Ophthalmic Epidemiology, 2014; 21(1): 39–44 ! Informa Healthcare USA, Inc. ISSN: 0928-6586 print / 1744-5086 online DOI: 10.3109/09286586.2013.867510
ORIGINAL ARTICLE
Characteristics of Undiagnosed Primary Open-Angle Glaucoma: The Tajimi Study Aiko Iwase1, Yasuyuki Suzuki2, Makoto Araie3,4 and the Tajimi Study Group5 Tajimi Iwase Eye Clinic, Tajimi, Gifu Prefecture, Japan, 2Department of Ophthalmology, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan, 3Kanto Central Hospital, Setagaya-ku, Tokyo, Japan, 4Department of Ophthalmology, University of Tokyo, Bunkyo-ku, Tokyo, Japan, and 5Japan Glaucoma Society, Tokyo, Japan
ABSTRACT Purpose: To evaluate the characteristics of patients with previously undiagnosed primary open-angle glaucoma (POAG) in the Tajimi Study. Methods: Background and ophthalmic examination data from 111 patients previously undiagnosed with POAG from the Tajimi Study, a population-based survey of glaucoma, were analyzed and compared with those of eight patients with previously diagnosed glaucoma. Results: The mean deviation (MD) and vertical cup-to-disc ratio (vC/D) of the worse eye of each patient averaged 5.5 decibels (dB) and 0.72 and 10.4 dB and 0.83, respectively, in undiagnosed and diagnosed POAG. In undiagnosed POAG, arcuate and partial arcuate patterns accounted for 50% of the pattern of the visual field (VF) damage, and 95% of patients presented with intraocular pressure of 21 mmHg or less (normal tension glaucoma). The undiagnosed group had better MD and smaller vC/D values in the worse eye and less involvement of bilateral VFs than the diagnosed group (p = 0.004–0.050 with Bonferroni correction), while other factors, including mean sensitivity of the binocular VF, showed no intergroup difference. Conclusion: The characteristics of Japanese patients with previously undiagnosed POAG indicated that bilateral evaluation of the optic disc and VF are important for identifying individuals with glaucoma. Keywords: Cup-to-disc ratio, open angle glaucoma, population-based, previously undiagnosed eyes, visual field
INTRODUCTION
patients with POAG were previously undiagnosed because they were unaware of the disease.11 To reduce visual impairment in elderly patients and the consequent economic burden on the healthcare system and society, early detection and management of POAG are important medically and from a public health standpoint. The 111 patients with previously undiagnosed POAG identified in the Tajimi Study is among the highest proportion in populationbased studies,11,14 which may provide a good opportunity to study three clinically important issues: the clinical features of otherwise undetected POAG in Japanese individuals, the visual status in cases that remained undetected, and any contributing factors related to failure to detect POAG.
Glaucoma is a leading cause of visual impairment worldwide.1,2 Among the glaucomas, primary openangle glaucoma (POAG) is the most common type in many population-based prevalence studies.3–14 Most patients with POAG do not notice that they have the disease, because POAG lacks apparent subjective symptoms until it progresses to the advanced stage. The Tajimi Study, a population-based glaucoma prevalence study carried out in Tajimi City, Japan, found that prevalence rates of POAG are as high as 3.9% in Japanese adults over 40 years of age.11 The Tajimi Study also showed that glaucoma is the second leading cause of bilateral low vision,15 and surprisingly, 93% of
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1
Received 26 August 2012; Revised 2 June 2013; Accepted 20 June 2013; Published online 15 January 2014 Correspondence: Aiko Iwase, MD, PhD, Tajimi Iwase Eye Clinic, 3-101-1, Honmachi, Tajimi, Gifu Prefecture, 507-0033, Japan. Tel: +81 572 25 1221. Fax: +81 572 24 5505. E-mail: [email protected]
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MATERIALS AND METHODS The subjects in the current study were part of those who participated in a population-based eye study of Japanese individuals aged 40 years or older, the Tajimi Study. In summary, of 54,165 inhabitants aged 40 years and older in Tajimi City on August 1, 2000, 4000 subjects were selected randomly and participated in the study. The investigation followed the tenets of the Declaration of Helsinki and the municipal statutes of Tajimi City for protecting personal information; the ethics committee of Tajimi City approved the study protocol. All participants provided written informed consent after the details of the study were explained fully. Among the 4000 subjects, 48 died and 82 were not residents of or had moved from Tajimi City during the screening period. Of the remaining 3870 persons, 