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Angle Closure Phenotypes in Siblings of Patients at Different Stages of Angle Closure
Reports Angle Closure Phenotypes in Siblings of Patients at Different Stages of Angle Closure Early detection and treatment of angle closure with laser peripheral iridotomy may prevent progression to more severe disease and vision loss. Screening for undiagnosed cases of angle closure should focus on identifying those at high risk of angle closure. Previous work from our group has demonstrated that siblings of individuals with known angle closure have a >1 in 3 risk of angle closure suggesting screening based on family history is likely to be high yield.1 When screening for angle closure, it is particularly important to identify eyes with manifest primary angle-closure glaucoma (PACG) or a high risk for future PACG owing to increased intraocular pressure (IOP) or peripheral anterior synechiae. Herein, we determine whether more severe stages of angle closure (primary angle closure [PAC] or PACG) are more prevalent amongst siblings of PAC/PACG probands as compared with siblings of PAC suspects (PACS). Aravind Eye Hospital Review Board approved the study protocol and all participants provided written informed consent. Probands were recruited from glaucoma patients visiting Aravind Eye Hospitals in Tamil Nadu, India. Probands were eligible if they were 30 years, had the diagnosis of PACS or PAC/PACG in 1 eye and had 1 sibling who was >30 years old and shared the same parents. Individuals were ineligible if they (1) were bilaterally pseudophakic, (2) had prior iridotomy, iridoplasty, or incisional glaucoma surgery in either eye, or (3) had signs or symptoms consistent with acute angle closure. All subjects underwent baseline ophthalmic examination by trained technicians including visual acuity with refraction, pachymetry, and A-scan. A masked glaucoma specialist completed a full slit-lamp examination, applanation tonometry, and gonioscopy as previously detailed.1 Findings in the more severely affected eye were used to classify probands as (1) PACS or (2) PAC/PACG. One sibling per proband was similarly classified as (1) open angle, (2) PACS or (3) PAC/ PACG. Angle closure stages were defined according to International Society for Geographic and Epidemiologic Ophthalmology guidelines modified to collapse PAC and PACG into a single category (PAC/PACG) owing to lack of reliable visual field data.1 Group differences in continuous and categorical variables were evaluated using Student t tests and chi-square tests, respectively. Sibling outcomes were evaluated using univariate and multivariable logistic regression models. We aimed to recruit 468 and 156 PACS and PAC/PACG sibling pairs based on a type I error probability of 0.05, a 3:1 ratio for PACS:PAC/PACG probands, a power of 0.8, and previously reported prevalence data.1 Analyses were performed using Stata 12 (StataCorp, College Station, TX). In all, 636 sibling pairs, including 482 PACS and 154 PAC/ PACG sibling pairs were studied. Siblings of PAC/PACG probands were older, more hyperopic, and had higher IOP than PACS siblings (P < 0.05 for all; Table 1, available at
www.aaojournal.org). In multivariable analyses adjusting for sibling age and gender, PAC/PACG siblings had a significantly higher IOP than PACS siblings (b ¼ þ1.2 mmHg; 95% confidence interval [CI], 0.6e1.8; P < 0.001), but did not demonstrate greater cup/disc ratios (P ¼ 0.2) or more frequent peripheral anterior synechiae (P ¼ 0.8). There was no difference in the prevalence of any angle closure (PACS, PAC, or PACG) among PACS siblings (32.8%) and PAC/ PACG siblings (35.1%; P ¼ 0.6). However, PAC/PACG was more prevalent among siblings of PAC/PACG probands compared with siblings of PACS probands (8.4% vs 3.5%, respectively; P ¼ 0.01; Figure 1). In multivariable models, neither sibling age (odds ratio [OR], 1.5 per 10-year increment; 95% CI, 0.98e2.2; P ¼ 0.06) nor female gender (OR, 1.3; 95% CI, 0.6e2.8; P ¼ 0.5) had a significant association with prevalent sibling PAC/PACG. In multivariable models, PAC/PACG siblings demonstrated a 2.3-fold higher odds (95% CI, 1.1e4.9; P ¼ 0.03) of prevalent PAC/PACG as compared with PACS siblings (Table 2, available at www.aaojournal.org). Our results demonstrate that siblings of South Indian PAC/PACG probands are more than twice as likely to demonstrate PAC/PACG compared with siblings of PACS probands. Both