Journal of the Neurological Sciences 339 (2014) 130–133

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Deep tiny flow voids along middle cerebral artery atherosclerotic occlusions: A high-resolution MR imaging study Wei-Hai Xu a,⁎,1, Ming-Li Li b,1, Jing-Wen Niu a, Feng Feng b, Zheng-Yu Jin b, Shan Gao a a b

Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

a r t i c l e

i n f o

Article history: Received 10 November 2013 Received in revised form 28 January 2014 Accepted 30 January 2014 Available online 6 February 2014 Keywords: Middle cerebral artery occlusion Magnetic resonance imaging Thrombosis Cerebral infarct Collaterals Intracranial atherosclerosis

a b s t r a c t Background and purpose: We aim to report the “deep tiny flow voids” (DTFV), a unique HR-MRI finding suggestive of deep collateral vessels along middle cerebral artery (MCA) occlusions. Methods: We retrospectively reviewed the HR-MRI data of 60 patients with unilateral MCA occlusion (32 symptomatic and 28 asymptomatic) and 205 control subjects with normal MCA on magnetic resonance angiography. The presence or absence of DTFV, defined as three or more flow voids along the occluded MCA on at least two consecutive T2-weighted image slices, was observed. The relationships among DTFV, clinical presentations, and infarct sizes were analyzed. Results: DTFV were identified in 20/28 (71%) patients with asymptomatic MCA occlusions, much more frequently than in the patients with symptomatic occlusions (5/32, 16%) (P b 0.001). There were 9 patients with a large territorial infarction (≥1/3 MCA distribution), none of whom had DTFV on HR-MRI. DTFV was not observed in any control subject. Conclusions: DTFV are pathological conditions and associated with relatively good imaging outcomes and asymptomatic MCA occlusions. The function and clinical implications of DTFV warrant further investigations. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Ischemic stroke due to middle cerebral artery (MCA) occlusion is common. A considerable proportion of acute MCA occlusions are caused by cardioembolism or carotid atheroembolism [1,2]. In patients with Asian ancestry, however, MCA atherothromboembolism is an important etiology given the high prevalence of intracranial atherosclerosis in this population [3,4]. Patients with MCA atherosclerotic occlusion may present with a large territorial infarct, a minor infarct or even be asymptomatic [3,5]. Individual variations in collateral vessels, often from ipsilateral anterior cerebral artery and posterior cerebral artery, were hypothesized to account for this heterogeneity [3]. However, the exact underlying vascular pathophysiology remains less well studied. Recently, high-resolution magnetic resonance imaging (HR-MRI) has been developed as a useful tool for the investigation of intracranial artery lesions [6,7]. Using HR-MRI, the vessel wall boundary and lumen can be identified in vivo [8]. According to our knowledge, the data of HR-MRI on the MCA occlusions has been lacking. In this study, we observed the cross-sectional HR-MRI images of MCA occlusions. We report a unique HR-MRI finding, the “deep tiny flow voids”

⁎ Corresponding author at: Shuaifuyuan 1, Dongcheng District, Beijing 100730, China. Tel./fax: +86 10 69156372. E-mail address: [email protected] (W.-H. Xu). 1 The first two authors contributed equally to the work. 0022-510X/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2014.01.042

(DTFV) along MCA occlusions, which suggest a new entity of collateral vessels. 2. Materials and methods 2.1. Subjects We retrospectively reviewed our institutional prospectively collected HR-MRI database (from January 2007 to August 2012). MCA atherosclerotic occlusion was defined as a complete signal loss of MCA trunk on magnetic resonance angiography (MRA) in the absence of an embolic cardiac or proximal large arterial source. Patients with unilateral symptomatic MCA occlusion were recruited if there was an ischemic stroke in the distribution of the occluded MCA within 1 month of stroke onset. Patients with unilateral symptomatic MCA occlusion were included if there was no history of cerebrovascular events or if an ischemic event occurred in a vascular territory outside the affected MCA. All patients received thorough evaluations, including clinical examinations, diffusion-weighted imaging, carotid duplex, transcranial Doppler, electrocardiogram and echocardiogram. Patients were excluded if they had any of the following characteristics:(1) coexistent N 50% ipsilateral internal carotid artery stenosis; (2) evidence of cardioembolism, including atrial fibrillation or recent myocardial infarction within 1 month; (3) age b40 years; (4) non-atherosclerotic vasculopathy such as vasculitis and arterial dissection, diagnosed by comprehensive laboratory work, vascular imaging, and clinical evaluation; (5) poor image

