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Retinopathy as an indicator of silent brain infarction in asymptomatic hypertensive subjects
Journal of the Neurological Sciences 252 (2007) 159 – 162 www.elsevier.com/locate/jns
Retinopathy as an indicator of silent brain infarction in asymptomatic hypertensive subjects Hyung-Min Kwon a , Beom Joon Kim b , Joo Youn Oh c , Sang Jin Kim c , Seung-Hoon Lee b , Byung-Hee Oh d , Byung-Woo Yoon b,⁎ b
d
a Department of Neurology, Kyunghee University East-West Neo Medical Center, Seoul, Republic of Korea Department of Neurology, Seoul National University Hospital, Yongon-dong 28, Chongno-gu, Seoul 110-744, Republic of Korea c Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
Received 27 July 2006; received in revised form 30 October 2006; accepted 7 November 2006 Available online 19 December 2006
Abstract Background and purpose: Silent brain infarction (SBI), which is cerebral target organ damage of hypertensive microangiopathies, is frequently seen in hypertensive patients. The purpose of this study is to investigate the relation between hypertensive retinopathy (HTR) and SBI in subjects without a history of stroke or transient ischemic attack. Methods: Five hundred-fifty hypertensive subjects without history of stroke or transient ischemic attack had brain MRI and retinal photographs taken. The presence of SBI was assessed from the MRI scans, which was defined as a lesion of at least 3 mm in diameter with typical imaging characteristics. The presence HTR was defined from digitized retinal photographs. Results: Seventy-seven subjects (14%) showed HTR (grade 1 in 46, grade 2 in 31 persons). A multivariate analysis showed that age (OR, 1.07; 95% CI, 1.03 to 1.10) and HTR (OR, 2.01 for grade 1; OR, 3.03 for grade 2) were the independent indicators for the presence of SBI. The higher the grade of HTR, the more prevalent SBI than persons with normal retina (by linear by linear association test, p = 0.001). Conclusion: HTR is associated with the presence of SBI. This finding suggests that retinal photography may be useful for identifying hypertensive subjects at increased risk of having SBI regardless of current blood pressure status. © 2006 Elsevier B.V. All rights reserved. Keywords: Hypertension; Retinal artery; Brain infarction; Magnetic resonance imaging
1. Introduction Silent brain infarction (SBI) is frequently seen in older hypertensive patients, especially when moderate hypertensive changes are found in major target organs [1]. Hypertension is the most well-known major risk factor for SBI [2–5]. The presence of an SBI can predict clinical overt stroke [1,3] or reduced cognitive functioning [5,6]. Therefore, hypertension and progression of its target organ damage are strongly correlated with the appearance of SBI. ⁎ Corresponding author. Tel.: +82 2 2072 2875; fax: +82 2 3673 1990. E-mail address: [email protected] (B.-W. Yoon). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.11.003
Funduscopy is recommended as part of the routine examination of hypertensive people. Retinal microvascular abnormalities have been suggested as signs of cerebral microvascular diseases, because the retinal arteries share common anatomic, embryologic, and physiologic characteristics with the cerebral microcirculation [7,8]. Some signs of retinopathy were related with a risk of newly diagnosed clinical stroke [9], reduced cognitive performance [10], cerebral white matter lesions [11], and cerebral atrophy [12]. However, few clinical data are available to support the claim that hypertensive retinopathy (HTR) is associated with the presence of SBI. The purpose of this study is to investigate the relationship between SBI and HTR in hypertensive subjects.
