mode image. Using the standard pulse r e p e t i t i o n f r e q u e n c y ( P R F ) s e t t i n g s a d j u s t e d f o r n o r m a l ﬂ ow veloc- ities, the image would suggest the wrong diagnosis of a mid-part M1-MCA occlusion (arrow).

M2-MCA-L frontal branch

M1-MCA-L

Fig. B5.6 TCCS ( tran stemp oral appro ach) , le ft-s ided inson atio n, midbrain plane. Reducing the PRF for better visualization of vessel with low ﬂ ow velocities, more distal parts of the left M1-MCA be- come visible. Doppler spectra analysis revealed a stenosis in the left mid M1-MCA with an intrastenotic ﬂ ow velocity of 328/220 cm/s in a depth of 50 mm. Note the severe turbulent ﬂ ow impairing the measurement of the true systolic and diastolic ﬂ ow.

M2-MCA-L parietal branch

Fig. B5.7 TCCS ( tran stemp oral appro ach) , le ft-s ided inson atio n, midbrain plane. Marked poststenotic ﬂ ow pattern in the left frontal (anterior) M2-MCA branch at a depth of 40 mm.

Conclusion

High-grade left proximal M1-MCA segment stenosis of hemodynamic relevance (>70%) with leptomeningeal collateral ﬂ ow via the left ACA and PCA. In addition, mild right M1-MCA and A1-ACA stenosis of ~50%.

Fig. B5.13 shows a schematic of the patient’s extra-

and intracranial brain-supplying arteries.

Fig. B5.8 TCCS ( tran stemp oral appro ach) , le ft-s ided i nson ation, midbrain plane. Marked poststenotic ﬂ ow pattern in the left parietal (posterior) M2-MCA branch at a depth of 39 mm.

Discussion

Clinical Aspects

The patient is a 31-year-old woman with a left-sided proximal high-grade M1-MCA stenosis with subsequent cortical ischemic brain infarction in the MCA territory. Because of her young age and lack of any extracranial arterial macroangiopathy, a primary intracranial stenosis with artery-to-artery embolism was considered. How-

Final Diagnosis

Ischemic brain infarction in the left MCA territory by artery-to-artery embolization caused by a left-sided hemodynamically relevant high-grade M1-MCA stenosis. Contralateral asymptomatic moderate M1-MCA and A1-ACA stenoses of unknown origin.

ever, a conﬁ dent diﬀ erentiation between a ﬁ xed steno- sis, a fresh local thrombus, a partially reopening embolus vasospasm, or a reversible vasoconstriction was not possible in the former acute state. The hypothesis of ﬁ xed stenoses could then be conﬁ rmed during the follow-up assessment 2 years later because the vascular status had remained unchanged.

225Discussion

A1-ACA-L

Fig. B5.9 TCCS (transt empo ral approac h), left -sided inso nation, midbrain plane. Raised ﬂ ow velocities in the left A1-ACA (157/72 cm/s) without turbulence. Because of the high-grade ipsilateral M1-MCA stenosis and the normal DSA ﬁ ndings, the in- creased ﬂ ow velocity was considered to indicate leptomeningeal collateral ﬂ ow to the MCA territory.

M1-MCA-R

P1/2-PCA-L

Fig. B5.10 TCCS (tran stemporal appro ach) , left -sid ed ins onati on, midbrain plane. Increased ﬂ ow velocities in the left P1/P2-PCA (82/30 cm/s), indicating leptomeningeal collateral ﬂ ow to the MCA territory.

A1-ACA-R

Fig. B5.11 TCCS (t rans tempora l ap proach) , right-s ided inso nati on, midbrain plane. Right M1-MCA with intrastenotic ﬂ ow velocity of 222/106 cm/s at a depth of 50 mm. Note that the ﬂ ow is not tur- bulent. No poststenotic ﬂ ow pattern was seen in the downstream segments (not shown).

