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Anterior Chamber Angles in Different Types of Mucopolysaccharidoses
Journal Pre-proof Anterior Chamber Angles in Different Types of Mucopolysaccharidoses Jia-Rong Zhang, Jen-Hung Wang, Hong-Zin Lin, Yuan-Chieh Lee PII:
S0002-9394(20)30012-X
DOI:
https://doi.org/10.1016/j.ajo.2020.01.007
Reference:
AJOPHT 11193
To appear in:
American Journal of Ophthalmology
Received Date: 28 July 2019 Revised Date:
16 December 2019
Accepted Date: 3 January 2020
Please cite this article as: Zhang J-R, Wang J-H, Lin H-Z, Lee Y-C, Anterior Chamber Angles in Different Types of Mucopolysaccharidoses, American Journal of Ophthalmology (2020), doi: https:// doi.org/10.1016/j.ajo.2020.01.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Abstract: Purpose: To evaluate the anterior chamber angle status and estimate the intraocular pressure (IOP) in patients with mucopolysaccharidoses (MPS) type I, II, IV, and VI. Design: Prospective cross-sectional study Methods: This study enrolled 27 consecutive MPS patients (8 patients with MPS I, 4 patients with MPS II, 9 patients with MPS IV, and 6 patients with MPS VI) and 20 normal controls. Anterior chamber angle status was evaluated by swept-source optical coherence tomography, and intraocular pressure (IOP) was estimated by the new-generation tonometer Corvis ST. Results: 12 eyes (6 patients) out of the 15 eyes (8 patients) with MPS I had very narrow angles or peripheral iridocorneal touches together with elevated IOP (80%). 6 eyes (3 patients) out of the 8 eyes (4 patients) with MPS II had plateau iris configuration, but all the 8 eyes had normal IOP. All the 18 eyes (9 patients) with MPS IV had normal angle structures, but 8 eyes (4 patients) had elevated IOP (44.4%). 9 eyes (5 patients) out of the 11 eyes (6 patients) with MPS VI had shallow but not closed angles (81.8%). Among these 9 eyes, 5 eyes had elevated IOP, and 4 out of these 5 eyes had IOP above 30 mmHg. The trabecular iris angles of MPS type I, II, VI were smaller than those of MPS type IV and control group. The angle recess areas of MPS type I and VI were smaller than those of MPS type IV and control group. Conclusions: MPS type I patients are prone to have glaucoma with narrow or closed angle; MPS type II patients tend to have plateau iris; MPS type IV patients are vulnerable to open-angle glaucoma; MPS type VI patients have narrow angles not as close as those of MPS type I. MPS type I, IV, and VI had higher IOP estimates than the control group, but only MPS I and IV had higher corrected IOP estimates than the control group. The ordinary IOP estimates in MPS VI patients may be falsely high due to clouded corneas and increased corneal rigidity. The swept-source optical coherence tomography helps ophthalmologist to investigate the angle structure and the pathophysiology of glaucoma caused by MPS.
Anterior Chamber Angles in Different Types of Mucopolysaccharidoses Jia-Rong Zhang1, Jen-Hung Wang2, Hong-Zin Lin1,3, Yuan-Chieh Lee1,3,4 1
Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
2
Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
3
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
4
Department of Ophthalmology and Visual Science, Tzu Chi University, Hualien, Taiwan
Short title: Ocular Angles in Mucopolysaccharidoses Word count of the manuscript text: 3689 Correspondence: Yuan-Chieh Lee Department of Ophthalmology, Buddhist Tzu Chi General Hospital No. 707, Sec. 3, Chung-Yung Road, Hualien, Taiwan 97002, R.O.C Tel.: +886-3-8561825, Ext: 12234 Fax: +886-3-8577161 Email addresses: [email protected]
1
Introduction Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) in tissues resulting in a wide spectrum of clinical phenotypes, including macrocephaly, facial dysmorphism, spinal stenosis, hepatosplenomegaly, umbilical hernia, inguinal hernia, heart valve abnormalities, sleep apnea, corneal clouding, and growth retardation. According to the affected metabolic pathway, MPS are categorized into seven types and more subtypes. Ocular complications are common in all types of MPS, which include corneal clouding, glaucoma, pigmentary retinopathy, optic disc swelling, or optic atrophy.1,2 However, the pathophysiology is not fully understood, partly due to the neglect of these rare diseases, and partly due to the difficulties of approach. By using spectral-domain optical coherence tomography (OCT), we had demonstrated the changes of the retina and choroid in the MPS type I, II, and VI, but not in type IVA in our previous study.3 Our findings also implicated the possible beneficial effect of enzyme replacement therapy.3 Nowadays, swept-source OCT provides better resolution through corneal opacities in evaluating the structure of the angle; while the new-generation tonometer (Corvis ST; Oculus Optikgeräte GmbH, Wetzlar, Germany) takes corneal thickness and rigidity into account and may provide better intraocular pressure (IOP) estimates. In this study, we utilize swept-source OCT to evaluate the angle structure and Corvis ST to estimate the IOP in patients with MPS type I, II, IV, and VI. Methods This cross-sectional study was carried out with approval from the Institutional Review Board (IRB103-162-A) prospectively. Informed Consent for the research was obtained from the patients. This study enrolled 20 normal controls and 27 consecutive MPS patients, including 8 patients with MPS I (4 male, 4 female), 4 patients with MPS II (all male), 9 patients with MPS IV (2 male, 7 female), and 6 patients with MPS VI (3 male, 3 female). 9 MPS patients were excluded due to being too young to cooperate, intellectual and developmental disability, or other comorbidities. The 20 normal patients (11 males, 9 females) were all younger than 30 years old, had normal ocular examination results and a spherical equivalent of higher than -6.0 D. Except for one Japanese (MPS I) and one Malaysian (MPS VI), the enrolled MPS patients and normal controls were all Han 2
Taiwanese. As MPS are rare diseases and their ocular problems are complicated, it is imperative that a senior ophthalmologist can afford a regular and comprehensive care for MPS patients. In this study, we had a senior ophthalmologist (Yuan-Chieh Lee, with expertise in cornea, glaucoma, retina, and pediatric ophthalmology), two junior ophthalmologists (Jia-Rong Zhang and Hong-Zin Lin, specialized in cornea and glaucoma respectively), and two technicians. All participants underwent a comprehensive eye examination including visual acuity, refraction, slit-lamp biomicroscopy, central corneal thickness (CCT), uncorrected-IOP (CVS-IOP) and corrected-IOP (CVS-IOPcorrected) measurements using Corvis ST. The corrected-IOP (CVS-IOPcorrected) was calculated according to the correction equation,4 which stated that CVS-IOPcorrected = (CCCT1 x CCVS-IOP + CCCT2) x Cage + C, where CCCT1, CCCT2 are parameters representing the effect of variation in CCT (mm). (For further information, please see appendix.) The central anterior chamber depth (ACD) and ocular axial length (AL) were measured with an optical biometer (Al-Scan; NIDEK Co. Ltd., Gamagori, Japan). All the OCT images were captured in a dimly lit room utilizing the DRI Triton swept-source OCT (Topcon, Tokyo, Japan) in the Line Anterior Segment mode (wavelength of laser: 1050 nm) to capture the anterior chamber angle images at 3 and 9 o’clock positions. The scan line was centered on the limbus with 6-mm scan size and the scan count was 64, and the participant was asked to look at the fixation target. The images were processed with the ImageJ (National Institutes of Health, Bethesda, MD) software to measure the status of angle opening. Because the clouded peripheral cornea obscured the identification of scleral spur and the apex in the iris recess in some types of MPS, the angle opening distance (AOD), trabecular iris angle (TIA), and angle recess area (ARA) were therefore defined as follows: the Schwalbe's line was identified first (point A), as it represents the termination of Descemet's membrane, then the point 500 µm posterior to the Schwalbe's line along the interior lining (point B) was marked. A perpendicular line was drawn from point A to the opposing anterior iris surface (point C), and the distance was defined as AOD. Another perpendicular line was drawn from point B to the opposing anterior iris surface (point D). One arm of the TIA passed through point A and B, and another arm of the TIA passed through point C and D. The ARA was defined as a triangular area
3
bordered by the anterior iris surface, corneal endothelium, and the AOD. This standard technique was illustrated in figure 1. Statistical Analysis Statistical mean differences of continuous data between different groups were analyzed with one-way analysis of variance or Kruskal-Wallis test. The Bonferroni correction was used as post-hoc analyses. The Chi-square test or Fisher's exact test was used to evaluate the association between two categorical variables. Generalized estimating equations model was adopted to evaluate the risk factors associated with the narrowing of the anterior chamber angle. All the data analyzed were pre-operative values. All the statistical analyses were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA). A P-value less than 0.05 was considered statistically significant.
