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1.  Zinn-Haller arterial ring observed by ICG angiography in high myopia 
The British Journal of Ophthalmology  1998;82(12):1357-1362.
AIMS—To delineate the entire Zinn-Haller arterial ring angiographically in vivo.
METHODS—382 highly myopic eyes (210 patients) with refractive errors greater than −8.25 D were examined using indocyanine green (ICG) videoangiography. A control group of 80 eyes (40 patients) had refractive errors within plano +/− 3 D.
RESULTS—The Zinn-Haller ring was visible in 206 of 382 highly myopic eyes (53.9%) by ICG angiography. Although only a part of the Zinn-Haller ring was visible in 162 of 206 eyes, in the remaining 44 eyes it was observed almost completely around the optic nerve head. No anastomotic channels between lateral and medial short posterior ciliary arteries were filled by ICG angiography. In 22 of the 44 eyes (50.0%) the Zinn-Haller ring was supplied by branches of the lateral and medial short posterior ciliary arteries; in seven eyes, it was supplied only by the lateral short posterior ciliary artery; and in seven eyes, it was supplied only by the medial short posterior ciliary artery. In none of the control subjects was the Zinn-Haller ring visible by ICG angiography.
CONCLUSIONS—The Zinn-Haller ring observed by ICG angiography was not a complete collateral circle between lateral and medial posterior ciliary arteries. Also, the patterns in supply vessels to the Zinn-Haller ring varied. ICG angiography made possible the detailed observation of the Zinn-Haller ring in human eyes in vivo.

 Keywords: Zinn-Haller circle; blood flow; optic nerve head; myopia
PMCID: PMC1722463  PMID: 9930263
2.  Morphological variations of the peripapillary circle of Zinn-Haller by flat section 
AIMS—To evaluate the morphometric and morphological variations of the circle of Zinn-Haller (CZH) in the human eye.
METHODS—42 human enucleated eyes were used in this study. After transverse flat thick sections were cut through the optic nerve and adjacent sclera, tissue sections were stained with haematoxylin and eosin or examined immediately by wet preparation under a light microscope. The average vessel diameter of the arterial circle and the average distance between the optic nerve head (ONH) and the arterial circle were determined. Various branching patterns of the CZH were also evaluated.
RESULTS—The vessel diameter of the arterial circle was 123 (SD 75) µm (range 20-230 µm). The distance of the CZH from the ONH margin was 403 (352) µm (0-1050 µm). The CZH gave off branches to the optic nerve and to the peripapillary choroid (PPC) with various branching patterns especially at the entry point of paraoptic short posterior ciliary artery.
CONCLUSIONS—The CZH exists within a variable distance from the ONH and its average diameter is similar to that of the central retinal vessels though it shows marked variation even in the same circle. The CZH also shows variable configurations in branching patterns. These variations may act as contributing factors that are responsible for the individual susceptibility of the anterior optic nerve and the PPC to circulatory disturbances.

PMCID: PMC1723100  PMID: 10381675
3.  Peripapillary Arterial Circle of Zinn-Haller: Location and Spatial Relationships with Myopia 
PLoS ONE  2013;8(11):e78867.
To measure histomorphometrically the location of the peripapillary arterial circle of Zinn-Haller (ZHAC) and assess its associations with axial length.
Using a light microscope, we measured the distance from the ZHAC to the peripapillary ring (optic disc border), the merging point of the dura mater with the posterior sclera (“dura-sclera point”), and the inner scleral surface. In the parapapillary region, we differentiated between beta zone (presence of Bruch's membrane, absence of retinal pigment epithelium) and gamma zone (absence of Bruch's membrane). The peripapillary scleral flange as roof of the orbital cerebrospinal fluid space was the connection between the end of the lamina cribrosa and the posterior full-thickness sclera starting at the dura-sclera point.
The study included 101 human globes (101 patients) with a mean axial length of 26.7±3.7 mm (range: 20.0–39.0 mm). The distance between the ZHAC and the peripapillary ring increased significantly with longer axial length (P<0.001; correlation coefficient r = 0.49), longer parapapillary gamma zone (P<0.001;r = 0.85), longer (P<0.001;r = 0.73) and thinner (P<0.001;r = −0.45) peripapillary scleral flange, and thinner sclera posterior to the equator (P<0.001). ZHAC distance to the peripapillary ring was not significantly associated with length of parapapillary beta zone (P = 0.33). Including only non-highly myopic eyes (axial length <26.5 mm), the ZHAC distance to the disc border was not related with axial length (P = 0.84). In non-highly myopic eyes, the ZHAC was located close to the dura-sclera point. With increasing axial length and decreasing thickness of the peripapillary scleral flange, the ZHAC was located closer to the inner scleral surface.
