Biomechanics of the optic nerve head

Biomechanical factors acting at the level of the lamina cribrosa (LC) are postulated to play a role in retinal ganglion cell dysfunction and loss in glaucoma. In support of this postulate, we now know that a number of cell types (including lamina cribrosa cells) are mechanosensitive. Here we briefly review data indicating cellular stretching, rate of stretching and substrate stiffness may be important mechanosensitivity factors in glaucoma. We then describe how experiments and finite element modeling can be used to quantify the biomechanical environment within the LC, and how this environment depends on IOP. Generic and individual-specific models both suggest that peripapillary scleral properties have a strong influence on LC biomechanics, which can be explained by the observation that scleral deformation drives much of the IOP-dependent straining of the LC. Elegant reconstructions of the LC in monkey eyes have shown that local strains experienced by LC cells depend strongly on laminar beam microarchitecture, which can lead to large local strain elevations. Further modeling, suitably informed by experiments, is needed to better understand lamina cribrosa biomechanics and how they may be involved in glaucomatous optic neuropathy.     

Reproducibility of topographic measures of the glaucomatous optic nerve head

AIMS/BACKGROUND—Laser scanning tomography provides an assessment of three dimensional optic disc topography. For the clinical purpose of follow up of glaucoma patients, the repeatability of the various measured variables is essential. In the present study, the reproducibility of morphometric variables calculated by the topographic scanning system, TopSS (Laser Diagnostic Technology, San Diego, CA) was investigated.
METHODS—Two independent measurements (30 minutes apart) each consisting of three complete images of the optic disc were performed on 16 eyes of 16 glaucoma patients using a TopSS. The instrument calculates 14 morphometric variables for the characterisation of the optic disc.
RESULTS—From the two tailed paired tests, all variables were seen to have good reproducibility. However, correlation and regression analyses showed that only the three variables, volume below, half depth area, and average cup depth, are acceptably reproducible.
CONCLUSION—The TopSS provides three variables which describe the physiological shape of the optic disc that have high reproducibility. These three variables might be useful for following the progression of optic disc changes in glaucoma patients.

Keywords: optic nerve head; scanning laser; glaucoma; tomography     

Quantitative assessment of the optic nerve head with the laser tomographic scanner

We describe the use of a laser tomographic scanner to objectively measure optic nerve head topography. A laser beam is focused on the optic disc using confocal imaging. Reflected light is detected only if it originates from a small region around the focal place of the special optics. Optic disc parameters are calculated from the measured values of confocal reflected light. In five glaucomatous eyes, maximum cup depth was between 0.33 mm and 0.58 mm. Cup volume was between 0.10 mm³ and 0.65 mm³; it correlated well with ophthalmoscopy. Comparared with conventional imaging systems, the laser tomographic scanner has certain advantages: 1) images can be obtained with miotic pupils; 2) clarity of media is not important; 3) low light intensity is employed; and 4) a real time image is obtained.     

3D morphometry of the human optic nerve head

Human optic nerve head (ONH) anatomy is of interest in glaucoma. Our goal was to carry out a morphometric study of the human ONH based on 3D reconstructions from histologic sections. A set of 10 human ONHs (from four pairs of eyes plus two singles) were reconstructed in an iterative procedure that required the resulting geometries to satisfy a set of quality control criteria. Five models corresponded to eyes fixed at 5 mmHg and the other five models to eyes fixed at 50 mmHg. Several aspects of ONH morphology were measured based on surface and point landmarks: the thicknesses of the lamina cribrosa (LC), the peripapillary sclera and the pre-laminar neural tissue (peripapillary and within the cup); the minimum distance between the anterior surface of the LC and the subarachnoid space; the surface area of the anterior and posterior surfaces of the LC; and the diameter of the scleral canal opening. Our results showed that about one third of the anterior LC surface was obscured from view from the front by the sclera. In all eyes the LC inserted into the pia mater, and not only into the sclera. The variations in ONH morphology between eyes of a pair exceeded, or were of the same order as, changes in morphology due to acute changes in IOP. The reconstruction and morphometry techniques introduced are suitable for application to the ONH. Comparison of measurements in eyes fixed at different pressures suggested small effects on geometry of the increase in IOP. A large variability in ONH morphology, even between contralateral eyes of different IOP, was observed. We conclude that reconstruction of human ONH anatomy from 3D histology is possible, but that large inter-individual anatomic variations make morphometric analysis of the ONH very difficult in the absence of large sample numbers. The insertion of the pia mater into the LC may have biomechanical implications and should be further investigated. Emerging clinical imaging techniques such as deep-scanning OCT will be limited to investigation of the central and mid-peripheral regions of the LC due to optical “occluding” by the peripapillary sclera.     