Results MPS I: One eye was excluded due to previous penetrating keratoplasty (PKP) and lacked of preoperative data. All the 15 eyes of 8 patients with MPS I had varying degrees of corneal opacities: 2 patients had mild opacity in the central cornea and moderate to severe opacity in the peripheral cornea, and 6 patients had severe corneal opacities. CCT was not measurable in 3 patients due to severe corneal opacity. Among the other 5 patients, CCT was 539.00 ± 36.22 µm in the right eye (N=4) and 526.40 ± 38.32 µm in the left eye (N=5). The IOP estimates were available in 13 eyes. Among these 13 eyes, 12 eyes (92.3%) had IOP greater than 20 mmHg, 7 eyes (53.8%) had corrected-IOP greater than 30 mmHg. The OCT imaging demonstrated the narrow angles or peripheral iridocorneal touches in 12 eyes (80%) (Figure 2), compatible with the elevated IOP estimates. TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 6.71 ± 11.50 °, 7.30 ± 10.53 °, 7.17 ± 14.34 °, and 7.41 ± 14.71 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.06 ± 0.10 mm2, 0.06 ± 0.07 mm2, 0.05 ± 0.08 mm2, and 0.06 ± 0.07 mm2. 4
A 25-year-old man among these MPS I patients had high IOP estimates and clouded corneas and received uneventful corneal transplantation in his both eyes. The postoperative IOP estimates were still high above 40 mmHg and refractory to medications. He underwent bilateral trabeculectomy and had good IOP measurements eventually. MPS II: Among 4 patients (total 8 eyes) with MPS II, a 27-year-old man had bilateral mild corneal opacities (25%), and the other three cases had clear corneas. CCT of the right eye and left eye were 547.25 ± 20.77 µm and 561.25 ± 26.99 µm respectively. All the MPS II patients had normal corrected-IOP (15.18 ± 3.50 mmHg and 14.38 ± 3.30 mmHg in the right eye and left eye) and normal retinal nerve fiber layer thickness. The ACD was 3.06 ± 0.79 mm in the right eye and 3.08 ± 0.83 mm in the left eye. OCT imaging revealed a plateau iris configuration in 3 patients (6 eyes, 75%) (Figure 3). TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 22.04 ± 14.54 °, 24.22 ± 10.59 °, 12.42 ± 9.29 °, and 21.04 ± 2.57 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.21 ± 0.11 mm2, 0.21 ± 0.11 mm2, 0.13 ± 0.04 mm2, and 0.11 ± 0.03 mm2, respectively. MPS IV: All 9 patients with MPS IV had mild to moderate clouded corneas bilaterally (total 18 eyes). The CCT was 513.00 ± 49.36 µm and 529.11 ± 62.32 µm in the right eye and the left eye (range: 408 µm to 612 µm). 4 patients (8 eyes) had bilateral elevated corrected-IOP estimates (44.4%). OCT revealed normal open-angle structures in all eyes (Figure 4). TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 39.75 ± 14.29 °, 35.88 ± 11.71 °, 31.88 ± 17.28 °, and 36.08 ± 10.84 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.28 ± 0.11 mm2, 0.25 ± 0.12 mm2, 0.27 ± 0.16 mm2, and 0.20 ± 0.08 mm2, respectively. MPS VI: One eye was excluded due to previous PKP and lacked of preoperative data. All the 11 eyes (100%) of the 6 patients with MPS VI had corneal opacities, and 8 (72.7%) were 5
severe. CCT of the right eye and left eye were 590.33 ± 160.55 µm and 575.00 ± 138.05 µm respectively. The IOP estimate was not available in 2 eyes (1 patient). 5 out of the rest 9 eyes (55.6%) had elevated IOP estimates, and 4 out of these 5 eyes had IOP estimates above 30 mmHg. OCT revealed a narrow angle in 9 eyes (5 patients, 81.8%) (Figure 5). TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 18.95 ± 6.67 °, 13.35 ± 8.11 °, 11.07 ± 7.95 °, and 17.15 ± 9.52 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.11 ± 0.08 mm2, 0.12 ± 0.05 mm2, 0.15 ± 0.06 mm2, and 0.12 ± 0.06 mm2, respectively. The 4 eyes with elevated IOP estimates above 30 mmHg had severe corneal opacities and underwent smooth corneal transplantation (2 PKP and 2 deep anterior lamellar keratoplasties). All the IOP estimates dropped to low tens without medication after corneal transplantation. The OCT also showed normal retinal nerve fiber layer thickness in these 4 eyes. Control group: A total of 20 cases were enrolled as the control group. Mean age was 14.00 ± 3.36 years old, and mean spherical equivalent refraction of the right eye and left eye were -2.21 ± 1.27D and -2.21 ± 1.18D, respectively. CCT of the right eye and left eye were 548.40 ± 40.66 µm and 548.85 ± 38.85 µm respectively. AS-OCT revealed normal open-angle in the control groups. TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 48.01 ± 9.28 °, 49.20 ± 7.88 °, 42.88 ± 6.55 °, and 45.13 ± 7.74 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.32 ± 0.11 mm2, 0.29 ± 0.11 mm2, 0.27 ± 0.09 mm2, 0.26 ± 0.11 mm2. Comparison between different types of MPS and control group MPS type I, II, VI were more hyperopic than MPS type IV and control group. The axial lengths of MPS type I, II, VI were significantly shorter than those of MPS type IV and control group. The TIAs of MPS type I, II, VI were smaller than those of MPS type IV and control group. The ARAs of MPS type I and VI were smaller than those of MPS type IV and control group. MPS type I, IV, and VI had higher uncorrected IOP estimates than the control group, and MPS type I had higher IOP estimates than MPS type II and IV. MPS I 6
and IV had higher corrected IOP estimates than the control group (Table 1). Multivariate analysis demonstrated that age was significantly correlated with TIA. The older the patients, the smaller the TIAs (table 2). The TIAs of MPS type I, II, IV, VI were 36.14 °, 17.25 °, 8.76 °, 30.61° smaller than that of the control group (table 2); while the ARAs of MPS type I and VI were significantly smaller than that of the control group by 0.195 mm2 and 0.149 mm2 respectively (table 3). Discussion Glaucoma has been reported in MPS I-S (Scheie syndrome),5 MPS I-H/S,6,7 MPS I-H (Hurler syndrome),8-10 MPS type II,11 MPS type IV (Morquio syndrome), and MPS type VI (Maroteaux-Lamy syndrome),1,2,12 and yet for several reasons remained a challenge when being identified in these patients. First, the measurement of IOP could be falsely raised due to the increased corneal thickness and rigidity.13 Study has demonstrated a moderate positive correlation between CCT and measured IOP.14 Second, the gonioscopic and ophthalmoscopic examinations could be obscured by corneal opacities.12 Third, the visual field data might be hard to obtain due to poor cooperation, or the results were difficult to interpret because of other combined ocular comorbidities.1 Nevertheless, we were able to analyze their IOP and angle status from the limited obtainable data using SS-OCT and Corvis ST. In MPS type I, glaucoma has been reported ranging from acute attack to chronic angle-closure glaucoma, and to described open-angle.5,6,8,9 However, all those reported cases lacked a clear gonioscopic view of the angle due to dense corneal opacities. Ahmed et al. reported one out of the five MPS type I patients in their study had bilateral angle-closure.15 Ashworth et al. reported only two patients with ocular hypertension and normal optic discs among 31 MPS type I patients. Both concluded a low incidence of ocular hypertension and glaucoma in patients with MPS type I.16 In contrast, our study revealed narrow to closed angles and elevated IOP estimates in 5 out of the 6 MPS type I patients with clear images. In the other 2 patients without discernable images, one showed a shallow anterior chamber under biomicroscopy. Our study revealed a much higher rate of angle closure in MPS type I. The angle closure caused by the accumulation of GAGs and abnormal thickening of the cornea, sclera, and iris has been described,5,6 and was compatible with our AS-OCT findings. Multivariate regression 7
analyses (Table 2 & 3) also indicated that patients with MPS type I have significantly narrower TIA and smaller ARA than the control group. On average, the TIA of MPS type I was 36.14 ° smaller than that of the control group, and the ARA of MPS type I was 0.195 mm2 smaller than that of the control group. Although a clear cornea was once used to distinguish MPS type II form other types of MPS, one out of our four MPS type II patients had bilateral mild corneal opacities. Elflein et al. used pentacam to analyze clinically clear corneas of MPS II and reported higher corneal density values than those of healthy subjects.17 Hence the corneas are not truly unaffected in MPS II patients, only to a minor degree. Besides the minor change of cornea, their visual acuity may also be affected by combined pigmented retinopathy or GAG accumulation related chorio-retinopathy.3 Acute angle-closure glaucoma was once reported with MPS type II, but no gonioscopic finding has been described.11 Our study revealed a plateau iris configuration without IOP elevation in 3 out of the 4 cases with MPS type II (75%). Multivariate regression tests indicated that patients with MPS type II have significantly narrower TIA than the control group but no such association was found in the analysis of ARA, which was compatible with the narrow-angle and deep central chamber of plateau iris configuration (Table 2 & 3). Previous histological studies reported fibrillogranular inclusions or membranolamellar inclusions within the corneal epithelium, keratocytes, and corneal endothelial cells without distortion the shape of individual cells; while those inclusions were most strikingly found in the pigmented and nonpigmented epithelium of the iris and ciliary body, which even lead to great distension of these cells.18,19 This might contribute to the mild corneal opacity and plateau iris configuration noted in our study. All 9 patients with MPS IV had clouded corneas, ranging from mild to moderate, but not as severe as those of MPS I and MPS type VI. On average, the TIA of MPS type I was 8.76 ° smaller than that of the control group, which suggests that together the moderate corneal opacification and thickened anterior chamber structures of MPS type IV caused a relatively narrower angle when compared with the control group. On the other hand, CCT and ARA were not significantly different from those of the control group. Although the AS-OCT showed normal open-angle structures in all of them, four patients (44.5%) had elevated IOP. Previous transmission electron microscopic study demonstrated fibrillogranular and multi-membranous membrane-bound inclusions 8
