|Year : 2016 | Volume
| Issue : 5 | Page : 358-363
Lamina depth and thickness correlate with glaucoma severity
Martha Kim1, Karine D Bojikian2, Mark A Slabaugh2, Leona Ding2, Philip P Chen2
1 Department of Ophthalmology, Dongguk University Ilsan Hospital, Goyang, Korea; Department of Ophthalmology, University of Washington, Seattle, WA, USA
2 Department of Ophthalmology, University of Washington, Seattle, WA, USA
|Date of Submission||02-Nov-2015|
|Date of Acceptance||30-Apr-2016|
|Date of Web Publication||6-Jul-2016|
Prof. Martha Kim
Department of Ophthalmology, Dongguk University Ilsan Hospital, 27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-773, Korea
Source of Support: None, Conflict of Interest: None
Purpose: To evaluate the correlation between lamina cribrosa (LC) morphology and glaucoma severity in patients with primary forms of open-angle glaucoma (OAG) using enhanced depth imaging spectral-domain optical coherence tomography (SD-OCT) and Humphrey visual field test (HVF). Subjects and Methods: Patients with OAG (n = 166), divided into normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) groups (n = 66 and n = 100), were imaged using SD-OCT to obtain horizontal B-scan images of the optic nerve head (ONH). Laminar depth (LD) and laminar thickness (LT) were measured at the center of ONH. Results: The mean (±standard deviation) values of LD, LT, and visual field mean deviation (MD) were 555.4 ± 142.3 μm, 179.9 ± 49.7 μm, and − 5.7 ± 6.4 dB, respectively. In the multivariate linear regression analysis, LD, LT, and intraocular pressure (IOP) were significantly correlated with MD (P = 0.007, P = 0.037, and P = 0.004, respectively). In the subgroup analyses, only LD was associated with MD in the NTG group (n = 66), whereas LT and IOP were correlated with MD in the HTG group (n = 100). Neither axial length nor central corneal thickness was associated with LD or LT. Conclusions: Glaucoma severity, as measured by HVF MD, shows significant correlations with LD and LT, with greater severity associated with increasing LD and decreasing LT. Normal- and high-tension OAG patients have different associations with LD and LT, which implies that the pathogenesis of these two entities might be different.
Keywords: Glaucoma, lamina cribrosa, optic nerve, optical coherence tomography
|How to cite this article:|
Kim M, Bojikian KD, Slabaugh MA, Ding L, Chen PP. Lamina depth and thickness correlate with glaucoma severity. Indian J Ophthalmol 2016;64:358-63
|How to cite this URL:|
Kim M, Bojikian KD, Slabaugh MA, Ding L, Chen PP. Lamina depth and thickness correlate with glaucoma severity. Indian J Ophthalmol [serial online] 2016 [cited 2020 Sep 21];64:358-63. Available from: http://www.ijo.in/text.asp?2016/64/5/358/185594
Primary forms of open-angle glaucoma (OAG) are characterized by a progressive optic neuropathy with typical optic nerve head (ONH) damage or glaucomatous visual field (VF) defects.  The lamina cribrosa (LC), a multi-layered sieve-like structure in the ONH, has been proposed as a primary site of axonal damage in glaucoma.  However, in the past, quantitative evaluation of LC tissue in vivo was not possible due to the presence of prelaminar neuroretinal tissue.
Improvements in technology have enabled optical coherence tomography (OCT) to provide high-resolution cross-sectional images of the ONH in vivo.  Furthermore, enhanced depth imaging (EDI) using spectral-domain (SD) OCT enables visualization of the LC in vivo. ,,,,,,,, Using this imaging method, studies on OAG have been performed to investigate the structure-function relationship between the morphology of LC and glaucoma severity. ,, Inoue et al.  showed a significant positive correlation between laminar thickness (LT) and retinal sensitivity in glaucoma by linear regression analysis. Park et al.  also reported a logarithmic correlation between LT and retinal sensitivity in OAG patients. Recently, Ren et al.  revealed that the anterior LC surface depth increased with worse VF status in younger eyes with high-risk ocular hypertension and early glaucoma. We investigated the correlation between LC morphology, including both LT and laminar depth (LD), and glaucoma severity using EDI SD-OCT and Humphrey VF (HVF) testing in OAG patients.
| Subjects and Methods|| |
The study was performed with the informed consent of the participants and followed the Declaration of Helsinki and was approved by the Institutional Review Board.