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2. Materials and methods 2.1. Subjects We studied 550 asymptomatic hypertensive subjects who visited Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea, from October 2003 through December 2004 and who underwent brain MRI and retinal photographs as part of their voluntary health check. Our participants were recruited from among subjects who visited our hospital to check their general health status. Subjects' ages ranged from 25 to 83. Their mean age was 59.3. Clinical information was gathered by and individual interview, and a physical examination was performed by physicians. All subjects had no history of stroke or transient ischemic attack both before and at the time of the study participation. They provided informed consent, and the study was approved by Institutional Review Board of Seoul National University Hospital. Hypertension was defined as systolic blood pressure (BP) ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or use of antihypertensive medication. A history of diabetes was defined as a fasting glucose ≥7.0 mmol/L (≥126 mg/dL) or as selfreported history of treatment for diabetes. Cigarette smoking status data were collected from a structured interview. The data available were limited to three smoking categories: never smoked, smoked in the past, and currently smoking. Baseline blood pressure, plasma glucose, high sensitivity C-reactive protein, total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were measured. Since fasting may affect lipid and glucose level, subjects were tested after fasting for N 8 h. 2.2. Cerebral MRI MRI tests were performed at 1.5 T using a CHORUS (ISOL technology Inc., Republic of Korea). The imaging protocol used consisted of; T2-weighted spin-echo (repetition time/ echo time [TR/TE] = 5800/96 ms), T1-weighted spin-echo (TR/TE = 520/14 ms), and fluid-attenuated inversion-recovery
(FLAIR) (TR/TE = 8500/96 ms, inversion time = 2100 ms) imaging. Images were obtained as 27 transaxial slices per scan. The thickness of the slice was 5 mm, with no interslice gap. Two trained neurologists (HM Kwon and BJ Kim) blinded to subject history and diagnosis assessed the presence of SBI on MR images. The κ value of agreement for SBI was 0.86 (p b 0.001). When the two investigators' decisions were different, SBI was scored by consensus. SBI was defined as a focal lesion of at least 3 mm in diameter [13], with signal intensity corresponding to liquid, i.e., hyperintense on T2-weighted images and hypointense on FLAIR images. Often lesions were surrounded by a hyperintense gliotic rim on FLAIR images. Dilated perivascular spaces were distinguished from SBI based on their locations (along perforating or medullary arteries, often bilaterally symmetrical, usually in the lower third of the basal ganglia) and by the absence of gliosis. The location of the SBI was classified by cerebral region as following: subcortical white matter, central gray matter (basal ganglia and thalamus), and infratentorial area (brainstem and cerebellum). 2.3. Retinal photographs Photographs of the retina were taken on two eyes after 5 min of dark adaptation using a fundus camera (Canon EOS D60, Canon Inc., Japan), digitized, and measured on the computer. Two trained ophthalmologists (JY Oh, SJ Kim), who were masked to participant characteristics and cerebral MRI grading, evaluated the photographic grading of HTR using the classification of Keith–Wagener–Barker [14]. This classification still remains the predominant and most useful schema [15]. The κ value of agreement for HTR was 0.62 (p b 0.001). When the two investigators' decisions were different, HTR was scored by consensus. This classification typically consists of four grades of HTR with increasing severity. The first two grades are the chronic stages and represent clinical findings commonly seen by ophthalmologists in their practice [14]. None of them had grade 3 or 4 HTR. Grade 1 consists of slight or modest narrowing of the retinal arterioles, with an arteriovenous ratio ≥ 1:2 (Fig. 1A); grade 2 consists of modest to severe narrowing of retinal arterioles
Fig. 1. Hypertensive retinopathy. The retinal arteries inferotemporal to the optic disc are narrowed (A, grade 1), and prominent arteriovenous nicking is seen at the arrow (B, grade 2).
H.-M. Kwon et al. / Journal of the Neurological Sciences 252 (2007) 159–162 Table 1 Baseline characteristics of subjects with/without silent brain infarction
Age, y Male gender Diabetes mellitus Smoking Never Past Current Systolic BP, mmHg Diastolic BP, mmHg Fasting glucose, mmol/L Total cholesterol, mmol/L LDL-cholesterol, mmol/L HDL-cholesterol, mmol/L Triglyceride, mmol/L a hs-CRP, mg/dL a Hypertensive retinopathy Normal HTR grade 1 HTR grade 2
161
Table 3 The outcome of SBI numbers divided into levels of severity of hypertensive retinopathy
Control (no SBI)
SBI
n = 489
n = 61
57.2 ± 9.3 333 (68.1) 105 (21.5)
63.1 ± 8.2 42 (68.9) 21 (34.4)
210 (42.9) 203 (41.5) 76 (15.5) 136.6 ± 14.9 91.2 ± 10.6 5.98 ± 1.41 5.27 ± 0.84 3.29 ± 0.78 1.33 ± 0.32 14.22 ± 8.10 0.19 ± 0.54
28 (45.9) 25 (41.0) 8 (13.1) 141.2 ± 17.7 c 90.3 ± 11.1 6.23 ± 1.57 5.29 ± 0.94 3.26 ± 1.00 1.31 ± 0.25 15.73 ± 12.57 0.24 ± 0.35
429 (87.7) 37 (7.6) 23 (4.7)
44 (72.1) 9 (14.8) b 8 (13.1) b
SBI b
Values are means ± SD or nos. of participants (percentage). a Statistical tests were performed using logarithmically transformed variables. b p b 0.001 vs control. c p b 0.05 vs control.
(focal or generalized), with an arteriovenous ratio b 1:2 or arteriovenous nicking (Fig. 1B). 2.4. Statistical analysis To analyze the relation between SBI and patient characteristics, we used the χ2 tests for categorical data and the Student's t tests for continuous data. Probability values were 2-tailed, and values of p b 0.05 were considered significant. We performed analysis of test for trend between the severity of HTR and the degree of SBI (linear by linear association test). We examined the association between HTR and SBI by controlling for age, gender, blood pressure, diabetes, and cholesterol as possible confounders. Logistic regression models were also used to determine the associations between clinical factors
Normal HTR grade 1 HTR grade 2 Total
0
1
≥2
429 (87.7) 37 (7.6) 23 (4.7) 489
35 (77.8) 5 (11.1) 5 (11.1) 45
9 (56.3) 4 (25.0) 3 (18.8) 16
Values are nos. of participants (percentage). p b 0.001 by linear by linear association test.
including HTR and cerebral lesions. All statistical analyses were performed using SPSS 11.5 for Windows (SPSS Inc). 3. Results Seventy-seven (14%) of the 550 individuals were found to have HTR. Of the 77 subjects with HTR, 60 had grade 1 HTR and 17 had grade 2 HTR. Sixty-one subjects (11.1%) had one or more SBI. A total of 96 SBI lesions were detected. The mean number of SBI was 1.6 (maximum SBI was 8). Also, 68% of SBI were located in the basal ganglia and thalamus, and 29% were in the subcortical white matter. No patients had cortical SBI in this study group. Table 1 shows the prevalence of HTR among subjects with and without SBI. When the subjects were divided into two groups, there were differences in age, systolic blood pressure, and HTR. Subjects with SBI were more likely to have HTR than those without. In terms of current use of antihypertensive agents, both group had similar proportion of antihypertensive medication (79% for control, 85% for SBI), which was statistically insignificant. Table 2 shows that HTR was associated with SBI, with odds ratios 2.01 for HTR grade 1, 3.03 for HTR grade 2. A multivariate analysis showed age and HTR are independently associated with the presence of SBI after adjusted for confounding factors. Table 3 shows that the outcome of SBI divided into levels of severity of hypertensive retinopathy. The higher HTR grade, the more for the number of SBI (by linear by linear association test, p = 0.001). 4. Discussion
Table 2 Odds ratios of SBI in relation with HTR Model 1 (not including BP levels) OR a 95% CI Age Male gender Systolic BP Diabetes Total cholesterol HTR grade 1 HTR grade 2
1.07 1.15 1.47 1.00 2.01 3.04
Model 2 (including BP levels)
p value OR a 95% CI
1.03–1.10 b0.001 1.06 0.63–2.10 0.659 1.13 1.01 0.79–2.72 0.223 1.45 0.99–1.01 0.521 1.00 0.92–4.76 0.077 2.17 1.23–7.52 0.016 2.98
p value
1.03–1.10 b0.001 0.62–2.08 0.692 0.99–1.03 0.192 0.78–2.68 0.243 0.99–1.01 0.581 0.95–4.96 0.066 1.20–7.42 0.019
a Odds ratios were calculated using logistic regression model after adjusting age, gender, blood pressure, diabetes, and cholesterol level.