3021 (78.1%) participated in the screening examinations. Details of the screening and definitive examinations were reported previously.11 The screening examinations included a medical history of past ocular diseases, ophthalmic examinations, and measurement of systemic parameters. The ocular examinations included measurement of visual acuity (VA), central corneal thickness measured with a specular-type pachmeter (SP-2000P, Topcon, Tokyo, Japan), intraocular pressure (IOP) measurement by Goldmann applanation tonometry, slit-lamp examination, evaluation of the angle width according to the method of van Herick and colleagues,16 fundus examination based on digital color photographs obtained through undilated pupils using a digital fundus camera system (NW6S, Topcon) with angles of 30 and 45 , and visual field (VF) screening using a frequency doubling technology screener (Carl Zeiss Meditec Inc Dublin, CA, USA) with the C20-1 screening test. VA was measured with full subjective refraction to obtain best-corrected VA, using the result obtained with an autorefractometer (KP-8100PA, Topcon). When participants could not come to the facility to be examined, doctors visited them in their homes or at hospital and performed the necessary examinations. Subjects were referred for a definitive examination if they were suspected of having ocular disorders or related conditions and/or if they met one or more of the following criteria: corrected VA 50.7; abnormal findings during the slit-lamp examination or on fundus photographs; IOP 419 mmHg; angle width grade 2 or less according to the method of van Herick and co-authors;16 findings in the optic disc, retina, or both suggestive of glaucoma or other ocular disease; and at least one abnormal test point in the frequency doubling technology VF test.17 The definitive examination included slit-lamp examination, gonioscopy, and optic nerve head and posterior pole fundus evaluation using a Goldmann
two-mirror lens (Haag-Streit, Koeniz, Switzerland), applanation tonometry, and VF testing with the Humphrey Field Analyzer (HFA) Central 30-2 Swedish Interactive Threshold Algorithm standard program (Carl Zeiss Meditec Inc). Unless contraindicated, pupils were dilated to obtain stereoscopic disc photographs (3-DX NM, Nidek, Gamagori, Japan) and observe the ocular fundus by indirect ophthalmoscopy. When the angle was thought to be occludable, the same examinations were performed through undilated pupils. Results of the HFA VF tests were examined, and only VFs that were unreliable were excluded (fixation losses 450%; false positives and negatives 450%).11 Abnormal VF data were defined based on the criteria proposed by Anderson and Patella.18 The hemifield was considered abnormal when the pattern deviation probability plot showed a cluster of 3 or more contiguous non-edge points having sensitivity with a probability55% in the upper or lower hemifield and in one of those with a probability 51%. A final glaucoma diagnosis was based on optic nerve head appearance including vertical cupto-disc (vC/D) ratio, rim width, nerve fiber layer defect, results of HFA VF testing, and the clinical records obtained through screening and definitive examinations. Anomalous discs, including tilted discs, were excluded. The criteria for a POAG diagnosis were based on the criteria of the International Society of Geographic and Epidemiologic Ophthalmology (ISGEO).14,19 Eyes with a history and/or findings suggestive of secondary IOP increases were excluded because of secondary glaucoma or suspicion of secondary glaucoma, and those with an occludable angle because of suspicion of primary angle closure glaucoma or its related conditions. As a result, 119 subjects were diagnosed with definitive POAG. Eight patients were previously diagnosed with POAG. General ophthalmologists had treated five patients with a diagnosis of POAG, but the patients did not meet the ISGEO criteria for definitive glaucoma, but did for glaucoma suspects. A total of 111 patients had not been diagnosed with POAG previously, 12 of them had undergone cataract extraction, and a general ophthalmologist had diagnosed three with a senile cataract and one with superficial punctate keratopathy in the past 10 years. The characteristics of systemic and ocular factors of patients with undiagnosed POAG were summarized and compared to those of patients who had been diagnosed with POAG. An intergroup comparison was performed using the unpaired t-test or Fisher’s exact probability test. The VF results of the undiagnosed patients were classified according to the classification used in the VF analysis in the Ocular Hypertension Treatment Study.20 Ophthalmic Epidemiology