distributed primarily in the cornea and trabecular meshwork in cases with MPS type IV,20 which might lead to elevated IOP with morphological open-angle as noted in our patients. As for MPS type VI, a previous histopathologic study suggested GAG accumulation in anterior segment structures and the trabecular meshwork, thus both angle-closure glaucoma and open-angle glaucoma had been reported.12 Another case series demonstrated a relatively high incidence (38%) of ocular hypertension in MPS VI patients compared to other types of MPS,16 in which a statistically significant correlation between IOP and the degree of corneal opacity was found in MPS VI patients. In our study, all the 6 patients with MPS VI developed significant corneal opacities, thickened anterior chamber structures, and narrow anterior chamber angles. On average, the TIA and the ARA was 30.61 ° and 0.149 mm2 smaller than that of the control group, respectively. Among the 9 eyes with reliable IOP estimates, 5 eyes (56%) had elevated IOP ranging from 29 mmHg to over 50 mmHg. Among these 5 eyes with elevated IOP, 4 eyes underwent corneal transplantations. Interestingly, the IOP estimates dropped to low tens postoperatively without IOP-lowering medication. The normal retinal nerve fiber layer thickness shown in OCT also align with the presumption that the preoperative IOP might not be truly high. Similar cases of IOP returning to normal after corneal transplantation have also been reported before,21,22 and suggested that the IOP estimates are often falsely high in MPS type VI due to corneal hysteresis and corneal resistance factor, either of which is positively correlated with the corneal clouding in MPS.23,24 Although the IOP estimates dropped to normal range after corneal transplantation in patients of MPS VI, the incidence of angle-closure glaucoma might increase as the disease progresses or the life expectancy extend with advances in treatment due to progressive ticking of anterior angle structures. There has been a report of an acute angle-closure glaucoma attack in a MPS type VI patient despite a prophylactic patent laser iridotomy,25 mainly because the angle closure in MPS type I and type VI is secondary to thickening of the cornea or other anterior chamber structure instead of pupillary block, and therefore the anterior chamber would not be deepened after iridectomy.12 Limitations
9
First, although MPS syndromes are highly variable in expressivity and clinical presentations, but we were only able to enroll a limited number of patients in each type of MPS, partly because MPS syndromes are relatively rare diseases. Caution should be taken when applying these results. Second, the AS-OCT was only performed for nasal and temporal angles instead of the entire angle structure, and the manufacturing company failed to provide normal range for angle structures. But, we had standardized technique of performing the OCT imaging, and enrolled a normal non-MPS control group for comparison. Third, the corrected IOP estimate with Corvis was not available in some patients with MPS type I and VI, especially in those with severe corneal opacities. Fourth, gonioscopic examination was not performed as we planned to do non-contact examinations for these MPS patients. The optic disc status was not analyzed because of corneal opacity interfering visualization and avoidance of mydriasis due to narrow angles in MPS I and VI patients, and other disc anomalies affecting interpretation.3 Visual field examination was not performed due to reduced reliability from lack of cooperation or ocular comorbidities interfering interpretation. We did not analyze the relationship between the best-corrected visual acuity and degree of corneal opacification, partly because the data could not be reliably obtained or quantified in some patients, and partly because the best-corrected visual acuity was affected not only by corneal opacity but also by other ocular comorbidities such as numerous retinopathy as our previous report.3 Fifth, the control group was relatively skewed myopic, which was a risk factor for open angle glaucoma. However, more than 60 % of children are myopic by the age of 12, and more than 80 % are myopic by the age of 15 in Taiwan.26 Since these MPS patients are mostly residents of Taiwan, the status of their angles should be compared with those of ordinary “normal” non-MPS residents of similar ages in Taiwan. But we still avoided the high myopic (<-6D) children as the control group. Besides, our study was to analyze the differences of the angle status and the IOP rather than the incidence of glaucoma. Our results showed that MPS type I, II and VI patients have shorter axial length and smaller TIA than not only the control group but also the MPS type IV patients, who are almost emmetropic. MPS type I and VI patients have smaller ARA than both the control group and the MPS type IV patients. As for IOP, it has been reported not associated with refractive status in children and adolescents.27,28
10
Conclusions MPS I patients are prone to have glaucoma with narrow or closed angles; MPS II patients tend to have plateau iris configuration; MPS IV patients have open angles; finally, MPS VI patients have narrow angles, but not as closed as those of MPS I. In terms of IOP estimates, MPS type I, IV, and VI were higher than the control group, whereas in terms of corrected IOP estimates, only MPS type I and IV were higher. The original IOP estimates in MPS VI patients may be falsely high due to clouded corneas and increased corneal rigidity. Although the pathophysiology of glaucoma in MPS is not well delineated yet, the swept-source OCT can assist ophthalmologist to investigate the anterior chamber angle status and the pathophysiology of glaucoma caused by MPS.
Acknowledgments/disclosure ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. There is no funding or financial support for this study. All authors have no financial disclosures. Full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis (J.R.Zhang, Y.C.Lee); concept and design (J.R.Zhang, Y.C.Lee); acquisition, analysis, or interpretation of data (J.R.Zhang, J.H.Wang, H.Z. Lin, Y.C.Lee); statistical analysis (J.R.Zhang, J.H.Wang, H.Z. Lin, Y.C.Lee); drafting of the manuscript (J.R.Zhang, J.H.Wang, Y.C.Lee); critical revision of the manuscript for important intellectual content (J.R.Zhang, Y.C.Lee).
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Lee A, Saw S, Gazzard G, Cheng A, Tan D. Intraocular pressure associations with refractive error and axial length in children. Br J Ophthalmol. 2004;88(1):5-7.
28.
Fern KD, Manny RE, Gwiazda J, et al. Intraocular pressure and central corneal thickness in the COMET cohort. Optom Vis Sci. 2012;89(8):1225-1234.
13
Appendix: Central corneal thickness (CCT) is the major correction factor for the Corvis tonometer, and age is the minor correction factor. The correction formula is as follows: CVS-IOPcorrected = (CCCT1 x CCVS-IOP + CCCT2) x Cage + C.4 Where CCCT1, CCCT2 are parameters representing the effect of variation in central corneal thickness (CCT) (mm); -7
2
-4
CCCT1 =4.67x10 xCCT –7.8x10 xCCT+0.63 -5
2
-3
CCCT2 =-1.73x10 xCCT +2.02x10 xCCT–0.97 CCVS-IOP = effect of variation in measured Corvis-IOP (mmHg) = 10 + (Corvis-IOP + 1.16) / 0.389 Cage = effect of variation in age (years) -5
2
-3
= -2.01 x 10 x age + 1.3 x 10 x age + 1.00 C = 1.50 mmHg
Figure Captions: Figure1. Standard technique of performing the anterior segment OCT illustrated with a control subject. Panel A and C, The OCT images of the nasal and temporal angles of right eye were captured from 3 o’clock and 9 o’clock areas in the Line Anterior Segment mode, centered on limbus, and the results were demonstrated in panel B and D. Panel B shows how to measure the trabecular iris angle (TIA), The Schwalbe's line was identified as point A, then the point 500-µm posterior to the Schwalbe's line along the interior lining was marked as point B. A perpendicular line was drawn from point A to the opposing anterior iris surface (point C), and the distance was defined as the angle opening distance (AOD). Another perpendicular line was drawn from point B to the opposing anterior iris surface (point D). The trabecular iris angle (TIA) was defined as angle formed by one arm passing through point A and B, and the other arm passed through point C and D. The illustrated TIA was 44°. Panel D demonstrates the angle recess area (ARA) as a triangular area bordered by the anterior iris surface, corneal endothelium, and the AOD. This illustrated ARA was 0.339 mm2.
14
Figure 2. Swept-source optical coherence tomography images of ocular angles in 3 patients with mucopolysaccharidoses type I. A and B, Scans showing closed temporal and nasal angles in the left eye of a 7-year-old girl. The TIA and ARA were 0° and 0 mm2. The IOP was 29.5 mmHg. C and D, A shallow temporal angle and a closed nasal angle of the right eye in a 37-year-old man. The IOP was 44 mmHg. The TIA of the temporal angle and nasal angle were 10.2° and 0°, respectively. The ARA of the temporal angle and nasal angle were 0.095 mm2 and 0.038 mm2, respectively. E and F, The closed temporal and nasal angles in the left eye of an 18-year-old man. The IOP was higher than 60 mmHg. The TIA and ARA were 0° and 0 mm2.
Figure 3. Swept-source optical coherence tomography images demonstrating plateau iris configuration in 3 patients with mucopolysaccharidoses type II. A and B, Scans of temporal and nasal angles in the left eye of a 27-year-old man. The TIA were 22.9° and 23°, respectively. The ARA were 0.113 mm2 and 0.222 mm2, respectively. The IOP was 15.5 mmHg. C, A scan of temporal angle in the right eye of a 50-year-old man. The TIA was 11.2°. The ARA was 0.135 mm2. The IOP was 13.5 mmHg. D, A scan of temporal angle in the left eye of the same patient as C. The TIA was 14.8°. The ARA was 0.114 mm2. The IOP was 15 mmHg. E, A scan of temporal angle in the right eye of a 53-year-old man. The TIA was 10.1°. The ARA was 0.178 mm2. The IOP was 11.3 mmHg. F, A scan of temporal angle in the left eye of the same patient as E. The TIA was 19.9°. The ARA was 0.137 mm2. The IOP was 10.3 mmHg. Figure 4. Swept-source optical coherence tomography images showing wide open angles in 3 patients with mucopolysaccharidoses type IV. A and B, Scans of temporal angle and nasal angle in the left eye of a 15-year-old girl. The TIA were 32.2° and 35.1°, respectively. The ARA were 0.31 mm2 and 0.254 mm2, respectively. The IOP was 48.5 mmHg. C and D, Scans of temporal angle and nasal angles in the left eye of a 20-year-old woman. The TIA were 48° and 46°, respectively. The ARA were 0.305 mm2 and 0.345 mm2, respectively. The IOP was 29 mmHg. E and F, Scans of temporal and nasal angles in the right eye of a 23-year-old woman. The TIA were 52.3° and 46.9°,
15
respectively. The ARA were 0.197 mm2 and 0.291 mm2, respectively. The IOP was 27 mmHg. Figure 5. Swept-source optical coherence tomography images showing shallow angles in 3 patients with mucopolysaccharidoses type VI. A and B, Scans of temporal and nasal angles in the left eye of an 11-year-old boy with severe corneal opacity. The TIA were 8.6° and 16.7°, respectively. The ARA were 0.059 mm2 and 0.087 mm2, respectively. The IOP was 29 mmHg. C and D, Scans of temporal and nasal angles in the right eye of an 18-year-old girl. The TIA were 3.3° and 15.5°, respectively. The ARA were 0.038 mm2 and 0.093 mm2, respectively. The IOP estimate was not available due to severe corneal opacity. E and F, Scans of temporal and nasal angle in the left eye of a 24-year-old woman. The TIA were 8.1° and 12.3°, respectively. The ARA were 0.058 mm2 and 0.15 mm2, respectively. The IOP was 17 mmHg.