The purpose of the present study was to investigate the relation between SBI and HTR. Subjects with HTR had about 2 to 3-fold greater risk of SBI than those without HTR. Hypertension is the most well-known major risk factor for stroke and is closely related to the appearance of SBI [2–5]. To determine the clinical significance of hypertension in the appearance of SBI, we tried to clarify the relation between hypertensive target organ damage such as HTR and SBI. This result shows that the progression of hypertensive changes in retinal microvessels is paralleled by that in the brain. Our results suggest that HTR can be an indicator of cerebral target organ damage in people with hypertension.
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Previous studies investigated the relation between HTR and echocardiographically determined left ventricular hypertrophy, which was a marker of other hypertensive target organ damage [16,17]. The odd for left ventricular hypertrophy in the presence of HTR was 2.22. Results from the present study were similar to those from the earlier studies. The presence of HTR increased the risk of SBI (OR, 2.01 for grade 1; OR, 3.04 for grade 2). Subjects with HTR had a high prevalence of SBI; for other retinal abnormalities the association was not found in this study. In multivariate analysis, HTR grade 1 showed a marginal significance for the presence of SBI. These results are consistent with a previous report that the higher grade of retinopathy is strongly associated with the risk of subclinical stroke [11,18]. SBI, which is due to occlusive-type microangiopathy of the cerebral vasculature, is well known to have a strong relationship with chronic hypertension [2–5]. In addition, SBI is also associated with the presence of end organ damage such as left ventricular hypertrophy [19]. Therefore, SBI is strongly related to hypertensive end organ damage such as HTR. This study has some limitations. First, there is a participant selection bias: most of the subjects are healthy volunteers who are concerned about their health status. Population-based studies show that 5–10% of people has microaneurysms, retinal hemorrhages and cotton wool spots (corresponds to HTR grade 3) [20]. Our population showed mild or moderate hypertension, so there was no acute hypertensive change of retina (HTR grade 3 or grade 4). The selection bias towards healthier individuals with hypertension may have considerably impacted the results. Second, since this is a cross-sectional study, it is possible that some of SBI detected by MRI may have preceded the retinal damage. A prospective and longitudinal study is needed to clarify the true impact of HTR on cerebral target organ damage. In conclusion, our research findings suggest that hypertensive people have prevalent SBI when retina vessels were damaged due to hypertension. This association was seen only in subjects with hypertension and more progressed retina damage regardless of current blood pressure status. Subjects with HTR should take careful brain MRI for the detection of SBI. Acknowledgments This research was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare (A060171 and A060263). References [1] Hougaku H, Matsumoto M, Kitagawa K, Harada K, Oku N, Itoh T, et al. Silent cerebral infarction as a form of hypertensive target organ damage in the brain. Hypertension 1992;20:816–20.
[2] Howard G, Wagenknecht LE, Cai J, Cooper L, Kraut MA, Toole JF. Cigarette smoking and other risk factors for silent cerebral infarction in the general population. Stroke 1998;29:913–7. [3] Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MMB. Prevalence and risk factors of silent brain infarcts in the populationbased Rotterdam Scan Study. Stroke 2002;33:21–5. [4] Kobayashi S, Okada K, Koide H, Bokura H, Yamaguchi S. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997;28: 1932–9. [5] Vermeer SE, Prins ND, Heijer T, Hofman A, Koudstaal PJ, Breteler MMB. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–22. [6] Price TR, Manolio TA, Kronmal RA, Kittner SJ, Yue NC, Robbins J, et al. Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults: the Cardiovascular Health Study (CHS) Collaborative Research Group. Stroke 1997;28: 1158–64. [7] Tso MOM, Jampol LM. Pathophysiology of hypertensive retinopathy. Ophthalmology 1982;89:1132–45. [8] Wong TY, Klein R, Klein BEK, Tielsch JM, Hubbard LD, Nieto FJ. Retinal microvascular abnormalities and their relations with hypertension, cardiovascular diseases and mortality. Surv Ophthalmol 2001;46: 59–80. [9] Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, et al. Retinal microvascular abnormalities and incident strokes: the Atherosclerosis Risk in Communities Study. Lancet 2001;358:1134–40. [10] Wong TY, Klein R, Sharrett AR, Nieto FJ, Boland LL, Couper DJ, et al. Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002;33:1487–92. [11] Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, et al. Risk in communities study: cerebral white matter lesion, retinopathy and incident clinical stroke. JAMA 2002;288:67–74. [12] Wong TY, Mosley Jr TH, Klein R, Klein BE, Sharrett AR, Couper DJ, et al. Atherosclerosis risk in communities study: retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle aged people. Neurology 2003;61:806–11. [13] Bokura H, Kobayashi S, Yamaguchi S. Distinguishing silent lacunar infarction from enlarged Virchow–Robin spaces: a magnetic resonance imaging and pathological study. J Neurol 1998;245:116–22. [14] Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1974;268: 336–45. [15] Luo BP, Brown GC. Update on the ocular manifestations of systemic arterial hypertension. Curr Opin Ophthalmol 2004;15:203–10. [16] Pose-Reino A, Gonzalez-Juanatey JR, Pastor C, Mendez I, Estevez JC, Alvarez D, et al. Clinical implications of white coat hypertension. Blood Press 1996;5:264–73. [17] Saitoh M, Matsuo K, Nomoto S, Kondoh T, Yanagawa T, Katoh Y, et al. Relationship between left ventricular hypertrophy and renal and retinal damage in untreated patients with essential hypertension. Intern Med 1998;37:576–80. [18] Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med 2004;351: 2310–7. [19] Selvetella G, Notte A, Maffei A, Calistri V, Scamardella V, Frati G, et al. Left ventricular hypertrophy is associated with asymptomatic cerebral damage in hypertensive patients. Stroke 2003;34:1766–70. [20] van den Born BJ, Hulsman CA, Hoekstra JB, Schlingemann RO, van Montfrans GA. Value of routine funduscopy in patients with hypertension: systematic review. BMJ 2005;331:73–6.
Retinopathy as an indicator of silent brain infarction in asymptomatic hypertensive subjects Hyung-Min Kwon a , Beom Joon Kim b , Joo Youn Oh c , Sang Jin Kim c , Seung-Hoon Lee b , Byung-Hee Oh d , Byung-Woo Yoon b,⁎ b
d
a Department of Neurology, Kyunghee University East-West Neo Medical Center, Seoul, Republic of Korea Department of Neurology, Seoul National University Hospital, Yongon-dong 28, Chongno-gu, Seoul 110-744, Republic of Korea c Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
Received 27 July 2006; received in revised form 30 October 2006; accepted 7 November 2006 Available online 19 December 2006
Abstract Background and purpose: Silent brain infarction (SBI), which is cerebral target organ damage of hypertensive microangiopathies, is frequently seen in hypertensive patients. The purpose of this study is to investigate the relation between hypertensive retinopathy (HTR) and SBI in subjects without a history of stroke or transient ischemic attack. Methods: Five hundred-fifty hypertensive subjects without history of stroke or transient ischemic attack had brain MRI and retinal photographs taken. The presence of SBI was assessed from the MRI scans, which was defined as a lesion of at least 3 mm in diameter with typical imaging characteristics. The presence HTR was defined from digitized retinal photographs. Results: Seventy-seven subjects (14%) showed HTR (grade 1 in 46, grade 2 in 31 persons). A multivariate analysis showed that age (OR, 1.07; 95% CI, 1.03 to 1.10) and HTR (OR, 2.01 for grade 1; OR, 3.03 for grade 2) were the independent indicators for the presence of SBI. The higher the grade of HTR, the more prevalent SBI than persons with normal retina (by linear by linear association test, p = 0.001). Conclusion: HTR is associated with the presence of SBI. This finding suggests that retinal photography may be useful for identifying hypertensive subjects at increased risk of having SBI regardless of current blood pressure status. © 2006 Elsevier B.V. All rights reserved. Keywords: Hypertension; Retinal artery; Brain infarction; Magnetic resonance imaging
1. Introduction Silent brain infarction (SBI) is frequently seen in older hypertensive patients, especially when moderate hypertensive changes are found in major target organs [1]. Hypertension is the most well-known major risk factor for SBI [2–5]. The presence of an SBI can predict clinical overt stroke [1,3] or reduced cognitive functioning [5,6]. Therefore, hypertension and progression of its target organ damage are strongly correlated with the appearance of SBI. ⁎ Corresponding author. Tel.: +82 2 2072 2875; fax: +82 2 3673 1990. E-mail address: [email protected] (B.-W. Yoon). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.11.003
Funduscopy is recommended as part of the routine examination of hypertensive people. Retinal microvascular abnormalities have been suggested as signs of cerebral microvascular diseases, because the retinal arteries share common anatomic, embryologic, and physiologic characteristics with the cerebral microcirculation [7,8]. Some signs of retinopathy were related with a risk of newly diagnosed clinical stroke [9], reduced cognitive performance [10], cerebral white matter lesions [11], and cerebral atrophy [12]. However, few clinical data are available to support the claim that hypertensive retinopathy (HTR) is associated with the presence of SBI. The purpose of this study is to investigate the relationship between SBI and HTR in hypertensive subjects.
