Acta Ophthalmologica 2014
may degrade it and further lead to proteolytic digestion of the corneal stroma. The location of the corneal melt at the inferior segment could support this hypothesis. Other possible factor that potentiates this response may lay in the AKC type I hypersensitivity reaction that liberates active mediators such as histamine, leukotriene and prostaglandins from mast cells, T cells and eosinophils that could amplify the concentration of proteolytic enzymes around the ICRS. If a corneal melt after ICRS in AD patients is diagnosed, the ICRS removal seems to be adequate. We suggest that patients with a history of AD/AKC treated with ICRS implantation should be performed by femtosecond laser-assisted system because the tunnel creation will be more uniform in depth. Special attention should be given to the edges of the tunnel and to the depth of the ICRS insertion. Patients should be followed carefully and informed to attend immediately at an ophthalmology practice in the case of ocular surface symptoms.
References Calonge M & Herreras JM (2007): Clinical grading of atopic keratoconjunctivitis. Curr Opin Allergy Clin Immunol 7: 442–445. Fini ME, Parks WC, Rinehart WB et al. (1996): Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury. Am J Pathol 149: 1287–1302. Holopainen JM, Robciuc A, Cafaro TA et al. (2012): Pro-inflammatory cytokines and gelatinases in climatic droplet keratopathy. Invest Ophthalmol Vis Sci 53: 3527–3535. Kugler LJ, Hill S, Sztipanovits D, Boerman H, Swartz TS & Wang MX (2011): Corneal melt of incisions overlying corneal ring segments: case series and literature review. Cornea 30: 968–971. Samimi S, Leger F, Touboul D & Colin J (2007): Histopathological findings after intracorneal ring segment implantation in keratoconic human corneas. J Cataract Refract Surg 33: 247–253. Tuft SJ, Kemeny DM, Dart JK & Buckley RJ (1991): Clinical features of atopic keratoconjunctivitis. Ophthalmology 98: 150–158.
Correspondence: Dr Juha M. Holopainen Department of Ophthalmology University of Helsinki, PO Box 220, 00029 HUS Helsinki, Finland Tel: +358 9 471 73110 Fax: +358 9 471 75100 Email: juha.holopainen@hus.fi
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Financial Disclosures: Helsinki University Central Hospital, Evald and Hilda Nissi Foundation, Mary and Georg C. Ehrnrooths Foundation, Finnish Eye Bank Foundation and the Finnish Eye Foundation.
Silent myocardial ischaemia in patients with diabetic retinopathy Kazuyoshi Ohtomo,1 Takashi Shigeeda,1 Akira Hirose,1 Takayuki Ohno,2 Osamu Kinoshita,2 Hideo Fujita,3 Jiro Ando,3 Ryozo Nagai,3 Shinichi Takamoto,2 Takashi Kadowaki4 and Satoshi Kato1 1
Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan; 2Department of Cardiovascular Surgery, The University of Tokyo Hospital, Tokyo, Japan; 3Department of Cardiology, The University of Tokyo Hospital, Tokyo, Japan; 4Department of Metabolic Disease, The University of Tokyo Hospital, Tokyo, Japan doi: 10.1111/aos.12362
Editor, ilent myocardial ischaemia (SMI), in which patients affected by coronary artery disease have a normal resting electrocardiogram (ECG) and no symptoms of angina, is predominant in diabetic people. The prevalence of SMI in diabetic patients is reported to be 7.6–12.6% (Koistinen 1990; Janand-Delenneet al.1999;Gokcelet al. 2003; Fornengo et al. 2006). The aim of this study was to investigate the frequency of SMI in diabetic patients with retinopathy and to explore the risk factors for SMI in these patients.