16
Table 1. Demographics and comparisons between MPS type I, II, IV, VI, and the control group. Item
MPS Control (C) Type I (M1)
Type II (M2)
Type IV (M4)
Type VI (M6)
N
20
8
4
9
6
Age (N=47)
14.00 ± 3.36
25.88 ± 15.33
35.00 ± 20.31
19.56 ± 6.54
19.00 ± 8.67
Gender
P-value
Post-hoc**
0.001*
C,M4,M6 < M1,M2
0.144
Male
11(55.0%)
4(50.0%)
4(100.0%)
2(22.2%)
3(50.0%)
Female
9(45.0%)
4(50.0%)
0(0.0%)
7(77.8%)
3(50.0%)
-2.21 ± 1.27
1.96 ± 1.82
4.09 ± 3.82
-0.69 ± 3.36
8.44 ± 0.63
<0.001*
C,M4 < M1 < M2,M6
0.55 ± 0.46
1.75 ± 0.90
1.31 ± 0.52
2.63 ± 1.55
0.88 ± 0.66
<0.001*
M4 > M6, C
-2.21 ± 1.18
4.63 ± 2.81
4.25 ± 3.62
0.33 ± 2.96
8.92 ± 1.45
<0.001*
C,M4 < M1,M2,M6
0.79 ± 0.62
1.08 ± 0.14
1.38 ± 0.48
3.39 ± 2.38
1.00 ± 0.66
<0.001*
M4 > C
CCT, OD (N=41)
548.40 ± 40.66
539.00 ± 36.22
547.25 ± 20.77
513.00 ± 49.36
590.33 ± 160.55
0.295
CCT, OS (N=42)
548.85 ± 38.85
526.40 ± 38.32
561.25 ± 26.99
529.11 ± 62.32
575.00 ± 138.05
0.616
15.85 ± 2.46
41.50 ± 15.28
15.50 ± 2.94
21.33 ± 6.40
29.88 ± 16.78
<0.001*
15.32 ± 2.47
33.71 ± 16.55
15.25 ± 2.66
23.28 ± 11.34
26.00 ± 9.43
<0.001*
15.70 ± 2.63
24.95 ± 5.16
15.18 ± 3.50
21.63 ± 5.47
18.50 ± 1.56
0.001*
15.13 ± 2.70
22.03 ± 8.81
14.38 ± 3.30
22.94 ± 9.28
20.77 ± 6.92
0.010*
SE, OD (N=39) Cylinder, OD (N=39) SE, OS (N=39) Cylinder, OS (N=39)
Uncorrected IOP, OD (N=43) Uncorrected IOP, OS (N=45) Corrected IOP, OD (N=37) Corrected IOP, OS (N=39)
C,M2,M4 < M1 & C < M6 C,M2 < M1 & C < M4,M6 C, M2 < M1 & C < M4 C < M4
AL, OD (N=40)
24.29 ± 0.76
21.52 ± 0.28
22.21 ± 1.62
23.82 ± 1.52
20.21 ± 0.43
<0.001*
M1,M2,M6 < M4,C
AL, OS (N=40)
24.40 ± 0.81
21.30 ± 0.55
22.12 ± 1.65
23.55 ± 1.51
20.26 ± 0.29
<0.001*
M1,M2,M6 < M4,C
48.01 ± 9.28
6.71 ± 11.50
22.04 ± 14.54
39.75 ± 14.29
18.95 ± 6.67
<0.001*
M1,M2,M6 < M4,C
49.20 ± 7.88
7.30 ± 10.53
24.22 ± 10.59
35.88 ± 11.71
13.35 ± 8.11
<0.001*
M1,M2,M6 < M4,C
42.88 ± 6.55
7.17 ± 14.34
12.42 ± 9.29
31.88 ± 17.28
11.07 ± 7.95
<0.001*
M1,M2,M6 < M4,C
45.13 ± 7.74
7.41 ± 14.71
21.04 ± 2.57
36.08 ± 10.84
17.15 ± 9.52
<0.001*
M1,M2,M6 < M4,C
0.32 ± 0.11
0.06 ± 0.10
0.21 ± 0.11
0.28 ± 0.11
0.11 ± 0.08
<0.001*
M1,M6 < M4,C
0.29 ± 0.11
0.06 ± 0.07
0.21 ± 0.11
0.25 ± 0.12
0.12 ± 0.05
<0.001*
M1,M6 < M4,C
0.27 ± 0.09
0.05 ± 0.08
0.13 ± 0.04
0.27 ± 0.16
0.15 ± 0.06
0.002*
M1,M6 < M4,C
0.26 ± 0.11
0.06 ± 0.07
0.11 ± 0.03
0.20 ± 0.08
0.12 ± 0.06
<0.001*
M1,M6 < M4,C
Temporal TIA, OD (N=43) Temporal TIA, OS (N=44) Nasal TIA, OD (N=41) Nasal TIA, OS (N=41) Temporal ARA, OD (N=44) Temporal ARA, OS (N=43) Nasal ARA, OD (N=42) Nasal ARA, OS (N=43)
Data are presented as n (%) or mean ± standard deviation. *p-value<0.05 was considered statistically significant. Statistical mean differences of continuous data between different groups were analyzed with one-way analysis of variance or Kruskal-Wallis test. Two categorical variables were analyzed with Chi-square test or Fisher's exact test. ** Post-hoc analysis was conducted with Bonferroni correction. Abbreviations: SE = spherical equivalent, measured in diopter; CCT = central corneal thickness, measured in µm; IOP = intraocular pressure, measured in mmHg; AL = axial length, measured in mm; TIA = trabecular iris angle, measured in degrees; ARA = angle recess area, measured in mm2.
Table 2. Factors associated with trabecular iris angle (TIA, in degrees) analyzed with generalized estimating equations model. Predictor
β
95% CI
p value
Intercept
50.19
(44.34,56.04)
<0.001*
Age
-0.37
(-0.64, -0.10)
0.008*
-
-
-
References
References
NA
0.24
(-4.32,4.80)
0.917
-
-
-
References
References
NA
-1.21
(-3.19,0.78)
0.233
-
-
-
References
References
NA
3.56
(1.25,5.86)
0.003*
-
-
-
References
References
NA
MPS Type I
-36.14
(-45.94, -26.34)
<0.001*
MPS Type II
-17.25
(-26.46, -8.03)
<0.001*
MPS Type IV
-8.76
(-15.77, -1.76)
0.014*
MPS Type VI
-30.61
(-35.97, -25.25)
<0.001*
Gender Female Male Laterality Left Right Location Nasal Temporal Type Control
Data are presented as β (95% CI). *p-value<0.05 was considered statistically significant.
Table 3. Factors associated with angle recess area (ARA, in mm2) analyzed with generalized estimating equations model. Predictor
β
95% CI
p value
Intercept
0.270
(0.209,0.332)
<0.001*
Age
-0.002
(-0.005,0.001)
0.107
-
-
-
References
References
NA
0.047
(-0.0004,0.094)
0.052
-
-
-
References
References
NA
0.02
(-0.005,0.045)
0.112
-
-
-
References
References
NA
0.026
(0.006,0.046)
0.010*
-
-
-
References
References
NA
MPS Type I
-0.195
(-0.267, -0.123)
<0.001*
MPS Type II
-0.071
(-0.180,0.039)
0.205
MPS Type IV
-0.004
(-0.062,0.054)
0.891
MPS Type VI
-0.149
(-0.205, -0.093)
<0.001*
Gender Female Male Laterality Left Right Location Nasal Temporal Type Control
Data are presented as β (95% CI). *p-value<0.05 was considered statistically significant.
Dr. Yuan-Chieh Lee is the chief of the department of ophthalmology, Buddhist Tzu Chi General Hospital and associate professor of Tzu Chi University, Hualien. He has interest in cornea, glaucoma, and retina. He has taken care of the ocular problems in mucopolysaccharidoses patients of Taiwan for a decade.
Jia-Rong Zhang, MD, was born and raised in Taiwan where she received her medical degree from Kaohsiung Medical University, Kaohsiung, Taiwan, in 2013 and completed a residency and fellowship in corneal and external diseases in Buddhist Tzu Chi General Hospital, Hualien, Taiwan in 2019. Dr Zhang is currently an attending physician of the Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien.