All patients were recruited prospectively from December 2011 to October 2012 from the glaucoma clinics. Subjects were recruited consecutively based on the availability of study personnel. All subjects received comprehensive ophthalmic examinations that included best-corrected visual acuity, Goldmann applanation tonometry, slit-lamp biomicroscopy, central corneal thickness measurement (PachPen, Accutome, Malvern, PA, USA), and axial length measurement (IOL Master, Carl Zeiss, Meditec Inc., Dublin CA, USA). All subjects also underwent VF testing using 24-2 Swedish Interactive Threshold Algorithm - Standard algorithm (Humphrey Field Analyzer; Carl Zeiss Meditec. Inc., Dublin, CA, USA) and ONH imaging by SD-OCT (Spectralis OCT, Heidelberg Engineering, Vista, CA, USA) within 6 months of the ophthalmic examination.
For inclusion in this study, eyes with OAG were required to have a best-corrected visual acuity of ≥20/40 with axial length <30 mm, presence of a normal anterior chamber and open-angle on slit lamp and gonioscopic examinations, a clear cornea, and not more than moderate cataract. Subjects with any other ophthalmic or neurologic condition that could result in VF defects were excluded from the study as they were those with a history of any refractive corneal surgery or intraocular surgery, except noncomplicated cataract surgery. When both eyes were eligible, one eye was randomly selected.
We defined OAG as having an open angle on gonioscopy and glaucomatous optic nerve damage (i.e., the presence of typical thinning of the neuroretinal rim or notching). Most patients also had an abnormal VF consistent with glaucoma. A glaucomatous VF change was defined as (1) outside normal limits on the Glaucoma Hemifield Test; (2) 3 abnormal points with P < 5% probability of being normal, 1 with P < 1% by pattern deviation; or (3) a pattern standard deviation of <5% as confirmed on two consecutive tests. The VF tests required a false-positive rate, false-negative rate, and fixation loss rate of <25%. Patients with historical untreated and treated intraocular pressure (IOP) ≤21 mmHg were classified as normal-tension glaucoma (NTG) while those with historical untreated or treated IOP >21 mmHg at least one measurement were classified as high-tension glaucoma (HTG). All patients diagnosed as NTG and HTG were treated with antiglaucoma medications when they enrolled in the present study.
Spectral-domain OCT of the ONH with EDI was obtained using the Heidelberg Spectralis OCT (Heidelberg Engineering, Vista, CA, USA). The methods have been described elsewhere in detail. ,,, In our study, 6 radial B-scans of the ONH centered at the center of the disc were produced in the EDI mode. Among these B-scans, the horizontal frame that passed through the center of ONH was selected. Only good-quality scans (i.e., quality score ≥16) were used for analysis. The IOP measured by Goldmann applanation tonometry on the same day that the patient underwent the OCT examination was recorded.
The anterior depth of the LC (laminar depth [LD]) was determined as the distance between the reference plane and the anterior LC surface at the center of ONH. The reference plane was defined as the line connecting the 2 termination points of Bruch's membrane on each B-scan. When the termination of Bruch's membrane was not clear or the insertion was oblique, the extrapolated extension of the line along with the Bruch's membrane surface was used as the reference plane [Figure 1]. If the ONH was tilted by myopic change, the deepest point on the horizontal plane was chosen for the measurement. The thickness of the LC (laminar thickness [LT]) was also measured on horizontal B-scan images. The LT was determined as the distance from the anterior LC surface to the posterior LC surface at the center of ONH. All measurements were performed using the software which was provided from Heidelberg SD-OCT. Interobserver reliability (as assessed by intraclass correlation coefficient [ICC]) was measured for LD and LT using two independent observers (MK, KDB) for a subset of the subjects.
|Figure 1: Representative reference planes (white-dotted lines) and lamina cribrosa (white lines). Infrared images (left column) show the radial section where the horizontal cross-sectional B-scans (right column) were acquired. (a) Example of the reference plane (white-dotted line) with clear Bruch's membrane termination (white arrow). (b) Example of unclear Bruch's membrane termination with border tissue (black arrowheads). The imaginary extension of the line along with the Bruch's membrane surface is used as reference plane (white-dotted line)|
Click here to view
Comparisons between NTG and HTG groups were performed using the independent t-test for continuous variables or Chi-square test for categorical variables. The relationships between the laminar morphology (LD and LT) and VF mean deviation (MD) were evaluated by linear regression analyses. The HVF MD was treated as the dependent variable and other variables including laminar parameters (LD and LT) as the independent variables in all regression analysis assessing the structure-function relationship. Variables with P < 0.2 in the univariate regression analysis were entered in each multivariate regression analysis. Statistical analyses were performed using SPSS Statistics software (version 17.0, SPSS Inc., Chicago, IL, USA). The level of statistical significance was set at P < 0.05.
| Results|| |
One hundred sixty-six patients were enrolled in the study. The subject characteristics are summarized in [Table 1]. Of the 166 patients, 66 patients had NTG and 100 patients had HTG. All parameters except IOP were not significantly different between NTG and HTG group. Ten patients were excluded due to poor EDI scan quality from this study.