S
This prospective study was conducted between November 2006 and April 2009. All patients gave informed consent. We enrolled 165 patients with diabetic retinopathy who met the following criteria: (i) diabetes with retinopathy, (ii) age 75 years or less, (iii) a normal resting ECG and (iv) no symptoms of angina or any other clinical evidence of coronary artery disease (CAD). Those who met the inclusion criteria underwent screening for CAD, which included an exercise treadmill test (ETT), coronary computed tomography (CCT) and thallium myocardial scintigraphy (TMS). The patients who showed a positive response in the screening test underwent coronary angiography (CAG), and those who showed a positive result were diagnosed with CAD, that is, SMI. The clinical characteristics of the subjects are shown in Table 1. The worse eye was used for the evaluation, and the retinopathy was grouped into two categories: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy (PDR). The estimated glomerular filtration rate (eGFR) was calculated using the following formula (Matsuo et al.2009): eGFR [ml/ (min1.73 m2)] = 194 9 Cre 1.094 9 Age 0.203 9 0.739 (if female). Statistical analysis was performed using SPSS for Windows (version 11.0; SPSS Chicago, IL, USA). p values 0.05 or less were regarded as statistically significant in this study. The performance of ETT was feasible in 147 patients, but the remaining 18 patients were considered ineligible for ETT because of severe visual deterioration, a diabetic foot ulcer and one-sided paralysis. ETT was judged negative in 95 patients, positive in 37 patients and non-diagnostic in 15
Table 1. Clinical characteristics of subjects. Number (male/female) Age (years) BMI (kg/m2) HbA1c (%) eGFR [ml/(min1.73 m2)] Usage of insulin (%) Type of DM (type 1/type 2) Retinopathy (PDR/NPDR)
165 (117/48) 57.6 (10.4) 24.4 (4.4) 7.2 (1.5) 69.0 (26.9) 45.5 9/156 58/107
BMI = body mass index, HbA1c = haemoglobin A1c, eGFR = estimated glomerular filtration rate, DM = diabetes mellitus, PDR = proliferative diabetic retinopathy, NPDR = non-proliferative diabetic retinopathy. Age, BMI, HbA1c, and eGFR values represent the format mean (standard deviation). [Correction made on the 26th of March after online publication: ‘Usage of insulin ()’ was corrected to ‘Usage of insulin (%)’ and ‘75/90’ was corrected to ‘45.5’].
Acta Ophthalmologica 2014
Normal resting ECG: 165 Those who cannot exercise: 18
Those who can exercise: 147 - First screening test -
33 patients
Exercise treadmill test : 147 Non - diagnostic:15
95
37
4 4
Thallium myocardial scintigraphy: 20 Coronary computed tomography: 13
Coronary angiography: 45 37
25
8
Diagnosis of silent myocardialischemia: 37
Follow- up: 128
Fig. 1. Results of the investigation for cardiac function. Heavy line, positive; dashed line, negative. We selected 165 patients with a normal resting electrocardiogram. Of the 147 patients who were able to take the treadmill test, 37 patients had positive results, 95 patients had negative results, and 15 patients were non-diagnostic; 18 patients were unable to exercise. Coronary computed tomography was performed in 13 of these 33 patients, and thallium myocardial scintigraphy was performed in 20 of these 33 patients; for each of these examinations, 4 patients had positive results. Forty-five patients who were positive in the first screening test subsequently underwent coronary angiography, and 37 of these patients showed positive results. The other 128 patients who were negative in the primary screening test and for coronary angiography were placed under observation.
patients due to inadequate load because of blood pressure elevation and foot pain. A total of 33 patients underwent TMS or CCT. TMS was carried out in 13 patients, four of whom were revealed to have perfusion defects. CCT was performed in the remaining 20 patients, which revealed coronary artery stenoses in four patients. Thus, 45 patients were positive for the first screening test and proceeded to CAG. CAG revealed coronary artery stenoses in 37 patients, whereas the results of angiography were considered normal in the remaining patients. No complications occurred during the procedures. In short, 45 patients (27.3%) had a positive response for the screening test, and 37 patients (22.4%) were revealed to have SMI (Fig. 1). The positive predictive value of CAD in the screening test was 82.2% (37/45). Univariate analysis results showed that age (p = 0.050, chi-square test) and male (p = 0.025, Mann–Whitney U-test) had significance and that there were no significances on other factors such as body mass index (BMI), HbA1c, eGFR, insulin usage, type of diabetes and retinopathy severity. Result of multiple logistic regression analysis showed that age [Odds ratio (OR) = 1.06, 95% confidence interval (95% CI) = 1.02–1.10] and male (OR = 3.31, 95% CI = 1.22–
8.99) were statistically significant risk factors for CAD. In this study, approximately 20% of diabetic patients with retinopathy were found to have accompanying subclinical CAD, which was ascertained by coronary angiography. Ophthalmologists should be aware of the high rate of this disease when examining these patients.