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quality due to motion artifact. For comparison, control subjects with bilateral normal MCA on MRA were selected from HR-MRI database. The ethics committee of the Peking Union Medical College Hospital approved this study. All patients or their relatives signing a written consent to participate. 2.2. HR-MR imaging The detailed imaging parameters of routine cranial MRI, MRA and HR-MRI were described previously [8]. All subjects were imaged using a 3 T magnetic resonance scanner (Signa VH/i, GE Medical Systems, Milwaukee, WI) and a standard 8-channel head coil. 3-dimensional MRA localizer (choosing maximum intensity projection images and source images of 3-dimensional time-of-flight MRA as topogram) was used to ensure the cross-sectional HR-MRI images were perpendicular to the M1 segment. Since the signals of the occluded MCA were absent, the contralateral MCA was considered as a symmetric counterpart and used as the reference. Image analysis was performed using a standard workstation (ADW4.2, GE Medical Systems, USA). In symptomatic patients, ischemic lesions were classified as a large territorial infarct (≥1/3 ipsilateral MCA distribution), or not. All the cross-sectional image slices of bilateral MCA on HR-MRI were analyzed. In our pilot study, a special phenomenon, i.e. deep tiny flow voids (DTFV) was revealed [9]. In this study, the presence or absence of DTFV, defined as three or more flow voids along the occluded MCA on at least two consecutive T2-weigthed image slices on HR-MRI, was recorded in each patient (Figs. 1 and 2). All images were reviewed by two experienced readers (W.-H. Xu and M.L. Li) who were blinded to the clinical details. Differences between the two observers were solved by consensus. Intraobserver (W.H. Xu) reproducibility for DTFV were tested in randomly selected ten cases (by re-evaluating the images two weeks after the first examination), which was good (k = 0.96, 95% CI 0.88–1.03). 2.3. Statistical analysis Quantitative data were described as mean ± standard deviation or percentage. Comparisons of data were conducted using Student's t-test. The Chi-square test was used to compare several rates or

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proportions. SPSS 12.0 software (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. 3. Results In the HR-MRI database, sixty-two patients with MCA occlusion (34 symptomatic and 28 asymptomatic) and 205 control subjects with 410 normal MCAs on MRA met the inclusion criterions and considered for recruitment. Two symptomatic patients were excluded due to poor image quality. Demographic data of the patients are described in Table 1. The average time from stroke onset to HR-MRI in the symptomatic subgroup was 9 ± 6 days. Nine patients had a large territory infarction on diffusion weighted imaging (≥1/3 ipsilateral MCA distribution). In the remaining patients, multiple infarcts were seen in 21 patients, while a single perforating artery infarct was observed in 2 patients. In the patients with asymptomatic occlusions, 12 had unspecific complaints such as headache and dizziness, and 2 with a stroke occurring in a vascular territory outside the occluded MCA. The findings of electrocardiogram and echocardiogram were unremarkable in all subjects. Routine medical treatments based on current guidelines, including the regimens for stroke risk factors control and antiplatelet, were given. No anticoagulation or interventional therapies were performed. DTFV were found in 20/28 (71%) patients with asymptomatic MCA occlusions, more frequently than in the patients with symptomatic occlusions (5/32, 16%) (P b 0.001). None of the nine patients with a large territorial infarction had DTFV on HR-MRI. DTFV was not observed in any control subject. 4. Discussion According to our knowledge, DTFV have not been described in previous literatures. It is known from microanatomy studies that perforators arise from the upper-dorsal part of MCA stem as flow dividers [10]. Since DTFV were observed along an occluded MCA stem, they were not normal perforators. The absence of DTFV in control subjects also supported that DTFV don't represent normal physiology conditions. Moyamoya disease, characterized by bilateral occlusive internal carotid arteries and abnormal vascular network at the base of brain, are common in Asians and may have multiple flow voids in Sylvian fissure