Characteristics of Undiagnosed POAG – Tajimi Study
were similar to those of normal Japanese adults.21,22 A total of 95% of patients were classified with normal tension glaucoma (NTG) with an IOP of 21 mmHg or lower;11,19 this percentage was higher than that of the diagnosed group (p = 0.014 without Bonferroni correction; Table 1). Overall, 30% of the undiagnosed patients had bilateral VA decreases. They had mild glaucomatous damage, with mean deviation (MD) and vC/D ratio of the eye with the worse MD of 5.5 decibels (dB) and 0.72, respectively, which were close to the upper limit in a normal population,19 and a mean sensitivity of the reconstructed binocular VFs23 averaging 27.4 dB. The MD of the eye with the worse MD was significantly negatively correlated with increasing age (r = 0.23, p = 0.016). Bilateral VF damage was significantly less and the MD and vC/D ratio of the worse MD side significantly better than those in the diagnosed group (33/111 (30%) vs 6/8 (75%), 5.5 vs 10.4 dB, 0.72 vs 0.83; p = 0.050, p = 0.016, and p = 0.004, respectively, with Bonferroni correction; Table 2). The sensitivity at each test point of the binocular VFs showed no intergroup differences. In 110 eyes with VF defects of 83 undiagnosed patients for whom reliable HFA results were obtained bilaterally, the arcuate pattern of the VF defects was seen most often in 27%,19 followed by partial arcuate
RESULTS
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Tables 1 and 2 show characteristics of patients with undiagnosed POAG (eyes) and those of diagnosed patients. Of 111 undiagnosed patients (52 men, 59 women), 35 (32%) had bilateral POAG, 28 had unilateral POAG and the other eye glaucoma suspect, and 48 had unilateral POAG. Of eight patients (five men, three women) diagnosed with POAG, six had bilateral POAG, and two unilateral POAG and the other eye glaucoma suspect. Four were treated and four were untreated. The systemic parameters of the patients with undiagnosed POAG did not have any characteristic features. Systemic hypertension (37%) was the most frequent systemic disorder followed by chronic headache (15%). The undiagnosed group tended to have fewer other ocular abnormalities (cataract, pterygium, corneal epitheliopathy or refractive error; p = 0.008 without Bonferroni correction) than the diagnosed group, which was probably due to younger age (p = 0.025 without Bonferroni correction), while other systemic abnormalities, smoking history, height, body weight, and blood pressure showed no intergroup differences. The patients with undiagnosed POAG were mildly myopic with no VA impairment, and IOP, inter-eye asymmetry, and central corneal thickness
TABLE 1. Ocular characteristics of previously undiagnosed and diagnosed primary open-angle glaucoma in the Tajimi Study.
Best corrected visual acuity in the better seeing eye (logMAR) Spherical equivalent refraction of eyes with worse refractive error Bilateral untreated IOP (mmHg) Asymmetric untreated IOP (mmHg) Bilateral central corneal thickness (mm)
Previously undiagnosed, mean ± SD (no. of patients)a
Previously diagnosed, mean ± SD (no. of patients)a
p Value
0.29 ± 0.02 (111)
0.27 ± 0.03 (8)
0.790
1.25 ± 3.75 (102)
0.03 ± 1.50 (4)
0.087
15.2 ± 2.8 (102) 0.62 ± 1.0 (102) 517 ± 29 (102)
17.3 ± 3.3 (4) 1.5 ± 1.0 (4) 533 ± 21 (4)
0.617 0.106 0.941
a
Results of various ocular examinations were not always available or reliable in some patients; the number of patients that could be used for analyses are shown. IOP, intraocular pressure; LogMAR, logarithm of the minimum angle of resolution; SD, standard deviation
TABLE 2. Visual functional characteristics of previously undiagnosed and diagnosed primary open-angle glaucoma eyes in the Tajimi Study. Previously undiagnosed, mean ± SD (no. of patients)a vC/D ratio of eye with worse MD Bilateral involvement of VF, n MD of eye with worse MD (dB) Mean sensitivity of binocular VFzc a
0.72 ± 0.09 33 5.5 ± 5.0 27.5 ± 3.2
(83) (111) (83) (83)
Previously diagnosed, mean ± SD (no. of patients)a 0.83 ± 0.05 6 10.4 ± 9.3 25.4 ± 4.9
(6) (8) (6) (6)
p Value 0.004b 0.050b 0.016b 0.263
The results of various ocular examinations were not always available or reliable in some patients; the number of patients that could be used for analyses are shown. Figures in parenthesis (83) and (6) are the number of eyes where visual field test results are reliable. b With Bonferroni correction. The intergroup comparison was performed only in subjects for which VF test results were reliable bilaterally.11,17 c Binocular VF were reconstructed from the results obtained in both eyes.23 MD, mean deviation; SD, standard deviation; vC/D, vertical cup-to-disc ratio; VF, visual field !