S0002-9394(20)30012-X
DOI:
https://doi.org/10.1016/j.ajo.2020.01.007
Reference:
AJOPHT 11193
To appear in:
American Journal of Ophthalmology
Received Date: 28 July 2019 Revised Date:
16 December 2019
Accepted Date: 3 January 2020
Please cite this article as: Zhang J-R, Wang J-H, Lin H-Z, Lee Y-C, Anterior Chamber Angles in Different Types of Mucopolysaccharidoses, American Journal of Ophthalmology (2020), doi: https:// doi.org/10.1016/j.ajo.2020.01.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Abstract: Purpose: To evaluate the anterior chamber angle status and estimate the intraocular pressure (IOP) in patients with mucopolysaccharidoses (MPS) type I, II, IV, and VI. Design: Prospective cross-sectional study Methods: This study enrolled 27 consecutive MPS patients (8 patients with MPS I, 4 patients with MPS II, 9 patients with MPS IV, and 6 patients with MPS VI) and 20 normal controls. Anterior chamber angle status was evaluated by swept-source optical coherence tomography, and intraocular pressure (IOP) was estimated by the new-generation tonometer Corvis ST. Results: 12 eyes (6 patients) out of the 15 eyes (8 patients) with MPS I had very narrow angles or peripheral iridocorneal touches together with elevated IOP (80%). 6 eyes (3 patients) out of the 8 eyes (4 patients) with MPS II had plateau iris configuration, but all the 8 eyes had normal IOP. All the 18 eyes (9 patients) with MPS IV had normal angle structures, but 8 eyes (4 patients) had elevated IOP (44.4%). 9 eyes (5 patients) out of the 11 eyes (6 patients) with MPS VI had shallow but not closed angles (81.8%). Among these 9 eyes, 5 eyes had elevated IOP, and 4 out of these 5 eyes had IOP above 30 mmHg. The trabecular iris angles of MPS type I, II, VI were smaller than those of MPS type IV and control group. The angle recess areas of MPS type I and VI were smaller than those of MPS type IV and control group. Conclusions: MPS type I patients are prone to have glaucoma with narrow or closed angle; MPS type II patients tend to have plateau iris; MPS type IV patients are vulnerable to open-angle glaucoma; MPS type VI patients have narrow angles not as close as those of MPS type I. MPS type I, IV, and VI had higher IOP estimates than the control group, but only MPS I and IV had higher corrected IOP estimates than the control group. The ordinary IOP estimates in MPS VI patients may be falsely high due to clouded corneas and increased corneal rigidity. The swept-source optical coherence tomography helps ophthalmologist to investigate the angle structure and the pathophysiology of glaucoma caused by MPS.
Anterior Chamber Angles in Different Types of Mucopolysaccharidoses Jia-Rong Zhang1, Jen-Hung Wang2, Hong-Zin Lin1,3, Yuan-Chieh Lee1,3,4 1
Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
2
Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
3
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
4
Department of Ophthalmology and Visual Science, Tzu Chi University, Hualien, Taiwan
Short title: Ocular Angles in Mucopolysaccharidoses Word count of the manuscript text: 3689 Correspondence: Yuan-Chieh Lee Department of Ophthalmology, Buddhist Tzu Chi General Hospital No. 707, Sec. 3, Chung-Yung Road, Hualien, Taiwan 97002, R.O.C Tel.: +886-3-8561825, Ext: 12234 Fax: +886-3-8577161 Email addresses: [email protected]
1
Introduction Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) in tissues resulting in a wide spectrum of clinical phenotypes, including macrocephaly, facial dysmorphism, spinal stenosis, hepatosplenomegaly, umbilical hernia, inguinal hernia, heart valve abnormalities, sleep apnea, corneal clouding, and growth retardation. According to the affected metabolic pathway, MPS are categorized into seven types and more subtypes. Ocular complications are common in all types of MPS, which include corneal clouding, glaucoma, pigmentary retinopathy, optic disc swelling, or optic atrophy.1,2 However, the pathophysiology is not fully understood, partly due to the neglect of these rare diseases, and partly due to the difficulties of approach. By using spectral-domain optical coherence tomography (OCT), we had demonstrated the changes of the retina and choroid in the MPS type I, II, and VI, but not in type IVA in our previous study.3 Our findings also implicated the possible beneficial effect of enzyme replacement therapy.3 Nowadays, swept-source OCT provides better resolution through corneal opacities in evaluating the structure of the angle; while the new-generation tonometer (Corvis ST; Oculus Optikgeräte GmbH, Wetzlar, Germany) takes corneal thickness and rigidity into account and may provide better intraocular pressure (IOP) estimates. In this study, we utilize swept-source OCT to evaluate the angle structure and Corvis ST to estimate the IOP in patients with MPS type I, II, IV, and VI. Methods This cross-sectional study was carried out with approval from the Institutional Review Board (IRB103-162-A) prospectively. Informed Consent for the research was obtained from the patients. This study enrolled 20 normal controls and 27 consecutive MPS patients, including 8 patients with MPS I (4 male, 4 female), 4 patients with MPS II (all male), 9 patients with MPS IV (2 male, 7 female), and 6 patients with MPS VI (3 male, 3 female). 9 MPS patients were excluded due to being too young to cooperate, intellectual and developmental disability, or other comorbidities. The 20 normal patients (11 males, 9 females) were all younger than 30 years old, had normal ocular examination results and a spherical equivalent of higher than -6.0 D. Except for one Japanese (MPS I) and one Malaysian (MPS VI), the enrolled MPS patients and normal controls were all Han 2
Taiwanese. As MPS are rare diseases and their ocular problems are complicated, it is imperative that a senior ophthalmologist can afford a regular and comprehensive care for MPS patients. In this study, we had a senior ophthalmologist (Yuan-Chieh Lee, with expertise in cornea, glaucoma, retina, and pediatric ophthalmology), two junior ophthalmologists (Jia-Rong Zhang and Hong-Zin Lin, specialized in cornea and glaucoma respectively), and two technicians. All participants underwent a comprehensive eye examination including visual acuity, refraction, slit-lamp biomicroscopy, central corneal thickness (CCT), uncorrected-IOP (CVS-IOP) and corrected-IOP (CVS-IOPcorrected) measurements using Corvis ST. The corrected-IOP (CVS-IOPcorrected) was calculated according to the correction equation,4 which stated that CVS-IOPcorrected = (CCCT1 x CCVS-IOP + CCCT2) x Cage + C, where CCCT1, CCCT2 are parameters representing the effect of variation in CCT (mm). (For further information, please see appendix.) The central anterior chamber depth (ACD) and ocular axial length (AL) were measured with an optical biometer (Al-Scan; NIDEK Co. Ltd., Gamagori, Japan). All the OCT images were captured in a dimly lit room utilizing the DRI Triton swept-source OCT (Topcon, Tokyo, Japan) in the Line Anterior Segment mode (wavelength of laser: 1050 nm) to capture the anterior chamber angle images at 3 and 9 o’clock positions. The scan line was centered on the limbus with 6-mm scan size and the scan count was 64, and the participant was asked to look at the fixation target. The images were processed with the ImageJ (National Institutes of Health, Bethesda, MD) software to measure the status of angle opening. Because the clouded peripheral cornea obscured the identification of scleral spur and the apex in the iris recess in some types of MPS, the angle opening distance (AOD), trabecular iris angle (TIA), and angle recess area (ARA) were therefore defined as follows: the Schwalbe's line was identified first (point A), as it represents the termination of Descemet's membrane, then the point 500 µm posterior to the Schwalbe's line along the interior lining (point B) was marked. A perpendicular line was drawn from point A to the opposing anterior iris surface (point C), and the distance was defined as AOD. Another perpendicular line was drawn from point B to the opposing anterior iris surface (point D). One arm of the TIA passed through point A and B, and another arm of the TIA passed through point C and D. The ARA was defined as a triangular area
3
bordered by the anterior iris surface, corneal endothelium, and the AOD. This standard technique was illustrated in figure 1. Statistical Analysis Statistical mean differences of continuous data between different groups were analyzed with one-way analysis of variance or Kruskal-Wallis test. The Bonferroni correction was used as post-hoc analyses. The Chi-square test or Fisher's exact test was used to evaluate the association between two categorical variables. Generalized estimating equations model was adopted to evaluate the risk factors associated with the narrowing of the anterior chamber angle. All the data analyzed were pre-operative values. All the statistical analyses were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA). A P-value less than 0.05 was considered statistically significant.
