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Relationship of retinal vascular caliber variation with intracranial arterial stenosis
Microvascular Research 108 (2016) 64–68
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Relationship of retinal vascular caliber variation with intracranial arterial stenosis☆ Eun-Jung Rhee a, Pil-Wook Chung b, Tien Y. Wong c, Su Jeong Song d,⁎ a
Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Departments of Neurology Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Singapore Eye Research Institute, Singapore National Eye Center, Duke-NUS Medical School National University of Singapore, Singapore d Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 25 April 2016 Revised 4 August 2016 Accepted 6 August 2016 Available online 7 August 2016 Keywords: Intracranial arterial stenosis Retinal vessel Transcranial doppler
a b s t r a c t Background & purpose: To investigate the associations of retinal vessel parameters with intracranial arterial stenosis (ICAS) assessed by Transcranial Doppler ultrasonography. Method: Data on transcranial Doppler ultrasonography and quantitative retinal vessel parameters from 627 participants in a health screening program were included in this study. ICAS was defined as N 50% intracranial arterial stenosis (ICAS) based on criteria modified from the stroke outcomes and neuroimaging of intracranial atherosclerosis (SONIA) trial assessed by transcranial Doppler (TCD) ultrasonography. A semi-automated computerassisted program (Singapore I Vessel Assessment) was used to measure the retinal vascular parameters from the photographs. Multivariate analysis was performed to identify which retinal vessel parameters were associated with increased risk of ICAS. Results: Among 627 participants, 24 (3.8%) had ICAS diagnosed by TCD. Subjects with ICAS had eyes with wider mean central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) in comparison to subjects without ICAS. Men (odds ratio [OR]:13.1, 95% confidence interval: 3.13–33.33) and a large standard deviation of mean arterial width (STDWa) were associated with ICAS (first vs. third tertile: OR ratio: 14.04, 95% confidence interval: 1.71–115.32; first vs. third tertile: OR ratio: 22.1, 95% confidence interval: 2.56–190.97) after adjusting for possible confounders. Conclusion: A large variation in retinal arteriolar diameter is associated with ICAS. This study suggests the possible relationship between retina vessel and early changes within the cerebrovascular network. © 2016 Elsevier Inc. All rights reserved.
Retina function as two way mirror which provides the outside visual input to visual cortex but also can provide information regarding cerebrovascular conditions to outside world. But until now, there have been inconsistent results of how or when retina vasculature reflects cerebrovascular conditions (Patton et al., 2005; Ikram et al., 2012; Cheung et al., 2007a; De Silva et al., 2009; De Silva et al., 2011; Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Knudtson et al., 2003; Witt et al., 2006; Cheung et al., 2013). The implications of retinal microvascular changes in the pathogenesis of cerebrovascular diseases are largely unknown until recently. Previous studies suggested that narrower arteriolar caliber and wider venular caliber are associated with ischemic stroke. Some study showed, in addition to vessel caliber change, other parameters indicative of tortuous vascular network
☆ The paper has not been published nor submitted simultaneously for publication elsewhere. ⁎ Corresponding author at: Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 110746, Republic of Korea. E-mail address: [email protected] (S.J. Song).
http://dx.doi.org/10.1016/j.mvr.2016.08.002 0026-2862/© 2016 Elsevier Inc. All rights reserved.
were associated with ischemic stroke. However, in other study, retinal vessel caliber was not related with intracranial stenosis (Patton et al., 2005; Ikram et al., 2012; Cheung et al., 2007a; De Silva et al., 2009; De Silva et al., 2011; Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Knudtson et al., 2003; Witt et al., 2006; Cheung et al., 2013). Intracranial arterial stenosis (ICAS) is a major cause of ischemic stroke, especially in Asians, with a reported prevalence of up to 50% (Guan et al., 2013). In addition to advances in treatment that improve the prognosis of ICAS-related stroke patients, detecting ICAS at an early stage can significantly improve stroke management and decrease socio-economic burden related to treatment. Transcranial Doppler (TCD) ultrasonography is a non-invasive, safe, and cost effective method to diagnose ICAS (Wong et al., 2007; Leng et al., 2014; Sacco et al., 1995; Standards of Medical Care in Diabetes, 2016). In this study, we analyzed quantitative retinal vascular parameters of participants with ICAS diagnosed by TCD. These findings were compared to measurements of those without ICAS to investigate the possibility that retinal vessel parameters are associated with early intracranial vascular change.
E.-J. Rhee et al. / Microvascular Research 108 (2016) 64–68
1. Method 1.1. Participants This cross-sectional study was a part of the Kangbuk Samsung Health Study, in which subjects were participants in a medical health checkup program at the Health Promotion Center of Kangbuk Samsung Hospital of Sungkyunkwan University in Seoul, Korea. The purpose of medical health checkup programs is to promote employee health through regular examinations and to enhance early detection of existing diseases. Most examinees are employees of various industrial companies and their family members from around the country. Employers largely cover the costs of the medical examinations, and a considerable proportion of examinees undergo health examinations annually or biannually. A total of 627 participants who underwent TCD from January 2011 to December 2011 and for whom gradable fundus photographs were available were included. The ophthalmic examinations, systemic examinations, and questionnaires for sociodemographic and behavioral characteristics were administered to each participant. The study was approved by the institutional review board of Kangbuk Samsung Hospital (KBSMC2015-01-003) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained prior to recruitment. 1.2. Anthropometric measurement and laboratory assessment Data on medical history, medication use, and health-related behaviors were collected through a self-administered questionnaire, while trained staff obtained physical measurements and serum biochemical parameters during health examinations. Body weight was measured with the participants in light clothing without shoes to the nearest 0.1 kg by using a digital scale. Height was measured to the nearest 0.1 cm. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Trained nurses measured sitting blood pressure with standard mercury sphygmomanometers. All subjects were examined after an overnight fast. The hexokinase method was used to measure fasting serum glucose concentrations (Hitachi Modular D2400; Roche, Tokyo, Japan). The total cholesterol and triglyceride concentrations were measured with an enzymatic calorimetric test. The selective inhibition method was used to evaluate the level of high-density lipoprotein cholesterol, and a homogeneous enzymatic calorimetric test was used to measure the level of low-density lipoprotein cholesterol. The presence of diabetes mellitus was determined according to the self-questionnaire results, as well as from the fasting serum blood glucose and glycated hemoglobin (HbA1c) levels of participants, as suggested by the American Diabetes Association (Standards of Medical Care in Diabetes, 2016). In brief, diabetes was defined as a fasting serum glucose level of ≥126 mg/dl or HbA1c of ≥6.5%, self-reported diabetes history, or current antidiabetic medication use. The presence of hypertension was determined if the subject was taking anti-hypertensive medication or had a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg (James et al., 2014). HbA1c was measured by immunoturbidimetric assay with a Cobra Integra 800 automatic analyzer (Roche Diagnostics, Basel, Switzerland) with a reference value of 4.4–6.4%. The methodology conformed to the Diabetes Control and Complications Trial and National Glycohemoglobin Standardization Program (NGSP) standards (List of NGSP Certified Methods, 2016).
