1 Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-141203 IOS Press 4 5 roo f 3 Chronic Brain Hypoperfusion due to Multi-Vessel Extracranial Atherosclerotic Disease: A Potentially Reversible Cause of Cognitive Impairment or P 2 Short Communication uth 1 8 a Stroke Unit, Department of Neurology, Brugmann University Hospital, Brussels, Belgium 9 b Nuclear Medicine Department, Brugmann University Hospital, Brussels, Belgium 10 c Second Department of Neurology, University of Athens, School of Medicine, “Attikon” University Hospital, Athens, dA 7 Apostolos Safourisa,∗ , Anne-Sophie Hambyeb , Claudine Sculiera , Sokratis G. Papageorgiouc , Vasdekis N. Spyrosd , Marie-Dominique Gazagnesa and Georgios Tsivgoulisc,e 6 Greece 12 d Third Department of Surgery, School of Medicine, University of Athens, Athens, Greece 13 e International Clinical Research Center, St. Anne’s University Hospital in Brno, Czech Republic cte 11 Accepted 29 May 2014 16 17 18 19 20 Abstract. A 62-year-old patient presented with persistent cognitive deficits 3 months after a right temporal ischemic stroke due to ipsilateral carotid occlusion. Work-up disclosed hemodynamically significant contralateral carotid artery stenosis and left subclavian steal phenomenon. Brain SPECT imaging revealed bihemispheric chronic brain hypoperfusion that substantially improved on repeat imaging when the subclavian steal was temporarily diminished by inflating a cuff around the left arm. Carotid endarterectomy of the asymptomatic carotid stenosis substantially ameliorated bihemispheric brain perfusion and reversed cognitive impairment. This case highlights that multi-vessel, extracranial atherosclerotic disease may cause chronic diffuse brain hypoperfusion that can be associated with cognitive impairment. rre 15 co 14 Keywords: Asymptomatic carotid stenosis, carotid endarterectomy, chronic brain hypoperfusion, SPECT, subclavian steal, transcranial Doppler 23 INTRODUCTION 24 25 26 27 Un 22 21 Cerebrovascular hemodynamic failure has been hypothesized to result in impairment of cognitive status both in asymptomatic and symptomatic patients with carotid steno-occlusive disease and independent ∗ Correspondence to: Dr. Apostolos Safouris, Place Van Gehuchten 4, 1020 Bruxelles, Belgium. Tel.: +32 4773281; Fax: +32 4773467; E-mail: safouris@yahoo.com. of the presence of an underlying cerebral infarction [1, 2]. The former hypothesis rendered carotid artery disease as a potentially reversible cause of dementia. However, evidence of reversibility has been supported by case reports and small non-controlled studies [2]. We discuss the case of a patient with multi-vessel atherosclerotic extracranial artery disease who presented with cognitive impairment due to bihemispheric brain hypoperfusion. Carotid surgery of the only extracranial vessel that supplied the whole ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved 28 29 30 31 32 33 34 35 36 37 A. Safouris et al. / Diffuse Extracranial Atherosclerotic Disease: A Reversible Cause of Cognitive Impairment rre cte dA uth or P roo f 2 39 40 41 42 43 44 45 46 47 48 intracranial circulation resulted in amelioration of perfusion deficits and resolution of cognitive deficits. Un 38 co Fig. 1. Baseline SPECT imaging (AI), SPECT imaging with a cuff around the left arm (AII), and substraction image (AIII) showing a moderately increased perfusion in both cerebral hemispheres following cuff inflation at 100 mmHg at the left arm due to reversal of subclavian steal syndrome leading to increased perfusion in anterior circulation. Baseline SPECT (BI), post-CEA SPECT (BII), and substraction image (BIII) showing diffusely ameliorated perfusion in both hemispheres following left carotid artery surgery. CASE DESCRIPTION A 62-year-old man presented with mild left hemiparesis (NIH Stroke Scale score: 4 points) due to an acute ischemic infarction in distribution of the temporal branch of right middle cerebral artery (Supplementary Figure 1A). The patient had no previous history of stroke or other neurological disorders. His medical history was significant for hypertension, hypercholesterolemia, and smoking. Physical exam- ination was remarkable for a left carotid murmur and substantial difference in blood pressure levels as measured in both arms: 110/50 mmHg on the right arm and 85/60 mmHg on the left arm. Diagnostic work-up revealed a thrombotic occlusion of the right internal carotid artery (Supplementary Figure 1B), a near-occlusion at the origin of left subclavian artery causing a subclavian steal syndrome (alternating flow in extracranial and intracranial left vertebral artery segments), and a