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DISCUSSION The optic disc and VF are damaged irreversibly in glaucoma. Therefore, early detection and treatment are important for preventing visual dysfunction caused by glaucoma,24,25 which is a leading cause of blindness or low vision worldwide.1,2 In the Tajimi Study, 93% patients with POAG were previously undiagnosed,11 which was one of the highest percentages in epidemiologic studies of glaucoma,3,9,13,26–40 and was similar to those reported in developing countries.13 Part of the reason may be that most patients had apparently normal IOP (Table 1), which made the diagnosis difficult. In addition, 53% of patients with POAG identified during epidemiologic screening had normal IOP values bilaterally compared to 14% of the self-selected patients.41 Most undiagnosed patients had mild glaucoma with relatively good binocular and a VFs (mean sensitivity, 27.5 dB) and a best-corrected VA of 40/50 or better in the better-seeing eye. It might have been difficult for most previously undiagnosed patients to know that they had an eye disease, consistent with the current results that according to their reports only 14% of undiagnosed patients had scheduled a consultation during the previous 10 years. Another reason may be that the current health check-up system for subjects 40 years and older in Japan does not routinely include examination of fundus photographs by ophthalmologists. More than 100 undiagnosed patients newly identified in the Tajimi Study may provide a good opportunity to estimate the clinical features of POAG that are undetected by eye care services. The average IOP of 15.2 mmHg and its inter-eye asymmetry of 0.6 mmHg were similar to the values found in normal participants in the Tajimi Study,21 and together with the very high proportion of NTG or POAG with normal IOP (95%) clearly indicated that the usefulness of IOP in screening for patients with POAG is limited, especially in Japan. Central corneal thickness was also similar to the normal value in the Japanese population.22 Although myopia is a significant risk factor for POAG in Japanese individuals,42 and previous studies have suggested that refraction may be useful in screening for undiagnosed POAG,31 an average refractive error in eyes with worse refractive error, 1.3 diopters, did not substantially differ from average ophthalmologically normal Japanese refraction (0.9 diopters),43 suggesting that it would be difficult to screen for POAG based on refraction in Japan. Based on the age and VF status of the current patients with undetected POAG and a normal IOP
(NTG) and reported natural history of NTG,44 it may be possible to roughly estimate the visual prognosis of these patients in the event that they remained unidentified. Although about three quarters of patients would not develop advanced VF damage (MD 515.0 dB) bilaterally at age 80 years, about one seventh of patients would develop advanced bilateral VF damage before reaching 80 years. The comparison of characteristics between the previously undiagnosed and diagnosed patients showed several differences. In the undiagnosed group, there were significantly fewer patients with bilateral VF damage and an IOP of 21 mmHg bilaterally, and the vC/D ratio and MD of the eye with the worse MD were significantly smaller or better in the undiagnosed patients compared with the diagnosed group, consistent with Swedish results,41 indicating that the undiagnosed group had substantially less damage than the diagnosed group. The difference in MD between the two groups was still significant when all the VF test results were included (4.9 ± 5.3 dB (n = 97) vs 11.0 ± 10.5 dB (n = 7), p = 0.001). Several factors have been suggested to be useful for differentiating undiagnosed from diagnosed glaucoma: the absence of visits to an eye care provider during the previous 2 years,31 eye care provided by opticians/optometrists,45,46 lower or higher IOP,31,46 hyperopia,46 not having myopia,31 male gender,40 smaller vC/D ratio,40 inter-eye IOP asymmetry,47 and unilateral involvement.48 The number of patients with diagnosed POAG was small in the current study and a comparison between the undiagnosed and diagnosed group was statistically underpowered. However, bilateral involvement and larger vC/D ratio were the factors that were more commonly seen in the patients with diagnosed POAG than in the undiagnosed patients. In addition to a large vC/D ratio (0.72) in the undiagnosed patients, the findings highlighted the importance of standardized ophthalmic examinations performed by ophthalmologists that include bilateral optic disc and VF testing, since opticians or orthoptists cannot perform fundus examinations in Japan. In summary, the current study reported clinical features of undiagnosed POAG and showed that bilateral evaluation of the optic disc and VFs facilitates identification of patients with glaucoma, not IOP, ametropia, or decreased VA. The results also allowed us to estimate the extent of VF damage at age 80 years of age in patients with undetected NTG if they remained unidentified.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Ophthalmic Epidemiology
Characteristics of Undiagnosed POAG – Tajimi Study Financial support for this study was provided by the Japan National Society for the Prevention of Blindness, Tokyo, Japan, and the Japan Ophthalmologists Association, Tokyo, Japan.
