A 47-year-old woman presented to her primary care physician (PCP) with severe left-sided headache localized in the retrobulbar and temporal region. The PCP suspected migraine and prescribed a nonsteroidal anti-inflammatory drug. But despite analgesic treatment, her headache continued, and she returned to her PCP 2 weeks later. At this visit, the PCP noticed new anisocoria with a miotic pupil on the left. Emergent magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of neck and brain revealed no acute or subacute cerebral lesions but a narrowing and semicircular wall hematoma of the left internal carotid artery (ICA) up the petrous segment (Figure 1). The wall hematoma resulted in almost complete occlusion of the arterial lumen. Hereafter, she was transferred to our stroke center, where we confirmed diagnosis of ICA dissection with incomplete Horner syndrome.
47岁女性主因严重的左侧头痛去看家庭医生（PCP），头痛位于眼球后和颞区。PCP怀疑是偏头痛给予非甾体类抗炎药物。尽管止痛治疗，患者仍头痛，2周后患者再次复诊。这次医生注意到患者瞳孔不等大，左侧瞳孔缩小。急诊行头颈磁共振平扫和磁共振血管成像，未见急性或亚急性脑部病灶，但提示左颈内动脉岩段狭窄管壁有半圆形的血肿（图1）。管壁血肿引起动脉管腔几乎完全闭塞。之后患者被转到卒中中心，在这里明确诊断为颈内动脉夹层伴不完全的霍纳综合征。
Extracranial and intracranial duplex sonography revealed a resistance flow profile in the dissected ICA indicating distal occlusion. Collateral circulation through the left posterior communicating artery maintained the blood flow in the left anterior and middle cerebral artery. Six days later a repeated ultrasound showed improving blood flow with only local flow accelerations in the distal extracranial portion of the dissected ICA. The patient was treated with aspirin 300 mg daily for 2 weeks followed by a dose reduction to 100 mg daily. During hospitalization, she remained clinically stable and was discharged home after 8 days.
颅外和颅内多普勒超声提示夹层的颈内动脉血流受阻表现提示远端闭塞。通过左侧后交通动脉的侧枝循环保证了左侧大脑前动脉和大脑中动脉的血流。6天后复查超声提示血流改善，夹层的颈内动脉颅外段远端局部血流速度增快。给予阿司匹林每天300mg，2周后剂量减到100mg/每天。住院期间，患者临床病情稳定，8天后出院回家。
At follow-up visit 3 months later, the patient reported fatigue, difficulty concentrating at work, and persistent left-sided headache. In addition, she had observed an asymmetrical flushing and sweating of her face during a strong hike (Figure 2). The neurological examination was otherwise normal, except for the preexisting left-sided miosis. Blood flow in the left ICA further improved but was still accelerated distally. The patient was told to continue the antiplatelet treatment with aspirin 100 mg daily.
3月后随访时，患者主诉乏力、工作中无法集中注意力，有左侧持续性头痛。而且，在一次高强度的徒步旅行时，发现患者面部不对称的潮红和出汗（图2）。神经系统检查除了之前存在的左侧瞳孔缩小外都正常。左侧ICA血流进一步改善，但远端仍血流快。告知患者继续用阿司匹林100mg/天抗血小板治疗。
We present a patient with a rare, nonischemic symptom of ICA dissection, which has been termed Harlequin sign.1
我们报道一例表现为少见的非缺血性症状的ICA夹层患者，被命名为丑角征。
Dissections of the carotid and vertebral artery are defined by the occurrence of an arterial wall hematoma. MRI with T1-weighted axial scan with fat-saturation technique is the preferred method to detect the mural hematoma in cervical artery dissection, but it can be missed within the first days after onset.2
发生动脉壁的血肿被定义为颈动脉和椎动脉夹层。MRI 使用压脂技术的T1加权轴位平扫是检测颈动脉夹层管壁血肿的首选方法，但发病头几天可能会漏诊。