hemodynamically significant (≥70%) stenosis of the left internal carotid artery (Fig. 2A–D). Left carotid artery stenosis was considered asymptomatic since no left hemispheric lesions were noted in brain magnetic resonance imaging (MRI) and the 49 50 51 52 53 54 55 56 57 58 59 60 61 62 3 dA uth or P roo f A. Safouris et al. / Diffuse Extracranial Atherosclerotic Disease: A Reversible Cause of Cognitive Impairment 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 patient denied any previous focal neurologic symptoms that could be attributed to left hemispheric transient ischemic attack (TIA). The patient did not report any episode of loss of consciousness or other neurological symptoms during the use of his left arm that could be attributed to the subclavian steal phenomenon which was also considered as asymptomatic. Neuropsychological testing disclosed a deficit of visuoconstructive skills, attention, low short-term memory scores, and consolidation deficits in verbal long-term memory. The patient’s Mini-Mental State Examination (MMSE) was 22/30. All these deficits were originally attributed to the right temporal infarction, and the patient was diagnosed with vascular dementia caused by a strategic infarction. The patient presented at follow-up at 3 months with no motor or sensory deficit but with persisting cognitive impairment. There were no behavioral symptoms including loss of self-control and apathy. Transcranial Color-Coded Duplex examination revealed a functional collateral intracranial circulation co 64 Un 63 rre cte Fig. 2. Cervical Duplex showing a hemodynamically significant (≥70%; Peak-Systolic Velocity: 421 cm/s, End-Diastolic Velocity: 143 cm/s) stenosis of left internal carotid artery (A). Transcranial Duplex showing a functional left posterior communicating artery directing flow from anterior to posterior circulation (B). Cervical Duplex showing alternating flow in transverse segment of left vertebral artery indicating a seconddegree subclavian steal phenomenon (C). Note the complete flow reversal (red arrow) toward the arm following hyperemia-ischemia arm test (cuff inflation at suprasystolic blood pressure values followed by abrupt cuff deflation). Transcranial Duplex showing alternating flow in the intracranial segment of left vertebral artery indicating a second-degree subclavian steal phenomenon affecting the intracranial circulation (D). Note the complete flow reversal (red arrow) toward the arm following hyperemia-ischemia arm test (cuff inflation at suprasystolic blood pressure values followed by abrupt cuff deflation. with left internal carotid artery being the sole vessel supplying the circle of Willis via patent anterior communicating artery and patent posterior communicating arteries (Supplementary Figure 2D). Interestingly, the subclavian steal syndrome affected the intracranial circulation with functional posterior communicating arteries directing flow from anterior to posterior circulation (Fig. 2B). Moreover, a bidirectional flow was documented in basilar artery with a retrograde systolic component (Fig. 2D). The hypothesis of a chronic bihemispheric hypoperfusion was raised given the diffuse cognitive deficits (not restricted to the right temporal lobe) and the patient underwent a brain single-photon emission computed tomography (SPECT) perfusion HMPAO - Tc99m 4 months post stroke, which detected perfusional anomalies that extended well beyond the ischemic lesions, concerning both hemispheres (Supplementary Figure 1C). In the interest of examining whether the subclavian steal phenomenon could have a significant impact on cerebral hemodynamics, transcranial 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 roo f 111 or P 110 ing arteries directing blood to the left upper limb at the expense of the entire brain circulation. As a consequence, the flow in the basilar artery was rendered bidirectional, draining blood from the anterior circulation via the left posterior communicating arteries [4], thus resulting in chronic bihemispheric hypoperfusion that was clinically manifested by cognitive impairment. Left CEA significantly improved brain perfusion as assessed by brain SPECT, which in turn alleviated patient’s cognitive deficits. Subclavian steal syndrome is a relatively frequent finding during cervical arteries duplex sonography. Although it is commonly asymptomatic, it should be noted that sometimes it may provoke posterior circulation TIA and may rarely require intervention especially when extending in the intracranial circulation [5, 6]. Interestingly, anterior circulation symptoms have been described in previous reports of subclavian steal