The interobserver reliability for LC measurements, determined using a randomly selected subgroup of sixty patients, was excellent (ICC = 0.972 and 0.779 for LD and LT, respectively) as judged by Fleiss criteria. 
The univariate regression analysis including all OAG patients showed that the LC parameters (LT and LD) and the IOP are significantly associated with the MD value [Table 2]. These variables remained significant after multivariate regression analysis (adjusted R2 = 0.096; P = 0.007, P = 0.037, and P = 0.004, respectively).
|Table 2: Univariate and multivariate regression analyses of visual field mean deviation in all patients (n=166)|
Click here to view
In the subgroup analysis of only NTG patients, the LD was associated with the MD both in univariate and multivariate analysis, whereas the LT and the IOP were not significantly associated with the MD [Table 3]. When only HTG patients were included, the LT and the IOP were significantly associated with the MD in univariate and multivariate analysis, but the LD was not associated with the MD [Table 4].
|Table 3: Univariate and multivariate regression analyses of visual field mean deviation in normal-tension glaucoma patients (n=66)|
Click here to view
|Table 4: Univariate and multivariate regression analyses of visual field mean deviation in high-tension glaucoma patients (n=100)|
Click here to view
| Discussion|| |
We found a small but significant correlation between glaucoma severity as measured by VF MD and LC parameters such as LT and LD in vivo using EDI SD-OCT. As glaucoma severity worsened, the LT was thinned and the LD was deepened in OAG patients. The level of IOP in these treated patients who had not undergone incisional glaucoma surgery was also associated with MD. In the subgroup analysis, the LT and IOP were significantly correlated with MD in the HTG group, whereas only the LD was significantly correlated with MD in the NTG group.
The concept of structure-function relationship in glaucoma patients is important for both grading the severity of disease and understanding the natural history of the condition.  Since the LC is considered to be an important site of axonal injury in glaucoma, many researchers have made efforts to visualize the LC and analyze the structure-function relationship between the LC and glaucoma severity. ,, There are cumulative data demonstrating the linear  or logarithmic  correlation between the LT and glaucoma severity. Consistent with previous studies, we found a significant correlation between the LT and the VF MD using linear regression analysis. Our results show that a structure-function relationship exists between LC measurements and functional loss in glaucoma, which could be important for understanding the pathophysiology of glaucoma, and potentially predicting its course.
Because glaucomatous ONH cupping is a common clinical feature of glaucoma and is a combination of two components - prelaminar and laminar cupping, it is unsurprising that the LD is deeper as the severity of glaucoma damage increases. Several postmortem studies in nonhuman primate experimental glaucoma have been described the posterior deformation ,, and outward migration  of LC in response to a chronic IOP elevation. However, before the EDI technique using SD-OCT was developed, quantitatively analyzing the LD in vivo was not possible. With the advent of technical improvements that allow EDI, several studies have examined LD change with human eyes in vivo after glaucoma surgery or IOP changes. ,,, Recently, studies have been performed focusing on the direct relationship between the LD and glaucoma. Furlanetto et al.  demonstrated that the central and mid-peripheral LC were located more posteriorly in glaucomatous eyes and eyes with VF defects as compared to normal eyes and fellow eyes with no VF defects. Ren et al.  reported the relation between the anterior LC surface depth and MD in early glaucoma (VF loss less severe than − 6 dB [MD]) or ocular hypertension patients. In their study, the LD increased with worse VF status in younger eyes but not in older eyes. In the present study, our data also showed a significant negative correlation between the LD and the MD.
In addition, our results showed that the association between the LC and glaucoma severity was different depending on the type of glaucoma and the association of IOP with glaucoma severity also differed with the type of glaucoma. Within the NTG group, the LD was significantly correlated with the MD, whereas the LT and the IOP were not. In contrast, the LT and the IOP were significantly correlated with the MD within the HTG group, but LD was not significantly correlated with the MD. These results could be explained in several ways. First, the pathogenesis of glaucomatous damage could differ between the NTG and the HTG group. Although the pathogenesis of OAG is still unclear, an elevated IOP is the single most important risk factor for the development or progression of glaucomatous optic neuropathy in HTG patients. ,, In contrast, there is evidence that in addition to IOP level and/or fluctuation, ocular and systemic vascular abnormalities affect the development and progression of NTG. ,, Recently, Killer et al.  demonstrated an impaired circulation of cerebrospinal fluid (CSF) in NTG patients using computed tomography cisternography of the brain. The impairment of CSF circulation in these NTG patients could result in reduced neurotoxin clearance along the optic nerve.  The high IOP in HTG may cause compressive change of LC while low CSF pressure in the subarachnoid space surrounding the LC may result in deepening of LC in NTG due to lack of structural or metabolic support. Thus, worsening disease in NTG could cause relatively more LC deepening than thinning. In contrast, the LC of HTG could be thinned as the disease progresses. If a relationship between LC change and glaucoma progression is established, clinicians could potentially use this relationship to evaluate the disease state and the risk of progression.