The distance between the ZHAC and the optic disc border is markedly enlarged in highly myopic eyes. Since the ZHAC is the main arterial source for the lamina cribrosa blood supply, the finding may be of interest for the pathogenesis of the increased glaucoma susceptibility in highly myopic eyes.
PMCID: PMC3815204  PMID: 24223862
4.  Peripapillary circle of Zinn-Haller revealed by fundus fluorescein angiography 
AIMS—To observe the vascular pattern of the peripapillary circle of Zinn-Haller in humans by fundus fluorescein angiography.
METHODS—307 cases (from 212 patients) of fundus fluorescein angiograms performed in patients with myopic degeneration were evaluated to find the circle of Zinn-Haller and to observe its fundus fluorescein angiographic features.
RESULTS—15 cases (from 13 patients) with the circle of Zinn-Haller were found. It appeared as concentric or zigzag-shaped vascular fillings within the temporal crescent region. All cases were observed in pathological myopia with peripapillary atrophy and a tilted disc. Each arterial circle showed variations in location and shape.
CONCLUSIONS—The temporal part of the circle of Zinn-Haller can be revealed by fundus fluorescein angiography particularly in pathological eyes with prominent peripapillary atrophy and a tilted disc. The morphological variation of this arterial circle should be considered.

PMCID: PMC1722287  PMID: 9349154
5.  Cerebrospinal Fluid Pressure and Glaucoma 
Eyes with normal-pressure glaucoma and those with high-pressure glaucoma can show a similar optic nerve head appearance, while eyes with vascular optic neuropathies show a markedly different optic disc appearance. Factors in addition to intraocular pressure (IOP) may thus play a role in the pathogenesis of glaucomatous optic neuropathy. Clinical and experimental studies showed that (1) physiologic associations between cerebrospinal fluid (CSF) pressure, systemic arterial blood pressure, IOP and body mass index exist; (2) a low CSF pressure was associated with the development of glaucomatous optic nerve damage in cats; (3) patients with normal (intraocular) pressure glaucoma had significantly lower CSF pressure and a higher trans lamina cribrosa pressure difference when compared to normal subjects; and (4) patients with normal- pressure glaucoma as compared with patients with high-pressure glaucoma have a significantly narrower orbital CSF space. A shallow orbital CSF space has been shown to be associated with a low CSF pressure. Due to anatomic reasons, the orbital CSF pressure and the optic nerve tissue pressure (and not the atmospheric pressure) form the retro-laminar counter-pressure against the IOP and are thus part of the trans-lamina cribrosa pressure difference and gradient. Assuming that an elevated trans-lamina cribrosa pressure difference and a steeper trans-lamina cribrosa pressure gradient are important for glaucomatous optic nerve damage, a low orbital CSF pressure would therefore play a role in the pathogenesis of normal-(intraocular) pressure glaucoma. Due to the association between CSF pressure and blood pressure, a low blood pressure could be indirectly involved.
PMCID: PMC3853781  PMID: 24349669
Cerebrospinal Fluid Pressure; Intraocular Pressure; Trans Lamina Cribrosa Pressure Gradient; Transcorneal Pressure Gradient; Glaucoma; Glaucomatous Optic Neuropathy; Normal- Pressure Glaucoma
6.  Reproducibility of Measuring Lamina Cribrosa Pore Geometry in Human and Nonhuman Primates with In Vivo Adaptive Optics Imaging 
Anterior lamina cribrosa pores were consistently imaged in vivo in normal human and macaque eyes across imaging sessions using adaptive optics (AO). Results suggest that AO imaging can be used to track laminar pore changes in vivo in glaucoma.
The ability to consistently resolve lamina cribrosa pores in vivo has applications in the study of optic nerve head and retinal disease mechanisms. Repeatability was assessed in imaging laminar pores in normal living eyes with a confocal adaptive optics scanning laser ophthalmoscope (AOSLO).
Reflectance images (840 nm) of the anterior lamina cribrosa were acquired using the AOSLO in four or more different sessions in two normal rhesus monkey eyes and three normal human eyes. Laminar pore areas, elongations (ratio of major to minor axes of the best-fit ellipse) and nearest neighbor distances were calculated for each session. Measurement repeatability was assessed across sessions.