The clinical course and follow-up investigations are often of paramount importance to clarify the stroke etiology. In our patient, the stable clinical and neurosonologic ﬁ nd- ings over several years were suggestive of ﬁ xed high-grade left-sided MCA stenosis and also moderate right-sided A1-ACA and M1-MCA stenoses. The permanence of the stenoses and also the absence of headaches typical of reversible cerebral vasoconstriction syndrome (RCVS) ruled this diagnosis out (for further reading of RCVS, see Case

36). As expected at her age, even considering her smoking, assessment of the extracranial brain-supplying arteries did not demonstrate any atherosclerosis. A cardiac embolic source, thrombophilia, vasculitis, or autoimmune disease could not be found. A hereditary cause was considered because of her mother suﬀ ering from stroke as a young adult but was not conﬁ rmed by genetic or metabolic tests. Can-

Fig. B5.12 TCCS (transtemporal approach), right-sided insonation, midbrain plane. Increased ﬂ ow velocities in the left A1-ACA (153/74 cm/s) with a moderate turbulent ﬂ ow pattern. In contrast to the contralateral side, a moderate stenosis had to be assumed as no high-grade M1-MCA or PCA stenosis was present.

nabis use was considered as a known cause of multifocal intracranial stenoses reported in the literature (Wolﬀ et al 2011, 2014) but was convincingly denied by the patient, as was the use of other illicit drugs. The moderate contralateral M1-MCA and A1-ACA stenoses argued against an intracranial dissection (for further reading, see Case 21 and Case 24). Because of the bilateral aﬀ ection of vessel segments near the carotid T, a moyamoya-like disease was discussed, but ﬁ nally considered unlikely because of the atypical asymmetry and the bilateral sparing of the distal ICA (for further reading, see Case 9). No migraine history was present, ruling out migraine-related vessel pathology (for further reading, see Case 22).

Finally, an intracranial atherosclerosis was discussed, which may also occur as isolated ﬁ ndings in the white population, and treatment tailored to this diagnosis

226 Case 5 Left M1 Middle Cerebral Artery Stenosis

Fig. B5.13 Schematic of the patient’s extra- and intracranial brain-supplying arteries. Right moderate M1-MCA and A1-ACA stenosis and left high-grade M1-MCA stenosis (circles). Collateralization of the left MCA territory via leptomeningeal collaterals from the left ACA and PCA (arrows).

(platelet inhibition and statin) was given for secondary stroke prevention (for further reading on intracranial stenosis, see also Chapter 5, “MCA Stenosis” under “Intracranial Pathology,” Case 25, and Case 44; for further reading on stroke in young people, see Case 6).

Atherosclerosis is well recognized as the major cause of vascular disease in the extracranial brain-supplying a r t e r i e s . I n c o n t r a s t , l i t t l e i s k n o w n a b o u t t h e i n c i d e n c e and prevalence of intracranial atherosclerotic lesions. Early autopsy studies in Western countries indicated that i n t r a c r a n i a l s t e n o - o c c l u s i v e d i s o r d e r s w e r e a n u n c o m m o n cause of stroke. However, in recent years, the literature indicates intracranial atherosclerosis more and more as a common etiology of cerebral ischemia. In white populations, intracranial atherosclerosis is found in ~5–10% of stroke patients (Caplan et al 1986, Sacco et al 1995), whereas in the Asian population and therefore worldwide it is the most common cause of strokes (Wong 2006). Data regarding the distribution of intracranial atherosclerosis is scarce. Most studies using CT angiography (CTA), MRA, DSA, and also autopsy studies consider the MCA as the major site of intracranial stenosis followed by the VA, but relevant vessel pathology is also often seen in the BA and ICA (Homburg et al 2011, J.T. Kim et al 2006, Mazighi et al 2008, Ovesen et al 2013). In our opinion, based on long-standing TCCS experience over many years, the proximal PCA is also an underestimated location because its visualization is limited in the above-mentioned angiographic methods.