Second, the structural properties of the LC might be different in the NTG patients and the HTG patients. Park et al.  demonstrated that the LT in the NTG group was significantly thinner from the early and mid-stages of glaucoma than that in the HTG group. With this result, the authors suggested that the thinner LC of the NTG group might have contributed to the development of retinal ganglion cell damage in a normal IOP range. We found the LT of the NTG group was not significantly thinner than that of the HTG group in the present study. Population differences, including the relatively long axial length of patients in the present study and differences in patient characteristics, including race, could be explanations for the discrepancy between our study and Park et al. Further longitudinal study is needed to determine the cause-effect relationship between glaucoma and LC morphology.
Several limitations must be acknowledged in this study. The precision of the relationship model was relatively low; in our model, the R2 for all OAG patients was 0.096 and the R2 for subgroup analysis models was 0.106 for HTG group and 0.061 for NTG group, which indicates that the explanatory power of these models is weak. Considering that glaucoma is a multifactorial disease with genetic and environmental components and the relatively poor agreement of optic disc structural changes with functional changes in glaucoma,  it seems unsurprising that these values were not stronger. In addition, the methods for measuring the depth and the thickness of the LC in vivo must be validated, especially for eyes with myopic tilted disc for which the configuration of LC may be different; this could influence the variability of measurements. However, in the present study, only five eyes showed a tilted disc configuration probably because most of the population of this study was Caucasian (69.3%). Thus, possible variability of measurement from myopic tilted disc could be minimized in this study. Furthermore, because of the cross-sectional nature of this study, it is not possible to determine the cause-effect relationship between the LC configuration and the glaucoma severity. Further prospective, longitudinal study is warranted.
| Conclusions|| |
We measured LC parameters including the LT and LD in vivo using EDI SD-OCT and demonstrated a significant correlation between the LC parameters and the VF MD in OAG patients. Our results show a structure-function relationship between the LC and peripheral visual sensitivity. In addition, our results suggest that the LC may be different or act differently according to the OAG subtype, NTG versus HTG. Further research in this area is warranted to confirm these findings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Allingham RR, Damji KF, Freedman SF, Moroi SE, Rhee DJ. Shields Textbook of Glaucoma. 6 th
ed., Philadelphia: Lippincott Williams and Wilkins, Wolters Kluwer; 2011.
Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol 1981;99:635-49.
Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, et al.
Optical coherence tomography. Science 1991;254:1178-81.
Srinivasan VJ, Adler DC, Chen Y, Gorczynska I, Huber R, Duker JS, et al.
Ultrahigh-speed optical coherence tomography for three-dimensional and en face imaging of the retina and optic nerve head. Invest Ophthalmol Vis Sci 2008;49:5103-10.
Inoue R, Hangai M, Kotera Y, Nakanishi H, Mori S, Morishita S, et al.
Three-dimensional high-speed optical coherence tomography imaging of lamina cribrosa in glaucoma. Ophthalmology 2009;116:214-22.
Kagemann L, Ishikawa H, Wollstein G, Brennen PM, Townsend KA, Gabriele ML, et al.
Ultrahigh-resolution spectral domain optical coherence tomography imaging of the lamina cribrosa. Ophthalmic Surg Lasers Imaging 2008;39 4 Suppl:S126-31.
Girard MJ, Strouthidis NG, Ethier CR, Mari JM. Shadow removal and contrast enhancement in optical coherence tomography images of the human optic nerve head. Invest Ophthalmol Vis Sci 2011;52:7738-48.
Lee EJ, Kim TW, Weinreb RN, Park KH, Kim SH, Kim DM. Visualization of the lamina cribrosa using enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2011;152:87-95.e1.
Park HY, Park CK. Diagnostic capability of lamina cribrosa thickness by enhanced depth imaging and factors affecting thickness in patients with glaucoma. Ophthalmology 2013;120:745-52.