Inter-individual variation in blood supply of the optic nerve head

There is no one standard pattern of the blood supply of the optic nerve head in all human eyes. There is a marked inter-individual variation in the blood supply of the optic nerve head, and the various factors which produce this include variations in (I) the anatomical pattern of blood supply, (II) the pattern of posterior ciliary artery (PCA) circulation (the main source of blood supply to the optic nerve head), and (III) the blood flow. The variations in the pattern of PCA circulation include the variations in (a) number of PCAs supplying an eye, (b) area of supply to the optic nerve head by each PCA, (c) location of the watershed zones between the various PCAs in relation to the optic nerve head, and (d) blood pressure in various PCAs as well as short PCAs. The variations in the blood flow in the optic nerve head can be produced by changes in (i) the intraocular pressure, (ii) mean blood pressure in the capillaries of the optic nerve head and (iii) peripheral vascular resistance. These variations are discussed in detail. A lack of appreciation of these complexities of the blood supply of the optic nerve head in health and disease is responsible for many of the current problems in the understanding of the role of vascular disturbances in anterior ischemic optic neuropathy, glaucoma, low-tension glaucoma and various ischemic disorders of the optic nerve head.     

Correlations between corneal and optic nerve head variables in healthy subjects and patients with primary open angle glaucoma

AIM: To correlate corneal variables (determined using the Pentacam) with optic nerve head (ONH) variables determined using the Heidelberg retina tomograph (HRT) in healthy subjects and patients diagnosed with primary open angle glaucoma (POAG). METHODS: Measurements were made in 75 healthy eyes and 73 eyes with POAG and correlations examined through Pearson correlation coefficients between the two sets of variables in the two subject groups. The corneal variables determined were corneal volume (CVol), central corneal thickness (CCT), overall corneal thickness (OvCT), the mean thickness of a circular zone centered at the corneal apex of 1 mm radius (zone I) and the mean thickness of several concentric rings, also centered at the apex until the limbus, each of 1 mm width (zones II to VI respectively). The ONH variables were determined using the HRT. RESULTS: The following pairs of variables were correlated in the control group: CCT-disc area (DAr) (-0.48; P<0.0001), Zone I-DAr (-0.503; P<0.0001) and Zone II-DAr (-0.443; P<0.0001); and in the POAG group: CCT-cup-to-disc area ratio (CDRa) (-0.402; P<0.0001), Zone I-CDRa (-0.418; P<0.0001), Zone II-CDRa (-0.405; P=0.006), Zone I-cup shape measure (CSM) (-0.415; P=0.002), Zone II-CSM (-0.405; P=0.001), Zone IV-height variation contour (HVC) (0.378; P=0.002); Zone V-HVC (0.388, P<0.0001).     

Optical coherence tomography evaluation of the optic nerve head neuro‐retinal rim in glaucoma

Clinical examination of the optic disc is a fundamental component of any ophthalmic evaluation, but it is especially important for diagnosis and management of glaucoma. The purpose of this article is to: (1) review the limitations inherent to clinical examination; (2) outline the rationale for adopting into clinical practice quantitative measures of the optic nerve head neuro‐retinal rim tissue integrity derived from current optical coherence tomography imaging approaches; (3) describe recent developments in this area; and (4) highlight a few avenues of active research that hold promise for future translation to clinical practice.     

人眼视神经乳头星形胶质细胞体外培养:Ⅰ.原代培养和传代试验

目的:探索人眼视神经乳头星形胶质细胞体外培养的方法,为进一步研究星形胶质细胞在青光眼性视神经病变中的作用打下基础。方法:取材新鲜人眼视神经乳头组织和筛板组织,进行星形胶质细胞和筛板细胞的体外培养与传代试验。结果:组织块培养4~8wk后,原代细胞开始生长,星形胶质细胞在形态学和生长特性上与筛板细胞明显不同,β1型星形胶质细胞可以在无血清的培养液中生长良好,通过无血清培养液选择性培养可以在第二代传代过程中分离出纯化的星形胶质细胞,并可在第三至第四代收获大量细胞以备后续的研究。结论:精细准确的组织解剖分离对于获得纯化细胞至关重要,采用无血清培养液选择分离获得星形胶质细胞方法经济简单,细胞纯度高,便于进一步储存和研究。     

Human optic nerve head astrocytes culture in vitro :I. the primary culture and passage