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velocity (MFV) cut-offs on TCD ultrasonography were used for identification of ≥50% stenosis according to the SONIA (stroke outcomes and neuroimaging of intracranial atherosclerosis) trial criteria (Feldmann et al., 2007): middle cerebral artery MFV N 100 cm/s, distal internal carotid artery MFV N90 cm/s, vertebral artery MFV N80 cm/s, and basilar artery MFV N80 cm/s. Because the anterior and posterior cerebral arteries were not evaluated in the SONIA trial, previously validated criteria for detection of ICAS in these vessels was adapted (Rumberger et al., 1999; Tsivgoulis et al., 2007; Tsivgoulis et al., 2008; Tsivgoulis et al., 2014): anterior cerebral artery MFV ≥80 cm/s and posterior cerebral artery MFV ≥80 cm/s. ICAS was diagnosed if at least one of the studied arteries showed evidence of stenosis. Subjects with poor temporal windows were excluded from the study. 1.4. Retinal photography & vascular parameters Fundus photographs were acquired using a nonmydriatic fundus camera (CR6-45NM; Canon Inc., Tokyo, Japan). We used a semi-automated computer-assisted program (Singapore I Vessel Assessment [SIVA], software version 3.0) to quantitatively measure the retinal vascular parameters from the photographs. SIVA automatically identifies the optic disc, places a grid with reference to the center of the optic disc, identifies vessel type, and calculates retinal vascular parameters (Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Thomas et al., 2014). Trained graders, unaware of participant characteristics, were responsible for the visual evaluation of SIVA automated measurement as well as manual measurement, if required, according to a standardized protocol (Ikram et al., 2013). The measured area was standardized and defined within the region between 0.5 and 2.0 disc diameters away from the disc margin, and all visible vessels coursing through the specified zone were measured. The detailed definitions and measurement methods for each retinal vascular parameter are previously explained elsewhere (Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014). In brief; retinal vascular caliber measurements were based on the revised Knudtson-Parr-Hubbard formula with arteriolar caliber summarized as central retinal arteriolar
1.3. TCD ultrasonography evaluation and diagnosis of ICAS A trained ultrasonographer performed TCD ultrasonography using single-channel TCD ultrasonography (Nicolet SONARA TCD system, Natus Medical Incorporated, San Carlos, CA). The following mean flow
Fig. 1. Representative photography showing retina vessel caliber measurement used in this study (Singapore I Vessel Assessment). B: zone B, C: zone C, red line indicate arteriole tracking, blue line indicate venule tracking.
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E.-J. Rhee et al. / Microvascular Research 108 (2016) 64–68
Table 1 The description for retinal vascular variables used in this study.
Table 3 Comparison of selected retinal vascular parameters of study participants.
Parameter
Description
Variable
With ICAS (n = 24)
Without ICAS (n = 603)
P value
CRAE CRVE AVR FractalDimC MWa STDWa BMWa STORTa MWv STDWv BMWv STORTv
Biggest six arterioles in zone C Biggest six veins in zone C Arteriole-venule ratio of zone C Fractal dimension Zone C mean width arteriole Zone C standard deviation arteriole Zone B mean width arteriole Simple tortuosity arteriole Zone C mean width venule Zone C standard deviation venule arteriole Zone B mean width venule Simple tortuosity venule
CRAE(μm) CRVE(μm) AVR FractalDimC MWa STDWa BMWa STORTa MWv STDWv BMWv STORTv
141.0 ± 20.6 200.0 ± 30.9 0.7 ± 0.1 1.3 ± 0.0 75.9 ± 11.5 13.4 ± 1.9 75.9 ± 11.5 1.1 ± 0.0 88.7 ± 12.9 11.2 ± 2.3 83.3 ± 14.5 1.1 ± 0.0
137.3 ± 19.7 195.9 ± 26.9 0.70 ± 0.1 1.3 ± 0.1 74.5 ± 11.1 12.4 ± 2.6 74.5 ± 11.1 1.1 ± 0.0 89.4 ± 13.0 10.9 ± 2.4 84.7 ± 13.2 1.1 ± 0.0
0.4 0.5 0.7 0.6 0.6 0.02 0.3 0.3 0.8 0.5 0.6 0.9
CRAE = central retinal artery equivalent; CRVE = central retinal vein equivalent; AVR =
equivalent and venular caliber summarized as central retinal venular equivalent (Fig. 1). The retinal vascular parameters used for statistical analysis in this study are shown in Table 1.
arteriole-venule ratio; FractalDimC = fractal dimension; MWa = mean width arteriole; STDWa = standard deviation of mean arterial width; sTORTa = simple tortuosity arteriole; sTORTv = simple tortuosity venule.
2. Results 1.5. Statistical analysis Person-specific data on prevalence and each risk factor was reported as either mean ± standard deviation (SD) or median and absolute numbers or percentages. The Chi-square test and independent sample t-tests were used to compare group variables when appropriate. Odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using logistic regression models. Following univariate analyses, multivariate logistic regression analyses were performed to identify independent risk factors for ICAS. All data were analyzed using the SPSS statistical software system version 18.0 (IBM SPSS Inc., Chicago, IL, USA). A P-value of b0.05 was considered to be statistically significant.
Table 2 Demographic features of the study participants. Variable
Age (years) Sex (%) Male Female Smoking (%) Never Past Current Pack/year Alcohol (amount/g) Frequency (per week) Hypertension (%) Diabetes mellitus (%) Body mass index (kg/m2) Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglyceride (mg/dL) Fasting blood glucose (mg/dL) HbA1c (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
Among 627 participants, 24 (3.8%) participants had ICAS. The demographic features and retinal vessel parameters of study participants are shown in Tables 2 & 3. Participants with ICAS had both wider CRAE and CRVE when compared to those without ICAS. The mean CRAE was 137.3 ± 19.7 μm for participants without ICAS, and 141.0 ± 20.6 μm for participants with ICAS. Additionally, CRVE for participants without and with ICAS was 195.8 ± 26.9 μm and 200.0 ± 30.8 μm, respectively. Participants with ICAS were more likely have hypertension and have large mean standard deviation of retinal arteriole width (STDWa) (independent-t-test, P ≤0.01, 0.03, 0.02 respectively). However, after adjusting for age, sex, hypertension, glucose, BMI, smoking, MWa, and CRAE, male sex, hypertension, MWa, and large STDWa was associated with increased risk of ICAS (Table 4). The subjects with the highest tertile of STDWa showed 22-fold increased risk for ICAS compared with the subjects with the lowest tertile of STDWa (Table 4). Fig. 2 represent large STDWa differences between 2 groups (with ICAS (A) and without ICAS(B)). These 2 eyes have same mean CRAE, which was 136 μm. But their STDWa for A (without ICAS) and for B (with ICAS) were 9.82 μm and 16.18 μm.