Kiumehr S, Park SC, Syril D, Teng CC, Tello C, Liebmann JM, et al. In vivo
evaluation of focal lamina cribrosa defects in glaucoma. Arch Ophthalmol 2012;130:552-9.
Lee EJ, Kim TW, Weinreb RN, Suh MH, Kang M, Park KH, et al.
Three-dimensional evaluation of the lamina cribrosa using spectral-domain optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci 2012;53:198-204.
Park HY, Jeon SH, Park CK. Enhanced depth imaging detects lamina cribrosa thickness differences in normal tension glaucoma and primary open-angle glaucoma. Ophthalmology 2012;119:10-20.
Ren R, Yang H, Gardiner SK, Fortune B, Hardin C, Demirel S, et al.
Anterior lamina cribrosa surface depth, age, and visual field sensitivity in the Portland progression project. Invest Ophthalmol Vis Sci 2014;55:1531-9.
Kim S, Sung KR, Lee JR, Lee KS. Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral-domain optical coherence tomography enhanced depth imaging. Ophthalmology 2013;120:1798-803.
Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496-500.
Fleiss JL. The Design and Analysis of Clinical Experiments. New York: Wiley; 1986.
Malik R, Swanson WH, Garway-Heath DF. 'Structure-function relationship' in glaucoma: Past thinking and current concepts. Clin Experiment Ophthalmol 2012;40:369-80.
Fontana L, Bhandari A, Fitzke FW, Hitchings RA. In vivo
morphometry of the lamina cribrosa and its relation to visual field loss in glaucoma. Curr Eye Res 1998;17:363-9.
Roberts MD, Grau V, Grimm J, Reynaud J, Bellezza AJ, Burgoyne CF, et al.
Remodeling of the connective tissue microarchitecture of the lamina cribrosa in early experimental glaucoma. Invest Ophthalmol Vis Sci 2009;50:681-90.
Yang H, Downs JC, Girkin C, Sakata L, Bellezza A, Thompson H, et al
. 3-D histomorphometry of the normal and early glaucomatous monkey optic nerve head: Lamina cribrosa and peripapillary scleral position and thickness. Invest Ophthalmol Vis Sci 2007;48:4597-607.
Yang H, Downs JC, Bellezza A, Thompson H, Burgoyne CF. 3-D histomorphometry of the normal and early glaucomatous monkey optic nerve head: Prelaminar neural tissues and cupping. Invest Ophthalmol Vis Sci 2007;48:5068-84.
Yang H, Williams G, Downs JC, Sigal IA, Roberts MD, Thompson H, et al.
Posterior (outward) migration of the lamina cribrosa and early cupping in monkey experimental glaucoma. Invest Ophthalmol Vis Sci 2011;52:7109-21.
Furlanetto RL, Park SC, Damle UJ, Sieminski SF, Kung Y, Siegal N, et al.
Posterior displacement of the lamina cribrosa in glaucoma: In vivo
interindividual and intereye comparisons. Invest Ophthalmol Vis Sci 2013;54:4836-42.
Reis AS, O'Leary N, Stanfield MJ, Shuba LM, Nicolela MT, Chauhan BC. Laminar displacement and prelaminar tissue thickness change after glaucoma surgery imaged with optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:5819-26.
Lee EJ, Kim TW, Weinreb RN, Kim H. Reversal of lamina cribrosa displacement after intraocular pressure reduction in open-angle glaucoma. Ophthalmology 2013;120:553-9.
Lee EJ, Kim TW, Weinreb RN. Variation of lamina cribrosa depth following trabeculectomy. Invest Ophthalmol Vis Sci 2013;54:5392-9.
Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J, et al.
Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109:1090-5.
Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103:1661-9.
Leske MC, Connell AM, Wu SY, Hyman LG, Schachat AP. Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol 1995;113:918-24.
Drance S, Anderson DR, Schulzer M. Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;131:699-708.
Sung KR, Lee S, Park SB, Choi J, Kim ST, Yun SC, et al.
Twenty-four hour ocular perfusion pressure fluctuation and risk of normal-tension glaucoma progression. Invest Ophthalmol Vis Sci 2009;50:5266-74.
Caprioli J, Coleman AL. Blood Flow in Glaucoma Discussion. Blood pressure, perfusion pressure, and glaucoma. Am J Ophthalmol 2010;149:704-12.
Killer HE, Miller NR, Flammer J, Meyer P, Weinreb RN, Remonda L, et al.
Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol 2012;96:544-8.
Wostyn P, De Groot V, Van Dam D, Audenaert K, De Deyn PP. Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma. Am J Ophthalmol 2013;156:5-14.e2.
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al.
The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701-13.
[Table 1], [Table 2], [Table 3], [Table 4]