Risk factors for intracranial atherosclerosis are similar to those for extracranial atherosclerosis and coronary artery disease. They include diabetes, hypertension, smoking, hypercholesterolemia, and also nonwhite ethnicity (Sacco et al 1995, Wityk et al 1996). Also, little is known about the natural course of intracranial stenoses. The WASI D (Wa rf ari n A spi rin Sy mpt oma tic I ntra cran ial D isease) study followed up 569 patients with symptomatic intracranial stenosis >50% over a mean period of 1.8 years and revealed recurrent stroke in 19%. Of these, 77% were located within the territory of the stenotic artery. The

stroke risk was substantially increased with stenosis ≥70%, and the authors also found women to be at greater risk. The most important modiﬁ able risk factors for an increased risk of recurrent stroke associated with intracranial atherosclerotic stenosis were raised blood pressure >140 mm Hg and cholesterol concentrations >5.2 mmol/L (Chaturvedi et al 2007). No correlation was found with the site of stenosis, with the initial clinical presentation, or with prior use of an antithrombotic medication (Kasner et al 2006). Similar ﬁ ndings were reported in a smaller pro- spective multicenter study of 102 symptomatic patients. In this trial 60.7% had a recurrent stroke or TIA within the territory of the stenotic artery during a mean follow-up of 23.4 months if the stenosis was hemodynamically signiﬁ cant (Mazighi et al 2006). Other prospective studies in patients with symptomatic MCA stenosis reported annual ipsilateral stroke rates ranging from 2.3% to 9.1% (Arenillas et al 2001, Gao et al 2004, Kern et al 2005). Asymptomatic MCA stenoses instead have a lower annual ipsilateral stroke rate ranging from 0% to 1.4%, which is comparable to the recurrence risk in asymptomatic extracranial ICA stenoses (Hennerici et al 1987, Kern et al 2005, Kremer et al 2004). Adequate collaterals in patients with ≥70% intracranial stenosis have reduced risk of recurrent stroke (Liebeskind et al 2011a). The main prognostic factors are also considered to be similar to those for extracranial atherosclerosis: These are, besides the above classical vascular risk factors, the site of stenosis, its extent, its activity (symptomatic or not, microembolic signals), its progression, its hemodynamic compromise, its plaque composition, and the presence of inﬂ ammation, in addition to gender and genetic background.

Data about the evolution of intracranial atherosclerosis over time are scarce. Both progression and regression have been reported, the latter probably mainly being attributed to resolution of intravascular thrombi (Akins et al 1998). Aggressive medical treatment alone may, however, lead to plaque regression. In a prospective study of 50 patients with acute strokes caused by an intracranial atherosclerotic stenosis intensive medical therapy with control of low-density lipoprotein, HbA blood pressure led to an overall regression of stenoses

, and systolic

from 79% at baseline to 63% in 12 months measured by 3D rotational angiography (Leung et al 2015). Progression of intracranial atherosclerosis has been positively correlated with further vascular events (Arenillas et al 2001). Also, the presence of microembolic signals assessed by transcranial Doppler (TCD) has been shown to independently predict the occurrence of future ischemic events (Gao et al 2004).

Therapeutic strategies are still controversial in patients with symptomatic intracranial atherosclerosis. Medical treatment intends to inﬂ uence risk factors and to control hypertension, diabetes, and hypercholesterolemia, and patients are advised to stop smoking. Regarding antithrombotic treatment so far aspirin, ticlopidine, clopidogrel, warfarin, and statins alone or in combination are in use. In 1995, the retrospective WASID trial demonstrated an annual recurrent stroke rate of 3.6% in the patient group treated with warfarin and 10.4% in the aspirin group ( Chimowitz et al 1995). On the basis of these results, a prospective randomized trial was started in symptomatic patients, but this study could not prove superiority of anticoagulation.

227Discussion

Instead, enrollment of patients was stopped because of adverse eﬀ ects of warfarin. During a mean follow-up of

1.8 years, death and major hemorrhage was signiﬁ cantly higher in the warfarin group compared with the aspirin group (9.7% versus 4.3% and 8.3% versus 3.2%, respectively) (Chimowitz et al 2005).

