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58 Cases of Ocular Ischemic Diseases Caused by Carotid Artery Stenosis Abstract PURPOSE: To evaluate the clinical characteristics and risk factors of ocular ischemic diseases caused by carotid artery stenosis. METHODS: This study was a retrospective review of 145 patients with carotid artery stenosis. Fifty-eight patients who had symptoms of ocular ischemic disease caused by carotid artery stenosis formed group A and the other 87 patients who only had carotid artery stenosis formed group B. We analyzed the causes and course of disease, and relative risk factors, by comparing the two groups. RESULTS: The degree of carotid artery stenosis in group A was higher than in group B. and group A had a greater decrease of ophthalmic artery flow. Male gender, hypertension, hyperlipidemia, and smoking were significantly related to carotid artery stenosis. Amaurosis fugax was the most common ocular symptom in group A. The ocular ischemic diseases mainly included ischemic optic neuropathy,central(branch)retinal artery occlusion,ophthalmoplegia externa, and ocular ischemic syndrome. CONCLUSIONS: There is a close relation between carotid artery stenosis and ocular ischemic diseases. Ophthalmologists must observe for ocular symptoms, which were the onset symptoms in some patients. Introduction The carotid artery is the main route by which the blood is supplied to the cerebrum and other areas of the head from the heart. Carotid artery stenosis refers to the stenosis of the lumen owing to carotid atherosclerotic plaque, arteritis, or fibromuscular dysplasia. Its incidence is high, accounting for 10% of the population older than 60 years. Carotid artery stenosis is one of the leading causes of ischemic stroke and patients usually arrive at neurological clinics with stroke symptoms of hemiplegia and homonymous hemianopia.[1] In recent years, an increasing number of patients with carotid artery stenosis have arrived at ophthalmological clinics because of eye discomfort. Therefore, these patients who have carotid artery stenosis accompanied by ocular ischemic presentations have received increasing attention.[2] We retrospectively reviewed the clinical data of patients with carotid artery stenosis who had been treated in departments of ophthalmology, intervention, and vascular surgery. Materials and Methods Subjects A total of 145 patients, who were residents in multiple cities of south China, with carotid artery stenosis from January 2002 to June 2007 were treated at our hospital. There were 81 male and 64 female patients; their mean age was 63.31±9.41 years (range, 25-87 years). Diagnoses were confirmed by carotid artery color Doppler ultrasound or digital subtraction angiography (DSA), and other primary ophthalmological conditions such as primary glaucoma, iridocyclitis, retinal vein occlusion, high myopia, retinitis pigmentosa, choroiditis, diabetic retinopathy, and other congenital fundus abnormalities were ruled out. Diagnostic criteria Patients were defined as having symptoms of ocular ischemia if they presented symptoms of transient syncope, flash, pain on the eye and perio rbital region, diplopia, and reduced eyesight. Patients were defined as having ocular ischemic disease when they presented signs of retinal artery occlusion, increased ocular pressure, rubeosis iridis, altered visual field, optic nerve atrophy, and patchy hemorrhage on the retina as confirmed by the determination of the degree of carotid artery stenosis, visual field , and visual acuity, as well as by fundus fluorescein angiography and visual electrophysiology. In the entity of ocular ischemic disease, ocular ischemic syndrome refers to a series of symptoms involving the eye and brain owing to the shortage of blood supply that is caused by chronic carotid artery occlusion or stenosis. Methods Clinical data for all the patients were reviewed retrospectively. Among the 145 patients, 58 had signs or symptoms of ocular ischemia (group A) and 87 had no signs nor symptoms of ocular ischemia (group B). An additional 57 patients without carotid artery stenosis who were matched by age were selected as controls. The site and degree of the stenosis were determined by angiography. Color Doppler ultrasound (Philips HD7) was used to examine the hemodynamics of the ophthalmic artery with a frequency of 10 MHz. Hemodynamic parameters of the ophthalmic artery of each patient were recorded, including systolic peak blood flow velocity (Psv), end-diastolic blood flow velocity (Edv), mean blood flow velocity (Vm), resistance index (RI), and pulse index (PI). Each parameter was measured three times and the mean value was used. Data were expressed as x±s or percentage. The t test and chi-square test were performed using SPSS version 14.0 software to compare the differences between groups. For factors that might influence the disease, univariate and unconditional logistic stepwise regression methods were used to adjust for confounding factors and analyze the interactions between factors. Factors that might influence the disease were screened out. Results 1. Age and gender predisposition for the disease: Among the 145 patients, there were 15 patients younger than 50 years, 31 between 51 and 60 years, 52 between 61 and 70 years, 35 between 71 and 80 years and 8 patients older than 80 years. The mean age of group A was older than group B but the difference was not significant (64.37±9.70 vs 62.45±11.27 years; P>0.05). 2. The site and degree of carotid artery stenosis: The most frequent sites of stenosis were bifurcation of the common carotid artery and the inlet of the internal carotid artery. There were 13 patients with right internal carotid artery stenosis, 11 with left internal carotid artery stenosis, and 121 with bilateral internal carotid artery stenosis. A significantly higher proportion of patients had bilateral involvement than unilateral involvement. Thirty-eight patients in group A (65.51%) had stenosis of more than 50% (43-100%; mean: 69.13±7.46%). The mean stenosis in group B was 48.34±9.23% (34-100%). There was a significant difference of stenosis degree between the two groups (P<0.05). 3. Risk factors for the development of carotid artery stenosis: In group A, there were 33 male and 25 female patients, 36 patients with concomitant hypertension, 31 patients with hyperlipidemia, and 28 patients with a history of smoking (smoking is defined as smoking one cigarette per day for 1 year or 18 packs per year). In group B, there were 49 male and 38 female patients, 46 patients with concomitant hypertension, 39 patients with hyperlipidemia, and 40 patients with a history of smoking. Univariate and unconditional logistic stepwise regression analyses showed that carotid artery stenosis was associated with gender (predilection in males), hyperlipidemia, hypertension, and smoking (odds ratios of 2.78,3.13 ,2.53 ,and 2.34, respectively; P < 0.05). 4. Constituent ratio of patients with ocular ischemia: Clinical presentations of ocular ischemia in group A included transient pre-syncope, pain in the eye and orbit, diplopia, hypopsia (defect in visual field), retinal hemorrhage or edema, and increased intraocular pressure. Transient pre-syncope was the most common symptom, and carotid artery stenosis was also associated with pain in the eye and orbit and hypopsia (defect in the visual field; P < 0.05; Table 1). Table 1 Constituent ratio of presentations of ocular ischemia (n=58) Signs and symptoms No. of patients constituent ratio (%) transient pre-syncope 27 46.55 pain in the eye and orbit 21 36.21 hypopsia (defect in visual field) 17 29.31 retinal hemorrhage or edema 15 25.87 diplopia 10 17.24 increased intraocular pressure 3 5.17 Note: Among the 58 patients shown in Table 1, some had two or more presentations 5. Constitution of ocular ischemic diseases: Categorization was based on the final diagnosis; there were 26 patients in group A who had been diagnosed as having ocular ischemic