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19. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;86:238–242. 20. Keltner JL, Johnson CA, Cello KE, et al. for the Ocular Hypertension Treatment Study Group. Classification of visual field abnormalities in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2003;121:643–650. 21. Kawase K, Tomidokoro A, Araie M, et al.; Tajimi Study Group; Japan Glaucoma Society. Ocular and systemic factors related to intraocular pressure in Japanese adults: the Tajimi Study. Br J Ophthalmol 2008;92:1175–1179. 22. Tomidokoro A, Araie M, Iwase A; Tajimi Study Group. Corneal thickness and relating factors in a populationbased study in Japan: the Tajimi Study. Am J Ophthalmol 2007;144:152–154. 23. Nelson-Quigg JM, Cello K, Johnson CA. Predicting binocular visual field sensitivity from monocular visual field results. Invest Ophthalmol Vis Sci 2000;41:2212–2221. 24. Kass MA, Heuer DK, Higginbotham EJ, et al. for the Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701–713. 25. Heijl A, Leske MC, Bengtsson B, et al.; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268–1279. 26. Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 1991;266:369–374. 27. Coffey M, Reidy A, Wormald R, et al. Prevalence of glaucoma in the west of Ireland. Br J Ophthalmol 1993;77: 17–21. 28. Dielemans I, Vingerling JR, Wolfs RC, et al. The prevalence of primary open-angle glaucoma in a population-based study in the Netherlands. The Rotterdam Study. Ophthalmology 1994;101:1851–1855. 29. Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103:1661–1669. 30. Dandona L, Dandona R, Srinivas M, et al. Open-angle glaucoma in an urban population in Southern India. The Andhra Pradesh Eye Disease Study. Ophthalmology 2000; 107:1702–1709. 31. Weih LM, Nanjan M, McCarty CA, Taylor HR. Prevalence and predictors of open-angle glaucoma: results from the Visual Impairment Project. Ophthalmology 2001;108: 1966–1972. 32. Ramakrishnan R, Nirmalan PK, Krishnadas R, et al. Glaucoma in a rural population of southern India. The Aravind Comprehensive Eye Survey. Ophthalmology 2003; 110:1484–1490. 33. Rotchford AP, Kirwan JF, Muller MA, et al. Temba glaucoma study: a population-based cross-sectional survey in urban South Africa. Ophthalmology 2003;110: 376–382. 34. Varma R, Ying-Lai M, Francis BA, et al.; Los Angeles Latino Eye Study Group. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology 2004;111:1439–1448. 35. Vijaya L, George R, Paul PG, et al. Prevalence of openangle glaucoma in a rural south Indian population. Invest Ophthalmol Vis Sci 2005;46:4461–4467. 36. Nizankowska MH, Kaczmarek R. Prevalence of glaucoma in the Wroclaw population: the Wroclaw epidemiological study. Ophthalmic Epidemiol 2005;12:363–371. 37. Friedman DS, Jampel HD, Mun˜oz B, West SK. The prevalence of open-angle glaucoma among blacks and
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Ophthalmic Epidemiology
ORIGINAL ARTICLE
Characteristics of Undiagnosed Primary Open-Angle Glaucoma: The Tajimi Study Aiko Iwase1, Yasuyuki Suzuki2, Makoto Araie3,4 and the Tajimi Study Group5 Tajimi Iwase Eye Clinic, Tajimi, Gifu Prefecture, Japan, 2Department of Ophthalmology, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan, 3Kanto Central Hospital, Setagaya-ku, Tokyo, Japan, 4Department of Ophthalmology, University of Tokyo, Bunkyo-ku, Tokyo, Japan, and 5Japan Glaucoma Society, Tokyo, Japan
ABSTRACT Purpose: To evaluate the characteristics of patients with previously undiagnosed primary open-angle glaucoma (POAG) in the Tajimi Study. Methods: Background and ophthalmic examination data from 111 patients previously undiagnosed with POAG from the Tajimi Study, a population-based survey of glaucoma, were analyzed and compared with those of eight patients with previously diagnosed glaucoma. Results: The mean deviation (MD) and vertical cup-to-disc ratio (vC/D) of the worse eye of each patient averaged 5.5 decibels (dB) and 0.72 and 10.4 dB and 0.83, respectively, in undiagnosed and diagnosed POAG. In undiagnosed POAG, arcuate and partial arcuate patterns accounted for 50% of the pattern of the visual field (VF) damage, and 95% of patients presented with intraocular pressure of 21 mmHg or less (normal tension glaucoma). The undiagnosed group had better MD and smaller vC/D values in the worse eye and less involvement of bilateral VFs than the diagnosed group (p = 0.004–0.050 with Bonferroni correction), while other factors, including mean sensitivity of the binocular VF, showed no intergroup difference. Conclusion: The characteristics of Japanese patients with previously undiagnosed POAG indicated that bilateral evaluation of the optic disc and VF are important for identifying individuals with glaucoma. Keywords: Cup-to-disc ratio, open angle glaucoma, population-based, previously undiagnosed eyes, visual field
INTRODUCTION
patients with POAG were previously undiagnosed because they were unaware of the disease.11 To reduce visual impairment in elderly patients and the consequent economic burden on the healthcare system and society, early detection and management of POAG are important medically and from a public health standpoint. The 111 patients with previously undiagnosed POAG identified in the Tajimi Study is among the highest proportion in populationbased studies,11,14 which may provide a good opportunity to study three clinically important issues: the clinical features of otherwise undetected POAG in Japanese individuals, the visual status in cases that remained undetected, and any contributing factors related to failure to detect POAG.