Results MPS I: One eye was excluded due to previous penetrating keratoplasty (PKP) and lacked of preoperative data. All the 15 eyes of 8 patients with MPS I had varying degrees of corneal opacities: 2 patients had mild opacity in the central cornea and moderate to severe opacity in the peripheral cornea, and 6 patients had severe corneal opacities. CCT was not measurable in 3 patients due to severe corneal opacity. Among the other 5 patients, CCT was 539.00 ± 36.22 µm in the right eye (N=4) and 526.40 ± 38.32 µm in the left eye (N=5). The IOP estimates were available in 13 eyes. Among these 13 eyes, 12 eyes (92.3%) had IOP greater than 20 mmHg, 7 eyes (53.8%) had corrected-IOP greater than 30 mmHg. The OCT imaging demonstrated the narrow angles or peripheral iridocorneal touches in 12 eyes (80%) (Figure 2), compatible with the elevated IOP estimates. TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 6.71 ± 11.50 °, 7.30 ± 10.53 °, 7.17 ± 14.34 °, and 7.41 ± 14.71 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.06 ± 0.10 mm2, 0.06 ± 0.07 mm2, 0.05 ± 0.08 mm2, and 0.06 ± 0.07 mm2. 4
A 25-year-old man among these MPS I patients had high IOP estimates and clouded corneas and received uneventful corneal transplantation in his both eyes. The postoperative IOP estimates were still high above 40 mmHg and refractory to medications. He underwent bilateral trabeculectomy and had good IOP measurements eventually. MPS II: Among 4 patients (total 8 eyes) with MPS II, a 27-year-old man had bilateral mild corneal opacities (25%), and the other three cases had clear corneas. CCT of the right eye and left eye were 547.25 ± 20.77 µm and 561.25 ± 26.99 µm respectively. All the MPS II patients had normal corrected-IOP (15.18 ± 3.50 mmHg and 14.38 ± 3.30 mmHg in the right eye and left eye) and normal retinal nerve fiber layer thickness. The ACD was 3.06 ± 0.79 mm in the right eye and 3.08 ± 0.83 mm in the left eye. OCT imaging revealed a plateau iris configuration in 3 patients (6 eyes, 75%) (Figure 3). TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 22.04 ± 14.54 °, 24.22 ± 10.59 °, 12.42 ± 9.29 °, and 21.04 ± 2.57 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.21 ± 0.11 mm2, 0.21 ± 0.11 mm2, 0.13 ± 0.04 mm2, and 0.11 ± 0.03 mm2, respectively. MPS IV: All 9 patients with MPS IV had mild to moderate clouded corneas bilaterally (total 18 eyes). The CCT was 513.00 ± 49.36 µm and 529.11 ± 62.32 µm in the right eye and the left eye (range: 408 µm to 612 µm). 4 patients (8 eyes) had bilateral elevated corrected-IOP estimates (44.4%). OCT revealed normal open-angle structures in all eyes (Figure 4). TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 39.75 ± 14.29 °, 35.88 ± 11.71 °, 31.88 ± 17.28 °, and 36.08 ± 10.84 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.28 ± 0.11 mm2, 0.25 ± 0.12 mm2, 0.27 ± 0.16 mm2, and 0.20 ± 0.08 mm2, respectively. MPS VI: One eye was excluded due to previous PKP and lacked of preoperative data. All the 11 eyes (100%) of the 6 patients with MPS VI had corneal opacities, and 8 (72.7%) were 5
severe. CCT of the right eye and left eye were 590.33 ± 160.55 µm and 575.00 ± 138.05 µm respectively. The IOP estimate was not available in 2 eyes (1 patient). 5 out of the rest 9 eyes (55.6%) had elevated IOP estimates, and 4 out of these 5 eyes had IOP estimates above 30 mmHg. OCT revealed a narrow angle in 9 eyes (5 patients, 81.8%) (Figure 5). TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 18.95 ± 6.67 °, 13.35 ± 8.11 °, 11.07 ± 7.95 °, and 17.15 ± 9.52 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.11 ± 0.08 mm2, 0.12 ± 0.05 mm2, 0.15 ± 0.06 mm2, and 0.12 ± 0.06 mm2, respectively. The 4 eyes with elevated IOP estimates above 30 mmHg had severe corneal opacities and underwent smooth corneal transplantation (2 PKP and 2 deep anterior lamellar keratoplasties). All the IOP estimates dropped to low tens without medication after corneal transplantation. The OCT also showed normal retinal nerve fiber layer thickness in these 4 eyes. Control group: A total of 20 cases were enrolled as the control group. Mean age was 14.00 ± 3.36 years old, and mean spherical equivalent refraction of the right eye and left eye were -2.21 ± 1.27D and -2.21 ± 1.18D, respectively. CCT of the right eye and left eye were 548.40 ± 40.66 µm and 548.85 ± 38.85 µm respectively. AS-OCT revealed normal open-angle in the control groups. TIA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 48.01 ± 9.28 °, 49.20 ± 7.88 °, 42.88 ± 6.55 °, and 45.13 ± 7.74 °. ARA of the temporal angle (OD), temporal angle (OS), nasal angle (OD), and nasal angle (OS) were 0.32 ± 0.11 mm2, 0.29 ± 0.11 mm2, 0.27 ± 0.09 mm2, 0.26 ± 0.11 mm2. Comparison between different types of MPS and control group MPS type I, II, VI were more hyperopic than MPS type IV and control group. The axial lengths of MPS type I, II, VI were significantly shorter than those of MPS type IV and control group. The TIAs of MPS type I, II, VI were smaller than those of MPS type IV and control group. The ARAs of MPS type I and VI were smaller than those of MPS type IV and control group. MPS type I, IV, and VI had higher uncorrected IOP estimates than the control group, and MPS type I had higher IOP estimates than MPS type II and IV. MPS I 6
and IV had higher corrected IOP estimates than the control group (Table 1). Multivariate analysis demonstrated that age was significantly correlated with TIA. The older the patients, the smaller the TIAs (table 2). The TIAs of MPS type I, II, IV, VI were 36.14 °, 17.25 °, 8.76 °, 30.61° smaller than that of the control group (table 2); while the ARAs of MPS type I and VI were significantly smaller than that of the control group by 0.195 mm2 and 0.149 mm2 respectively (table 3). Discussion Glaucoma has been reported in MPS I-S (Scheie syndrome),5 MPS I-H/S,6,7 MPS I-H (Hurler syndrome),8-10 MPS type II,11 MPS type IV (Morquio syndrome), and MPS type VI (Maroteaux-Lamy syndrome),1,2,12 and yet for several reasons remained a challenge when being identified in these patients. First, the measurement of IOP could be falsely raised due to the increased corneal thickness and rigidity.13 Study has demonstrated a moderate positive correlation between CCT and measured IOP.14 Second, the gonioscopic and ophthalmoscopic examinations could be obscured by corneal opacities.12 Third, the visual field data might be hard to obtain due to poor cooperation, or the results were difficult to interpret because of other combined ocular comorbidities.1 Nevertheless, we were able to analyze their IOP and angle status from the limited obtainable data using SS-OCT and Corvis ST. In MPS type I, glaucoma has been reported ranging from acute attack to chronic angle-closure glaucoma, and to described open-angle.5,6,8,9 However, all those reported cases lacked a clear gonioscopic view of the angle due to dense corneal opacities. Ahmed et al. reported one out of the five MPS type I patients in their study had bilateral angle-closure.15 Ashworth et al. reported only two patients with ocular hypertension and normal optic discs among 31 MPS type I patients. Both concluded a low incidence of ocular hypertension and glaucoma in patients with MPS type I.16 In contrast, our study revealed narrow to closed angles and elevated IOP estimates in 5 out of the 6 MPS type I patients with clear images. In the other 2 patients without discernable images, one showed a shallow anterior chamber under biomicroscopy. Our study revealed a much higher rate of angle closure in MPS type I. The angle closure caused by the accumulation of GAGs and abnormal thickening of the cornea, sclera, and iris has been described,5,6 and was compatible with our AS-OCT findings. Multivariate regression 7
analyses (Table 2 & 3) also indicated that patients with MPS type I have significantly narrower TIA and smaller ARA than the control group. On average, the TIA of MPS type I was 36.14 ° smaller than that of the control group, and the ARA of MPS type I was 0.195 mm2 smaller than that of the control group. Although a clear cornea was once used to distinguish MPS type II form other types of MPS, one out of our four MPS type II patients had bilateral mild corneal opacities. Elflein et al. used pentacam to analyze clinically clear corneas of MPS II and reported higher corneal density values than those of healthy subjects.17 Hence the corneas are not truly unaffected in MPS II patients, only to a minor degree. Besides the minor change of cornea, their visual acuity may also be affected by combined pigmented retinopathy or GAG accumulation related chorio-retinopathy.3 Acute angle-closure glaucoma was once reported with MPS type II, but no gonioscopic finding has been described.11 Our study revealed a plateau iris configuration without IOP elevation in 3 out of the 4 cases with MPS type II (75%). Multivariate regression tests indicated that patients with MPS type II have significantly narrower TIA than the control group but no such association was found in the analysis of ARA, which was compatible with the narrow-angle and deep central chamber of plateau iris configuration (Table 2 & 3). Previous histological studies reported fibrillogranular inclusions or membranolamellar inclusions within the corneal epithelium, keratocytes, and corneal endothelial cells without distortion the shape of individual cells; while those inclusions were most strikingly found in the pigmented and nonpigmented epithelium of the iris and ciliary body, which even lead to great distension of these cells.18,19 This might contribute to the mild corneal opacity and plateau iris configuration noted in our study. All 9 patients with MPS IV had clouded corneas, ranging from mild to moderate, but not as severe as those of MPS I and MPS type VI. On average, the TIA of MPS type I was 8.76 ° smaller than that of the control group, which suggests that together the moderate corneal opacification and thickened anterior chamber structures of MPS type IV caused a relatively narrower angle when compared with the control group. On the other hand, CCT and ARA were not significantly different from those of the control group. Although the AS-OCT showed normal open-angle structures in all of them, four patients (44.5%) had elevated IOP. Previous transmission electron microscopic study demonstrated fibrillogranular and multi-membranous membrane-bound inclusions 8