diseases (Figs 1 and 2). Table 2 Constitution of ocular ischemic diseases (n=26) diseases No. of patient constituent ratio(%) Ischemic optic nerve disorders 9 34.61 Ocular ischemic syndrome 6 23.08 Retinal central (branch) vein occlusion 5 19.23 External ophthalmoplegia 4 15.39 Neovascular glaucoma 2 7.69 6. Comparisons of hemodynamic parameters among three groups: Compared with the control group, ophthalmic artery perfusion of patients in group A and B was reduced remarkably (Tables 3 and 4). Some parameters (Psv, Edv and RI) of group A were also reduced compared with group B (Table 5). Table 3 Comparisons of hemodynamic parameters between group A and the control group (x±s) Groups Psv(cm/s) Edv(cm/s) Vm(cm/s) Group A 9.12 ±2.28 7.03 ±1.35 RI 8.09 ±1.85 1.17±0.06 PI 1.69±0.29 Control group 29.23±3.63 21.84±2.89 26.83±3.36 0.31±0.09 0.57±0.13 t value 24.486 21.125 P value <0.01 <0.01 26.241 <0.01 28.687 <0.01 18.065 <0.01 Table 4 Comparisons of hemodynamic parameters between group B and the control group (x±s) Groups Psv(cm/s) Edv(cm/s) Vm(cm/s) RI Group B 14.37±2.74 12.57 ±2.04 14.15 ±2.78 0.73±0.09 PI 1.16±0.23 Control group 29.23±3.63 21.84±2.89 26.83±3.36 0.31±0.09 0.57±0.13 t value P value 4.675 0.029 3.512 3.357 5.574 0.041 0.043 0.023 4.493 0.031 Table 5 Comparisons of hemodynamic parameters between group A and B (x±s) Groups Psv(cm/s) Edv(cm/s) Vm(cm/s) RI PI 1.17±0.06 1.69±0.29 Group B 14.37±2.74 12.57 ±2.04 14.15 ±2.78 0.73±0.09 1.16±0.23 Group A 9.12 ±2.28 7.03 ±1.35 8.09 ±1.85 3.161 2.825 2.454 3.687 1.876 P value 0.046 0.049 0.057 0.038 0.067 t value Discussion The blood supply to the eye comes from the retinal central vascular system of the ophthalmic artery and the ciliary vascular system. The ophthalmic artery stems from the ipsilateral internal carotid artery. If occlusion or stenosis occurs in the carotid artery, the blood perfusion to the ophthalmic artery becomes insufficient, leading to signs and symptoms of anterior and posterior ocular ischemia. These series of presentations are collectively termed ischemic ophthalmopathy, which includes retinal central (branch) vein occlusion; external ophthalmoplegia; ischemic optic nerve disorders; ocular ischemic syndrome; and neovascular glaucoma. The clinical manifestations in the acute phase are transient pre-syncope and retinal central (branch) vein occlusion. If the condition remains untreated, the chronic presentations of this disorder include chronic ocular ischemic syndrome and hypoperfusion retinopathy, which ultimately will lead to neovascular glaucoma and permanent blindness. [3, 4] It has been reported that ischemic ophthalmopathy secondary to carotid artery stenosis most commonly affects the elderly. The aged usually have concomitant systemic diseases, such as hypertension, diabetes mellitus, coronary artery diseases, and hyperlipidemia, which directly or indirectly aggravate atherosclerosis of the carotid artery, and ensuing ocular ischemia. [3, 5] In the present study, the patients in groups A and B were older, with a mean age of 63.31±9.41 years. Univariate and unconditional logistic stepwise regression analyses showed that the development of carotid artery stenosis was associated with gender (male), hypertension, hyperlipidemia, and smoking. It is well known that hyperlipidemia is important risk factors for vascular sclerosis. Females are less likely to be affected by the disorder, which is attributable to the protective effect of estrogen on the cardiovascular system. Cigarette smoking may aggravate ischemia and spasm of the ophthalmic artery, and thus is an important risk factor. Our study showed that presentations of ophthalmic ischemia secondary to carotid artery stenosis are protean, primarily including transient pre-syncope, pain in the eye and orbit, diplopia, hypopsia (defect of visual field), retinal hemorrhage or edema, and increased intraocular pressure. Of these presentations, transient pre-syncope was the most common. Some patients may present