Glaucoma is a leading cause of visual impairment worldwide.1,2 Among the glaucomas, primary openangle glaucoma (POAG) is the most common type in many population-based prevalence studies.3–14 Most patients with POAG do not notice that they have the disease, because POAG lacks apparent subjective symptoms until it progresses to the advanced stage. The Tajimi Study, a population-based glaucoma prevalence study carried out in Tajimi City, Japan, found that prevalence rates of POAG are as high as 3.9% in Japanese adults over 40 years of age.11 The Tajimi Study also showed that glaucoma is the second leading cause of bilateral low vision,15 and surprisingly, 93% of
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Received 26 August 2012; Revised 2 June 2013; Accepted 20 June 2013; Published online 15 January 2014 Correspondence: Aiko Iwase, MD, PhD, Tajimi Iwase Eye Clinic, 3-101-1, Honmachi, Tajimi, Gifu Prefecture, 507-0033, Japan. Tel: +81 572 25 1221. Fax: +81 572 24 5505. E-mail: [email protected]
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MATERIALS AND METHODS The subjects in the current study were part of those who participated in a population-based eye study of Japanese individuals aged 40 years or older, the Tajimi Study. In summary, of 54,165 inhabitants aged 40 years and older in Tajimi City on August 1, 2000, 4000 subjects were selected randomly and participated in the study. The investigation followed the tenets of the Declaration of Helsinki and the municipal statutes of Tajimi City for protecting personal information; the ethics committee of Tajimi City approved the study protocol. All participants provided written informed consent after the details of the study were explained fully. Among the 4000 subjects, 48 died and 82 were not residents of or had moved from Tajimi City during the screening period. Of the remaining 3870 persons, 3021 (78.1%) participated in the screening examinations. Details of the screening and definitive examinations were reported previously.11 The screening examinations included a medical history of past ocular diseases, ophthalmic examinations, and measurement of systemic parameters. The ocular examinations included measurement of visual acuity (VA), central corneal thickness measured with a specular-type pachmeter (SP-2000P, Topcon, Tokyo, Japan), intraocular pressure (IOP) measurement by Goldmann applanation tonometry, slit-lamp examination, evaluation of the angle width according to the method of van Herick and colleagues,16 fundus examination based on digital color photographs obtained through undilated pupils using a digital fundus camera system (NW6S, Topcon) with angles of 30 and 45 , and visual field (VF) screening using a frequency doubling technology screener (Carl Zeiss Meditec Inc Dublin, CA, USA) with the C20-1 screening test. VA was measured with full subjective refraction to obtain best-corrected VA, using the result obtained with an autorefractometer (KP-8100PA, Topcon). When participants could not come to the facility to be examined, doctors visited them in their homes or at hospital and performed the necessary examinations. Subjects were referred for a definitive examination if they were suspected of having ocular disorders or related conditions and/or if they met one or more of the following criteria: corrected VA 50.7; abnormal findings during the slit-lamp examination or on fundus photographs; IOP 419 mmHg; angle width grade 2 or less according to the method of van Herick and co-authors;16 findings in the optic disc, retina, or both suggestive of glaucoma or other ocular disease; and at least one abnormal test point in the frequency doubling technology VF test.17 The definitive examination included slit-lamp examination, gonioscopy, and optic nerve head and posterior pole fundus evaluation using a Goldmann
two-mirror lens (Haag-Streit, Koeniz, Switzerland), applanation tonometry, and VF testing with the Humphrey Field Analyzer (HFA) Central 30-2 Swedish Interactive Threshold Algorithm standard program (Carl Zeiss Meditec Inc). Unless contraindicated, pupils were dilated to obtain stereoscopic disc photographs (3-DX NM, Nidek, Gamagori, Japan) and observe the ocular fundus by indirect ophthalmoscopy. When the angle was thought to be occludable, the same examinations were performed through undilated pupils. Results of the HFA VF tests were examined, and only VFs that were unreliable were excluded (fixation losses 450%; false positives and negatives 450%).11 Abnormal VF data were defined based on the criteria proposed by Anderson and Patella.18 The hemifield was considered abnormal when the pattern deviation probability plot showed a cluster of 3 or more contiguous non-edge points having sensitivity with a probability55% in the upper or lower hemifield and in one of those with a probability 51%. A final glaucoma diagnosis was based on optic nerve head appearance including vertical cupto-disc (vC/D) ratio, rim width, nerve fiber layer defect, results of HFA VF testing, and the clinical records obtained through screening and definitive examinations. Anomalous discs, including tilted discs, were excluded. The criteria for a POAG diagnosis were based on the criteria of the International Society of Geographic and Epidemiologic Ophthalmology (ISGEO).14,19 Eyes with a history and/or findings suggestive of secondary IOP increases were excluded because of secondary glaucoma or suspicion of secondary glaucoma, and those with an occludable angle because of suspicion of primary angle closure glaucoma or its related conditions. As a result, 119 subjects were diagnosed with definitive POAG. Eight