A transient dual platelet inhibition therapy might reduce the early stroke risk in patients with a symptomatic intracranial stenosis. In the Clopidogrel plus Aspirin for Infarction Reduction (CLAIR) study, patients received clopidogrel (300 mg loading dose followed by 75 mg/day) + aspirin (75–160 mg/day), or aspirin alone if they had become symptomatic with an intracranial MCA or ICA stenosis within the last 7 days. Patients with the double platelet inhibition showed signiﬁ cantly lower numbers of microembolic signals (detected by TCD) on days 2 and 7 than those patients on aspirin alone (X. Wang et al 2013). In a combined analysis with data of the CARESS study (patients with extracranial carotid stenosis >50% that had recently become symptomatic), patients on aspirin alone demonstrated a signiﬁ cantly higher stroke recurrence rate (Wong et al 2010). The data favors dual platelet inhibition, at least for some weeks, assuming an initial instable plaque constellation.

Considering the high risk of stroke recurrence despite the use of antithrombotic treatments, endoluminal revascularization, intracranial angioplasty, and stenting have emerged as promising alternatives as in extracranial ICA diseases. Early results using balloon-expandable coronary stents were disappointing as morbidity rates of up to 20% were reported. Since then, stents designed particularly for intracranial use have been developed. The SSYLVIA (Stenting of Symptomatic Atherosclerotic Lesions in the Ver tebral or In tracr anial A rterie s) stud y looked at s afet y and feasibility of intracranial stents in 43 symptomatic and 18 asymptomatic intracranial stenoses ≥50%. Successful stent placement was achieved in 95% of patients. Strokes occurred in 6.6% of patients within 30 days and in 7.3% between 30 days and 1 year. Restenosis was observed in a high proportion of 35% of patients, however (SSYLVIA Study Investigators 2004). Two following prospective multicenter studies reported comparable results using a self-expanding stent (wingspan) for intracranial stenoses. In the ﬁ rst study including 45 patients, ipsilat- eral stroke/death rate was 4.5% within the ﬁ rst month, 7% after 6 months. The overall stroke rate and mortality were 9.7% and 2.3%, respectively. The mean grade of stenosis before, immediately after stenting, and at 6 months follow-up was 75%, 32%, and 28%, respectively (Bose et al 2007). The second study, which included 78 patients, reported an immediate decrease of stenosis from 75% to 27% after stenting. The 30-day rate of major periprocedural neurologic complication and death was 6.1% (n = 5). As four of these patients died, the mortality rate was 5%. New ischemic lesions on MR diﬀ usion-weighted imaging were seen in a high proportion (34.2%) of which 77% were asymptomatic (Fiorella et al 2007).

Based on these ﬁ rst experiences and taking into ac- count the increasing expertise and material progress,

Management for Preventing Recurrent Stroke in Intracranial Stenosis) started in 2008 recruiting patients with intracranial stenosis of 70–99% and a cerebral ischemia (TIA

or stroke) 30 days before. The intention of the trial was to show superiority of a combined intensiﬁ ed medical treat- ment with angioplasty and stenting compared with intensiﬁ ed medical treatment alone. Because of unexpected high rate of side eﬀ ects among the interventional group the trial was stopped prematurely in 2011 after recruitment of 451 patients. Stroke and death within 30 days were signiﬁ cantly higher among patients treated with a stent than in those treated with medical therapy alone (14.7% versus 5.8%). Even after 1 year, the proportion remained almost unchanged: 20% in the stent group and 12.2% in the medical group (Chimowitz et al 2011, Derdeyn et al

2014). The high periprocedural complication rate was largely due to perforator territory stroke and reperfusion hemorrhage. Without these two types of complications, the periprocedural risk was similar to that of previous registries and the medical arm of SAMMPRIS. The bad results in the stenting group occurred independently of whether or not the patients were on antithrombotic therapy, had hypoperfusion symptoms, or high-grade stenosis (Lutsep et al 2015b). The multicenter, randomized VISSIT (the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy) trial, conducted in parallel with SAMMPRIS, was halted after 112 patients of a planned sample size of 250 has been enrolled, after the negative results from SAMMPRIS. Again, negative results were reported with stroke or TIA signiﬁ cantly more often in stented patients (36.2%) compared with medically treated patients (15.1%) within the ﬁ rst year (Zaidat et al 2015). In contrast, in a nonran- domized Chinese study also conducted in parallel, including 154 symptomatic patients with solely hemodynamic events, poor collaterals, and stenoses of the ICA, MCA, BA, or VA, a low 30-day composite stroke, myocardial infarction, or death rate of 4.4% was reported after stenting and/ or angioplasty (Miao et al 2015).