distributed primarily in the cornea and trabecular meshwork in cases with MPS type IV,20 which might lead to elevated IOP with morphological open-angle as noted in our patients. As for MPS type VI, a previous histopathologic study suggested GAG accumulation in anterior segment structures and the trabecular meshwork, thus both angle-closure glaucoma and open-angle glaucoma had been reported.12 Another case series demonstrated a relatively high incidence (38%) of ocular hypertension in MPS VI patients compared to other types of MPS,16 in which a statistically significant correlation between IOP and the degree of corneal opacity was found in MPS VI patients. In our study, all the 6 patients with MPS VI developed significant corneal opacities, thickened anterior chamber structures, and narrow anterior chamber angles. On average, the TIA and the ARA was 30.61 ° and 0.149 mm2 smaller than that of the control group, respectively. Among the 9 eyes with reliable IOP estimates, 5 eyes (56%) had elevated IOP ranging from 29 mmHg to over 50 mmHg. Among these 5 eyes with elevated IOP, 4 eyes underwent corneal transplantations. Interestingly, the IOP estimates dropped to low tens postoperatively without IOP-lowering medication. The normal retinal nerve fiber layer thickness shown in OCT also align with the presumption that the preoperative IOP might not be truly high. Similar cases of IOP returning to normal after corneal transplantation have also been reported before,21,22 and suggested that the IOP estimates are often falsely high in MPS type VI due to corneal hysteresis and corneal resistance factor, either of which is positively correlated with the corneal clouding in MPS.23,24 Although the IOP estimates dropped to normal range after corneal transplantation in patients of MPS VI, the incidence of angle-closure glaucoma might increase as the disease progresses or the life expectancy extend with advances in treatment due to progressive ticking of anterior angle structures. There has been a report of an acute angle-closure glaucoma attack in a MPS type VI patient despite a prophylactic patent laser iridotomy,25 mainly because the angle closure in MPS type I and type VI is secondary to thickening of the cornea or other anterior chamber structure instead of pupillary block, and therefore the anterior chamber would not be deepened after iridectomy.12 Limitations
9
First, although MPS syndromes are highly variable in expressivity and clinical presentations, but we were only able to enroll a limited number of patients in each type of MPS, partly because MPS syndromes are relatively rare diseases. Caution should be taken when applying these results. Second, the AS-OCT was only performed for nasal and temporal angles instead of the entire angle structure, and the manufacturing company failed to provide normal range for angle structures. But, we had standardized technique of performing the OCT imaging, and enrolled a normal non-MPS control group for comparison. Third, the corrected IOP estimate with Corvis was not available in some patients with MPS type I and VI, especially in those with severe corneal opacities. Fourth, gonioscopic examination was not performed as we planned to do non-contact examinations for these MPS patients. The optic disc status was not analyzed because of corneal opacity interfering visualization and avoidance of mydriasis due to narrow angles in MPS I and VI patients, and other disc anomalies affecting interpretation.3 Visual field examination was not performed due to reduced reliability from lack of cooperation or ocular comorbidities interfering interpretation. We did not analyze the relationship between the best-corrected visual acuity and degree of corneal opacification, partly because the data could not be reliably obtained or quantified in some patients, and partly because the best-corrected visual acuity was affected not only by corneal opacity but also by other ocular comorbidities such as numerous retinopathy as our previous report.3 Fifth, the control group was relatively skewed myopic, which was a risk factor for open angle glaucoma. However, more than 60 % of children are myopic by the age of 12, and more than 80 % are myopic by the age of 15 in Taiwan.26 Since these MPS patients are mostly residents of Taiwan, the status of their angles should be compared with those of ordinary “normal” non-MPS residents of similar ages in Taiwan. But we still avoided the high myopic (<-6D) children as the control group. Besides, our study was to analyze the differences of the angle status and the IOP rather than the incidence of glaucoma. Our results showed that MPS type I, II and VI patients have shorter axial length and smaller TIA than not only the control group but also the MPS type IV patients, who are almost emmetropic. MPS type I and VI patients have smaller ARA than both the control group and the MPS type IV patients. As for IOP, it has been reported not associated with refractive status in children and adolescents.27,28
10
Conclusions MPS I patients are prone to have glaucoma with narrow or closed angles; MPS II patients tend to have plateau iris configuration; MPS IV patients have open angles; finally, MPS VI patients have narrow angles, but not as closed as those of MPS I. In terms of IOP estimates, MPS type I, IV, and VI were higher than the control group, whereas in terms of corrected IOP estimates, only MPS type I and IV were higher. The original IOP estimates in MPS VI patients may be falsely high due to clouded corneas and increased corneal rigidity. Although the pathophysiology of glaucoma in MPS is not well delineated yet, the swept-source OCT can assist ophthalmologist to investigate the anterior chamber angle status and the pathophysiology of glaucoma caused by MPS.
Acknowledgments/disclosure ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. There is no funding or financial support for this study. All authors have no financial disclosures. Full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis (J.R.Zhang, Y.C.Lee); concept and design (J.R.Zhang, Y.C.Lee); acquisition, analysis, or interpretation of data (J.R.Zhang, J.H.Wang, H.Z. Lin, Y.C.Lee); statistical analysis (J.R.Zhang, J.H.Wang, H.Z. Lin, Y.C.Lee); drafting of the manuscript (J.R.Zhang, J.H.Wang, Y.C.Lee); critical revision of the manuscript for important intellectual content (J.R.Zhang, Y.C.Lee).
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Connell P, McCreery K, Doyle A, Darcy F, O'Meara A, Brosnahan D. Central corneal thickness and its relationship to intraocular pressure in mucopolysaccararidoses-1 following bone marrow transplantation. J AAPOS. 2008;12(1):7-10.
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Ahmed TY, Turnbull AM, Attridge NF, et al. Anterior segment OCT imaging in mucopolysaccharidoses type I, II, and VI. Eye (Lond). 2014;28(3):327-336.
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Ashworth JL, Biswas S, Wraith E, Lloyd IC. The ocular features of the mucopolysaccharidoses. Eye (Lond). 2006;20(5):553-563.
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Elflein HM, Hofherr T, Berisha-Ramadani F, et al. Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme. Br J Ophthalmol. 2013;97(7):829-833.
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McDonnell JM, Green WR, Maumenee IH. Ocular histopathology of systemic mucopolysaccharidosis, type II-A (Hunter syndrome, severe). Ophthalmology. 1985;92(12):1772-1779.
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Topping TM, Kenyon KR, Goldberg MF, Maumenee AE. Ultrastructural ocular pathology of Hunter's syndrome: systemic mucopolysaccharidosis type II. Arch Ophthalmol. 1971;86(2):164-177.
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Iwamoto M, Nawa Y, Maumenee IH, Young-Ramsaran J, Matalon R, Green WR. Ocular histopathology and ultrastructure of Morquio syndrome (systemic mucopolysaccharidosis IV A). Graefes Arch Clin Exp Ophthalmol. 1990;228(4):342-349.
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13
Appendix: Central corneal thickness (CCT) is the major correction factor for the Corvis tonometer, and age is the minor correction factor. The correction formula is as follows: CVS-IOPcorrected = (CCCT1 x CCVS-IOP + CCCT2) x Cage + C.4 Where CCCT1, CCCT2 are parameters representing the effect of variation in central corneal thickness (CCT) (mm); -7
2
-4
CCCT1 =4.67x10 xCCT –7.8x10 xCCT+0.63 -5
2
-3
CCCT2 =-1.73x10 xCCT +2.02x10 xCCT–0.97 CCVS-IOP = effect of variation in measured Corvis-IOP (mmHg) = 10 + (Corvis-IOP + 1.16) / 0.389 Cage = effect of variation in age (years) -5
2
-3
= -2.01 x 10 x age + 1.3 x 10 x age + 1.00 C = 1.50 mmHg
Figure Captions: Figure1. Standard technique of performing the anterior segment OCT illustrated with a control subject. Panel A and C, The OCT images of the nasal and temporal angles of right eye were captured from 3 o’clock and 9 o’clock areas in the Line Anterior Segment mode, centered on limbus, and the results were demonstrated in panel B and D. Panel B shows how to measure the trabecular iris angle (TIA), The Schwalbe's line was identified as point A, then the point 500-µm posterior to the Schwalbe's line along the interior lining was marked as point B. A perpendicular line was drawn from point A to the opposing anterior iris surface (point C), and the distance was defined as the angle opening distance (AOD). Another perpendicular line was drawn from point B to the opposing anterior iris surface (point D). The trabecular iris angle (TIA) was defined as angle formed by one arm passing through point A and B, and the other arm passed through point C and D. The illustrated TIA was 44°. Panel D demonstrates the angle recess area (ARA) as a triangular area bordered by the anterior iris surface, corneal endothelium, and the AOD. This illustrated ARA was 0.339 mm2.
14
Figure 2. Swept-source optical coherence tomography images of ocular angles in 3 patients with mucopolysaccharidoses type I. A and B, Scans showing closed temporal and nasal angles in the left eye of a 7-year-old girl. The TIA and ARA were 0° and 0 mm2. The IOP was 29.5 mmHg. C and D, A shallow temporal angle and a closed nasal angle of the right eye in a 37-year-old man. The IOP was 44 mmHg. The TIA of the temporal angle and nasal angle were 10.2° and 0°, respectively. The ARA of the temporal angle and nasal angle were 0.095 mm2 and 0.038 mm2, respectively. E and F, The closed temporal and nasal angles in the left eye of an 18-year-old man. The IOP was higher than 60 mmHg. The TIA and ARA were 0° and 0 mm2.