patients were previously diagnosed with POAG. General ophthalmologists had treated five patients with a diagnosis of POAG, but the patients did not meet the ISGEO criteria for definitive glaucoma, but did for glaucoma suspects. A total of 111 patients had not been diagnosed with POAG previously, 12 of them had undergone cataract extraction, and a general ophthalmologist had diagnosed three with a senile cataract and one with superficial punctate keratopathy in the past 10 years. The characteristics of systemic and ocular factors of patients with undiagnosed POAG were summarized and compared to those of patients who had been diagnosed with POAG. An intergroup comparison was performed using the unpaired t-test or Fisher’s exact probability test. The VF results of the undiagnosed patients were classified according to the classification used in the VF analysis in the Ocular Hypertension Treatment Study.20 Ophthalmic Epidemiology
Characteristics of Undiagnosed POAG – Tajimi Study
were similar to those of normal Japanese adults.21,22 A total of 95% of patients were classified with normal tension glaucoma (NTG) with an IOP of 21 mmHg or lower;11,19 this percentage was higher than that of the diagnosed group (p = 0.014 without Bonferroni correction; Table 1). Overall, 30% of the undiagnosed patients had bilateral VA decreases. They had mild glaucomatous damage, with mean deviation (MD) and vC/D ratio of the eye with the worse MD of 5.5 decibels (dB) and 0.72, respectively, which were close to the upper limit in a normal population,19 and a mean sensitivity of the reconstructed binocular VFs23 averaging 27.4 dB. The MD of the eye with the worse MD was significantly negatively correlated with increasing age (r = 0.23, p = 0.016). Bilateral VF damage was significantly less and the MD and vC/D ratio of the worse MD side significantly better than those in the diagnosed group (33/111 (30%) vs 6/8 (75%), 5.5 vs 10.4 dB, 0.72 vs 0.83; p = 0.050, p = 0.016, and p = 0.004, respectively, with Bonferroni correction; Table 2). The sensitivity at each test point of the binocular VFs showed no intergroup differences. In 110 eyes with VF defects of 83 undiagnosed patients for whom reliable HFA results were obtained bilaterally, the arcuate pattern of the VF defects was seen most often in 27%,19 followed by partial arcuate
RESULTS
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Tables 1 and 2 show characteristics of patients with undiagnosed POAG (eyes) and those of diagnosed patients. Of 111 undiagnosed patients (52 men, 59 women), 35 (32%) had bilateral POAG, 28 had unilateral POAG and the other eye glaucoma suspect, and 48 had unilateral POAG. Of eight patients (five men, three women) diagnosed with POAG, six had bilateral POAG, and two unilateral POAG and the other eye glaucoma suspect. Four were treated and four were untreated. The systemic parameters of the patients with undiagnosed POAG did not have any characteristic features. Systemic hypertension (37%) was the most frequent systemic disorder followed by chronic headache (15%). The undiagnosed group tended to have fewer other ocular abnormalities (cataract, pterygium, corneal epitheliopathy or refractive error; p = 0.008 without Bonferroni correction) than the diagnosed group, which was probably due to younger age (p = 0.025 without Bonferroni correction), while other systemic abnormalities, smoking history, height, body weight, and blood pressure showed no intergroup differences. The patients with undiagnosed POAG were mildly myopic with no VA impairment, and IOP, inter-eye asymmetry, and central corneal thickness
TABLE 1. Ocular characteristics of previously undiagnosed and diagnosed primary open-angle glaucoma in the Tajimi Study.
Best corrected visual acuity in the better seeing eye (logMAR) Spherical equivalent refraction of eyes with worse refractive error Bilateral untreated IOP (mmHg) Asymmetric untreated IOP (mmHg) Bilateral central corneal thickness (mm)
Previously undiagnosed, mean ± SD (no. of patients)a
Previously diagnosed, mean ± SD (no. of patients)a
p Value
0.29 ± 0.02 (111)
0.27 ± 0.03 (8)
0.790
1.25 ± 3.75 (102)
0.03 ± 1.50 (4)
0.087
15.2 ± 2.8 (102) 0.62 ± 1.0 (102) 517 ± 29 (102)
17.3 ± 3.3 (4) 1.5 ± 1.0 (4) 533 ± 21 (4)
0.617 0.106 0.941
a
Results of various ocular examinations were not always available or reliable in some patients; the number of patients that could be used for analyses are shown. IOP, intraocular pressure; LogMAR, logarithm of the minimum angle of resolution; SD, standard deviation
TABLE 2. Visual functional characteristics of previously undiagnosed and diagnosed primary open-angle glaucoma eyes in the Tajimi Study. Previously undiagnosed, mean ± SD (no. of patients)a vC/D ratio of eye with worse MD Bilateral involvement of VF, n MD of eye with worse MD (dB) Mean sensitivity of binocular VFzc a
0.72 ± 0.09 33 5.5 ± 5.0 27.5 ± 3.2
(83) (111) (83) (83)
Previously diagnosed, mean ± SD (no. of patients)a 0.83 ± 0.05 6 10.4 ± 9.3 25.4 ± 4.9
(6) (8) (6) (6)
p Value 0.004b 0.050b 0.016b 0.263
The results of various ocular examinations were not always available or reliable in some patients; the number of patients that could be used for analyses are shown. Figures in parenthesis (83) and (6) are the number of eyes where visual field test results are reliable. b With Bonferroni correction. The intergroup comparison was performed only in subjects for which VF test results were reliable bilaterally.11,17 c Binocular VF were reconstructed from the results obtained in both eyes.23 MD, mean deviation; SD, standard deviation; vC/D, vertical cup-to-disc ratio; VF, visual field !