P value
3. Discussion
0.3 0.001
For more than a decade, retinal vessel diameter has commonly been associated with various systemic pathologic vascular diseases such as stroke and heart disease (Patton et al., 2005; Ikram et al., 2012; Cheung et al., 2007a; De Silva et al., 2009; De Silva et al., 2011; Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Cheung et al., 2007b; Sherman, 1981). More recently, in addition to measuring vessel diameter, the clinical importance of unique retinal
With ICAS (n =
Without ICAS (n =
24)
603)
41.1 ± 4.3
40.2 ± 3.6
16(67) 8(33)
549(91) 54(9)
11(46) 4(17) 9(37) 5.5 ± 6.8 16.2 ± 19.0 1.9 ± 1.4 10(42) 0 24.3 ± 2.3 213.7 ± 29.2 52.7 ± 15.0 132.3 ± 30.3 149.9 ± 74.7 91.2 ± 7.8
258(43) 195(32) 149(25) 5.6 ± 7.4 13.8 ± 20.1 1.6 ± 1.2 119(20) 34(6) 24.3 ± 3.1 204.2 ± 35.0 53.1 ± 12.6 127.0 ± 31.8 137.8 ± 81.0 97.0 ± 16.0
1.0 0.6 0.3 0.02 0.6 1.0 0.2 0.9 0.4 0.5 0.1
5.6 ± 0.3 121.5 ± 13.7
5.7 ± 0.6 118.2 ± 12.4
0.5 0.2
77.9 ± 9.5
75.4 ± 9.1
0.2
0.2
Table 4 Multivariate analysis for STDWa for intracranial sclerosis. Variable
Odd ratio
95% C.I.
P value
Age (years) Sex (male) BMI Glucose Hypertension (yes) STDWa First tertile Second tertile Third tertile BigCRAE MWa
0.93 10.31 1.02 0.95 5.80
0.84–1.04 3.13–33.33 0.88–1.19 0.897–1.01 1.992–16.86
0.206 0.000 0.787 0.071 0.001
Referent 14.04 22.12 1.05 0.88
1.71–115.32 2.56–190.97 0.99–1.11 0.79–0.99
0.014 0.005 0.099 0.031
ICAS = intracranial arterial stenosis; HDL-C = high-density lipoprotein cholesterol; LDL-C
BMI = body mass index; STDWa = standard deviation of mean arterial width; CRAE =
= low-density lipoprotein cholesterol; HbA1c = glycated hemoglobin.
central retinal artery equivalent; MWa = mean width arteriole.
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Fig. 2. Representative photographs for retina vessel caliber measurement between eye with ICAS and without.
vessel features and association with other systemic vascular conditions has been evaluated. These unique retinal vessel features include vessel tortuosity, vessel wall light reflex, and deviation of vessel diameter. And based on earlier studies by Hilal et al., these features are associated with earlier findings of systemic vascular conditions (Hilal et al., 2014). Although we did not find significant associations for most retinal vascular parameters and transcranial ultrasonography findings, our finding showed that rather than the absolute diameter of retinal arterioles, a large variation of arteriole diameter within the eye is associated with ICAS. This result may corroborate to previous findings that spatial changes of retinal vessels are associated with systemic vascular pathologic conditions (Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; De Silva et al., 2012; Cheung et al., 2007b). However, we are uncertain on the rationale for a more significant association of STDWa with increased risk of ICAS rather than with absolute retinal vessel diameter or other parameters. There is a study that conventional retinal vascular parameters (e.g. retinal arteriolar or venular caliber, focal arteriolar narrowing, or arteriovenous nicking) does not reflect the change of large artery disease and new spatial or morphometric parameter (e.g. arteriolar light reflex) is more closely associated with large artery diseases (De Silva et al., 2011). Our study also showed that ICAS was not associated with retina vascular diameter but associated with STDWa. We speculate that since the retinal vessel is very small, there is a narrow range in which the retinal vessel diameter can dilate or constrict. Thus, the change in diameter is not sufficient to reflect early stages of cerebral vessel stenosis. Retinal vessel variations within the eye may thus precede statistically significant vessel diameter change. So based on this result and Murray's law, we assume that patients with ICAS, the diameter of retina arteriole must have significant variation within the eye (Sherman, 1981). But to confirm our hypothesis, additional research is needed that is able to evaluate temporal changes of both retinal vessel and cerebrovascular changes starting from earliest stage of the disease. There are several strengths of this study. First, a unique feature that distinguishes our study from the previous studies is that the findings are based on the earliest changes of cerebrovascular pathology. Our study also included a large number of participants with objective assessment of both retinal fundus images (using a validated computer-assisted program) and cerebrovascular changes (standardized assessment using TCD). In contrast to most studies based on clinical events or expensive MRI findings, our study involved a simple cerebral imaging technique
that has the potential to allow detecting earlier cerebrovascular change analysis before clinically evident condition begins. Our study also has several limitations. First, because of the cross-sectional nature of the data, the temporal relationship between retinal microvasculature and ICAS cannot be examined. Further analysis of a prospective study cohort is needed to confirm our findings. Second, the participants in this study were recruited from an annual medical health-screening program. There is consequently a possibility of selection bias, affecting the demographic features of the study. Our study participants were asymptomatic and apparently healthy adults and this might affect the prevalence of ICAS in our study. And in Korea, since more male participants receive annual health examination than female, larger proportion of the total study participants were of the male sex. However, we adjusted all possible confounding factors in multivariate analysis to minimize the potential confounding effect. In summary, our findings provide possibility of retinal vascular imaging as a non-invasive and simple method to identify ICAS in the subclinical stage of cerebrovascular pathology. The clinical implication of our findings needs more verification by other studies in future. Grant None. Conflict of interest None of the authors have any proprietary interests or conflicts of interest related to this submission. Financial disclosure None to declare. References Cheung, N., Islam, F.M., Jacobs Jr., D.R., Sharrett, A.R., Klein, R., Polak, J.F., Cotch, M.F., Klein, B.E., Ouyang, P., Wong, T.Y., 2007a. Arterial compliance and retinal vascular caliber in cerebrovascular disease. Ann. Neurol. 62 (6), 618–624. Cheung, N., Sharrett, A.R., Klein, R., Criqui, M.H., Islam, F.M., Macura, K.J., Cotch, M.F., Klein, B.E., Wong, T.Y., 2007b. Aortic distensibility and retinal arteriolar narrowing: the multi-ethnic study of atherosclerosis. Hypertension 50, 617–622.