References Fornengo P, Bosio A, Epifani G, Pallisco O, Mancuso A & Pascale C (2006): Prevalence of silent myocardial ischaemia in new-onset middle-aged Type 2 diabetic patients without other cardiovascular risk factors. Diabet Med 23: 775–779. Gokcel A, Aydin M, Yalcin F et al. (2003): Silent coronary artery disease in patients with type 2 diabetes mellitus. Acta Diabetol 40: 176–180. Janand-Delenne B, Savin B, Habib G, Bory M, Vague P & Lassmann-Vague V (1999): Silent myocardial ischemia in patients with diabetes: who to screen. Diabetes Care 22: 1396–1400. Koistinen MJ (1990): Prevalence of asymptomatic myocardial ischaemia in diabetic subjects. BMJ 301: 92–95. Matsuo S, Imai E, Horio M et al. (2009): Revised equations for estimated GFR from scrum creatinine in japan. Am J Kidney Dis 53: 982–992.
Correspondence: Kazuyoshi Ohtomo Department of Ophthalmology The University of Tokyo Hospital 7-3-1 Hongo Bunkyo-ku Tokyo, 113-8655, Japan Tel: + 81-3-3815-5411 Fax: + 81-3-3817-0798 Email: [email protected]
Risk of ischaemic stroke associated with intravitreal bevacizumab – a hospitalbased case-crossover study Ming-Hung Hsieh,1 Chia-Chin Liao1 and Jen-Chieh Lin1,2 1
Department of Ophthalmology, Taipei City Hospital, Heping Fuyoy Branch, Taipei, Taiwan; 2Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan doi: 10.1111/aos.12361
Editor, ntravitreal use of bevacizumab might affect collateral circulation around atherosclerotic vessels and lead to ischaemic cerebrovascular adverse effects (Kamba & McDonald 2007). The present study aims to further evaluate the potential association between the development of cerebrovascular events and intravitreal use of bevacizumab. We conducted a retrospective casecrossover study of Taiwanese patients with ischaemic cerebrovascular events from 1 January 2007 to 30 June 2011 (according to ICD-9-CM codes in electronic chart database) who were aged ≥20 years. The index date was then defined as the date of hospitalization. The case period was defined as 1–30 days before the index date, and the control period, as 121–150 days before the index date. We doubled case period and control period into 1–60 and 91–150 days before the index date, respectively, as a sensitivity analysis. The main exposure of interest in this study was intravitreal bevacizumab use. We also identified any comorbid conditions and the use of
I
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may degrade it and further lead to proteolytic digestion of the corneal stroma. The location of the corneal melt at the inferior segment could support this hypothesis. Other possible factor that potentiates this response may lay in the AKC type I hypersensitivity reaction that liberates active mediators such as histamine, leukotriene and prostaglandins from mast cells, T cells and eosinophils that could amplify the concentration of proteolytic enzymes around the ICRS. If a corneal melt after ICRS in AD patients is diagnosed, the ICRS removal seems to be adequate. We suggest that patients with a history of AD/AKC treated with ICRS implantation should be performed by femtosecond laser-assisted system because the tunnel creation will be more uniform in depth. Special attention should be given to the edges of the tunnel and to the depth of the ICRS insertion. Patients should be followed carefully and informed to attend immediately at an ophthalmology practice in the case of ocular surface symptoms.
References Calonge M & Herreras JM (2007): Clinical grading of atopic keratoconjunctivitis. Curr Opin Allergy Clin Immunol 7: 442–445. Fini ME, Parks WC, Rinehart WB et al. (1996): Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury. Am J Pathol 149: 1287–1302. Holopainen JM, Robciuc A, Cafaro TA et al. (2012): Pro-inflammatory cytokines and gelatinases in climatic droplet keratopathy. Invest Ophthalmol Vis Sci 53: 3527–3535. Kugler LJ, Hill S, Sztipanovits D, Boerman H, Swartz TS & Wang MX (2011): Corneal melt of incisions overlying corneal ring segments: case series and literature review. Cornea 30: 968–971. Samimi S, Leger F, Touboul D & Colin J (2007): Histopathological findings after intracorneal ring segment implantation in keratoconic human corneas. J Cataract Refract Surg 33: 247–253. Tuft SJ, Kemeny DM, Dart JK & Buckley RJ (1991): Clinical features of atopic keratoconjunctivitis. Ophthalmology 98: 150–158.
Correspondence: Dr Juha M. Holopainen Department of Ophthalmology University of Helsinki, PO Box 220, 00029 HUS Helsinki, Finland Tel: +358 9 471 73110 Fax: +358 9 471 75100 Email: juha.holopainen@hus.fi
e492
Financial Disclosures: Helsinki University Central Hospital, Evald and Hilda Nissi Foundation, Mary and Georg C. Ehrnrooths Foundation, Finnish Eye Bank Foundation and the Finnish Eye Foundation.
Silent myocardial ischaemia in patients with diabetic retinopathy Kazuyoshi Ohtomo,1 Takashi Shigeeda,1 Akira Hirose,1 Takayuki Ohno,2 Osamu Kinoshita,2 Hideo Fujita,3 Jiro Ando,3 Ryozo Nagai,3 Shinichi Takamoto,2 Takashi Kadowaki4 and Satoshi Kato1 1
Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan; 2Department of Cardiovascular Surgery, The University of Tokyo Hospital, Tokyo, Japan; 3Department of Cardiology, The University of Tokyo Hospital, Tokyo, Japan; 4Department of Metabolic Disease, The University of Tokyo Hospital, Tokyo, Japan doi: 10.1111/aos.12362
Editor, ilent myocardial ischaemia (SMI), in which patients affected by coronary artery disease have a normal resting electrocardiogram (ECG) and no symptoms of angina, is predominant in diabetic people. The prevalence of SMI in diabetic patients is reported to be 7.6–12.6% (Koistinen 1990; Janand-Delenneet al.1999;Gokcelet al. 2003; Fornengo et al. 2006). The aim of this study was to investigate the frequency of SMI in diabetic patients with retinopathy and to explore the risk factors for SMI in these patients.
S
This prospective study was conducted between November 2006 and April 2009. All patients gave informed consent. We enrolled 165 patients with diabetic retinopathy who met the following criteria: (i) diabetes with retinopathy, (ii) age 75 years or less, (iii) a normal resting ECG and (iv) no symptoms of angina or any other clinical evidence of coronary artery disease (CAD). Those who met the inclusion criteria underwent screening for CAD, which included an exercise treadmill test (ETT), coronary computed tomography (CCT) and thallium myocardial scintigraphy (TMS). The patients who showed a positive response in the screening test underwent coronary angiography (CAG), and those who showed a positive result were diagnosed with CAD, that is, SMI. The clinical characteristics of the subjects are shown in Table 1. The worse eye was used for the evaluation, and the retinopathy was grouped into two categories: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy (PDR). The estimated glomerular filtration rate (eGFR) was calculated using the following formula (Matsuo et al.2009): eGFR [ml/ (min1.73 m2)] = 194 9 Cre 1.094 9 Age 0.203 9 0.739 (if female). Statistical analysis was performed using SPSS for Windows (version 11.0; SPSS Chicago, IL, USA). p values 0.05 or less were regarded as statistically significant in this study. The performance of ETT was feasible in 147 patients, but the remaining 18 patients were considered ineligible for ETT because of severe visual deterioration, a diabetic foot ulcer and one-sided paralysis. ETT was judged negative in 95 patients, positive in 37 patients and non-diagnostic in 15
Table 1. Clinical characteristics of subjects. Number (male/female) Age (years) BMI (kg/m2) HbA1c (%) eGFR [ml/(min1.73 m2)] Usage of insulin (%) Type of DM (type 1/type 2) Retinopathy (PDR/NPDR)
165 (117/48) 57.6 (10.4) 24.4 (4.4) 7.2 (1.5) 69.0 (26.9) 45.5 9/156 58/107
BMI = body mass index, HbA1c = haemoglobin A1c, eGFR = estimated glomerular filtration rate, DM = diabetes mellitus, PDR = proliferative diabetic retinopathy, NPDR = non-proliferative diabetic retinopathy. Age, BMI, HbA1c, and eGFR values represent the format mean (standard deviation). [Correction made on the 26th of March after online publication: ‘Usage of insulin ()’ was corrected to ‘Usage of insulin (%)’ and ‘75/90’ was corrected to ‘45.5’].