Fig. 1. In a patient with right-middle cerebral artery (MCA) occlusion (A) and a small infarct on diffusion-weighted images (B), normal flow void was absent (arrows, C and D). Deep tiny flow voids (arrow heads, C and D) can be seen along the occluded MCA stem on consecutive T2-weighted images of high-resolution MRI. In another patient with a MCA occlusion (E) and a large territory infarct (F), the normal flow void was absent (arrows, G and H), and no deep tiny flow voids were seen.

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W.-H. Xu et al. / Journal of the Neurological Sciences 339 (2014) 130–133

Fig. 2. In an asymptomatic middle cerebral artery (MCA) occlusion (arrow, A), normal flow void was absent while multiple deep tiny flow voids (arrows, B and C) were identified on two consecutive T2-weighted image slices of high-resolution MRI. For comparison, the images of a normal MCA are displayed (D, E, and F).

[11]. In this study, the patients only had unilateral MCA occlusion and were relatively old with high prevalence of traditional stroke risk factors. Although rare adult cases with unilateral Moyamoya disease were reported [12], the DTFV shouldn't be diagnosed as typical Moyamoya vessels. There has been no digital subtraction angiography (DSA) study focusing on the collateral vessels along MCA occlusions. Several studies have suggested the magnitude of leptomeningeal collaterals on DSA does not correlate with the severity of perfusion deficits in patients with MCA occlusion [13,14]. It was hypothesized that leptomeningeal collateral vessels less than 100 μm in diameter may account for that [13]. Learning from the studies on coronary atherosclerotic occlusions, both arteriogenesis (the process of maturation or de novo growth of collateral conduits) and angiogenesis (the sprouting of new capillaries from post capillary venules) may occur [15,16]. The triggering factors include hypoxia/ischemia and local changes in shear stress at the occlusive sites. Previous studies have provided supportive evidence that such phenomena also occur in the brain [17]. We hypothesize that DTFV along occluded MCA represent the “tip of the iceberg” of deep collaterals

formation. They may be a subtype of deep leptomeningeal collaterals or originate from arteriogenesis/or angiogenesis. Interestingly, DTFV were relatively common in asymptomatic MCA occlusions, uncommon in symptomatic MCA occlusion and never revealed in patients with a large territorial infarction. Further studies are required to investigate the function and clinical implications of DTFV. Our study with retrospective design has several limitations. First, the inclusion rate was slow (60 patients in 5 years) and the patients were not consecutive. Potential selection bias may occur. Second, the average time from stroke onset to HR-MRI in the stroke patients was 9 ± 6 days. This was a large range which may influence the results, given it is not known when and how long it would take for DTFV to develop. Third, the uncommon origins of emboli such as paroxysmal cardiac arrhythmia, low-grade carotid atherosclerosis and aortic atherosclerosis were not systematically investigated. It's possible that a small proportion of MCA occlusions, which were blocked by upstream emboli, was misdiagnosed and recruited. Finally, DSA and brain perfusion evaluations were not performed in the patients, which prevent further analysis.

Table 1 Demographic and clinical data.

Age (yrs) Male Hypertension Diabetes mellitus Hypercholesterolemia Smoker MCAO: middle cerebral artery occlusion.