68
E.-J. Rhee et al. / Microvascular Research 108 (2016) 64–68
Cheung, C.Y., Tay, W.T., Ikram, M.K., Ong, Y.T., De Silva, D.A., Chow, K.Y., et al., 2013. Retinal microvascular changes and risk of stroke: the Singapore Malay Eye Study. Stroke 44 (9), 2402–2408. Cheung, C.Y., Ong, Y.-T., Ikram, M.K., Ong, S.Y., Li, X., Hilal, S., Catindig, J.-A.S., Venketasubramanian, N., Yap, P., Seow, D., Chen, C.P., Wong, T.Y., 2014. Microvascular network alterations in the retina of patients with Alzheimer's disease. Alzheimers Dement. 10, 135–142. De Silva, D.A., Liew, G., Wong, M.C., Chang, H.M., Chen, C., Wang, J.J., Baker, M.L., Hand, P.J., Rochtchina, E., Liu, E.Y., Mitchell, P., Lindley, R.I., Wong, T.Y., 2009. Retinal vascular caliber and extracranial carotid disease in patients with acute ischemic stroke: the Multi-Centre Retinal Stroke (MCRS) study. Stroke 40 (12), 3695–3699. De Silva, D.A., Manzano, J.J., Woon, F.P., Liu, E.Y., Lee, M.P., Gan, H.Y., Chen, C.P., Chang, H.M., Mitchell, P., Wang, J.J., Lindley, R.I., Wong, T.Y., Wong, M.C., 2011. Associations of retinal microvascular signs and intracranial large artery disease. Stroke 42 (3), 812–814. De Silva, D.A., Woon, F.P., Manzano, J.J., Liu, E.Y., Chang, H.M., Chen, C., Wang, J.J., Mitchell, P., Kingwell, B.A., Cameron, J.D., Lindley, R.I., Wong, T.Y., Wong, M.C., Behalf of the Multi-Centre Retinal Stroke Study Collaborative Group, 2012. The relationship between aortic stiffness and changes in retinal microvessels among Asian ischemic stroke patients. J. Hum. Hypertens. 26, 716–722. Feldmann, E., Wilterdink, J.L., Kosinski, A., Lynn, M., Chimowitz, M.I., Sarafin, J., et al., 2007. Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial investigators. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 68, 2099–2106. Guan, J., Zhou, Q., Ouyang, H., Zhang, S., Lu, Z., 2013. The diagnostic accuracy of TCD for intracranial arterial stenosis/occlusion in patients with acute ischemic stroke: the importance of time interval between detection of TCD and CTA. Neurol. Res. 35, 930–936. Hilal, S., Saini, M., Tan, C.S., Catindig, J.A., Koay, W.I., Lee, W.Y., Niessen, W.J., Vrooman, H.A., Wong, T.Y., Chen, C., Ikram, M.K., Venketasubramanian, N., 2014. Cerebral microbleeds and cognition in a Chinese population. Alzheimer Dis. Assoc. Disord. 28, 106–122. Ikram, M.K., Cheung, C.Y.L., T.Y., et al., 2012. Retinal pathology as biomarker for cognitive impairment and Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 83, 917–922. Ikram, M.K., Ong, Y.T., Cheung, C.Y., Wong, T.Y., 2013. Retinal vascular caliber measurements: clinical significance, current knowledge and future perspectives. Ophthalmologica 229, 125–136. James, P.A., Oparil, S., Carter, B.L., et al., 2014. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311, 507–520.
Knudtson, M.D., Lee, K.E., Hubbard, L.D., et al., 2003. Revised formulas for summarizing retinal vessel diameters. Curr. Eye Res. 27, 143–149. Leng, X., Wong, K.S., Liebeskind, D.S., 2014. Evaluating intracranial atherosclerosis rather than intracranial stenosis. Stroke 45, 645–651. List of NGSP Certified Methods, 2016. Available at http://www.ngsp.org/docs/methods. pdf Lastly accessed 16th, January . Ong, Y.T., De Silva, D.A., Cheung, C.Y., Chang, H.M., Chen, C.P., Wong, M.C., Wong, T.Y., Ikram, M.K., 2013. Microvascular structure and network in the retina of patients with ischemic stroke. Stroke 44, 2121–2127. Patton, N., Aslam, T., Macgillivray, T., Pattie, A., Deary, I.J., Dhillon, B., 2005. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J. Anat. 206, 319–348. Rumberger, J.A., Brundage, B.H., Rader, D.J., Kondos, G., 1999. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin. Proc. 74, 243–252. Sacco, R.L., Kargman, D.E., Zamanillo, M.C., 1995. Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction: the Northern Manhattan Stroke Study. Neurology 45, 659–663. Sherman, T.F., 1981. On connecting large vessels to small. The meaning of Murray's law. J. Gen. Physiol. 78 (4), 431–453. Standards of Medical Care in Diabetes-2016, 2016. Summary of revisions. Diabetes Care 39 (Suppl. 1), S4–S5. Thomas, G.N., Ong, S.Y., Tham, Y.C., et al., 2014. Measurement of macular fractal dimension using a computer-assisted program. Invest. Ophthalmol. Vis. Sci. 55, 2237–2243. Tsivgoulis, G., Sharma, V.K., Lao, A.Y., Malkoff, M.D., Alexandrov, A.V., 2007. Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia. Stroke 38, 1245–1249. Tsivgoulis, G., Sharma, V.K., Hoover, S.L., Lao, A.Y., Ardelt, A.A., Malkoff, M.D., et al., 2008. Applications and advantages of power motion-mode Doppler in acute posterior circulation cerebral ischemia. Stroke 39, 1197–1204. Tsivgoulis, G., Vadikolias, K., Heliopoulos, I., Katsibari, C., Voumvourakis, K., Tsakaldimi, S., et al., 2014. Prevalence of symptomatic intracranial atherosclerosis in Caucasians: a prospective, multicenter, transcranial Doppler study. J. Neuroimaging 24, 11–17. Witt, N., Wong, T.Y., Hughes, A.D., Chaturvedi, N., Klein, B.E., Evans, R., et al., 2006. Abnormalities of retinal microvascular structure and risk of mortality from ischemic heart disease and stroke. Hypertension 47 (5), 975–981. Wong, K.S., Ng, P.W., Tang, A., Liu, R., Yeung, V., Tomlinson, B., 2007. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 68, 2035–2038.