Pore areas ranged from 90 to 4365 μm2 in monkeys and 154 to 6637 μm2 in humans. Mean variabilities in measuring pore area and elongation (i.e., mean of the standard deviation of measurements made across sessions for the same pores) were 50 μm2 (6.1%) and 0.13 (6.7%), respectively, in monkeys and 113 μm2 (8.3%) and 0.17 (7.7%), respectively, in humans. Mean variabilities in measuring nearest neighbor distances were 1.93 μm (5.2%) in monkeys and 2.79 μm (4.1%) in humans. There were no statistically significant differences in any pore parameters across sessions (ANOVA, P > 0.05).
The anterior lamina cribrosa was consistently imaged in vivo in normal monkey and human eyes. The small intersession variability in normal pore geometry suggests that AOSLO imaging could be used to measure and track changes in laminar pores in vivo during glaucomatous progression.
PMCID: PMC3176071  PMID: 21546533
To demonstrate that specific distributions of integrin-based focal mechanoreceptors exist in primate optic nerve heads, suitable for translating stress and strain into the cellular responses of glaucomatous optic neuropathy.
Normal human (N = 20) and rhesus monkey (N = 14) optic nerve heads and 32 glaucomatous optic nerve heads were processed for immunohistochemistry to determine the structural distribution of integrin subunits α1, α2, α3, α4, α5, α6, αv, β1, β2, β3, and β4. Labeling patterns in glaucoma specimens were compared with those of normal eyes.
In all specimens, cells within collagenous laminar beams and sclera failed to label with any integrin antibodies. In normal eyes, α2, α3, α6, β1, and β4 antibodies localized to astrocytes along the margins of laminar beams and within glial columns. α3, α5, α6, αv, β1, and β4 labeled vascular endothelial cells. In severely damaged glaucoma specimens, cells anterior to the compressed lamina cribrosa displayed persistent label for α2, α3, β1, and β4, whereas label for α4 increased and α6 was decreased.
Integrins α2β1, α3β1, α6β1, and α6β4 may provide attachment for astrocytes to basement membranes via laminin, providing opportunities to sense changes in stress and strain within and anterior to the lamina cribrosa. Vascular endothelial cell stress may be mediated by integrins α3β1, α6β1, and α6β4, along with α5β1 and αvβ1. In advanced damage, reduced α6 label and variable label for ββ 4 anterior to the lamina cribrosa suggests astrocyte migration. Increased label for α4 subunits suggests activation of microglia.
PMCID: PMC1809896  PMID: 17471356
8.  Glaucoma masqueraders: Diagnosis by spectral domain optical coherence tomography 
Saudi Journal of Ophthalmology  2012;26(4):433-440.
Advances in optic nerve and retinal imaging have dramatically changed the care of glaucoma patients, complementing the importance of the clinical exam of the optic nerve and automated perimetry in making the diagnosis of glaucoma. Computerized imaging, however, does not replace the clinical exam, as there can be overlap in the appearance of non-glaucomatous optic neuropathies with glaucoma.
The spectral domain optic coherence tomography (SD-OCT) images of five patients with non-glaucomatous optic nerve pathology are presented.
The first patient had bilateral temporal thinning on OCT imaging and subsequent positive syphilis testing. The second patient had a glaucomatous-appearing inferior arcuate scotoma and associated superior thinning on OCT; these findings were due to buried optic nerve head drusen, clearly appreciated on OCT of the optic nerve head. Bilateral diffuse macular thinning, with preservation of the superior and inferior fiber bundles, was seen in the third patient, who had multiple sclerosis, with no clinical history of optic neuritis. Dense and marked thinning of a macular half, respecting the horizontal meridian, is seen in two patients, one patient with non-arteritic anterior ischemic optic neuropathy and lastly, in a patient with hemi-retinal vein occlusion.
SD-OCT of the optic nerve and retina complements the essential clinical examination of patients with glaucomatous and non-glaucomatous optic neuropathies.
PMCID: PMC3729362  PMID: 23961029
OCT; Glaucoma; Optic neuropathy; Macular OCT
9.  Hypodense Regions (Holes) in the Retinal Nerve Fiber Layer in Frequency-Domain OCT Scans of Glaucoma Patients and Suspects 
Hypodense regions (holes) are seen in the retinal nerve fiber layer of patients with glaucomatous optic neuropathy. These holes can occur in the eyes of glaucoma suspects with normal visual fields and are probably due to local axon loss.