Figure 3. Swept-source optical coherence tomography images demonstrating plateau iris configuration in 3 patients with mucopolysaccharidoses type II. A and B, Scans of temporal and nasal angles in the left eye of a 27-year-old man. The TIA were 22.9° and 23°, respectively. The ARA were 0.113 mm2 and 0.222 mm2, respectively. The IOP was 15.5 mmHg. C, A scan of temporal angle in the right eye of a 50-year-old man. The TIA was 11.2°. The ARA was 0.135 mm2. The IOP was 13.5 mmHg. D, A scan of temporal angle in the left eye of the same patient as C. The TIA was 14.8°. The ARA was 0.114 mm2. The IOP was 15 mmHg. E, A scan of temporal angle in the right eye of a 53-year-old man. The TIA was 10.1°. The ARA was 0.178 mm2. The IOP was 11.3 mmHg. F, A scan of temporal angle in the left eye of the same patient as E. The TIA was 19.9°. The ARA was 0.137 mm2. The IOP was 10.3 mmHg. Figure 4. Swept-source optical coherence tomography images showing wide open angles in 3 patients with mucopolysaccharidoses type IV. A and B, Scans of temporal angle and nasal angle in the left eye of a 15-year-old girl. The TIA were 32.2° and 35.1°, respectively. The ARA were 0.31 mm2 and 0.254 mm2, respectively. The IOP was 48.5 mmHg. C and D, Scans of temporal angle and nasal angles in the left eye of a 20-year-old woman. The TIA were 48° and 46°, respectively. The ARA were 0.305 mm2 and 0.345 mm2, respectively. The IOP was 29 mmHg. E and F, Scans of temporal and nasal angles in the right eye of a 23-year-old woman. The TIA were 52.3° and 46.9°,
15
respectively. The ARA were 0.197 mm2 and 0.291 mm2, respectively. The IOP was 27 mmHg. Figure 5. Swept-source optical coherence tomography images showing shallow angles in 3 patients with mucopolysaccharidoses type VI. A and B, Scans of temporal and nasal angles in the left eye of an 11-year-old boy with severe corneal opacity. The TIA were 8.6° and 16.7°, respectively. The ARA were 0.059 mm2 and 0.087 mm2, respectively. The IOP was 29 mmHg. C and D, Scans of temporal and nasal angles in the right eye of an 18-year-old girl. The TIA were 3.3° and 15.5°, respectively. The ARA were 0.038 mm2 and 0.093 mm2, respectively. The IOP estimate was not available due to severe corneal opacity. E and F, Scans of temporal and nasal angle in the left eye of a 24-year-old woman. The TIA were 8.1° and 12.3°, respectively. The ARA were 0.058 mm2 and 0.15 mm2, respectively. The IOP was 17 mmHg.
16
Table 1. Demographics and comparisons between MPS type I, II, IV, VI, and the control group. Item
MPS Control (C) Type I (M1)
Type II (M2)
Type IV (M4)
Type VI (M6)
N
20
8
4
9
6
Age (N=47)
14.00 ± 3.36
25.88 ± 15.33
35.00 ± 20.31
19.56 ± 6.54
19.00 ± 8.67
Gender
P-value
Post-hoc**
0.001*
C,M4,M6 < M1,M2
0.144
Male
11(55.0%)
4(50.0%)
4(100.0%)
2(22.2%)
3(50.0%)
Female
9(45.0%)
4(50.0%)
0(0.0%)
7(77.8%)
3(50.0%)
-2.21 ± 1.27
1.96 ± 1.82
4.09 ± 3.82
-0.69 ± 3.36
8.44 ± 0.63
<0.001*
C,M4 < M1 < M2,M6
0.55 ± 0.46
1.75 ± 0.90
1.31 ± 0.52
2.63 ± 1.55
0.88 ± 0.66
<0.001*
M4 > M6, C
-2.21 ± 1.18
4.63 ± 2.81
4.25 ± 3.62
0.33 ± 2.96
8.92 ± 1.45
<0.001*
C,M4 < M1,M2,M6
0.79 ± 0.62
1.08 ± 0.14
1.38 ± 0.48
3.39 ± 2.38
1.00 ± 0.66
<0.001*
M4 > C
CCT, OD (N=41)
548.40 ± 40.66
539.00 ± 36.22
547.25 ± 20.77
513.00 ± 49.36
590.33 ± 160.55
0.295
CCT, OS (N=42)
548.85 ± 38.85
526.40 ± 38.32
561.25 ± 26.99
529.11 ± 62.32
575.00 ± 138.05
0.616
15.85 ± 2.46
41.50 ± 15.28
15.50 ± 2.94
21.33 ± 6.40
29.88 ± 16.78
<0.001*
15.32 ± 2.47
33.71 ± 16.55
15.25 ± 2.66
23.28 ± 11.34
26.00 ± 9.43
<0.001*
15.70 ± 2.63
24.95 ± 5.16
15.18 ± 3.50
21.63 ± 5.47
18.50 ± 1.56
0.001*
15.13 ± 2.70
22.03 ± 8.81
14.38 ± 3.30
22.94 ± 9.28
20.77 ± 6.92
0.010*
SE, OD (N=39) Cylinder, OD (N=39) SE, OS (N=39) Cylinder, OS (N=39)
Uncorrected IOP, OD (N=43) Uncorrected IOP, OS (N=45) Corrected IOP, OD (N=37) Corrected IOP, OS (N=39)
C,M2,M4 < M1 & C < M6 C,M2 < M1 & C < M4,M6 C, M2 < M1 & C < M4 C < M4
AL, OD (N=40)
24.29 ± 0.76
21.52 ± 0.28
22.21 ± 1.62
23.82 ± 1.52
20.21 ± 0.43
<0.001*
M1,M2,M6 < M4,C
AL, OS (N=40)
24.40 ± 0.81
21.30 ± 0.55
22.12 ± 1.65
23.55 ± 1.51
20.26 ± 0.29
<0.001*
M1,M2,M6 < M4,C
48.01 ± 9.28
6.71 ± 11.50
22.04 ± 14.54
39.75 ± 14.29
18.95 ± 6.67
<0.001*
M1,M2,M6 < M4,C
49.20 ± 7.88
7.30 ± 10.53
24.22 ± 10.59
35.88 ± 11.71
13.35 ± 8.11
<0.001*
M1,M2,M6 < M4,C
42.88 ± 6.55
7.17 ± 14.34
12.42 ± 9.29
31.88 ± 17.28
11.07 ± 7.95
<0.001*
M1,M2,M6 < M4,C
45.13 ± 7.74
7.41 ± 14.71
21.04 ± 2.57
36.08 ± 10.84
17.15 ± 9.52
<0.001*
M1,M2,M6 < M4,C
0.32 ± 0.11
0.06 ± 0.10
0.21 ± 0.11
0.28 ± 0.11
0.11 ± 0.08
<0.001*
M1,M6 < M4,C
0.29 ± 0.11
0.06 ± 0.07
0.21 ± 0.11
0.25 ± 0.12
0.12 ± 0.05
<0.001*
M1,M6 < M4,C
0.27 ± 0.09
0.05 ± 0.08
0.13 ± 0.04
0.27 ± 0.16
0.15 ± 0.06
0.002*
M1,M6 < M4,C
0.26 ± 0.11
0.06 ± 0.07
0.11 ± 0.03
0.20 ± 0.08
0.12 ± 0.06
<0.001*
M1,M6 < M4,C
Temporal TIA, OD (N=43) Temporal TIA, OS (N=44) Nasal TIA, OD (N=41) Nasal TIA, OS (N=41) Temporal ARA, OD (N=44) Temporal ARA, OS (N=43) Nasal ARA, OD (N=42) Nasal ARA, OS (N=43)
Data are presented as n (%) or mean ± standard deviation. *p-value<0.05 was considered statistically significant. Statistical mean differences of continuous data between different groups were analyzed with one-way analysis of variance or Kruskal-Wallis test. Two categorical variables were analyzed with Chi-square test or Fisher's exact test. ** Post-hoc analysis was conducted with Bonferroni correction. Abbreviations: SE = spherical equivalent, measured in diopter; CCT = central corneal thickness, measured in µm; IOP = intraocular pressure, measured in mmHg; AL = axial length, measured in mm; TIA = trabecular iris angle, measured in degrees; ARA = angle recess area, measured in mm2.
Table 2. Factors associated with trabecular iris angle (TIA, in degrees) analyzed with generalized estimating equations model. Predictor
β
95% CI
p value
Intercept
50.19
(44.34,56.04)
<0.001*
Age
-0.37
(-0.64, -0.10)
0.008*
-
-
-
References
References
NA
0.24
(-4.32,4.80)
0.917
-
-
-
References
References
NA
-1.21
(-3.19,0.78)
0.233
-
-
-
References
References
NA
3.56
(1.25,5.86)
0.003*
-
-
-
References
References
NA
MPS Type I
-36.14
(-45.94, -26.34)
<0.001*
MPS Type II
-17.25
(-26.46, -8.03)
<0.001*
MPS Type IV
-8.76
(-15.77, -1.76)
0.014*
MPS Type VI
-30.61
(-35.97, -25.25)
<0.001*
Gender Female Male Laterality Left Right Location Nasal Temporal Type Control
Data are presented as β (95% CI). *p-value<0.05 was considered statistically significant.
Table 3. Factors associated with angle recess area (ARA, in mm2) analyzed with generalized estimating equations model. Predictor
β
95% CI
p value
Intercept
0.270
(0.209,0.332)
<0.001*
Age
-0.002
(-0.005,0.001)
0.107
-
-
-
References
References
NA
0.047
(-0.0004,0.094)
0.052
-
-
-
References
References
NA
0.02
(-0.005,0.045)
0.112
-
-
-
References
References
NA
0.026
(0.006,0.046)
0.010*
-
-
-
References
References
NA
MPS Type I
-0.195
(-0.267, -0.123)
<0.001*
MPS Type II
-0.071
(-0.180,0.039)
0.205
MPS Type IV
-0.004
(-0.062,0.054)
0.891
MPS Type VI
-0.149
(-0.205, -0.093)
<0.001*
Gender Female Male Laterality Left Right Location Nasal Temporal Type Control
Data are presented as β (95% CI). *p-value<0.05 was considered statistically significant.
Dr. Yuan-Chieh Lee is the chief of the department of ophthalmology, Buddhist Tzu Chi General Hospital and associate professor of Tzu Chi University, Hualien. He has interest in cornea, glaucoma, and retina. He has taken care of the ocular problems in mucopolysaccharidoses patients of Taiwan for a decade.
Jia-Rong Zhang, MD, was born and raised in Taiwan where she received her medical degree from Kaohsiung Medical University, Kaohsiung, Taiwan, in 2013 and completed a residency and fellowship in corneal and external diseases in Buddhist Tzu Chi General Hospital, Hualien, Taiwan in 2019. Dr Zhang is currently an attending physician of the Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien.