Anterior Segment Optical Coherence Tomography Parameters in Subtypes of Primary Angle Closure

Abstract

Purpose.: To compare anterior segment parameters, assessed by anterior segment optical coherence tomography (ASOCT), in subjects categorized as primary angle closure suspect (PACS), primary angle closure (PAC), primary angle closure glaucoma (PACG), and previous acute PAC (APAC); and to identify factors associated with APAC.

Methods.: This was a prospective ASOCT study of 425 subjects with angle closure (176 PACS, 66 PAC, 125 PACG, and 58 APAC). Customized software was used to measure ASOCT parameters, including angle opening distance (AOD750), trabecular–iris space area (TISA750), anterior chamber depth, width, area and volume (ACD, ACW, ACA, ACV), iris thickness (IT750), iris area (IAREA), and lens vault (LV). Mean differences in anterior segment parameters were evaluated by analysis of covariance (ANCOVA) adjusted for age, sex, and pupil diameter (PD).

Results.: Comparison among the different subgroups showed that ACD, ACA, and ACV were smallest, and IT750 thickest in the APAC group compared with the other subgroups (P < 0.001). LV was greatest in the APAC group (1218 ± 34 μm) followed by PAC (860 ± 31 μm), PACG (845 ± 23 μm), and PACS (804 ± 19 μm), respectively (P = <0.001). While the APAC group had the narrowest angles, the PACS group had the widest (P < 0.001 for both AOD750 and TISA750). Logistic regression showed that greater LV (P = <0.001), narrower TISA750 (P = <0.001), and thicker IT750 (P = 0.007) were the major determinants of APAC.

Conclusions.: Eyes with APAC had the narrowest angles, smallest anterior segment dimensions, thickest iris, and largest LV compared with PACS, PAC, and PACG. LV, TISA750, and IT750 were the major determinants of APAC.

Introduction

Primary angle closure glaucoma (PACG), a leading cause of ocular morbidity, affects an estimated 16 million people worldwide with 4 million suffering from bilateral blindness. This number is projected to increase to 5.3 million by year 2020. ^1–3 Population-based studies have shown that PACG has greater prevalence in persons of Asian ethnicity than in Europeans and Africans. ^2–6  

Foster et al. proposed a scheme that subdivides angle closure disease into primary angle closure suspect (PACS), primary angle closure (PAC), and primary angle closure glaucoma (PACG). ⁷ Acute primary angle closure (APAC), which can occur in any of these stages, has higher incidence in parts of Asia such as in Singapore, where the reported incidence was 12.2 per 100,000 per year in those aged 30 years and older. ⁸ A study on the long term outcome of APAC reported that 17.8% of subjects were blind in the attack eye and half had glaucomatous optic nerve damage after several years. ⁸ In a retrospective case series of 137 eyes with PACG, Quek et al. found that over 10 years, one-third of subjects had visual field progression and 7% developed blindness, despite treatment. Visual field progression was more likely in eyes with higher mean overall IOP and a history of APAC. ^9,10 Because of the blinding nature of APAC, identification of patients at risk for APAC is paramount. 

Using anterior segment optical coherence tomography (ASOCT), recent studies have identified novel anatomic factors associated with angle closure, namely smaller anterior chamber area (ACA), width (ACW) and volume (ACV), thicker iris with greater curvature, and increased lens vault (LV). ^11–14 However, it is not known how these parameters differ in the subtypes of angle closure. The objectives of this study were to evaluate and compare anterior segment parameters in patients with different stages of angle closure disease using ASOCT, and to identify factors associated with APAC. 

Methods

This prospective observational comparative study was approved by the institutional review board of the Singapore Eye Research Institute and was conducted in adherence to the tenets of the Declaration of Helsinki. Written informed consent was obtained from each subject. 

Subjects aged 40 years and above, diagnosed with angle closure disease, classified as PACS, PAC, PACG, and previous APAC were recruited from glaucoma clinics of the Singapore National Eye Center. Each subject underwent a standardized ophthalmic examination, which included visual acuity assessment, slit-lamp examination, stereoscopic evaluation of the optic disc using a 78-diopter (D) lens (Volk Optical, Inc., Mentor, OH), and IOP measurement with Goldmann applanation tonometry (Haag-Streit, Koniz, Switzerland). A-scan ultrasonography (Model US-800; Nidek Co., Ltd., Tokyo, Japan) was used to measure axial length (AXL) and lens thickness (LT). 

Gonioscopy was performed by an experienced examiner in the dark using a Goldmann 2-mirror lens (Haag-Streit AG, Bern, Switzerland) at 16× magnification. Indentation gonioscopy was carried out using a Sussman 4-mirror lens (Ocular Instruments, Inc., Bellevue, WA) to establish the presence and degree of peripheral anterior synechiae (PAS), defined as abnormal adhesions of the iris to the angle that were at least half a clock hour in width and were present to the level of the anterior trabecular meshwork or higher. 

Four subgroups of angle closure patients were examined: 

1.  
   PACS was diagnosed in patients with narrow angles (defined as eyes in which at least 180° of the posterior pigmented trabecular meshwork was not visible on gonioscopy in the primary position of gaze without indentation) with IOP less than or equal to 21 mm Hg, healthy optic disc, and without PAS;
2.  
   PAC was diagnosed in eyes with narrow angles, healthy optic discs, and visual fields, but with elevated IOP (defined as an IOP >21 mm Hg), and/or PAS;
3.  
   PACG was diagnosed on the basis of narrow angles with glaucomatous optic neuropathy (GON, defined as vertical cup-to-disc ratio [CDR] ≥0.7, CDR asymmetry >0.2, and/or focal notching) with compatible visual field loss on static automated perimetry (SITA Standard algorithm with a 24- 2 test pattern; Humphrey Visual Field Analyzer II; Carl Zeiss Meditec, Dublin, CA). This was defined as Glaucoma Hemifield Test outside normal limits; a cluster of three or more, nonedge, contiguous points on the pattern deviation plot, not crossing the horizontal meridian with a probability of less than 5% being present in age-matched normals (one of which was <1%); and an abnormal pattern standard deviation (PSD) with a P value less than 5% occurring in the healthy population, and fulfilling the test reliability criteria (fixation losses < 20%, false positives < 33%, and/or false negatives < 33%); and
4.  
   APAC was diagnosed in patients with the following criteria: presence of any two of the following symptoms: ocular or peri-ocular pain, nausea and/or vomiting, an antecedent history of intermittent blurring of vision with haloes, presenting IOP of greater than 21 mm Hg; and presence of at least 3 of the following signs: conjunctival injection, corneal epithelial edema, middilated pupil, and shallow anterior chamber.

Anterior Segment Optical Coherence Tomography Imaging and Analysis

All ASOCT (Visante; Carl Zeiss Meditec) examinations were done after laser peripheral iridotomy (LPI). A single operator, masked to the results of clinical findings, performed ASOCT on each participant under standardized dark conditions (0 lux). Scans were centered on the pupil and taken along the horizontal axis (nasal–temporal angles at 0°–180°) using the standard anterior segment single-scan protocol. To obtain the best-quality image, the examiner adjusted the saturation and noise and optimized the polarization for each scan during the examination. Because several scans were acquired by the ASOCT device, the examiner chose the best image, with no motion or image artifacts caused by the eyelids. 

One cross-sectional, horizontal ASOCT scan of the nasal and temporal angles was evaluated for each subject. These images were processed using customized software, the Zhongshan Angle Assessment Program (ZAAP; Guangzhou, China) ¹⁵ by a single experienced observer (MEN) who was masked to clinical data. The only observer input was to determine the location of the scleral spurs. The algorithm then automatically calculated the anterior segment parameters. The following parameters as illustrated in the Figure were measured: angle opening distance at 750 μm (AOD750) from the scleral spur; trabecular–iris space area at 750 μm from the scleral spur (TISA750); ARA, iris thickness at 750 μm from the scleral spur (IT750); iris curvature (ICURV), iris area (IAREA), anterior chamber depth (ACD), ACW, ACA, ACV, and LV. 

Figure

 

ASOCT image showing the measurements of AOD750, TISA750, IT750, iris curvature, ACD, ACW, angle recess area (ARA), and LV. SS, scleral spur.

Statistical Analysis

One eye of each subject was analyzed. The study eye was randomly selected for bilateral cases, whereas the affected eye was used in unilateral cases. Comparisons of the mean values of ASOCT findings in PACS, PAC, PACG, and APAC were performed. Differences in mean values of parametric data among different subtypes of angle closure were analyzed after adjusting for age, sex, and pupil diameter (PD) using one-way ANCOVA with Bonferroni method for multiple comparisons. Data was expressed as mean ± SE. Multivariate logistic regression analysis was performed to identify determinants of APAC and odds ratios with 95% confidence interval (CI) were reported. A stepwise selection algorithm was done to determine the contribution of each parameter to APAC. Statistical Package for Social Sciences version 17.0 (SPSS, Inc., Chicago, IL) was used in the statistical analysis, and statistical significance was assumed at P less than 0.05 levels. 

Results

A total of 425 subjects were included in the study. The majority of subjects were Chinese (95%) and female (69%). The mean age of the subjects was 65 years (range, 43–93 years). Of the 425 subjects, 176 (41%) were diagnosed as PACS, 66 (16%) PAC, 125 (29%) PACG, and 58 (14%) had previous APAC. Patients with APAC had the shortest AL. There was no significant difference in lens thickness among the subtypes of angle closure disease (Table 1). The mean values of the anterior chamber angle parameters are summarized in Table 2. There was a significant difference in the angle parameters (AOD, TISA, and ARA) between APAC and PAC, PACG, PACS; PACS and PAC; PACS and PACG (all with P < 0.05); however, there was no significant difference in these parameters between PAC and PACG. The APAC group had the narrowest angles. 

Table 1

 

Demographic Features of Subjects With Different Subtypes of Primary Angle Closure Disease

Variable	PACS, n = 176	PAC, n = 66	PACG, n = 125	APAC, n = 58	P Value
Sex
Female N (%)	135 (76.7)	41 (62.1)	74 (52.9)	42 (72.4)	<0.01
Ethnicity
Chinese N (%)	168 (95.5)	61 (92.4)	118 (94.4)	56 (96.6)	0.73
Others* N (%)	8 (4.5)	5 (7.6)	7 (5.6)	2 (3.4)
Age ± SD, y	63.07 ± 7.36	65.56 ± 7.89	69.22 ± 10.12	61.50 ± 7.33	<0.01†
AXL	22.73 ± 0.07	22.74 ± 0.12	22.88 ± 0.90	22.47 ± 0.13	0.11
LT	4.25 ± 0.08	3.95 ± 0.12	3.97 ± 0.09	4.19 ± 0.13	0.06
PD ± SD, mm	3.85 ± 0.06	3.75 ± 0.09	3.69 ± 0.07	4.07 ± 0.10	0.017‡

*  Others (Malays, Indians, and others).

†  PACS versus PACG P < 0.01; PAC versus PACG P = 0.03; PAC versus APAC P = 0.04; and PACG versus APAC P < 0.01.

‡  PACG versus APAC P < 0.01.

Table 2

 

Mean Anterior Chamber Angle Parameters Using ASOCT

Parameter	PACS, n = 176	PAC, n = 66	PACG, n = 125	APAC, n = 58	P Value
AOD750 ± SE, mm	0.28 ± 0.007	0.24 ± 0.012	0.23 ± 0.009	0.13 ± 0.013	<0.001*
TISA750 ± SE, mm2	0.15 ± 0.004	0.12 ± 0.006	0.11 ± 0.005	0.08 ± 0.006	<0.001†
ARA ± SE, mm2	0.18 ± 0.005	0.13 ± 0.007	0.12 ± 0.006	0.09 ± 0.008	<0.001‡

*  APAC versus PAC, PACG, and PACS, PACS versus PACG P < 0.001; PAC versus PACS P = 0.03.