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42 A. Iwase et al. in 23%, altitudinal in 16%, paracentral in 15%, unclassified in 10%, total loss in 6%, and nasal step and/or temporal wedge in 3%.
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DISCUSSION The optic disc and VF are damaged irreversibly in glaucoma. Therefore, early detection and treatment are important for preventing visual dysfunction caused by glaucoma,24,25 which is a leading cause of blindness or low vision worldwide.1,2 In the Tajimi Study, 93% patients with POAG were previously undiagnosed,11 which was one of the highest percentages in epidemiologic studies of glaucoma,3,9,13,26–40 and was similar to those reported in developing countries.13 Part of the reason may be that most patients had apparently normal IOP (Table 1), which made the diagnosis difficult. In addition, 53% of patients with POAG identified during epidemiologic screening had normal IOP values bilaterally compared to 14% of the self-selected patients.41 Most undiagnosed patients had mild glaucoma with relatively good binocular and a VFs (mean sensitivity, 27.5 dB) and a best-corrected VA of 40/50 or better in the better-seeing eye. It might have been difficult for most previously undiagnosed patients to know that they had an eye disease, consistent with the current results that according to their reports only 14% of undiagnosed patients had scheduled a consultation during the previous 10 years. Another reason may be that the current health check-up system for subjects 40 years and older in Japan does not routinely include examination of fundus photographs by ophthalmologists. More than 100 undiagnosed patients newly identified in the Tajimi Study may provide a good opportunity to estimate the clinical features of POAG that are undetected by eye care services. The average IOP of 15.2 mmHg and its inter-eye asymmetry of 0.6 mmHg were similar to the values found in normal participants in the Tajimi Study,21 and together with the very high proportion of NTG or POAG with normal IOP (95%) clearly indicated that the usefulness of IOP in screening for patients with POAG is limited, especially in Japan. Central corneal thickness was also similar to the normal value in the Japanese population.22 Although myopia is a significant risk factor for POAG in Japanese individuals,42 and previous studies have suggested that refraction may be useful in screening for undiagnosed POAG,31 an average refractive error in eyes with worse refractive error, 1.3 diopters, did not substantially differ from average ophthalmologically normal Japanese refraction (0.9 diopters),43 suggesting that it would be difficult to screen for POAG based on refraction in Japan. Based on the age and VF status of the current patients with undetected POAG and a normal IOP
(NTG) and reported natural history of NTG,44 it may be possible to roughly estimate the visual prognosis of these patients in the event that they remained unidentified. Although about three quarters of patients would not develop advanced VF damage (MD 515.0 dB) bilaterally at age 80 years, about one seventh of patients would develop advanced bilateral VF damage before reaching 80 years. The comparison of characteristics between the previously undiagnosed and diagnosed patients showed several differences. In the undiagnosed group, there were significantly fewer patients with bilateral VF damage and an IOP of 21 mmHg bilaterally, and the vC/D ratio and MD of the eye with the worse MD were significantly smaller or better in the undiagnosed patients compared with the diagnosed group, consistent with Swedish results,41 indicating that the undiagnosed group had substantially less damage than the diagnosed group. The difference in MD between the two groups was still significant when all the VF test results were included (4.9 ± 5.3 dB (n = 97) vs 11.0 ± 10.5 dB (n = 7), p = 0.001). Several factors have been suggested to be useful for differentiating undiagnosed from diagnosed glaucoma: the absence of visits to an eye care provider during the previous 2 years,31 eye care provided by opticians/optometrists,45,46 lower or higher IOP,31,46 hyperopia,46 not having myopia,31 male gender,40 smaller vC/D ratio,40 inter-eye IOP asymmetry,47 and unilateral involvement.48 The number of patients with diagnosed POAG was small in the current study and a comparison between the undiagnosed and diagnosed group was statistically underpowered. However, bilateral involvement and larger vC/D ratio were the factors that were more commonly seen in the patients with diagnosed POAG than in the undiagnosed patients. In addition to a large vC/D ratio (0.72) in the undiagnosed patients, the findings highlighted the importance of standardized ophthalmic examinations performed by ophthalmologists that include bilateral optic disc and VF testing, since opticians or orthoptists cannot perform fundus examinations in Japan. In summary, the current study reported clinical features of undiagnosed POAG and showed that bilateral evaluation of the optic disc and VFs facilitates identification of patients with glaucoma, not IOP, ametropia, or decreased VA. The results also allowed us to estimate the extent of VF damage at age 80 years of age in patients with undetected NTG if they remained unidentified.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Ophthalmic Epidemiology
Characteristics of Undiagnosed POAG – Tajimi Study Financial support for this study was provided by the Japan National Society for the Prevention of Blindness, Tokyo, Japan, and the Japan Ophthalmologists Association, Tokyo, Japan.
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