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Relationship of retinal vascular caliber variation with intracranial arterial stenosis☆ Eun-Jung Rhee a, Pil-Wook Chung b, Tien Y. Wong c, Su Jeong Song d,⁎ a
Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Departments of Neurology Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Singapore Eye Research Institute, Singapore National Eye Center, Duke-NUS Medical School National University of Singapore, Singapore d Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 25 April 2016 Revised 4 August 2016 Accepted 6 August 2016 Available online 7 August 2016 Keywords: Intracranial arterial stenosis Retinal vessel Transcranial doppler
a b s t r a c t Background & purpose: To investigate the associations of retinal vessel parameters with intracranial arterial stenosis (ICAS) assessed by Transcranial Doppler ultrasonography. Method: Data on transcranial Doppler ultrasonography and quantitative retinal vessel parameters from 627 participants in a health screening program were included in this study. ICAS was defined as N 50% intracranial arterial stenosis (ICAS) based on criteria modified from the stroke outcomes and neuroimaging of intracranial atherosclerosis (SONIA) trial assessed by transcranial Doppler (TCD) ultrasonography. A semi-automated computerassisted program (Singapore I Vessel Assessment) was used to measure the retinal vascular parameters from the photographs. Multivariate analysis was performed to identify which retinal vessel parameters were associated with increased risk of ICAS. Results: Among 627 participants, 24 (3.8%) had ICAS diagnosed by TCD. Subjects with ICAS had eyes with wider mean central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) in comparison to subjects without ICAS. Men (odds ratio [OR]:13.1, 95% confidence interval: 3.13–33.33) and a large standard deviation of mean arterial width (STDWa) were associated with ICAS (first vs. third tertile: OR ratio: 14.04, 95% confidence interval: 1.71–115.32; first vs. third tertile: OR ratio: 22.1, 95% confidence interval: 2.56–190.97) after adjusting for possible confounders. Conclusion: A large variation in retinal arteriolar diameter is associated with ICAS. This study suggests the possible relationship between retina vessel and early changes within the cerebrovascular network. © 2016 Elsevier Inc. All rights reserved.
Retina function as two way mirror which provides the outside visual input to visual cortex but also can provide information regarding cerebrovascular conditions to outside world. But until now, there have been inconsistent results of how or when retina vasculature reflects cerebrovascular conditions (Patton et al., 2005; Ikram et al., 2012; Cheung et al., 2007a; De Silva et al., 2009; De Silva et al., 2011; Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Knudtson et al., 2003; Witt et al., 2006; Cheung et al., 2013). The implications of retinal microvascular changes in the pathogenesis of cerebrovascular diseases are largely unknown until recently. Previous studies suggested that narrower arteriolar caliber and wider venular caliber are associated with ischemic stroke. Some study showed, in addition to vessel caliber change, other parameters indicative of tortuous vascular network
☆ The paper has not been published nor submitted simultaneously for publication elsewhere. ⁎ Corresponding author at: Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 110746, Republic of Korea. E-mail address: [email protected] (S.J. Song).
http://dx.doi.org/10.1016/j.mvr.2016.08.002 0026-2862/© 2016 Elsevier Inc. All rights reserved.
were associated with ischemic stroke. However, in other study, retinal vessel caliber was not related with intracranial stenosis (Patton et al., 2005; Ikram et al., 2012; Cheung et al., 2007a; De Silva et al., 2009; De Silva et al., 2011; Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Knudtson et al., 2003; Witt et al., 2006; Cheung et al., 2013). Intracranial arterial stenosis (ICAS) is a major cause of ischemic stroke, especially in Asians, with a reported prevalence of up to 50% (Guan et al., 2013). In addition to advances in treatment that improve the prognosis of ICAS-related stroke patients, detecting ICAS at an early stage can significantly improve stroke management and decrease socio-economic burden related to treatment. Transcranial Doppler (TCD) ultrasonography is a non-invasive, safe, and cost effective method to diagnose ICAS (Wong et al., 2007; Leng et al., 2014; Sacco et al., 1995; Standards of Medical Care in Diabetes, 2016). In this study, we analyzed quantitative retinal vascular parameters of participants with ICAS diagnosed by TCD. These findings were compared to measurements of those without ICAS to investigate the possibility that retinal vessel parameters are associated with early intracranial vascular change.
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1. Method 1.1. Participants This cross-sectional study was a part of the Kangbuk Samsung Health Study, in which subjects were participants in a medical health checkup program at the Health Promotion Center of Kangbuk Samsung Hospital of Sungkyunkwan University in Seoul, Korea. The purpose of medical health checkup programs is to promote employee health through regular examinations and to enhance early detection of existing diseases. Most examinees are employees of various industrial companies and their family members from around the country. Employers largely cover the costs of the medical examinations, and a considerable proportion of examinees undergo health examinations annually or biannually. A total of 627 participants who underwent TCD from January 2011 to December 2011 and for whom gradable fundus photographs were available were included. The ophthalmic examinations, systemic examinations, and questionnaires for sociodemographic and behavioral characteristics were administered to each participant. The study was approved by the institutional review board of Kangbuk Samsung Hospital (KBSMC2015-01-003) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained prior to recruitment. 1.2. Anthropometric measurement and laboratory assessment Data on medical history, medication use, and health-related behaviors were collected through a self-administered questionnaire, while trained staff obtained physical measurements and serum biochemical parameters during health examinations. Body weight was measured with the participants in light clothing without shoes to the nearest 0.1 kg by using a digital scale. Height was measured to the nearest 0.1 cm. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Trained nurses measured sitting blood pressure with standard mercury sphygmomanometers. All subjects were examined after an overnight fast. The hexokinase method was used to measure fasting serum glucose concentrations (Hitachi Modular D2400; Roche, Tokyo, Japan). The total cholesterol and triglyceride concentrations were measured with an enzymatic calorimetric test. The selective inhibition method was used to evaluate the level of high-density lipoprotein cholesterol, and a homogeneous enzymatic calorimetric test was used to measure the level of low-density lipoprotein cholesterol. The presence of diabetes mellitus was determined according to the self-questionnaire results, as well as from the fasting serum blood glucose and glycated hemoglobin (HbA1c) levels of participants, as suggested by the American Diabetes Association (Standards of Medical Care in Diabetes, 2016). In brief, diabetes was defined as a fasting serum glucose level of ≥126 mg/dl or HbA1c of ≥6.5%, self-reported diabetes history, or current antidiabetic medication use. The presence of hypertension was determined if the subject was taking anti-hypertensive medication or had a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg (James et al., 2014). HbA1c was measured by immunoturbidimetric assay with a Cobra Integra 800 automatic analyzer (Roche Diagnostics, Basel, Switzerland) with a reference value of 4.4–6.4%. The methodology conformed to the Diabetes Control and Complications Trial and National Glycohemoglobin Standardization Program (NGSP) standards (List of NGSP Certified Methods, 2016).