AIM: To culture astrocytes from human donor eyes in order to understand the function of astrocytes in remodelling events in the glaucomatous optic nerve head (ONH). METHODS: Primary cultures were prepared by explantation of human ONH tissue in order to get astrocytes. Laminar criborsa (LC) cells were prepared concurrently for com- parison. Astrocyte cultures could be separated from LC cells by selecting medium. Similar procedures were used for LC. RESULTS: Primary cells grew from human optic nerve head explants 4-8 weeks after explantation. Astrocytes had different morphologies and growth characteristics from LC cells. Type 1B astrocyte cells could grow in medium without FBS. Purified cultures were obtained by second passage and could be harvested by third to fifth passage, which were prepared to use for further study, including being characterized by positive glial fibrillary acidic protein (GFAP) and neural cell adhesion molecule (NCAM) staining. CONCLUSION: Precise dissection of fragment is the most important step to get clear explants for primary culture. Economic and rapid method could be useful to select cells by different mediums, which will help us to get more purified cells for further study.     

Predicted extension, compression and shearing of optic nerve head tissues

Glaucomatous optic neuropathy may be in part due to an altered biomechanical environment within the optic nerve head (ONH) produced by an elevated intraocular pressure (IOP). Previous work has characterized the magnitude of the IOP-induced deformation of ONH tissues but has not focused specifically on the mode of deformation (strain), i.e. whether the ONH tissues and cells are stretched, compressed or sheared. Circumstantial evidence indicates that the mode of deformation has biological consequences. Here we use computational models to study the different modes of deformation that occur in an ONH as a result of an increase in IOP. One generic and three individual-specific 3D models of the human ONH were reconstructed as previously described. Each model consisted of five tissue regions: pre and post-laminar neural tissue, lamina cribrosa, sclera and pia mater. Finite element methods were then used to predict the biomechanical response to changes in IOP. For each model we computed six local measures of strain, including the magnitude and direction of maximum stretching, maximum compression and maximum shearing strain. We compared the spatial and population distributions of the various measures of strain by using semi-quantitative (contour plots) and quantitative (histograms) methods. For all models, as IOP increased, the tissues of the ONH were subjected simultaneously to various modes of strain, including compression, extension and shearing. The highest magnitudes of all modes of strain occurred within the neural tissue regions. There were substantial differences in the magnitudes of the various modes of strain, with the largest strains being in compression, followed by shearing and finally by extension. The biomechanical response of an individual-specific ONH to changes in IOP is complex and cannot be fully captured by one measure of deformation. We predict that cells within the ONH are subjected to very different modes of deformation as IOP increases. The largest deformations are compressive, followed by shearing and stretching. Models of IOP-induced RGC damage need to be further refined by characterizing the cellular response to these different modes of strain.     

Association between corneal biomechanical properties and optic nerve head morphology in newly diagnosed glaucoma patients

Background: To investigate the association between corneal biomechanics and optic nerve head morphology in newly diagnosed primary open‐angle glaucoma patients. Design: Hospital based prospective study. Participants: Forty‐two untreated newly diagnosed primary open‐angle glaucoma patients. Methods: Patients underwent corneal hysteresis measurement using the Ocular Response Analyzer and confocal scanning laser ophthalmoscopy for optic nerve head topography evaluation. One eye was selected randomly for analysis. Data collected included age, race, gender, intraocular pressure and central corneal thickness. Main Outcome Measures: Multiple regression analysis (controlling for baseline intraocular pressure and disc area) was used to investigate factors associated with the following optic nerve head topographic parameters: linear cup‐to‐disc ratio and mean cup depth. Results: Mean age of participants was 66.7 ± 11.8 years. Corneal hysteresis was the only factor significantly associated with both mean cup depth (correlation coefficient [r] = ?0.34, P = 0.03) and cup‐to‐disc ratio (r = ?0.41, P = 0.01). Central corneal thickness was significantly associated with mean cup depth (r = ?0.35, P = 0.02), but not with cup‐to‐disc ratio (r = ?0.25, P = 0.13). Although a trend towards a positive association between age and cup‐to‐disc ratio was identified (r = 0.26, P = 0.08), age was not significantly associated with mean cup depth (r = 0.06, P = 0.72). When comparing fellow eyes of patients with bilateral glaucoma, the eye with higher corneal hysteresis had smaller cup‐to‐disc ratio in 75% of the cases. Conclusions: In untreated newly diagnosed primary open‐angle glaucoma patients, those with thinner corneas and mainly lower corneal hysteresis values had a larger cup‐to‐disc ratio and deeper cup, independently of intraocular pressure values and disc size.     

Factors associated with topographic changes of the optic nerve head induced by acute intraocular pressure reduction in glaucoma patients

Purpose

To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG).

Methods

Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient''s systemic and ocular characteristics.

Results

A total of 42 patients were included (mean age, 66.7±11.8 years). After a mean IOP reduction of 47.3±11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P<0.01), but not in mean cup depth (P=0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r²=0.17, P<0.01) and diabetes diagnosis (r²⩾0.21, P<0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r²=0.30, P<0.01). Age, race, disc area, and CCT were not significant (P⩾0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P<0.01).

Conclusions

Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.     

Glutamate level in optic nerve head is increased by artificial elevation of intraocular pressure in rabbits

Neurons can be damaged by the activation of glutamate receptors, but whether glutamate is related to the development of glaucomatous optic neuropathy is still controversial. The purpose of this study was to measure the acute changes in the glutamate levels in the optic nerve head (ONH) of rabbits induced by an artificial elevation of the intraocular pressure (IOP). A concentric microdialysis probe was inserted into the ONH of rabbits via the pars plana. The probe was perfused with Ringer's solution, and the levels of glutamate in 10-min dialysate samples were measured repeatedly using high-performance liquid chromatography. After the glutamate level was stabilized for at least 60 min, the IOP was adjusted to three levels; 120 mm Hg (n=11), 60 mm Hg (n=12), and 15 mm Hg (control group; n=11). The IOP was altered by changing the height of a bottle of Ringer's solution, which was connected to the anterior chamber by a 23-gauge needle. The IOP levels were maintained for 60 min, and the glutamate levels were determined every 10 min during the 60 min. The mean basal levels of glutamate in the 10-min dialysate were not significantly different among the three groups. The glutamate levels remained unchanged and stable in the controls, but elevation of the IOP significantly increased the level of the glutamate in the dialysate (IOP60, P=0.012; and IOP120, P=0.005: repeated measures ANOVA). Elevation of the IOP causes an increase in the glutamate levels in the ONH of rabbits. This suggests a possible interaction between glutamate metabolism and the IOP in the ONH.     

Isolated metastasis to the optic nerve

A case of isolated optic nerve metastasis from breast carcinoma is described. Intraocular tumor was discovered three months following a radical mastectomy and was confined to the optic nerve head and distal optic nerve. Following X-irradiation treatment, central retinal vascular occlusion, rubeosis, and neovascular glaucoma developed during the fifteen months before enucleation. The clinicopathologic features of this case are discussed and the literature reviewed.     

Genetic and ultrasound study of abnormalities of the optic nerve head

The authors, after reviewing the literature, particularly the classification of optic nerve-head abnormalities, describe several clinical cases dealing especially with the notable diagnostic possibilities of ultrasound examination.     

Comparison of glaucoma progression evaluated with Heidelberg retina tomograph II versus optic nerve head stereophotographs

BACKGROUND: To compare disease progression in glaucoma evaluated by means of the Heidelberg retina tomograph (HRT II) or by expert clinical assessment of colour stereophotographs of the optic nerve head (ONH). METHODS: One eye each of 54 subjects with glaucoma was reviewed using the HRT II and ONH stereophotographs. The ONH stereophotographs were assessed twice each for glaucomatous progression by 2 expert observers (Drs. Buys and Trope). They were considered to be in agreement if their results were the same in 3 of 4 assessments. Progression on the HRT II was defined by using the topographic change analysis (TCA). The clinical assessments were the reference standard used to determine sensitivity and specificity of the HRT II TCA. RESULTS: The expert observers were in agreement in 50 subjects (92%). Concordance between the HRT II and ONH stereophotographs assessments was obtained in 35 patients (65%); 16 patients (30%) showed progression on HRT II only, while 3 patients (6%) showed progression on stereophotographs only. When these results were used to perform a post hoc analysis, HRT II sensitivity increased from 70% to 78% and specificity increased from 63.6% to 70%. The positive predictive value of the HRT II rose from 30.4% to 47.8%, while the negative predictive value remained at 90.3%. INTERPRETATION: Our results demonstrate only fair agreement between HRT II and clinical judgment of ONH stereophotographs for progression in glaucomatous eyes. At present, HRT II progression alone should not indicate a treatment change. HRT II change must be evaluated in conjunction with other clinical features of deterioration before altering therapy.     

Changes of optic nerve head microcirculation in high myopia

AIM: To analyze the correlation of age, spherical equivalent (SE), and axial length (AL) with the microcirculation of optic nerve head (ONH) in high myopia (HM).METHODS: In this cross-sectional clinical study, 164 right eyes were included. Optical coherence tomography angiography (OCTA) was used to detect ONH vessel density. Eyes were classified based on age, SE, and AL. Groups of Age1, Age2, and Age3 were denoted for age classification (Age1<20y, 20y≤Age2<30y, Age3≥30y); Groups SE1, SE2, and SE3 for the SE classification (-9≤SE1<-6 D, -12≤SE2<-9 D, SE3<-12 D); Groups AL1, AL2, AL3, and AL4 for the AL classification (AL1<26 mm, 26≤AL2<27 mm, 27≤AL3<28 mm, AL4≥28 mm).RESULTS: No significant difference was observed in vessel density among the Age1, Age2, and Age3 groups (all P>0.05) and the SE1, SE2, and SE3 groups (all P>0.05). No significant difference was observed in the intrapapillary vascular density (IVD) among AL1, AL2, AL3, and AL4 groups (P>0.05). However, a significant decrease was found in the peripapillary vascular density (PVD) in the AL1, AL2, AL3, and AL4 groups (F=3.605, P=0.015), especially in the inferotemporal (IT; F=6.25, P<0.001), temporoinferior (TI; F=2.865, P=0.038), and temporosuperior (TS; F=6.812, P<0.001) sectors. The IVD was correlated with age (r=-0.190, P<0.05) but not with SE or AL (P>0.05). The PVD was correlated with AL (r=-0.236, P<0.01) but not with age or SE (P>0.05).CONCLUSION: With the increase of AL, the IVD remains stable while the PVD decreases, especially in the three directions of temporal (IT, TI, and TS). The main cause of microcirculation reduction may be related to AL elongation rather than an increase in age or SE.     

Detecting optic nerve head deformation and retinal nerve fiber layer thinning in glaucoma progression

The application of digital imaging technologies including confocal scanning laser ophthalmoscopy (CSLO), optical coherence tomography (OCT), and scanning laser polarimetry (SLP) has significantly improved the detection of optic nerve head (ONH) deformation and progressive retinal nerve fiber layer (RNFL) thinning for assessment of glaucoma progression. Algorithms for change analysis such as topographic change analysis and guided progression analysis perform event analysis of serial ONH surface height topology maps and RNFL thickness/RNFL retardance maps, respectively, providing a topographical display of the location of significant change. With spectral-domain OCT, it is feasible to delineate and measure the lamina cribrosa surface depth in addition to ONH surface depth and RNFL thickness. Growing evidence from experimental and clinical studies indicates that ONH and lamina cribrosa deformation can be observed prior to detectable RNFL thinning and functional loss in glaucoma. These findings lend support to the notion that upon detection of ONH/lamina cribrosa deformation, a time window for therapeutic intervention for better outcomes may exist. The ONH and the lamina cribrosa are therefore important targets for monitoring glaucoma progression. This review summarizes the latest findings comparing the performance of OCT, CSLO, and SLP for detection of progressive ONH and RNFL damages in glaucoma patients and the clinical implication and limitations of studying the morphological alteration of the ONH, lamina cribrosa, and RNFL in the assessment of glaucoma progression.     

Iris colour, optic disc dimensions, degree and progression of glaucomatous optic nerve damage

PURPOSE: To evaluate whether iris colour influences size and shape of the optic nerve head and risk for glaucoma progression. METHODS: The hospital-based observational study included 1973 eyes of 1012 Caucasian subjects with ocular hypertension or chronic open-angle glaucoma. For all patients, colour stereo optic disc photographs were evaluated, and corneal pachymetry and achromatic perimetry were performed. Main outcome measures were optic nerve head parameters, the development or progression of visual field defects and iris colour. RESULTS: In most of the study groups, size of the optic disc, neuroretinal rim, alpha zone and beta zone of parapapillary atrophy, retinal vessel diameter and central corneal thickness did not differ significantly between eyes with blue, green, brown and mixed iris colour. In the normal-pressure glaucoma group, neuroretinal rim area was smallest in the population with mixed-coloured eyes and largest in the group of eyes with brown irides (P = 0.001 after correction for inter-eye dependency and multiple testing). For the ocular hypertensive subjects and glaucoma patients with follow-up examinations, the rate of development or progression of glaucomatous visual field loss was not significantly associated with iris colour (P = 0.060). CONCLUSIONS: In Caucasian subjects, iris colour does not have a major association with the size of the optic nerve head structures, central corneal thickness and retinal arterial diameter. In Caucasian patients with ocular hypertension or chronic open-angle glaucoma, an influence of iris colour on the risk for development or progression of glaucomatous visual field defects could not be confirmed.