Acta Ophthalmologica 2014
Normal resting ECG: 165 Those who cannot exercise: 18
Those who can exercise: 147 - First screening test -
33 patients
Exercise treadmill test : 147 Non - diagnostic:15
95
37
4 4
Thallium myocardial scintigraphy: 20 Coronary computed tomography: 13
Coronary angiography: 45 37
25
8
Diagnosis of silent myocardialischemia: 37
Follow- up: 128
Fig. 1. Results of the investigation for cardiac function. Heavy line, positive; dashed line, negative. We selected 165 patients with a normal resting electrocardiogram. Of the 147 patients who were able to take the treadmill test, 37 patients had positive results, 95 patients had negative results, and 15 patients were non-diagnostic; 18 patients were unable to exercise. Coronary computed tomography was performed in 13 of these 33 patients, and thallium myocardial scintigraphy was performed in 20 of these 33 patients; for each of these examinations, 4 patients had positive results. Forty-five patients who were positive in the first screening test subsequently underwent coronary angiography, and 37 of these patients showed positive results. The other 128 patients who were negative in the primary screening test and for coronary angiography were placed under observation.
patients due to inadequate load because of blood pressure elevation and foot pain. A total of 33 patients underwent TMS or CCT. TMS was carried out in 13 patients, four of whom were revealed to have perfusion defects. CCT was performed in the remaining 20 patients, which revealed coronary artery stenoses in four patients. Thus, 45 patients were positive for the first screening test and proceeded to CAG. CAG revealed coronary artery stenoses in 37 patients, whereas the results of angiography were considered normal in the remaining patients. No complications occurred during the procedures. In short, 45 patients (27.3%) had a positive response for the screening test, and 37 patients (22.4%) were revealed to have SMI (Fig. 1). The positive predictive value of CAD in the screening test was 82.2% (37/45). Univariate analysis results showed that age (p = 0.050, chi-square test) and male (p = 0.025, Mann–Whitney U-test) had significance and that there were no significances on other factors such as body mass index (BMI), HbA1c, eGFR, insulin usage, type of diabetes and retinopathy severity. Result of multiple logistic regression analysis showed that age [Odds ratio (OR) = 1.06, 95% confidence interval (95% CI) = 1.02–1.10] and male (OR = 3.31, 95% CI = 1.22–
8.99) were statistically significant risk factors for CAD. In this study, approximately 20% of diabetic patients with retinopathy were found to have accompanying subclinical CAD, which was ascertained by coronary angiography. Ophthalmologists should be aware of the high rate of this disease when examining these patients.
References Fornengo P, Bosio A, Epifani G, Pallisco O, Mancuso A & Pascale C (2006): Prevalence of silent myocardial ischaemia in new-onset middle-aged Type 2 diabetic patients without other cardiovascular risk factors. Diabet Med 23: 775–779. Gokcel A, Aydin M, Yalcin F et al. (2003): Silent coronary artery disease in patients with type 2 diabetes mellitus. Acta Diabetol 40: 176–180. Janand-Delenne B, Savin B, Habib G, Bory M, Vague P & Lassmann-Vague V (1999): Silent myocardial ischemia in patients with diabetes: who to screen. Diabetes Care 22: 1396–1400. Koistinen MJ (1990): Prevalence of asymptomatic myocardial ischaemia in diabetic subjects. BMJ 301: 92–95. Matsuo S, Imai E, Horio M et al. (2009): Revised equations for estimated GFR from scrum creatinine in japan. Am J Kidney Dis 53: 982–992.
Correspondence: Kazuyoshi Ohtomo Department of Ophthalmology The University of Tokyo Hospital 7-3-1 Hongo Bunkyo-ku Tokyo, 113-8655, Japan Tel: + 81-3-3815-5411 Fax: + 81-3-3817-0798 Email: [email protected]
Risk of ischaemic stroke associated with intravitreal bevacizumab – a hospitalbased case-crossover study Ming-Hung Hsieh,1 Chia-Chin Liao1 and Jen-Chieh Lin1,2 1
Department of Ophthalmology, Taipei City Hospital, Heping Fuyoy Branch, Taipei, Taiwan; 2Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan doi: 10.1111/aos.12361
Editor, ntravitreal use of bevacizumab might affect collateral circulation around atherosclerotic vessels and lead to ischaemic cerebrovascular adverse effects (Kamba & McDonald 2007). The present study aims to further evaluate the potential association between the development of cerebrovascular events and intravitreal use of bevacizumab. We conducted a retrospective casecrossover study of Taiwanese patients with ischaemic cerebrovascular events from 1 January 2007 to 30 June 2011 (according to ICD-9-CM codes in electronic chart database) who were aged ≥20 years. The index date was then defined as the date of hospitalization. The case period was defined as 1–30 days before the index date, and the control period, as 121–150 days before the index date. We doubled case period and control period into 1–60 and 91–150 days before the index date, respectively, as a sensitivity analysis. The main exposure of interest in this study was intravitreal bevacizumab use. We also identified any comorbid conditions and the use of
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