160
H.-M. Kwon et al. / Journal of the Neurological Sciences 252 (2007) 159–162
2. Materials and methods 2.1. Subjects We studied 550 asymptomatic hypertensive subjects who visited Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea, from October 2003 through December 2004 and who underwent brain MRI and retinal photographs as part of their voluntary health check. Our participants were recruited from among subjects who visited our hospital to check their general health status. Subjects' ages ranged from 25 to 83. Their mean age was 59.3. Clinical information was gathered by and individual interview, and a physical examination was performed by physicians. All subjects had no history of stroke or transient ischemic attack both before and at the time of the study participation. They provided informed consent, and the study was approved by Institutional Review Board of Seoul National University Hospital. Hypertension was defined as systolic blood pressure (BP) ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or use of antihypertensive medication. A history of diabetes was defined as a fasting glucose ≥7.0 mmol/L (≥126 mg/dL) or as selfreported history of treatment for diabetes. Cigarette smoking status data were collected from a structured interview. The data available were limited to three smoking categories: never smoked, smoked in the past, and currently smoking. Baseline blood pressure, plasma glucose, high sensitivity C-reactive protein, total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were measured. Since fasting may affect lipid and glucose level, subjects were tested after fasting for N 8 h. 2.2. Cerebral MRI MRI tests were performed at 1.5 T using a CHORUS (ISOL technology Inc., Republic of Korea). The imaging protocol used consisted of; T2-weighted spin-echo (repetition time/ echo time [TR/TE] = 5800/96 ms), T1-weighted spin-echo (TR/TE = 520/14 ms), and fluid-attenuated inversion-recovery
(FLAIR) (TR/TE = 8500/96 ms, inversion time = 2100 ms) imaging. Images were obtained as 27 transaxial slices per scan. The thickness of the slice was 5 mm, with no interslice gap. Two trained neurologists (HM Kwon and BJ Kim) blinded to subject history and diagnosis assessed the presence of SBI on MR images. The κ value of agreement for SBI was 0.86 (p b 0.001). When the two investigators' decisions were different, SBI was scored by consensus. SBI was defined as a focal lesion of at least 3 mm in diameter [13], with signal intensity corresponding to liquid, i.e., hyperintense on T2-weighted images and hypointense on FLAIR images. Often lesions were surrounded by a hyperintense gliotic rim on FLAIR images. Dilated perivascular spaces were distinguished from SBI based on their locations (along perforating or medullary arteries, often bilaterally symmetrical, usually in the lower third of the basal ganglia) and by the absence of gliosis. The location of the SBI was classified by cerebral region as following: subcortical white matter, central gray matter (basal ganglia and thalamus), and infratentorial area (brainstem and cerebellum). 2.3. Retinal photographs Photographs of the retina were taken on two eyes after 5 min of dark adaptation using a fundus camera (Canon EOS D60, Canon Inc., Japan), digitized, and measured on the computer. Two trained ophthalmologists (JY Oh, SJ Kim), who were masked to participant characteristics and cerebral MRI grading, evaluated the photographic grading of HTR using the classification of Keith–Wagener–Barker [14]. This classification still remains the predominant and most useful schema [15]. The κ value of agreement for HTR was 0.62 (p b 0.001). When the two investigators' decisions were different, HTR was scored by consensus. This classification typically consists of four grades of HTR with increasing severity. The first two grades are the chronic stages and represent clinical findings commonly seen by ophthalmologists in their practice [14]. None of them had grade 3 or 4 HTR. Grade 1 consists of slight or modest narrowing of the retinal arterioles, with an arteriovenous ratio ≥ 1:2 (Fig. 1A); grade 2 consists of modest to severe narrowing of retinal arterioles
Fig. 1. Hypertensive retinopathy. The retinal arteries inferotemporal to the optic disc are narrowed (A, grade 1), and prominent arteriovenous nicking is seen at the arrow (B, grade 2).
H.-M. Kwon et al. / Journal of the Neurological Sciences 252 (2007) 159–162 Table 1 Baseline characteristics of subjects with/without silent brain infarction
Age, y Male gender Diabetes mellitus Smoking Never Past Current Systolic BP, mmHg Diastolic BP, mmHg Fasting glucose, mmol/L Total cholesterol, mmol/L LDL-cholesterol, mmol/L HDL-cholesterol, mmol/L Triglyceride, mmol/L a hs-CRP, mg/dL a Hypertensive retinopathy Normal HTR grade 1 HTR grade 2
161
Table 3 The outcome of SBI numbers divided into levels of severity of hypertensive retinopathy
Control (no SBI)
SBI
n = 489
n = 61
57.2 ± 9.3 333 (68.1) 105 (21.5)
63.1 ± 8.2 42 (68.9) 21 (34.4)
210 (42.9) 203 (41.5) 76 (15.5) 136.6 ± 14.9 91.2 ± 10.6 5.98 ± 1.41 5.27 ± 0.84 3.29 ± 0.78 1.33 ± 0.32 14.22 ± 8.10 0.19 ± 0.54
28 (45.9) 25 (41.0) 8 (13.1) 141.2 ± 17.7 c 90.3 ± 11.1 6.23 ± 1.57 5.29 ± 0.94 3.26 ± 1.00 1.31 ± 0.25 15.73 ± 12.57 0.24 ± 0.35
429 (87.7) 37 (7.6) 23 (4.7)
44 (72.1) 9 (14.8) b 8 (13.1) b
SBI b
Values are means ± SD or nos. of participants (percentage). a Statistical tests were performed using logarithmically transformed variables. b p b 0.001 vs control. c p b 0.05 vs control.
(focal or generalized), with an arteriovenous ratio b 1:2 or arteriovenous nicking (Fig. 1B). 2.4. Statistical analysis To analyze the relation between SBI and patient characteristics, we used the χ2 tests for categorical data and the Student's t tests for continuous data. Probability values were 2-tailed, and values of p b 0.05 were considered significant. We performed analysis of test for trend between the severity of HTR and the degree of SBI (linear by linear association test). We examined the association between HTR and SBI by controlling for age, gender, blood pressure, diabetes, and cholesterol as possible confounders. Logistic regression models were also used to determine the associations between clinical factors
Normal HTR grade 1 HTR grade 2 Total
0
1
≥2
429 (87.7) 37 (7.6) 23 (4.7) 489
35 (77.8) 5 (11.1) 5 (11.1) 45
9 (56.3) 4 (25.0) 3 (18.8) 16
Values are nos. of participants (percentage). p b 0.001 by linear by linear association test.