†  APAC versus PAC, PACG, and PACS, PACS versus PAC, PACS versus PACG P < 0.001.

‡  PACS versus PAC, PACG, and APAC, PAC versus APAC P < 0.001; PACG versus APAC P = 0.005.

When compared with the other groups, there was a significant difference between mean ACD value of APAC and the rest of the other subtypes of angle closure disease (all with P < 0.001) with the APAC group having the smallest mean ACD (Table 3). Likewise, APAC group had the lowest mean value in ACA and ACV and they were significantly different when compared with the rest of the subtypes (P < 0.001). Comparison of iris parameters (Table 4) showed that the iris was thickest in the APAC group, and a significant difference in IT750 was noted between APAC and PACS, PAC, PACG (all P < 0.05). LV was also found to be the greatest in the APAC group, with a significant difference between APAC and PACS, PAC, PACG (all with P < 0.001). 

Table 3

 

Anterior Segment Parameters Using ASOCT

Parameter	PACS, n = 176	PAC, n = 66	PACG, n = 125	APAC, n = 58	P Value
ACD ± SE, mm	2.17 ± 0.02	2.13 ± 0.03	2.15 ± 0.03	1.74 ± 0.04	<0.001*
ACW ± SE, mm	11.24 ± 0.03	11.37 ± 0.05	11.37 ± 0.04	11.32 ± 0.05	0.04†
ACA ± SE, mm2	15.92 ± 0.17	15.64 ± 0.28	15.68 ± 0.21	12.51 ± 0.30	<0.001‡
ACV ± SE, mm2	102.7 ± 1.32	101.0 ± 2.12	100.7 ± 1.61	78.9 ± 2.31	<0.001§

*  APAC versus PAC, PACG, and PACS, P < 0.001.

†  No significant difference in any of the pairwise comparisons.

‡  APAC versus PAC, PACG, and PACS; P < 0.001.

§  APAC versus PAC, PACG, and PACS; P < 0.001.

Table 4

 

Iris and Lens Parameters Using ASOCT

Parameter	PACS, n = 176	PAC, n = 66	PACG, n = 125	APAC, n = 58	P Value
IT750 ± SE, mm	0.46 ± 0.01	0.47 ± 0.01	0.47 ± 0.01	0.52 ± 0.01	0.002*
IAREA ± SE, mm2	1.55 ± 0.02	1.56 ± 0.03	1.61 ± 0.03	1.59 ± 0.04	0.24
ICURV ± SE, mm	0.20 ± 0.01	0.18 ± 0.01	0.17 ± 0.01	0.18 ± 0.01	0.10
LV ± SE, μm	804 ± 19	860 ± 31	845 ± 23	1218 ± 34	<0.001†

 IT750, IT2000, iris thickness at 750 μm from the scleral spur.

*  APAC versus PACS P < 0.001; APAC versus PACG P = 0.02; APAC versus PAC P = 0.04.

†  APAC versus PAC, PACG, and PACS P < 0.001.

A multivariate logistic regression analysis was performed (Table 5) to determine which among the anterior segment parameters were associated with APAC. It was found that shallower ACD, greater LV, thicker iris, narrower angle width, and younger age were significant determinants of APAC (R ² = 55.6%). The individual contribution of each variable as determined by stepwise regression analysis were 33.3% by ACD, 13.2% by TISA750, 3.2% by LV, 2.7% by age, and 1.8% by IT750, with the overall contribution of the model being 54.2%. 