The SAMMPRIS trial gives important insights into

the eﬃ cacy of medical treatment of symptomatic in- tracranial atherosclerotic stenoses. The huge diﬀ er- ence of the low 5.8% 30-day-stroke recurrence rate in the SAMMPRIS study compared with the 10.7% stroke rate in the WASID trial is probably caused by the early dual platelet inhibition therapy with clopidogrel and aspirin. The continuing low 1-year SAMMPRIS stroke recurrence rate of 12.2% (WASID 25%) seems to be related to a more aggressive treatment of vascular risk factors comprising intensiﬁ ed lowering of blood pressure (<140 mm Hg) and LDL (<1.81 mmol/L), as well as to a lifestyle- modifying program.

On the basis of the current data, patients with a <70% intracranial stenosis and a vascular event (TIA or stroke) that occurred more than 30 days ago should be treated with single antiplatelet therapy alone as well as with an intensiﬁ ed vascular risk factor management. Patients with a 70– 99% intracranial stenosis and a vascular event within the past 30 days should be treated with dual antiplatelet therapy for 90 days, followed by long-term single antiplatelet therapy with concomitant intensiﬁ ed vascular risk factor management. Long-term dual platelet inhibition therapy cannot be routinely recommended, as this is associated with an increased risk of life-threatening hemorrhages as has been shown in the MATCH and CHARISMA studies (Bhatt et al 2006, Diener et al 2004). Intracranial stent placement, however, may still be considered in high-grade

228 Case 5 Left M1 Middle Cerebral Artery Stenosis

stenosis with hemodynamic infarct patterns and recurrent hemodynamic TIAs despite blood pressure optimization or in patients with recurrent embolic events under optimal and maximal medical therapy. Stent placement is probably also required in most cases with mechanical recanalization of stenosis-associated vessel occlusion.

Angiologic and Anatomic Aspects

Ultrasound is now widely available, and is one of the principal noninvasive tools for the evaluation of intracranial steno-occlusive artery disease. In general, intracranial stenoses are characterized using direct and indirect ultrasound criteria, both of which contribute to the grading of stenoses. Direct signs are locally raised intrastenotic ﬂ ow velocities and turbulences. Indirect signs are reduced velocities in the altered pre- and/or poststenotic vessel segments, and/or poststenotic ﬂ ow patterns as well as raised velocities in collateral vessels (for further information see also Chapter 5, “Ultrasound Criteria of Stenoses” under “Stenoses and Occlusions,” and “Intracranial Collateral Pathways in ICA Occlusive Processes” under “Collateral Pathways”). Despite several TCD studies that have described the detection of intracranial stenoses, there are no uniform internationally accepted criteria, as there are for example in extracranial carotid artery stenosis (de Bray et al 1988, Felberg et al 2002, Ley-Pozo and Ringelstein 1990, Mattle et al 1988, Röther et al 1994). Comparing TCD with TOF-MRA or DSA, sensitivity, speciﬁ city, and positive and negative predictive values of 94%, 91%, 78%, and 98%, respectively, have been reported (Felberg et al

2002). In 132 acute stroke patients, TCD showed a sensitivity and speciﬁ city of 79% and 94% compared with CTA (Tsivgoulis et al 2007). For ≥50% MCA stenosis using DSA as the reference method, pooled from six reports, a sensitivity of 92%, speciﬁ city of 92%, positive predictive value of 88%, and negative predictive value of 98% for a mean ﬂ ow velocity cut-oﬀ of 80 cm/s were reported (Navarro et al 2007). Less favorable results were seen in the SONIA (Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis) trial. The study included 407 patients from the WASID trial and compared the accuracy of TCD and MRA to diagnose an intracranial stenosis >50% compared with DSA. For TCD, >50% stenosis was deﬁ ned as an aver- age maximum velocity: >100 cm/s for the MCA, >90 cm/s for the ICA, and >80 cm/s for the BA and VA. The MR A criteria were a lumen reduction >50% or the presence of a ﬂ ow gap. Applying these criteria, positive and negative predictive values for TCD were 36% and 86% and for MRA 59% and 91%, respectively. It was concluded that TCD and MRA can exclude but not reliably conﬁ rm a stenosis >50% (Feldmann et al 2007). For the ascertainment of hemodynamically relevant stenoses using TCD a new ratio has been suggested considering the stenotic and prestenotic ﬂ ow velocity (SPR). An SPR ≥3 and a mean velocity >120 cm/s yielded a sensitivity and speciﬁ city of 68% and 95% for the detection of a ≥70% MCA stenosis. Considering an asymmetry index >30% (velocity diﬀ erence compared with the homologous contralateral side) or with the presence of a downstream ﬂ ow pattern alteration (poststenotic ﬂ ow pattern) the sensitivity even increased to 91% but the speciﬁ city decreased to 80% (Zhao et al 2011).