To better understand hypodense regions (holes) that appear in the retinal nerve fiber layer (RNFL) of frequency-domain optical coherence tomography (fdOCT) scans of patients with glaucoma and glaucoma suspects.
Peripapillary circle (1.7-mm radius) and cube optic disc fdOCT scans were obtained on 208 eyes from 110 patients (57.4 ± 13.2 years) with glaucomatous optic neuropathy (GON) and 45 eyes of 45 controls (48.0 ± 12.6 years) with normal results of fundus examination. Holes in the RNFL were identified independently by two observers on the circle scans.
Holes were found in 33 (16%) eyes of 28 (25%) patients; they were not found in any of the control eyes. Twenty-four eyes had more than one hole. Although some holes were relatively large, others were small. In general, the holes were located adjacent to blood vessels; only three eyes had isolated holes that were not adjacent to a vessel. The holes tended to be in the regions that are thickest in healthy controls and were associated with arcuate defects in patients. Holes were not seen in the center of the temporal disc region. They were more common in the superior (25 eyes) than in the inferior (15 eyes) disc. Of the 30 eyes with holes with reliable visual fields, seven were glaucoma suspect eyes with normal visual fields.
The holes in the RNFL seen in patients with GON were probably due to a local loss of RNFL fibers and can occur in the eyes of glaucoma suspects with normal visual fields.
PMCID: PMC3207719  PMID: 21791587
10.  Posterior (Outward) Migration of the Lamina Cribrosa and Early Cupping in Monkey Experimental Glaucoma 
Three-dimensional histomorphometric reconstructions of the optic nerve heads from both eyes of nine monkeys with unilateral early experimental glaucoma suggest that progressive outward migration of the lamina cribrosa is a component of early cupping in monkey experimental glaucoma.
To quantify the lamina cribrosa insertion into the peripapillary sclera and optic nerve pia in normal (N) and early experimental glaucoma (EEG) monkey eyes.
Perfusion-fixed optic nerve heads (ONHs) from 21 animals were digitally reconstructed three dimensionally and delineated. Anterior Laminar Insertion Position (ALIP), Posterior Laminar Insertion Position (PLIP), Laminar Insertion Length (LIL; distance between the anterior and posterior laminar insertions), and Scleral Thickness (at the Anterior Sub-arachnoid space) were calculated for each ONH. Animals were pooled into four groups based on the kill condition (N vs. EEG) and perfusion IOP (10, 30, or 45 mm Hg) of each eye: N10-N10 (n = 6), N30/45-N10 (n = 6), EEG10-N10 (n = 3), and EEG30/45-N10 (n = 6). Glaucomatous EEG versus N eye differences in each group and each animal were required not only to achieve statistical significance (P < 0.05) but also to exceed physiologic intereye differences within the bilaterally normal groups.
ALIP was significantly posterior (outward) in the EEG compared with N10 eyes of the EEG30/45-N10 group and 5 of 9 individual EEG eyes (difference range, 12–49 μm). PLIP was significantly posterior in the EEG eyes of both EEG groups and in 6 of 9 individual EEG eyes (range, 25–83 μm). LIL ranged from 90 to 190 μm in normal eyes and was significantly increased within the EEG eyes of both EEG groups and in 7 of 9 individual EEG eyes (difference range, 30–47 μm).
Posterior migration of the lamina cribrosa is a component of early cupping in monkey EEG.
PMCID: PMC3207714  PMID: 21715355
11.  Trans-Lamina Cribrosa Pressure Difference and Open-Angle Glaucoma. The Central India Eye and Medical Study 
PLoS ONE  2013;8(12):e82284.
To assess associations of the trans-lamina cribrosa pressure difference (TLCPD) with glaucomatous optic neuropathy.
The population-based Central India Eye and Medical Study included 4711 subjects. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44 Body Mass Index[kg/m2]+0.16 Diastolic Blood Pressure[mmHg]−0.18×Age[Years] −1.91. TLCPD was IOP–CSFP.
Mean TLCPD was 3.64±4.25 mm Hg in the non-glaucomatous population and 9.65±8.17 mmHg in the glaucomatous group. In multivariate analysis, TLCPD was associated with older age (P<0.001; standardized coefficient beta:0.53; regression coefficient B:0.18; 95% confidence interval (CI):0.17, 0.18), lower body mass index (P<0.001; beta: −0.28; B: −0.36; 95%CI: −0.38, −0.31), lower diastolic blood pressure (P<0.001; beta: −0.31; B: −0.12; 95%CI: −0.13, −0.11), higher pulse (P<0.001; beta:0.05; B:0.02; 95%CI:0.01,0.2), lower body height (P = 0.02; beta: −0.02; B: −0.01; 95%CI: −0.02,0.00), higher educational level (P<0.001; beta:0.04; B:0.15; 95%CI:0.09,0.22), higher cholesterol blood concentrations (P<0.001; beta:0.04; B:0.01; 95%CI:0.01,0.01), longer axial length (P = 0.006; beta:0.03; B:0.14; 95%CI:0.04,0.24), thicker central cornea (P<0.001; beta:0.15; B:0.02; 95%CI:0.02,0.02), higher corneal refractive power (P<0.001; beta:0.07; B:0.18; 95%CI:0.13,0.23) and presence of glaucomatous optic neuropathy (P<0.001; beta:0.11; B:3.43; 95%CI:2.96,3.99). Differences between glaucomatous subjects and non-glaucomatous subjects in CSFP were more pronounced for open-angle glaucoma (OAG) than for angle-closure glaucoma (ACG) (3.0 mmHg versus 1.8 mmHg), while differences between glaucomatous subjects and non-glaucomatous subjects in IOP were higher for ACG than for OAG (8.5 mmHg versus 3.0 mmHg). Presence of OAG was significantly associated with TLCPD (P<0.001; OR:1.24; 95%CI:1.19,1.29) but not with IOP (P = 0.08; OR:0.96; 95%CI:0.91,1.00). Prevalence of ACG was significantly associated with IOP (P = 0.04; OR:1.19; 95%CI:1.01,1.40) but not with TLCPD (P = 0.92).
In OAG, but not in ACG, calculated TLCPD versus IOP showed a better association with glaucoma presence and amount of glaucomatous optic neuropathy. It supports the notion of a potential role of low CSFP in the pathogenesis of open-angle glaucoma.
PMCID: PMC3855749  PMID: 24324767
12.  A Biomechanical Paradigm for Axonal Insult Within the Optic Nerve Head 
Experimental eye research  2010;93(2):120-132.
Rosario Hernandez
This article is dedicated to Rosario Hernandez for her warm support of my own work and her genuine enthusiasm for the work of her colleagues throughout her career. I first met Rosario as a research fellow in Harry Quigley’s laboratory between 1991 and 1993. Along with Harry, John Morrison, Elaine Johnson, Abe Clark, Colm O’Brien and many others, Rosario’s work has provided lamina cribrosa astrocyte cellular mechanisms that are biomechanically plausible and in so doing provided credibility to early notions of the optic nerve head (ONH) as a biomechanical structure.
We owe a large intellectual debt to Rosario for her dogged persistence in the characterization of the ONH astrocyte and lamina cribrosacyte in age and disease. Two questions run through her work and remain of central importance today. First, how do astrocytes respond to and alter the biomechanical environment of the ONH and the physiologic stresses created therein? Second, how do these physiologic demands on the astrocyte influence their ability to deliver the support to retinal ganglion cell axon transport and flow against the translaminar pressure gradient?
The purpose of this article is to summarize what is known about the biomechanical determinants of retinal ganglion cell axon physiology within the ONH in the optic neuropathy of aging and Glaucoma. My goal is to provide a biomechanical framework for this discussion. This framework assumes that the ONH astrocytes and glia fundamentally support and influence both the lamina cribrosa extracellular matrix and retinal ganglion cell axon physiology. Rosario Hernandez was one of the first investigators to recognize the implications of this unique circumstance. Many of the ideas contained herein have been initially presented within or derived from her work (Hernandez, M.R., 2000. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 19, 297–321.; Hernandez, M.R., Pena, J.D., 1997. The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 115, 389–395.).
PMCID: PMC3128181  PMID: 20849846
Glaucoma; Acute IOP elevation; Optic Nerve Head; Neural Canal; Lamina Cribrosa Position and Thickness; Peripapillary Scleral Position and Thickness; Post-NCO Total Prelaminar Volume
13.  The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head 
Aim: To study the normal distributions of mitochondria and voltage gated Na+ channels in the human optic nerve head in order to gain insight into the potential mechanisms of optic nerve dysfunction seen in the inherited optic neuropathies.