Table 5

 

Logistic Regression Analysis of Determinants of Acute Angle Closure (APAC Versus PACS, PAC, PACG)

Baseline Characteristic	Age and Sex Adjusted Univariate OR (95% CI)	P Value	Multivariate Adjusted OR (95% CI), R 2 = 55.6%	P Value
Age, y	0.95 (0.91–0.98)	0.001	0.92 (0.88–0.97)	0.003
Ethnicity, reference = non-Chinese	2.00 (0.45–9.00)	0.36
Sex, reference = male	1.13 (0.61–2.12)	0.69	0.58 (0.24–1.43)	0.24
AXL	0.71 (0.51–1.00)	0.053	0.77 (0.46–1.31)	0.34
LT	1.05 (0.78–1.42)	0.74
ACD	0.003 (0.001–0.014)	<0.001	0.12 (0.01–1.19)	0.07
ACW	1.34 (0.65–2.74)	0.43
ACA	0.51 (0.43–0.62)	<0.001
ACV	0.92 (0.90–0.94)	<0.001
LV	1.006 (1.004–1.007)	<0.001	1.004 (1.002–1.007)	0.001
AOD750	0.98 (0.98–0.99)	<0.001
TISA750	0.97 (0.96–0.98)	<0.001	0.98 (0.97–0.99)	<0.001
ARA	0.98 (0.97–0.99)	<0.001
IT750	68 (6.6–704.8)	<0.001	104 (2.8–3878)	0.01
IAREA	0.78 (0.29–2.11)	0.62
ICURV	0.41 (0.02–6.94)	0.23	0.22 (0.006–8.31)	0.41
PD	1.66 (1.13–2.44)	0.01	0.76 (0.42–1.35)	0.35

 Significant difference noted as P < 0.05.

Discussion

Our study on the biometric differences between subtypes of angle closure showed that whilst the APAC group had the smallest anterior segment dimensions, with large LV and thick iris, the PACS group had the widest angles, with thinner iris and small LV. The biometric parameters of PAC and PACG were not significantly different from each other. This is consistent with recent findings from another study on the subtypes of angle closure in Iranian patients using ASOCT. Moghimi and colleagues ¹⁶ found that patients with acute PACG had the least mean ACD, AOD500, TISA500, and largest LV when compared with other subtypes. However, IT was not measured. 

Ultrasound biomicroscopy (UBM) based differences in angle closure subtypes among North Indians were described by Sihota and colleagues. ¹⁷ Similar to our findings on ASOCT-based parameters, they also observed that the mean AOD and TISA of their APAC group were the smallest compared with PACG and PAC. However, the APAC and PACG subjects in their study had thinner irides when compared with PAC and POAG, which is not in agreement with our study. Wang et al. has also reported that increased IT was associated with angle closure. ¹² The discrepant findings may be due to either the interval between acute attack and the capture of ASOCT images, or the differences in IT between Indian and Chinese eyes. While the interval between the acute attack and ASOCT imaging in our subjects was 2.1 ± 3.4 years, this information was not provided in the study by Sihota et al. 

In a cross-sectional study from Singapore, the presence of an increased LV was strongly associated with angle closure (odds ratio [OR] 48.1; 95% CI). ¹³ This was independent of lens thickness and lens position. Likewise, LV was found to be greatest in the APAC group and this was significantly different from that of PAC and PACG (P = 0.003, P = 0.001, respectively). This is similar to our finding that LV was greatest in the APAC group and least in the PACS group. Foo et al. postulated that a larger LV would occupy more space in the anterior chamber resulting in decreased ACA and ACV. ¹⁸  

Interestingly, the PACS eyes, which represent the earliest stage of the angle closure disease spectrum, had wider anterior chamber angles as well as a more spacious anterior chamber characterized by larger ACA, ACV, deeper ACD, and a smaller LV compared with the other subgroups. This suggests that PACG disease progression may be associated with changes in anterior segment dimensions with decreasing anterior chamber volume with increasing severity of disease. However, definitive association between progression and biometric alterations can only be established by a prospective longitudinal study. Additionally, the absence of significant differences in many ocular biometric parameters between PAC and PACG hints at the possibility of other nonanatomical influences, such as dynamic changes in the iris or choroid to be possibly associated with disease progression. ^14,19  

ASOCT parameters of APAC were significantly different from the three other subtypes of angle closure. Interestingly, on logistic regression analysis we found that shallower ACD, smaller TISA750, and greater LV and IT750, as well as younger age were strongly and independently associated with APAC. The individual contributions were 33.3% by ACD, 13.2% by TISA750, 3.2% by LV, 2.7% by age, and 1.8% by IT750 using forward, stepwise logistic regression analysis. LV and IT contribute to the ACD by themselves and their independent contribution could have been diminished. 

Studies have reported ACD as a risk factor in the development of PACG. ^16,20,21 Moreover, some have proposed that the shallower the ACD, the higher the risk for an acute attack. ^16,21 Lan et al. studied the biometric differences in acute and chronic PACG and found that the ACD of eyes with acute angle closure as well as the fellow eyes were significantly shallower than chronic angle closure. ²² Likewise, in an ASOCT study of the subtypes of PAC, Moghimi noted that the mean ACD was smallest in the acute eyes followed by the fellow eyes, with the chronic group having the deepest anterior chambers. This further emphasizes the importance of a shallow ACD in the predisposition to an acute attack. In a population-based study, Sng and co-workers showed that LV was a major determinant of ACD contributing to 58% of its variability. ²⁰ The role of LV in angle closure has been well-established and could have an important role in predisposing eyes to APAC. Similar to our findings, Moghimi found LV to be highest in the acute eyes compared with the other subtypes, and it was significantly greater than chronic PACG and PACS (P < 0.001 and P = 0.007, respectively). ¹⁶  

In a community-based study by Wang et al., increased IT was shown to be independently associated with angle closure. ²³ In another study they postulated that the thicker peripheral iris may crowd the angle more, particularly in eyes with shallow ACD and predispose them to angle closure. ¹² The independent association of IT750 with the diagnosis of APAC (after adjusting for PD) found in our study might be construed as a prerequisite for the acute attack or as a possible effect of the acute attack on the dilator musculature leading to permanently rolled up iris in the periphery. However, these findings should be interpreted with caution, as firstly, the number of subjects in the APAC group in our study was limited. Secondly, the “threshold” amount of LV that may push a “crowded” angle into an acute attack is undefined and needs to be explored. Lastly, due to the cross-sectional nature of our study, we cannot assign causal relationship for the determinants of APAC. 

Amongst all the parameters mentioned, ACD is the most easily evaluated with accessible screening tools including A-scan ultrasonography, optical pachymetry, and slit-lamp biomicroscopy. Assessment of anterior chamber depth particularly peripherally, may potentially identify individuals at risk for acute attack, hence, making ACD an important indicator of APAC risk in the clinical setting. 

Our study had some limitations. Only static anterior segment parameters were evaluated, thus, dynamic parameters such as changes in the choroid or the iris with dilation were not included. ^14,19 Our findings may not be extrapolated to all populations and evaluation of these parameters in other ethnic groups should likewise be considered. 

In summary, we have compared ASOCT parameters of different subtypes of angle closure. Eyes with APAC had the narrowest angles, thickest irides, and largest LV. ASOCT findings, including anterior chamber angle parameters, IT, LV of PAC, and PACG were not significantly different. ACD, TISA750, and LV are important variables that were associated with APAC and may play a role in APAC pathogenesis. 

Acknowledgments

Supported by grants from the National Research Foundation and the National Medical Research Council, Singapore. 

Disclosure: C.P. Guzman, None; T. Gong, None; M.E. Nongpiur, None; S.A. Perera, None; A.C. How, None; H.K. Lee, None; L. Cheng, None; M. He, None; M. Baskaran, None; T. Aung, Carl Zeiss Meditec (F, R)