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velocity (MFV) cut-offs on TCD ultrasonography were used for identification of ≥50% stenosis according to the SONIA (stroke outcomes and neuroimaging of intracranial atherosclerosis) trial criteria (Feldmann et al., 2007): middle cerebral artery MFV N 100 cm/s, distal internal carotid artery MFV N90 cm/s, vertebral artery MFV N80 cm/s, and basilar artery MFV N80 cm/s. Because the anterior and posterior cerebral arteries were not evaluated in the SONIA trial, previously validated criteria for detection of ICAS in these vessels was adapted (Rumberger et al., 1999; Tsivgoulis et al., 2007; Tsivgoulis et al., 2008; Tsivgoulis et al., 2014): anterior cerebral artery MFV ≥80 cm/s and posterior cerebral artery MFV ≥80 cm/s. ICAS was diagnosed if at least one of the studied arteries showed evidence of stenosis. Subjects with poor temporal windows were excluded from the study. 1.4. Retinal photography & vascular parameters Fundus photographs were acquired using a nonmydriatic fundus camera (CR6-45NM; Canon Inc., Tokyo, Japan). We used a semi-automated computer-assisted program (Singapore I Vessel Assessment [SIVA], software version 3.0) to quantitatively measure the retinal vascular parameters from the photographs. SIVA automatically identifies the optic disc, places a grid with reference to the center of the optic disc, identifies vessel type, and calculates retinal vascular parameters (Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Thomas et al., 2014). Trained graders, unaware of participant characteristics, were responsible for the visual evaluation of SIVA automated measurement as well as manual measurement, if required, according to a standardized protocol (Ikram et al., 2013). The measured area was standardized and defined within the region between 0.5 and 2.0 disc diameters away from the disc margin, and all visible vessels coursing through the specified zone were measured. The detailed definitions and measurement methods for each retinal vascular parameter are previously explained elsewhere (Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014). In brief; retinal vascular caliber measurements were based on the revised Knudtson-Parr-Hubbard formula with arteriolar caliber summarized as central retinal arteriolar
1.3. TCD ultrasonography evaluation and diagnosis of ICAS A trained ultrasonographer performed TCD ultrasonography using single-channel TCD ultrasonography (Nicolet SONARA TCD system, Natus Medical Incorporated, San Carlos, CA). The following mean flow
Fig. 1. Representative photography showing retina vessel caliber measurement used in this study (Singapore I Vessel Assessment). B: zone B, C: zone C, red line indicate arteriole tracking, blue line indicate venule tracking.
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Table 1 The description for retinal vascular variables used in this study.
Table 3 Comparison of selected retinal vascular parameters of study participants.
Parameter
Description
Variable
With ICAS (n = 24)
Without ICAS (n = 603)
P value
CRAE CRVE AVR FractalDimC MWa STDWa BMWa STORTa MWv STDWv BMWv STORTv
Biggest six arterioles in zone C Biggest six veins in zone C Arteriole-venule ratio of zone C Fractal dimension Zone C mean width arteriole Zone C standard deviation arteriole Zone B mean width arteriole Simple tortuosity arteriole Zone C mean width venule Zone C standard deviation venule arteriole Zone B mean width venule Simple tortuosity venule
CRAE(μm) CRVE(μm) AVR FractalDimC MWa STDWa BMWa STORTa MWv STDWv BMWv STORTv
141.0 ± 20.6 200.0 ± 30.9 0.7 ± 0.1 1.3 ± 0.0 75.9 ± 11.5 13.4 ± 1.9 75.9 ± 11.5 1.1 ± 0.0 88.7 ± 12.9 11.2 ± 2.3 83.3 ± 14.5 1.1 ± 0.0
137.3 ± 19.7 195.9 ± 26.9 0.70 ± 0.1 1.3 ± 0.1 74.5 ± 11.1 12.4 ± 2.6 74.5 ± 11.1 1.1 ± 0.0 89.4 ± 13.0 10.9 ± 2.4 84.7 ± 13.2 1.1 ± 0.0
0.4 0.5 0.7 0.6 0.6 0.02 0.3 0.3 0.8 0.5 0.6 0.9
CRAE = central retinal artery equivalent; CRVE = central retinal vein equivalent; AVR =
equivalent and venular caliber summarized as central retinal venular equivalent (Fig. 1). The retinal vascular parameters used for statistical analysis in this study are shown in Table 1.
arteriole-venule ratio; FractalDimC = fractal dimension; MWa = mean width arteriole; STDWa = standard deviation of mean arterial width; sTORTa = simple tortuosity arteriole; sTORTv = simple tortuosity venule.
2. Results 1.5. Statistical analysis Person-specific data on prevalence and each risk factor was reported as either mean ± standard deviation (SD) or median and absolute numbers or percentages. The Chi-square test and independent sample t-tests were used to compare group variables when appropriate. Odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using logistic regression models. Following univariate analyses, multivariate logistic regression analyses were performed to identify independent risk factors for ICAS. All data were analyzed using the SPSS statistical software system version 18.0 (IBM SPSS Inc., Chicago, IL, USA). A P-value of b0.05 was considered to be statistically significant.
Table 2 Demographic features of the study participants. Variable
Age (years) Sex (%) Male Female Smoking (%) Never Past Current Pack/year Alcohol (amount/g) Frequency (per week) Hypertension (%) Diabetes mellitus (%) Body mass index (kg/m2) Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglyceride (mg/dL) Fasting blood glucose (mg/dL) HbA1c (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
Among 627 participants, 24 (3.8%) participants had ICAS. The demographic features and retinal vessel parameters of study participants are shown in Tables 2 & 3. Participants with ICAS had both wider CRAE and CRVE when compared to those without ICAS. The mean CRAE was 137.3 ± 19.7 μm for participants without ICAS, and 141.0 ± 20.6 μm for participants with ICAS. Additionally, CRVE for participants without and with ICAS was 195.8 ± 26.9 μm and 200.0 ± 30.8 μm, respectively. Participants with ICAS were more likely have hypertension and have large mean standard deviation of retinal arteriole width (STDWa) (independent-t-test, P ≤0.01, 0.03, 0.02 respectively). However, after adjusting for age, sex, hypertension, glucose, BMI, smoking, MWa, and CRAE, male sex, hypertension, MWa, and large STDWa was associated with increased risk of ICAS (Table 4). The subjects with the highest tertile of STDWa showed 22-fold increased risk for ICAS compared with the subjects with the lowest tertile of STDWa (Table 4). Fig. 2 represent large STDWa differences between 2 groups (with ICAS (A) and without ICAS(B)). These 2 eyes have same mean CRAE, which was 136 μm. But their STDWa for A (without ICAS) and for B (with ICAS) were 9.82 μm and 16.18 μm.