About two thirds of patients with cervical artery dissection present with stroke or transient ischemic attack and headache or neckpain. Local symptoms (ie, Horner syndrome, cranial- nerve palsy, cervical root injury, and tinnitus) occur in about one third of all cases.3 These local symptoms are caused by an eccentric expansion of the mural hematoma, which leads to compression and stretching of nearby structures (sympathetic-nerve fibers, which proceed along the carotid artery, cranial-nerves, and cervical roots).2 A typical local sign is Horner syndrome, which is defined by the occurrence of pupillary miosis and eyelid ptosis with or without facial anhidrosis. In ICA dissection, Horner syndrome is caused by local disruption of sympathetic fibers at the level of ICA. Another, only rarely observed local sign with the same underlying pathophysiology, is the Harlequin sign. Patients with Harlequin sign complain about asymmetrical facial flushing and sweating.1
大约三分之二的颈动脉夹层患者表现为卒中或短暂性脑缺血发作和头痛或颈部疼痛。约三分之一的患者会出现局灶性症状（如霍纳综合征、颅神经麻痹、颈神经根损伤和耳鸣）。这些局灶性症状是由血管壁血肿偏心扩张导致临近结构的受压和牵拉引起的（沿着颈动脉走行的交感神经纤维，颅神经和颈神经根）。典型的局灶性体征是霍纳综合征，即出现瞳孔缩小和眼睑下垂，伴或不伴面部无汗。颈内动脉夹层时，在颈内动脉水平的交感神经纤维局部破坏导致的霍纳综合征。另一个罕见的病理生理机制相同的局灶性体征就是丑角征，患者会主诉不对称的面部潮红和出汗。
The sympathetic pathway consists of 3 neurons. The first- order neuron originates in the posterior hypothalamus, the second in the intermediolateral cell column at spinal cord level C8-T2, and the third in the superior cervical ganglion near by the bifurcation of the common carotid artery.4 Third-order neurons carry 2 different types of sympathetic fibers: oculosympathetic and vaso-/sudomotor fibers. Oculosympathetic fibers ascend along the ICA and innervate the iris dilator muscle and the superior tarsal muscle. Oculosympathetic pathway injury results in ipsilateral Horner syndrome. The vaso-/ sudomotor fibers separate at the level of carotid bifurcation. Fibers innervating ipsilateral blood vessels and sweat glands of the medial forehead and nose travel along the ICA, whereas fibers for the remaining facial areas proceed along the external carotid artery. Therefore, postganglionic lesions along the ICA result in ipsilateral paleness and anhidrosis of the medial forehead and nose, whereas preganglionic lesions impair the ipsilateral half of the face. The Harlequin sign comprises both pre- and postganglionic injury of vaso-/sudomotor fibers.4
交感神经通路包括三级神经元。一级神经元起自下丘脑后部，二级神经元位于脊髓C8-T2之间的中间外侧柱，三级神经元在颈上神经节临近颈总动脉的分叉处。三级神经元含有两种不同类型的交感神经纤维:眼动交感纤维和血管舒缩-泌汗纤维。眼动交感纤维与ICA伴行向上支配虹膜开大肌和上睑板肌。眼动交感神经通路受损导致同侧霍纳综合征。血管舒缩-泌汗纤维在颈动脉分叉处分离出来。沿着ICA走行的纤维支配同侧前额内侧和鼻部的血管和汗腺，而支配面部其余区域的纤维与颈外动脉伴行。因此，沿着ICA交感神经节后病变会引起同侧前额内侧和鼻部的苍白和无汗，而节前病变影响同侧半边脸。丑角征是血管-泌汗纤维节前节后纤维同时受累所致。
Harlequin sign is rarely observed in ICA dissection and is restricted to 2 case reports in literature only. Both patients had left-sided ICA dissection and reported contralateral, hemifacial flushing, and sweating during physical exertion a few weeks after diagnosis of ICA dissection. Photographs of both patients showed a pale ipsilateral forehead and nose.5,6 As in our case, Horner syndrome preceded the Harlequin sign by weeks in both patients. The recognition of Harlequin sign might have been delayed because patients had avoided physical exertion during earlier stages of ICA dissection. A secondary enlargement of the wall hematoma or a recurrent dissection as reasons of a delayed development of Harlequin’s sign cannot be excluded, but seem unlikely to us. Furthermore, it remains unclear why Horner syndrome is much more frequently observed than Harlequin sign in ICA dissection although oculosympathetic fibers have a close anatomic relationship to vaso- and sudomotor fibers. In some cases, Harlequin sign might have already been resolved completely when patients start physical exercises or they simply did not realize it, especially in case of mild severity.