with two or more of these symptoms. However, ophthalmic ischemic symptoms such as transient pre-syncope may be caused by the alteration of ophthalmic hemodynamics (hypoperfusion) and cerebral vascular spasm, or even thrombosis of the retinal arterioles by detached emboli from atherosclerotic plaque of the ipsilateral carotid artery. Gong yan et al [6] also found that carotid artery stenosis is the most common underlying disorder in patients with transient pre-syncope, followed by cardiogenic disorders such as atrial fibrillation. Some patients in our study came to the ophthalmological clinic because of “transient pre-syncope” or “pain in the orbit.” This informs us that caution should be raised in patients with such symptoms, and carotid artery color Doppler ultrasound should be performed for the early diagnosis and intervention of this disorder. Zhao Jun et al [7] analyzed the association between varieties of ophthalmic ischemic diseases with the carotid artery and found that the incidence of carotid artery stenosis was remarkably increased in patients with symptoms of retinal central (branch) vein occlusion, external ophthalmoplegia, ocular ischemic syndrome, and neovascular glaucoma. However, the constituents of ophthalmic ischemic disorders were not investigated. Our study showed that ischemic optic nerve disorder had the highest constituent ratio in ophthalmic ischemic disorders, followed by ocular ischemic syndrome, retinal central (branch) vein occlusion. And external ophthalmoplegia, and those with neovascular glaucoma had the least common presentation. In our cohort study, three cases of ischemic optic nerve disorder and two cases of retinal branch vein occlusion were found to be caused by carotid artery stenosis on routine ophthalmological examination (Figs. 1 and 2). Thus, in evaluating patients with ophthalmic ischemic disorders of unknown origin, ophthalmologists should adopt the notion of system instead of “to treat only where the pain is.” Carotid artery stenosis is usually severe when symptoms of ophthalmic ischemia are present. [8,9] Our study showed that ophthalmic artery perfusion was reduced in patients with carotid artery stenosis. More than 65% of the patients with ischemic presentations had stenosis of more than 50%, and their ophthalmic artery perfusion reduction was more than in those patients with silent carotid artery stenosis (group B). We propose that ophthalmic ischemic presentations may occur when the perfusion is reduced to a threshold due to progression of carotid artery stenosis. Therefore, the presentation of ophthalmic ischemic symptoms can be used to predict the severity of carotid artery stenosis. [10,11] In the present study we reviewed retrospectively clinical data and explored the clinical features and risk factors of ophthalmic ischemia disorders secondary to carotid artery stenosis from a variety of perspectives. The results showed that ophthalmic ischemic symptoms secondary to carotid artery stenosis are indicative of severe stenosis, and that ophthalmic symptoms may be the initial presentations of carotid artery stenosis. Ophthalmologists must be cautious with these symptoms and obtain data from relevant examinations to identify the underlying causes. Early intervention may be effective in the treatment of carotid artery stenosis and reducing incidence of ophthalmic and cerebral complications. Acknowledgments The authors thank all patients, We are grateful to the State Key Laboratory of Ophthalmology at Zhongshan Ophthalmic Center, Sun Yat-sen University. References [1] Faries PL,Chaer RA,Patel S ,Lin SC, DeRubertis B, Kent KC. Current management of extracranial carotid artery disease. Vasc Endovascular Surg,2006,40:165-175. [2] Kastumi Hoya, Eiharu Morikawa, Akira Tamura .Common Carotid Artery Stenosis and Amaurosis Fugax .Journal of Stroke and Cerebrovascular Diseases, 2008, 17( 1) 1-4 [3] Zhao HQ; Pan XD; Wang JH; Zhang Y. The common etiologies of carotid stenosis. Cerebrovascular Diseases Foreign Medical Sciences. 