P value
3. Discussion
0.3 0.001
For more than a decade, retinal vessel diameter has commonly been associated with various systemic pathologic vascular diseases such as stroke and heart disease (Patton et al., 2005; Ikram et al., 2012; Cheung et al., 2007a; De Silva et al., 2009; De Silva et al., 2011; Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; Cheung et al., 2014; Cheung et al., 2007b; Sherman, 1981). More recently, in addition to measuring vessel diameter, the clinical importance of unique retinal
With ICAS (n =
Without ICAS (n =
24)
603)
41.1 ± 4.3
40.2 ± 3.6
16(67) 8(33)
549(91) 54(9)
11(46) 4(17) 9(37) 5.5 ± 6.8 16.2 ± 19.0 1.9 ± 1.4 10(42) 0 24.3 ± 2.3 213.7 ± 29.2 52.7 ± 15.0 132.3 ± 30.3 149.9 ± 74.7 91.2 ± 7.8
258(43) 195(32) 149(25) 5.6 ± 7.4 13.8 ± 20.1 1.6 ± 1.2 119(20) 34(6) 24.3 ± 3.1 204.2 ± 35.0 53.1 ± 12.6 127.0 ± 31.8 137.8 ± 81.0 97.0 ± 16.0
1.0 0.6 0.3 0.02 0.6 1.0 0.2 0.9 0.4 0.5 0.1
5.6 ± 0.3 121.5 ± 13.7
5.7 ± 0.6 118.2 ± 12.4
0.5 0.2
77.9 ± 9.5
75.4 ± 9.1
0.2
0.2
Table 4 Multivariate analysis for STDWa for intracranial sclerosis. Variable
Odd ratio
95% C.I.
P value
Age (years) Sex (male) BMI Glucose Hypertension (yes) STDWa First tertile Second tertile Third tertile BigCRAE MWa
0.93 10.31 1.02 0.95 5.80
0.84–1.04 3.13–33.33 0.88–1.19 0.897–1.01 1.992–16.86
0.206 0.000 0.787 0.071 0.001
Referent 14.04 22.12 1.05 0.88
1.71–115.32 2.56–190.97 0.99–1.11 0.79–0.99
0.014 0.005 0.099 0.031
ICAS = intracranial arterial stenosis; HDL-C = high-density lipoprotein cholesterol; LDL-C
BMI = body mass index; STDWa = standard deviation of mean arterial width; CRAE =
= low-density lipoprotein cholesterol; HbA1c = glycated hemoglobin.
central retinal artery equivalent; MWa = mean width arteriole.
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Fig. 2. Representative photographs for retina vessel caliber measurement between eye with ICAS and without.
vessel features and association with other systemic vascular conditions has been evaluated. These unique retinal vessel features include vessel tortuosity, vessel wall light reflex, and deviation of vessel diameter. And based on earlier studies by Hilal et al., these features are associated with earlier findings of systemic vascular conditions (Hilal et al., 2014). Although we did not find significant associations for most retinal vascular parameters and transcranial ultrasonography findings, our finding showed that rather than the absolute diameter of retinal arterioles, a large variation of arteriole diameter within the eye is associated with ICAS. This result may corroborate to previous findings that spatial changes of retinal vessels are associated with systemic vascular pathologic conditions (Ikram et al., 2013; Ong et al., 2013; Hilal et al., 2014; De Silva et al., 2012; Cheung et al., 2007b). However, we are uncertain on the rationale for a more significant association of STDWa with increased risk of ICAS rather than with absolute retinal vessel diameter or other parameters. There is a study that conventional retinal vascular parameters (e.g. retinal arteriolar or venular caliber, focal arteriolar narrowing, or arteriovenous nicking) does not reflect the change of large artery disease and new spatial or morphometric parameter (e.g. arteriolar light reflex) is more closely associated with large artery diseases (De Silva et al., 2011). Our study also showed that ICAS was not associated with retina vascular diameter but associated with STDWa. We speculate that since the retinal vessel is very small, there is a narrow range in which the retinal vessel diameter can dilate or constrict. Thus, the change in diameter is not sufficient to reflect early stages of cerebral vessel stenosis. Retinal vessel variations within the eye may thus precede statistically significant vessel diameter change. So based on this result and Murray's law, we assume that patients with ICAS, the diameter of retina arteriole must have significant variation within the eye (Sherman, 1981). But to confirm our hypothesis, additional research is needed that is able to evaluate temporal changes of both retinal vessel and cerebrovascular changes starting from earliest stage of the disease. There are several strengths of this study. First, a unique feature that distinguishes our study from the previous studies is that the findings are based on the earliest changes of cerebrovascular pathology. Our study also included a large number of participants with objective assessment of both retinal fundus images (using a validated computer-assisted program) and cerebrovascular changes (standardized assessment using TCD). In contrast to most studies based on clinical events or expensive MRI findings, our study involved a simple cerebral imaging technique
that has the potential to allow detecting earlier cerebrovascular change analysis before clinically evident condition begins. Our study also has several limitations. First, because of the cross-sectional nature of the data, the temporal relationship between retinal microvasculature and ICAS cannot be examined. Further analysis of a prospective study cohort is needed to confirm our findings. Second, the participants in this study were recruited from an annual medical health-screening program. There is consequently a possibility of selection bias, affecting the demographic features of the study. Our study participants were asymptomatic and apparently healthy adults and this might affect the prevalence of ICAS in our study. And in Korea, since more male participants receive annual health examination than female, larger proportion of the total study participants were of the male sex. However, we adjusted all possible confounding factors in multivariate analysis to minimize the potential confounding effect. In summary, our findings provide possibility of retinal vascular imaging as a non-invasive and simple method to identify ICAS in the subclinical stage of cerebrovascular pathology. The clinical implication of our findings needs more verification by other studies in future. Grant None. Conflict of interest None of the authors have any proprietary interests or conflicts of interest related to this submission. Financial disclosure None to declare. References Cheung, N., Islam, F.M., Jacobs Jr., D.R., Sharrett, A.R., Klein, R., Polak, J.F., Cotch, M.F., Klein, B.E., Ouyang, P., Wong, T.Y., 2007a. Arterial compliance and retinal vascular caliber in cerebrovascular disease. Ann. Neurol. 62 (6), 618–624. Cheung, N., Sharrett, A.R., Klein, R., Criqui, M.H., Islam, F.M., Macura, K.J., Cotch, M.F., Klein, B.E., Wong, T.Y., 2007b. Aortic distensibility and retinal arteriolar narrowing: the multi-ethnic study of atherosclerosis. Hypertension 50, 617–622.