sibling groups had a substantially higher prevalence of angle closure compared with the general South Indian population (33%-35% vs 1.25%e7.5%),2 suggesting strong heritability of angle closure phenotype.1 The majority of siblings with angle closure had PACS with a considerably lower rate of PAC/PACG in both groups. Although the prevalence of PAC/PACG in PACS siblings was comparable with that previously reported for this population (0.9%e3.7%),3 PAC/PACG siblings had nearly 3 times the population prevalence of PAC/PACG. These data suggest that siblings of PAC/PACG patients have a much greater risk of more severe stages of angle closure compared with siblings of patients with PACS. Siblings of PAC/PACG probands had higher IOP than siblings of PACS probands. This effect persisted even after excluding siblings with PAC/PACG diagnosis (P ¼ 0.002; data not shown). However, we found minimal differences in ocular biometric features between the 2 groups, suggesting that A-scan parameters do not explain the higher IOP seen in PAC/PACG siblings. It is possible that some eyes are less tolerant of iridotrabecular contact. In these eyes, factors such as duration of iridotrabecular contact and trabecular response to contact, likely results in subclinical trabecular meshwork damage and IOP increases.4 Our results may reflect different sets of genetic risk factors that determine the presence or absence of iridotrabecular contact and progression to downstream sequelae (IOP increases, peripheral anterior synechiae formation, and glaucoma damage). Alternatively, it is possible that PAC/PACG probands and their siblings have a longer duration of iridotrabecular contact or share other environmental factors that predispose to development of PAC/ PACG after iridotrabecular contact. Given the greater prevalence of PAC/PACG in PAC/PACG siblings independent of sibling age, earlier onset of iridotrabecular contact in this group is possible.
1
Ophthalmology Volume -, Number -, Month 2016 PRADEEP Y. RAMULU, MD, PHD1 RENGARAJ VENKATESH, MD2 1
Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland; Aravind Eye Hospital, Pondicherry, Tamil Nadu, India; 3Aravind Eye Hospital, Tirunelveli, Tamil Nadu, India; 4Aravind Eye Hospital, Coimbatore, Tamil Nadu, India; 5Aravind Eye Hospital, Madurai, Tamil Nadu, India 2
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Supported by Research to Prevent Blindness and Morton F. Goldberg Director’s Discovery Fund. The funding organizations had no role in the design or conduct of this research.
Figure 1. Prevalence of sibling angle closure by proband angle closure status. Data are presented as percentage of siblings with open angles (OA), primary angle-closure suspect (PACS) and primary angle closure/primary angle-closure glaucoma (PAC/PACG) in each proband group. *P < 0.05.
Strengths of our study include a large sample size and use of masked gonioscopic graders. However, our cross-sectional design prohibits the ability to decipher causality. In addition, it was not possible to determine with certainty that angle closure alone was responsible for increases in IOP and/or glaucomatous changes in the PAC/PACG group, and mixed mechanism glaucoma cannot be ruled out.5 The greater prevalence of PAC/PACG observed in PAC/PACG siblings suggests that this is a particularly important group to screen. Screening of PACS siblings to identify (mostly) uncomplicated iridotrabecular contact may also be important, although this is less clear given the unknown likelihood of progression to PAC/PACG in this group. If progression is rare, screening PACS siblings may result in unnecessary effort. Aggressive screening of PAC/PACG siblings may be of greater benefit in identifying those with manifest glaucoma damage or at high risk of future damage.
NAZLEE ZEBARDAST, MD, MS1 SRINIVASAN KAVITHA, MD2 KRISHNAMURTHY PALANISWAMY, MD2 SABYASACHI SENGUPTA, DNB, FRCS2 MOHIDEEN ABDUL KADER, MD3 GANESH RAMAN, MD4 SHARMILA REDDY, MD5
2
Author Contributions: Conception and design: Ramulu, Venkatesh Analysis and interpretation: Zebardast, Ramulu Data collection: Zebardast, Palaniswamy, Sengupta, Kader, Raman, Reddy, Ramulu, Venkatesh Obtained funding: Not applicable Overall responsibility: Zebardast, Kavitha, Palaniswamy, Sengupta, Kader, Raman, Reddy, Ramulu, Venkatesh Correspondence: Rengaraj Venkatesh, MD, Aravind Eye Hospital, Cuddalore Main Road,Thavalakuppam, Pondicherry 605 007, India. E-mail: [email protected].