including HTR and cerebral lesions. All statistical analyses were performed using SPSS 11.5 for Windows (SPSS Inc). 3. Results Seventy-seven (14%) of the 550 individuals were found to have HTR. Of the 77 subjects with HTR, 60 had grade 1 HTR and 17 had grade 2 HTR. Sixty-one subjects (11.1%) had one or more SBI. A total of 96 SBI lesions were detected. The mean number of SBI was 1.6 (maximum SBI was 8). Also, 68% of SBI were located in the basal ganglia and thalamus, and 29% were in the subcortical white matter. No patients had cortical SBI in this study group. Table 1 shows the prevalence of HTR among subjects with and without SBI. When the subjects were divided into two groups, there were differences in age, systolic blood pressure, and HTR. Subjects with SBI were more likely to have HTR than those without. In terms of current use of antihypertensive agents, both group had similar proportion of antihypertensive medication (79% for control, 85% for SBI), which was statistically insignificant. Table 2 shows that HTR was associated with SBI, with odds ratios 2.01 for HTR grade 1, 3.03 for HTR grade 2. A multivariate analysis showed age and HTR are independently associated with the presence of SBI after adjusted for confounding factors. Table 3 shows that the outcome of SBI divided into levels of severity of hypertensive retinopathy. The higher HTR grade, the more for the number of SBI (by linear by linear association test, p = 0.001). 4. Discussion
Table 2 Odds ratios of SBI in relation with HTR Model 1 (not including BP levels) OR a 95% CI Age Male gender Systolic BP Diabetes Total cholesterol HTR grade 1 HTR grade 2
1.07 1.15 1.47 1.00 2.01 3.04
Model 2 (including BP levels)
p value OR a 95% CI
1.03–1.10 b0.001 1.06 0.63–2.10 0.659 1.13 1.01 0.79–2.72 0.223 1.45 0.99–1.01 0.521 1.00 0.92–4.76 0.077 2.17 1.23–7.52 0.016 2.98
p value
1.03–1.10 b0.001 0.62–2.08 0.692 0.99–1.03 0.192 0.78–2.68 0.243 0.99–1.01 0.581 0.95–4.96 0.066 1.20–7.42 0.019
a Odds ratios were calculated using logistic regression model after adjusting age, gender, blood pressure, diabetes, and cholesterol level.
The purpose of the present study was to investigate the relation between SBI and HTR. Subjects with HTR had about 2 to 3-fold greater risk of SBI than those without HTR. Hypertension is the most well-known major risk factor for stroke and is closely related to the appearance of SBI [2–5]. To determine the clinical significance of hypertension in the appearance of SBI, we tried to clarify the relation between hypertensive target organ damage such as HTR and SBI. This result shows that the progression of hypertensive changes in retinal microvessels is paralleled by that in the brain. Our results suggest that HTR can be an indicator of cerebral target organ damage in people with hypertension.
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Previous studies investigated the relation between HTR and echocardiographically determined left ventricular hypertrophy, which was a marker of other hypertensive target organ damage [16,17]. The odd for left ventricular hypertrophy in the presence of HTR was 2.22. Results from the present study were similar to those from the earlier studies. The presence of HTR increased the risk of SBI (OR, 2.01 for grade 1; OR, 3.04 for grade 2). Subjects with HTR had a high prevalence of SBI; for other retinal abnormalities the association was not found in this study. In multivariate analysis, HTR grade 1 showed a marginal significance for the presence of SBI. These results are consistent with a previous report that the higher grade of retinopathy is strongly associated with the risk of subclinical stroke [11,18]. SBI, which is due to occlusive-type microangiopathy of the cerebral vasculature, is well known to have a strong relationship with chronic hypertension [2–5]. In addition, SBI is also associated with the presence of end organ damage such as left ventricular hypertrophy [19]. Therefore, SBI is strongly related to hypertensive end organ damage such as HTR. This study has some limitations. First, there is a participant selection bias: most of the subjects are healthy volunteers who are concerned about their health status. Population-based studies show that 5–10% of people has microaneurysms, retinal hemorrhages and cotton wool spots (corresponds to HTR grade 3) [20]. Our population showed mild or moderate hypertension, so there was no acute hypertensive change of retina (HTR grade 3 or grade 4). The selection bias towards healthier individuals with hypertension may have considerably impacted the results. Second, since this is a cross-sectional study, it is possible that some of SBI detected by MRI may have preceded the retinal damage. A prospective and longitudinal study is needed to clarify the true impact of HTR on cerebral target organ damage. In conclusion, our research findings suggest that hypertensive people have prevalent SBI when retina vessels were damaged due to hypertension. This association was seen only in subjects with hypertension and more progressed retina damage regardless of current blood pressure status. Subjects with HTR should take careful brain MRI for the detection of SBI. Acknowledgments This research was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare (A060171 and A060263). References [1] Hougaku H, Matsumoto M, Kitagawa K, Harada K, Oku N, Itoh T, et al. Silent cerebral infarction as a form of hypertensive target organ damage in the brain. Hypertension 1992;20:816–20.
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