Accurate vessel identiﬁ cation is a major concern in TCD. TCCS easily overcomes this shortcoming, ensuring unequivocal vessel identiﬁ cation in most cases. Compar- ative studies controlled by DSA are rare. In one of them TCCS diﬀ erentiated correctly between MCA main stem stenosis and intracranial distal ICA stenosis in seven patients and between MCA main stem and branch stenosis in four patients, while TCD failed in these two subgroups (Klötzsch et al 2000).

One relevant study comparing TCCS and DSA reported data on peak systolic velocity values. For MCA main stem stenosis, ﬂ ow velocities of >220 cm/s and >155 cm/s were reported to ensure the deﬁ nite presence of a >50% or <50% stenosis with a sensitivity, speciﬁ city, and positive and negative predictive values of 100% for >50% stenosis, and 94%, 100%, 95%, and 100%, respectively, for <50% stenosis (Baumgartner et al 1999). Angle correction was applied only if a straight vessel segment of ~2 cm was present. Such a long, straight intracranial vessel course is the exception and not the rule in either young or elderly patients, and angle correction is therefore not generally recommended in order to avoid velocity overestimation and wrong grading of stenosis. More easily applicable are the TCCS consensus recommendations to apply angle correction if the sample volume can be positioned in a satisfactorily long vessel segment aligned with the direction of the vessel in the color-mode image (Nedelmann et al 2009b). Considering this criterion, angle correction may be possible in a straight vessel segment of 1 cm if the sample volume is centered in the mid part of the visible vessel. Care should be taken when interpreting raised ﬂ ow velocities. Besides a stenosis, other causes of ﬂ ow velocity increase may be present such as a vascular malformation or hyperemia (e.g., caused by head trauma, subarachnoid hemorrhage, or severe anemia). A circumscribed focal velocity increase may help to diﬀ erentiate these pathologies.

In our case, a circumscribed, markedly increased intrastenotic systolic M1-MCA ﬂ ow velocity of 320 cm/s, a mild poststenotic ﬂ ow pattern distal to the stenosis, and the mild activation of leptomeningeal collateral pathways via a raised ipsilateral A1-ACA and PCA ﬂ ow facilitated the diagnosis of a hemodynamically relevant high-grade stenosis of at least 70%. However, considering the severe poststenotic ﬂ ow pattern in the M2-MCA branches and the missing insular branches signals in the TOF-MRA, a stenosis of >90% has to be assumed.

Diﬀ erentiation between stenosis and hyperperfusion is one important task when using ultrasound assessment. In our case, there was no doubt about the right-sided A1ACA stenosis which was characterized by a moderately increased ﬂ an almos

ow velocity. The contralateral A1-ACA revealed t identic

al ﬂ ow signal. Because of the ipsilateral high-grade M1-MCA stenosis it was impossible to distinguish between a focal concomitant stenosis and a hyperperfusion state to compensate for the M1-MCA stenosis. Analyzing the ipsilateral A2-ACA would have been helpful. In case of normal A2-ACA ﬂ ow velocities an A1-ACA ﬂ ow rise would have to be interpreted as a stenosis, whereas raised A2-ACA velocities would rather suggest hyperperfusion. Of course, both phenomena could potentially be present at the same time and this could then not be differentiated by TCCS alone. In our case the TOF-MRA ruled out a stenosis, as no lumen irregularity could be detected.

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