68
E.-J. Rhee et al. / Microvascular Research 108 (2016) 64–68
Cheung, C.Y., Tay, W.T., Ikram, M.K., Ong, Y.T., De Silva, D.A., Chow, K.Y., et al., 2013. Retinal microvascular changes and risk of stroke: the Singapore Malay Eye Study. Stroke 44 (9), 2402–2408. Cheung, C.Y., Ong, Y.-T., Ikram, M.K., Ong, S.Y., Li, X., Hilal, S., Catindig, J.-A.S., Venketasubramanian, N., Yap, P., Seow, D., Chen, C.P., Wong, T.Y., 2014. Microvascular network alterations in the retina of patients with Alzheimer's disease. Alzheimers Dement. 10, 135–142. De Silva, D.A., Liew, G., Wong, M.C., Chang, H.M., Chen, C., Wang, J.J., Baker, M.L., Hand, P.J., Rochtchina, E., Liu, E.Y., Mitchell, P., Lindley, R.I., Wong, T.Y., 2009. Retinal vascular caliber and extracranial carotid disease in patients with acute ischemic stroke: the Multi-Centre Retinal Stroke (MCRS) study. Stroke 40 (12), 3695–3699. De Silva, D.A., Manzano, J.J., Woon, F.P., Liu, E.Y., Lee, M.P., Gan, H.Y., Chen, C.P., Chang, H.M., Mitchell, P., Wang, J.J., Lindley, R.I., Wong, T.Y., Wong, M.C., 2011. Associations of retinal microvascular signs and intracranial large artery disease. Stroke 42 (3), 812–814. De Silva, D.A., Woon, F.P., Manzano, J.J., Liu, E.Y., Chang, H.M., Chen, C., Wang, J.J., Mitchell, P., Kingwell, B.A., Cameron, J.D., Lindley, R.I., Wong, T.Y., Wong, M.C., Behalf of the Multi-Centre Retinal Stroke Study Collaborative Group, 2012. The relationship between aortic stiffness and changes in retinal microvessels among Asian ischemic stroke patients. J. Hum. Hypertens. 26, 716–722. Feldmann, E., Wilterdink, J.L., Kosinski, A., Lynn, M., Chimowitz, M.I., Sarafin, J., et al., 2007. Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial investigators. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 68, 2099–2106. Guan, J., Zhou, Q., Ouyang, H., Zhang, S., Lu, Z., 2013. The diagnostic accuracy of TCD for intracranial arterial stenosis/occlusion in patients with acute ischemic stroke: the importance of time interval between detection of TCD and CTA. Neurol. Res. 35, 930–936. Hilal, S., Saini, M., Tan, C.S., Catindig, J.A., Koay, W.I., Lee, W.Y., Niessen, W.J., Vrooman, H.A., Wong, T.Y., Chen, C., Ikram, M.K., Venketasubramanian, N., 2014. Cerebral microbleeds and cognition in a Chinese population. Alzheimer Dis. Assoc. Disord. 28, 106–122. Ikram, M.K., Cheung, C.Y.L., T.Y., et al., 2012. Retinal pathology as biomarker for cognitive impairment and Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 83, 917–922. Ikram, M.K., Ong, Y.T., Cheung, C.Y., Wong, T.Y., 2013. Retinal vascular caliber measurements: clinical significance, current knowledge and future perspectives. Ophthalmologica 229, 125–136. James, P.A., Oparil, S., Carter, B.L., et al., 2014. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311, 507–520.
Knudtson, M.D., Lee, K.E., Hubbard, L.D., et al., 2003. Revised formulas for summarizing retinal vessel diameters. Curr. Eye Res. 27, 143–149. Leng, X., Wong, K.S., Liebeskind, D.S., 2014. Evaluating intracranial atherosclerosis rather than intracranial stenosis. Stroke 45, 645–651. List of NGSP Certified Methods, 2016. Available at http://www.ngsp.org/docs/methods. pdf Lastly accessed 16th, January . Ong, Y.T., De Silva, D.A., Cheung, C.Y., Chang, H.M., Chen, C.P., Wong, M.C., Wong, T.Y., Ikram, M.K., 2013. Microvascular structure and network in the retina of patients with ischemic stroke. Stroke 44, 2121–2127. Patton, N., Aslam, T., Macgillivray, T., Pattie, A., Deary, I.J., Dhillon, B., 2005. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J. Anat. 206, 319–348. Rumberger, J.A., Brundage, B.H., Rader, D.J., Kondos, G., 1999. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin. Proc. 74, 243–252. Sacco, R.L., Kargman, D.E., Zamanillo, M.C., 1995. Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction: the Northern Manhattan Stroke Study. Neurology 45, 659–663. Sherman, T.F., 1981. On connecting large vessels to small. The meaning of Murray's law. J. Gen. Physiol. 78 (4), 431–453. Standards of Medical Care in Diabetes-2016, 2016. Summary of revisions. Diabetes Care 39 (Suppl. 1), S4–S5. Thomas, G.N., Ong, S.Y., Tham, Y.C., et al., 2014. Measurement of macular fractal dimension using a computer-assisted program. Invest. Ophthalmol. Vis. Sci. 55, 2237–2243. Tsivgoulis, G., Sharma, V.K., Lao, A.Y., Malkoff, M.D., Alexandrov, A.V., 2007. Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia. Stroke 38, 1245–1249. Tsivgoulis, G., Sharma, V.K., Hoover, S.L., Lao, A.Y., Ardelt, A.A., Malkoff, M.D., et al., 2008. Applications and advantages of power motion-mode Doppler in acute posterior circulation cerebral ischemia. Stroke 39, 1197–1204. Tsivgoulis, G., Vadikolias, K., Heliopoulos, I., Katsibari, C., Voumvourakis, K., Tsakaldimi, S., et al., 2014. Prevalence of symptomatic intracranial atherosclerosis in Caucasians: a prospective, multicenter, transcranial Doppler study. J. Neuroimaging 24, 11–17. Witt, N., Wong, T.Y., Hughes, A.D., Chaturvedi, N., Klein, B.E., Evans, R., et al., 2006. Abnormalities of retinal microvascular structure and risk of mortality from ischemic heart disease and stroke. Hypertension 47 (5), 975–981. Wong, K.S., Ng, P.W., Tang, A., Liu, R., Yeung, V., Tomlinson, B., 2007. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 68, 2035–2038.