References 1. Kavitha S, Zebardast N, Palaniswamy K, et al. Family history is a strong risk factor for prevalent angle closure in a South Indian population. Ophthalmology 2014;121:2091–7. 2. Vijaya L, George R, Arvind H, et al. Prevalence of angleclosure disease in a rural southern Indian population. Arch Ophthalmol 2006;124:403–9. 3. Garudadri C, Senthil S, Khanna RC, et al. Prevalence and risk factors for primary glaucomas in adult urban and rural populations in the Andhra Pradesh Eye Disease Study. Ophthalmology 2010;117:1352–9. 4. Narayanaswamy A, Zheng C, Perera SA, et al. Variations in iris volume with physiologic mydriasis in subtypes of primary angle closure glaucoma. Invest Ophthalmol Vis Sci 2013;54:708–13. 5. Sihota R, Vashisht P, Sharma A, et al. Anterior segment optical coherence tomography characteristics in an Asian population. J Glaucoma 2012;21:180–5.
www.aaojournal.org). In multivariable analyses adjusting for sibling age and gender, PAC/PACG siblings had a significantly higher IOP than PACS siblings (b ¼ þ1.2 mmHg; 95% confidence interval [CI], 0.6e1.8; P < 0.001), but did not demonstrate greater cup/disc ratios (P ¼ 0.2) or more frequent peripheral anterior synechiae (P ¼ 0.8). There was no difference in the prevalence of any angle closure (PACS, PAC, or PACG) among PACS siblings (32.8%) and PAC/ PACG siblings (35.1%; P ¼ 0.6). However, PAC/PACG was more prevalent among siblings of PAC/PACG probands compared with siblings of PACS probands (8.4% vs 3.5%, respectively; P ¼ 0.01; Figure 1). In multivariable models, neither sibling age (odds ratio [OR], 1.5 per 10-year increment; 95% CI, 0.98e2.2; P ¼ 0.06) nor female gender (OR, 1.3; 95% CI, 0.6e2.8; P ¼ 0.5) had a significant association with prevalent sibling PAC/PACG. In multivariable models, PAC/PACG siblings demonstrated a 2.3-fold higher odds (95% CI, 1.1e4.9; P ¼ 0.03) of prevalent PAC/PACG as compared with PACS siblings (Table 2, available at www.aaojournal.org). Our results demonstrate that siblings of South Indian PAC/PACG probands are more than twice as likely to demonstrate PAC/PACG compared with siblings of PACS probands. Both sibling groups had a substantially higher prevalence of angle closure compared with the general South Indian population (33%-35% vs 1.25%e7.5%),2 suggesting strong heritability of angle closure phenotype.1 The majority of siblings with angle closure had PACS with a considerably lower rate of PAC/PACG in both groups. Although the prevalence of PAC/PACG in PACS siblings was comparable with that previously reported for this population (0.9%e3.7%),3 PAC/PACG siblings had nearly 3 times the population prevalence of PAC/PACG. These data suggest that siblings of PAC/PACG patients have a much greater risk of more severe stages of angle closure compared with siblings of patients with PACS. Siblings of PAC/PACG probands had higher IOP than siblings of PACS probands. This effect persisted even after excluding siblings with PAC/PACG diagnosis (P ¼ 0.002; data not shown). However, we found minimal differences in ocular biometric features between the 2 groups, suggesting that A-scan parameters do not explain the higher IOP seen in PAC/PACG siblings. It is possible that some eyes are less tolerant of iridotrabecular contact. In these eyes, factors such as duration of iridotrabecular contact and trabecular response to contact, likely results in subclinical trabecular meshwork damage and IOP increases.4 Our results may reflect different sets of genetic risk factors that determine the presence or absence of iridotrabecular contact and progression to downstream sequelae (IOP increases, peripheral anterior synechiae formation, and glaucoma damage). Alternatively, it is possible that PAC/PACG probands and their siblings have a longer duration of iridotrabecular contact or share other environmental factors that predispose to development of PAC/ PACG after iridotrabecular contact. Given the greater prevalence of PAC/PACG in PAC/PACG siblings independent of sibling age, earlier onset of iridotrabecular contact in this group is possible.
1
Ophthalmology Volume -, Number -, Month 2016 PRADEEP Y. RAMULU, MD, PHD1 RENGARAJ VENKATESH, MD2 1
Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland; Aravind Eye Hospital, Pondicherry, Tamil Nadu, India; 3Aravind Eye Hospital, Tirunelveli, Tamil Nadu, India; 4Aravind Eye Hospital, Coimbatore, Tamil Nadu, India; 5Aravind Eye Hospital, Madurai, Tamil Nadu, India 2
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Supported by Research to Prevent Blindness and Morton F. Goldberg Director’s Discovery Fund. The funding organizations had no role in the design or conduct of this research.
Figure 1. Prevalence of sibling angle closure by proband angle closure status. Data are presented as percentage of siblings with open angles (OA), primary angle-closure suspect (PACS) and primary angle closure/primary angle-closure glaucoma (PAC/PACG) in each proband group. *P < 0.05.
Strengths of our study include a large sample size and use of masked gonioscopic graders. However, our cross-sectional design prohibits the ability to decipher causality. In addition, it was not possible to determine with certainty that angle closure alone was responsible for increases in IOP and/or glaucomatous changes in the PAC/PACG group, and mixed mechanism glaucoma cannot be ruled out.5 The greater prevalence of PAC/PACG observed in PAC/PACG siblings suggests that this is a particularly important group to screen. Screening of PACS siblings to identify (mostly) uncomplicated iridotrabecular contact may also be important, although this is less clear given the unknown likelihood of progression to PAC/PACG in this group. If progression is rare, screening PACS siblings may result in unnecessary effort. Aggressive screening of PAC/PACG siblings may be of greater benefit in identifying those with manifest glaucoma damage or at high risk of future damage.
NAZLEE ZEBARDAST, MD, MS1 SRINIVASAN KAVITHA, MD2 KRISHNAMURTHY PALANISWAMY, MD2 SABYASACHI SENGUPTA, DNB, FRCS2 MOHIDEEN ABDUL KADER, MD3 GANESH RAMAN, MD4 SHARMILA REDDY, MD5
2
Author Contributions: Conception and design: Ramulu, Venkatesh Analysis and interpretation: Zebardast, Ramulu Data collection: Zebardast, Palaniswamy, Sengupta, Kader, Raman, Reddy, Ramulu, Venkatesh Obtained funding: Not applicable Overall responsibility: Zebardast, Kavitha, Palaniswamy, Sengupta, Kader, Raman, Reddy, Ramulu, Venkatesh Correspondence: Rengaraj Venkatesh, MD, Aravind Eye Hospital, Cuddalore Main Road,Thavalakuppam, Pondicherry 605 007, India. E-mail: [email protected].
References 1. Kavitha S, Zebardast N, Palaniswamy K, et al. Family history is a strong risk factor for prevalent angle closure in a South Indian population. Ophthalmology 2014;121:2091–7. 2. Vijaya L, George R, Arvind H, et al. Prevalence of angleclosure disease in a rural southern Indian population. Arch Ophthalmol 2006;124:403–9. 3. Garudadri C, Senthil S, Khanna RC, et al. Prevalence and risk factors for primary glaucomas in adult urban and rural populations in the Andhra Pradesh Eye Disease Study. Ophthalmology 2010;117:1352–9. 4. Narayanaswamy A, Zheng C, Perera SA, et al. Variations in iris volume with physiologic mydriasis in subtypes of primary angle closure glaucoma. Invest Ophthalmol Vis Sci 2013;54:708–13. 5. Sihota R, Vashisht P, Sharma A, et al. Anterior segment optical coherence tomography characteristics in an Asian population. J Glaucoma 2012;21:180–5.