丑角征在颈动脉夹层中罕见，文献也仅有2例报道。两位患者均为左侧ICA夹层，诊断夹层后数周体育运动时出现对侧半面部潮红和出汗。两位患者的照片显示同侧前额部和鼻子苍白。与本例患者一样，两位患者也是在霍纳综合征数周后出现丑角征。由于患者在ICA夹层早期避免体育运动，所以对丑角征的识别已经延误了。迟发丑角征的原因也不能排除血管壁血肿的继发扩大或夹层复发，似乎不大可能。而且，仍不清楚ICA夹层时为什么霍纳综合征比丑角征更常见，虽然眼动交感纤维解剖上与血管-泌汗纤维的关系很紧密。有些患者，当他们开始锻炼时可能丑角征已完全缓解了或者他们没有意识到，尤其是程度很轻时。
Harlequin sign is not specific for ICA dissection. But in this case, the deficiency of vaso-/sudomotor fibers should be restricted to the ipsilateral medial forehead and nose. In published reports, several other causes of Harlequin sign have been reported with injury to the sympathetic pathway at different levels.4
丑角征不是ICA夹层特异性的体征。但本例中，血管-泌汗纤维的受累应局限在同侧前额内侧和鼻。发表的病例报道中，报道过几个其它原因的丑角征，损伤了交感神经通路的不同水平。
Patients with cervical artery dissection should be treated with antiplatelets or anticoagulants to prevent future cerebrovascular ischemic events. At present, there is equipoise, whether antiplatelets or anticoagulants are more effective. The decision to use aspirin in our patient was based on pathophysiological consideration as proposed by the CADISP group in 2007.7 In our patient, the following criteria were arguments in favor of aspirin: (1) purely local, nonischemic symptoms; (2) no ischemic brain lesions on MRI scan, and (3) involvement of intracranial segments of the ICA as the latter might point toward higher risk of subarachnoid hemorrhage.7 Nevertheless,the available level of evidence for antithrombotic treatment decisions in cervical artery dissection is relatively low and currently has to be based on purely observational data. At least, 3 systematic meta-analyses across such observational, nonrandomized studies comparing both treatment approaches showed contradictory results.8–10 One meta-analysis revealed a trend in favor of anticoagulants in preventing the composite end point death or disability, whereas in turn symptomatic intracranial hemorrhages and major extracranial hemorrhages solely occurred in the anticoagulation group.8 Another reported no difference in risk of stroke and death between both treatment groups.9 A third analysis showed a superiority of antiplatelets in preventing the composite outcome of ischemic stroke, intracranial hemorrhage, or death.10 But authors of the latter admitted that when the meta-analysis was confined to studies of higher methodological quality, this benefit was not found. Thus, randomized-controlled studies (RCTs) are warranted. A UK-based RCT (ie, Cervical Artery Dissection in Stroke Study [CADISS]) is under way.9 Because of the (expectedly) low frequency of clinical end points, the use of surrogate outcomes, for example, ischemic and hemorrhagic lesions on MRI, may be a reasonable alternative approach. Such RCT was indeed launched in September 2013 in Switzerland: The TREAT-CAD study aims at demonstrating noninferiority of aspirin as compared with vitamin K antagonists in ICA dissection patients with regard to a composite outcome of clinical or imaging end points of brain ischemia or bleeds, or death (Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection, TREAT-CAD. NCT02046460. www.clinicaltrials.gov).
颈动脉夹层患者应给予抗血小板或抗凝剂来预防脑血管缺血性事件的发生。目前，抗血小板还是抗凝剂更有效伯仲难分。本患者决定给予阿司匹林是基于2007年CADISP研究组提出的病理生理学考虑。下面的标准支持应用阿司匹林：1）单纯局灶性的，非缺血性症状；2）MRI扫描上没有缺血性脑部病灶，3）ICA颅内段受累因此蛛网膜下腔出血的风险更高。但是，对颈动脉夹层决定抗栓治疗的现有的证据水平相对低，目前不得不单纯依靠观察的数据。至少有3个这样的观察性、非随机化研究的系统荟萃分析，比较了两种治疗方法，显示结果相互矛盾。一项荟萃分析显示倾向抗凝预防复合终点事件死亡或残疾，但同时症状性颅内出血和严重的颅外出血仅见于抗凝组。另一项研究报道两治疗组卒中和死亡的风险两组无差异。第三个分析表明在预防缺血性卒中、颅内出血或死亡的复合预后方面抗血小板治疗更有优势。但其作者也承认，当荟萃分析仅限于方法学质量更高的那些研究时，未发现获益。因此，需要随机对照研究(RCTs)。英国的一项RCT研究（卒中研究中的颈动脉夹层 [CADISS]正在进行中。由于预期的临床终点事件发生率低，使用了替代的预后评价，如MRI上的缺血和出血病灶，作为合理的替代方法。这样的RCT研究实际上2013年9月在瑞典进行过：TREAT-CAD研究目的是揭示对于ICA夹层患者在临床和影像学复合终点事件-脑缺血、出血或死亡方面阿司匹林与维生素K拮抗剂疗效相当（颈动脉夹层的生物标志物和抗栓治疗，TREAT-CAD. NCT02046460. www.clinicaltrials.gov）
In the present case, we decided to continue the treatment with 100 mg of aspirin until morphological and blood flow changes in the dissected ICA will be completely resolved on MRI/A and neurosonography.
对于本患者，我们继续给予100mg阿司匹林治疗，直到MRI/A和神经超声显示夹层的ICA形态学和血流方面都完全恢复正常为止。
Teaching Points
· Asymmetrical facial flushing (Harlequin sign) is a rare and nonspecific symptom of ICA dissection for which physicians should be aware.
· In ICA dissection, Harlequin sign and Horner syndrome are caused by injury of sympathetic fibers, which ascend along the ICA.
· At present, MRI scan with axial T1-weighted fat saturation sequences is the preferred method to confirm diagnosis of ICA dissection.
· The type of antithrombotic treatment (antiplatelets versus anticoagulants) to prevent cerebrovascular events after ICA dissection is still under debate.
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