Symptomatic MCAO (n = 32)

Asymptomatic MCAO (n = 28)

P

57 ± 13 17 25 10 10 15

53 ± 8 17 20 7 10 13

0.49 0.17 0.20 0.20 0.20 0.20

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In summary, DTFV is a unique HR-MRI finding that is associated with relatively good imaging outcomes and asymptomatic MCA occlusions. Our findings provided new insights into the pathophysiology of MCA atherosclerotic diseases. Conflict of interest None. Acknowledgment Study funding: Supported by Peking Union Medical College (PUMC) Youth Fund and the Fundamental Research Funds for the Central Universities of China (NCET-12-0069). References [1] Olsen TS, Skriver EB, Herning M. Cause of cerebral infarction in the carotid territory. Its relation to the size and the location of the infarct and to the underlying vascular lesion. Stroke 1985;16:459–66. [2] Lhermitte F, Gautier JC, Derouesne C. Nature of occlusions of the middle cerebral artery. Neurology 1970;20:82–8. [3] Ueda S, Fujitsu K, Inomori S, Kuwabara T. Thrombotic occlusion of the middle cerebral artery. Stroke 1992;23:1761–6. [4] Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008;39:2396–9.

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[5] Kang BS, Kwon HM, Ryu WS, Lee YS. Prognosis of symptomatic and asymptomatic middle cerebral artery occlusion. Cerebrovasc Dis 2008;26:489–93. [6] Klein IF, Lavallee PC, Touboul PJ, Schouman-Claeys E, Amarenco P. In vivo middle cerebral artery plaque imaging by high-resolution MRI. Neurology 2006;67:327–9. [7] Swartz RH, Bhuta SS, Farb RI, Agid R, Willinsky RA, Terbrugge KG, et al. Intracranial arterial wall imaging using high-resolution 3-Tesla contrast-enhanced MRI. Neurology 2009;72:627–34. [8] Xu WH, Li ML, Gao S, Ni J, Zhou LX, Yao M, et al. In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis. Atherosclerosis 2010;212:507–11. [9] Wei-Hai Xu M-LL, Gao Shan, Ni Jun, Zhou Li-Xin, Yao Ming, Peng Bin, et al. Deep tiny collateral vessels along with occluded middle cerebral artery as an important source of collateral flow. Stroke 2010;41. [10] Marinkovic SV, Kovacevic MS, Marinkovic JM. Perforating branches of the middle cerebral artery. Microsurgical anatomy of their extracerebral segments. J Neurosurg 1985;63:266–71. [11] Kim JM, Jung KH, Sohn CH, Park J, Moon J, Han MH, et al. High-resolution MR technique can distinguish moyamoya disease from atherosclerotic occlusion. Neurology 2013;80:775–6. [12] Wanifuchi H, Takeshita M, Aoki N, Kawamata T, Shiokawa K, Izawa M, et al. Adult moyamoya disease progressing from unilateral to bilateral involvement. Neurol Med Chir (Tokyo) 1996;36:87–90. [13] Khatri R, Rodriguez GJ, Suri MF, Vazquez G, Ezzeddine MA. Leptomeningeal collateral response and computed tomographic perfusion mismatch in acute middle cerebral artery occlusion. J Vasc Interv Neurol 2011;4:1–4. [14] Zhu M, Dai J, Li S. Cerebral angiography and MR perfusion images in patients with ischemic cerebral vascular disease. Chin Med J 2002;115:1687–91. [15] Simons M. Angiogenesis: where do we stand now? Circulation 2005;111: 1556–66. [16] van Royen N, Piek JJ, Schaper W, Fulton WF. A critical review of clinical arteriogenesis research. J Am Coll Cardiol 2009;55:17–25. [17] Wei L, Erinjeri JP, Rovainen CM, Woolsey TA. Collateral growth and angiogenesis around cortical stroke. Stroke 2001;32:2179–84.

Deep tiny flow voids along middle cerebral artery atherosclerotic occlusions: a high-resolution MR imaging study.

We aim to report the "deep tiny flow voids" (DTFV), a unique HR-MRI finding suggestive of deep collateral vessels along middle cerebral artery (MCA) o...
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