2004,12(7):497-499 [4] Tang WQ; Wei SH; Li S,Clinical analysis of ocular manifestations related to carotid artery stenosis. Chinese Journal of Ocular Fundus Diseases,.2006,6(22) :376-378 [5] Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. Addendum to the supplement to the guidelines for the management of transient ischemic attacks. Stroke, 2003, 31:1001 [6] Arnold M, Nedeltchev K, Sturzenegger M, Schroth G, Loher TJ, Stepper F, Remonda L, Bassetti C, Mattle HP. Thrombolysis in patients with acute stroke caused by cervical artery dissection: analysis of 9 patients and review of the literature .Arch Neurol, 2002, 59 :549-553 . [7] Zhao J; Hu LN; Wei SH. Clinical significance of ocular ischemia disease on predicted the happening of carotid stenosis. International Journal of Ophthalmology.2009,9(2):361-362 [8] Yang WL; Liu SM; Liu L,Color Doppler analysis of ocular vessel blood velocity in normal eyes. Chinese Journal of Ocular Fundus Diseases,1997,13:99-101 [9]Hoya K, Morikawa E, Tamura A, Saito I. Common carotid artery stenosis and amaurosis fugax. J Stroke Cerebrovasc Dis. 2008 Jan-Feb;17(1):1-4 [10]Costa VP, Kuzniec S, Molnar LJ, et al. The effects of carotid endarterectomy on the retrobulbar circulation of patients with severe occlusive carotid artery disease. Ophthalmology, 1999,106:306-310. [11]Sivalingam A, Brown GC, Magargal LE. The ocular ischemic syndrome Part III: visual prognosis and the effect of treatment. Int Ophthalmol,1991,15:15-20. prolonged fluorescein filling time in upper retinal branch artery Fig 1 Series presentations of retinal branch artery occlusion caused by carotid artery stenosis (Zhao, male, 67 years old) Fig. 1c: Color Doppler ultrasound shows blood flow disturbance in carotid artery secondary to carotid artery stenosis. Fig. 1a: Photo of the fundus shows occlusion in the retinal branch artery. Fig 1d: Carotid artery color Doppler ultrasound shows patent carotid artery lumen after carotid endarterectomy. Fig. 1b: FFA shows significantly Fig. 1e: Pathology endarterectomy shows of carotid atherosclerosis and attendant calcification in the intima Fig. 2b: FFA shows leakage of fluorescein in optic disc and suspected formation of retinal arteriovenous anastomosis. of the internal carotid artery Fig.2 Series presentations of retinal branch artery occlusion caused by carotid artery stenosis (Wu, female, 72 years old). Fig. 2c: Carotid artery color Doppler ultrasound shows severe stenosis of the carotid artery. Fig.2a: Photo of the fundus shows occlusion in the retinal branch artery Fig. 2d: Ophthalmic artery color Doppler ultrasound shows remarkably reduced ophthalmic artery perfusion. Fig. 2f: Pathology of carotid endarterectomy Fig. 2e: TCD shows increased resistance shows fibrotic thickening and hyaline in the carotid siphon (indicating carotid changes in arterial wall, and slit-like artery stenosis) cholesterol crystal. 审稿意见: 本文主要研究颈动脉狭窄所致眼缺血综合征的危险因素以及一些血流参数的变化,对临床有一定 参考价值,内容新颖。但是存在一些问题,请修改: 一、摘要结论部分不简练。 已做简化修改。 二、虽然本文研究对象是医院诊治的来自中国南部的病人,但是并不能代表中国南部的整体情况, 也没有交代中国南部的概念。如果是以人群为基础的研究,本文未进行整群抽样,如果是以医院 为基础,那么应对医院按流行病学方法进行选择,因为所在医院有来自南部的病人就认为代表中 国南部很不科学。题目中的“中国南部”的表达的确存在不合理之处,已做相应修改,删除“中 国南部”。 三、应交代颈动脉狭窄以及眼缺血综合征的诊断标准。如何界定吸烟史?应交代入选标准以及排 除标准。已在文中列出颈动脉狭窄以及眼缺血综合征的诊断标准。界定吸烟史:确定吸烟的标准 为,每天吸一只,连续吸一年以上,或每年累计达 18 包以上,符合条件者界定为吸烟。 四、方法第三行中“58 had symptoms of ocular ischemia (group A)”,完全按症状分组是否 合理?正常对照是否也要行颈动脉血管造影?如行,是否知情同意并通过伦理讨论,这一点未提 及。结果部分第一段年龄比较可用表格显示。已做修改:(1)有眼部缺血症状或体征者归 A 组, 无眼部缺血症状或体征归 B 组。(2)我们在对正常对照组行颈动脉血管造影检查前,均已口头 告知患者并征得了患者的同意。但并未签署同意书。(3)结果部分中第一段年龄的比较,由于 用文字可以完整表述,故未用表格显示。 五、提供表 2 中眼科疾病的诊断标准。是否可提供清晰度更高的图?已在文中列出眼科疾病的诊 断标准。抱歉,暂未能提供清晰度更高的图。 六、结果部分第三段危险因素的比较应用表显示,仅有 p 值是不够的,还应给出 OR 值。已做相 应修改。 七、结果部分第四段应进行率的比较,应有 P 值。已做相应修改。 八、删去讨论部分的"diabetes mellitus is important risk factors for vascular slerosis." 及"In earkly phase of reduced ophthtalmic perusion secondary to carotid artery stenosis, visual function is not significantly impaired." 已删除相应内容。 九、补充支持研究结果的参考文献。已补充相应文献 衷心感谢编辑部老师的接纳!