syndrome with concomitant carotid disease [7]. Notably, we provide hemodynamic evidence using repeat SPECT imaging that even transient reduction of subclavian steal by cuff inflation at the affected arm may result in substantial improvement of anterior circulation perfusion. Moreover, inflating a cuff at suprasystolic blood pressures levels at the ipsilateral (to the subclavian artery) arm may constitute a potentially safe and effective measure to improve intracranial circulation during CEA in patients with carotid artery stenosis and concomitant subclavian artery syndrome. However, larger case series are needed to provide more additional evidence whether this maneuver reduces the risk of periprocedural stroke in this specific group of patients. A carotid stenosis is considered asymptomatic in the absence of ischemic stroke or TIA in the distribution of the affected artery. Its treatment is mostly medical with CEA being considered as a therapeutic option in selected patients that present with a stenosis ≥70% [8]. However, we considered left carotid artery stenosis in our patient as symptomatic since our hemodynamic work-up disclosed the left carotid artery as the sole vessel supplying the circle of Willis via patent and functional anterior and posterior communicating arteries. Consequently, we hypothesized that (i) the cognitive impairment in our patient may be attributed to the diffuse brain hypoperfusion instead of post-stroke dementia and (ii) the cerebral hypoperfusion may be improved following carotid surgery. The fact that asymptomatic carotid stenosis has been previously correlated with cognitive impairment and brain imaging abnormalities lends support to our hypothesis [9, 10]. The resolution of cognitive deficits in our dA 109 cte 108 rre 107 Doppler was repeated by inflating a cuff around the left arm to 100 mmHg during examination. This intervention reduced the severity of the steal phenomenon in the left vertebral artery but also improved the flow at the basilar artery where the persistence of retrograde component was minimal. A complete flow reversal towards the arm was noted both in extra- and intracranial vertebral artery segments following cuff deflation (Fig. 2C-D). Brain SPECT was repeated under the same conditions (a cuff inflated on the left arm at 100 mmHg 10 minutes before to 20 minutes after injection). Subtraction images showed moderate improvement of perfusion, not only on the periphery of the right ischemic area but also at the entire left cerebral hemisphere (Fig. 1, AI-AIII). The patient was referred for vascular surgery and underwent left carotid endarterectomy (CEA) under the hypothesis that improving flow of left carotid artery would result in amelioration of brain perfusion, which in turn might induce a meaningful improvement in cognition. The intervention was also conducted with concomitant inflation of a cuff at 100 mmHg around the left arm as a prophylactic measure for perioperative stroke during the occlusion of the left carotid artery given the previous SPECT data showing amelioration in bihemispheric perfusion due to partial reversal of subclavian steal syndrome. The patient experienced no complication following carotid surgery. Post-operative brain SPECT indeed showed a discrete improvement of brain perfusion of the right hemisphere around the area of ischemia (temporal lobe) and a marked improvement of the perfusion of the left frontal, parietal and temporal lobes (Fig. 1, BI-BIII). Both the patient and his relatives noted a substantial cognitive improvement followed by amelioration in instrumental activities of daily living. His MMSE was 27/30. The patient declined repeating a detailed neuropsychological testing. co 106 CONCLUSIONS Un 105 A. Safouris et al. / Diffuse Extracranial Atherosclerotic Disease: A Reversible Cause of Cognitive Impairment uth 4 In patients with bilateral hemodynamically significant atherosclerotic carotid artery disease brain may be perfused by collateral circulation via the posterior cerebral and external carotid arteries [3]. Among different collaterals, the posterior communicating arteries maintain a crucial role in ensuring blood flow to the anterior circulation by reversing their normal posterograde flow. In the described case, normal collaterality was compromised by the subclavian steal phenomenon of the left vertebral artery with posterior communicat- 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 A. Safouris et al. / Diffuse Extracranial Atherosclerotic Disease: A Reversible Cause of Cognitive Impairment 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 Dr. Georgios Tsivgoulis has been supported by European Regional Development Fund - Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123). Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2368). SUPPLEMENTARY MATERIAL The supplementary figure is available in the electronic version of this article: http://dx.doi.org/10.32 33/JAD-141203. REFERENCES [1] [4] [5] [6] [7] [8] [9] Marshall RS, Festa JR, Cheung YK, Chen R, Pavol MA, Derdeyn CP, Clarke WR, Videen TO, Grubb RL, Adams HP, Powers WJ, Lazar RM (2012) Cerebral hemodynamics and cognitive impairment: Baseline data from the RECON trial. Neurology 78, 250-255. roo f 213 [3] or P 212 rre 211 co 210 Un 209 Sasoh M, Ogasawara K, Kuroda K, Okuguchi T, Terasaki K, Yamadate K, Ogawa A (2003) Effects of EC-IC bypass surgery on cognitive impairment in patients with hemodynamic cerebral ischemia. Surg Neurol 59, 455-460. Liebeskind DS (2003) Collateral circulation. Stroke 34, 22792284. Harper C, Cardullo PA, Weyman AK, Patterson RB (2008) Transcranial Doppler ultrasonography of the basilar artery in patients with retrograde vertebral artery flow. J Vasc Surg 48, 859-864. Labropoulos N, Nandivada P, Bekelis K (2010) Prevalence and impact of the subclavian steal syndrome. Ann Surg 252, 166-170. Tan TY, Schminke U, Lien LM, Tegeler CH (2002) Subclavian steal syndrome: Can the blood pressure difference between arms predict the severity of steal? J Neuroimaging 12, 131135. Hennerici M, Klemm C, Rautenberg W (1988) The subclavian steal phenomenon: A common vascular disorder with rare neurologic deficits. Neurology 38, 669-673. Ricotta JJ, Aburahma A, Ascher E, Eskandari M, Faries P, Lal BK (2011) Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease: Executive summary. Society for Vascular Surgery J Vasc Surg 54, 832836. Cheng HL, Lin CJ, Soong BW, Wang PN, Chang FC, Wu YT, Chou KH, Lin CP, Tu PC, Lee IH (2012) Impairments in cognitive function and brain connectivity in severe asymptomatic carotid stenosis. Stroke 43, 2567-2573. Balucani C, Viticchi G, Falsetti L, Silvestrini M (2012) Cerebral hemodynamics and cognitive performance in bilateral asymptomatic carotid stenosis. Neurology 79, 1788-1795. Takaiwa A, Kuwayama N, Akioka N, Kurosaki K, Hayashi N, Endo S, Kuroda S (2013) Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis. Acta Neurochir (Wien) 155, 627-633. Chen YH, Lin MS, Lee JK, Chao CL, Tang SC, Chao CC, Chiu MJ, Wu YW, Chen YF, Shih TF, Kao HL (2012) Carotid stenting improves cognitive function in asymptomatic cerebral ischemia. Int J Cardiol 157, 104-107. Grunwald IQ, Papanagiotou P, Reith W, Backens M, Supprian T, Politi M, Vedder V, Zercher K, Muscalla B, Haass A, Krick CM (2010) Influence of carotid artery stenting on cognitive function. Neuroradiology 52, 61-66. Lin CJ, Tu PC, Chern CM, Hsiao FJ, Chang FC, Cheng HL, Tang CW, Lee YC, Chen WT, Lee IH (2014) Connectivity features for identifying cognitive impairment in presymptomatic carotid stenosis. PLoS One 9, e85441. Marshall RS, Festa JR, Cheung YK, Pavol MA, Derdeyn CP, Clarke WR, Videen TO, Grubb RL, Slane K, Powers WJ, Lazar RM, Investigators RECON (2014) On behalf of the RECON Investigators. Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON) trial: Main results. Neurology 82, 744-751. uth ACKNOWLEDGMENTS 208 [2] dA 232 207 [10] [11] cte 231 patient coupled with the substantial improvement in bihemispheric perfusion on SPECT imaging is in line with recent reports that documented benefit on cognitive functions post CEA [11] or stenting [12, 13] of otherwise asymptomatic carotid stenosis. There are still limited data to explain the deleterious effects of chronic brain hypoperfusion on cognitive function. A recent study revealed diffuse cognitive deficits and disrupted brain connectivity as measured by MRI fractional anisotropy in patients with asymptomatic carotid stenosis [14]. However, it should be acknowledged that whether chronic brain hypoperfusion should be aggressively treated by CEA in cognitively impaired patients with concomitant multi-vessel asymptomatic stenoses of cervical arteries remains an unproven challenge given the recent negative results of Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON) trial [15]. In conclusion, the present case highlights that multivessel, extracranial atherosclerotic disease may cause chronic diffuse brain hypoperfusion that can be associated with significant cognitive impairment. Carotid revascularization procedures in the presence of functional intracranial collateral circulation may lead to resolution of brain hypoperfusion and reversal of cognitive deficits. 206 [12] [13] [14] [15] 5 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301