Methods: Five fresh frozen human optic nerves were studied. Longitudinally orientated, serial cryosections of optic nerve head were cut for mitochondrial enzyme histochemistry and immunolabelling for cytochrome c oxidase (COX) subunits and voltage gated Na+ channel subtypes (Nav 1.1, 1.2, 1.3, and 1.6).
Results: A high density of voltage gated Na+ channels (subtypes Nav 1.1, 1.3, and 1.6) in the unmyelinated, prelaminar, and laminar optic nerve was found. This distribution co-localised both with areas of high COX activity and strong immunolabelling for COX subunits I and IV.
Conclusions: Increased numbers of mitochondria in the prelaminar optic nerve have previously been interpreted as indicating a mechanical hold up of axoplasmic flow at the lamina cribrosa. These results suggest that this increased mitochondrial density serves the higher energy requirements for electrical conduction in unmyelinated axons in the prelaminar and laminar optic nerve and is not a reflection of any mechanical restriction. This could explain why optic neuropathies typically occur in primary inherited mitochondrial diseases such as Leber’s hereditary optic neuropathy, myoclonic epilepsy with ragged red fibres (MERRF), and Leigh’s syndrome. Secondary mitochondrial dysfunction has also been reported in dominant optic atrophy, Friedreich’s ataxia, tobacco alcohol amblyopia, Cuban epidemic optic neuropathy, and chloramphenicol optic neuropathy. These diseases are rare but these findings challenge the traditional theories of optic nerve structure and function and may suggest an alternative approach to the study of commoner optic neuropathies such as glaucoma.
PMCID: PMC1771975  PMID: 14736793
mitochondria; myelination; optic nerve; sodium channels
14.  Age related compliance of the lamina cribrosa in human eyes 
AIMS—To investigate changes in the mechanical compliance of ex vivo human lamina cribrosa with age.
METHODS—A laser scanning confocal microscope was used to image the surface of the fluorescently labelled lamina cribrosa in cadaver eyes. A method was developed to determine changes in the volume and strain of the lamina cribrosa created by increases in pressure. The ability of the lamina cribrosa to reverse its deformation on removal of pressure was also measured.
RESULTS—Volume and strain measurements both demonstrated that the lamina cribrosa increased in stiffness with age and the level of pressure applied. The ability of the lamina cribrosa to regain its original shape and size on removal of pressure appeared to decrease with age, demonstrating an age related decrease in resilience of the lamina cribrosa.
CONCLUSIONS—The mechanical compliance of the human lamina cribrosa decreased with age. Misalignment of compliant cribriform plates in a young eye may exert a lesser stress on nerve axons, than that exerted by the rigid plates of an elderly lamina cribrosa. The resilience of the lamina cribrosa also decreased with age, suggesting an increased susceptibility to plastic flow and permanent deformation. Such changes may be of importance in the explanation of age related optic neuropathy in primary open angle glaucoma.

PMCID: PMC1723411  PMID: 10684845
15.  Alterations in the morphology of lamina cribrosa pores in glaucomatous eyes 
Aims: To determine alterations which occur in the size and shape of lamina cribrosa (LC) pores in glaucomatous eyes over a period of time.
Methods: Baseline and follow up optic disc photographs were retrospectively studied in 39 eyes of 39 patients with glaucoma. Only eyes with a vertical cup to disc ratio equal to or greater than 0.6 were included in the study. In addition, all selected eyes had to have serial optic disc photographs obtained at least 3 years apart allowing clear visualisation of LC surface. The association of the alterations in LC surface morphology with patient specific and eye specific characteristics was statistically analysed.
Results: During a mean study period of 3.90 (SD 0.7) years, individual pore size (mean pore area to disc area ratio) exhibited a significant decrease between baseline and follow up measurements of each eye (p<0.0001). However, during the study period, total pore area to disc area ratio did not change (p>0.05), and the change in pore shape in some eyes (from circular to more oval and elongated) was statistically insignificant (p = 0.12). Although a relation was detectable between the optic disc and lamina cribrosa parameters at a given time, which reflects cumulative effects, during the study period, there was no significant association between the changes of the LC parameters and neural tissue damage. The rate and the magnitude of the changes in individual pore size during the study period were not significantly different among the eyes exhibiting progressive neural rim damage and those staying stable (p>0.05).
Conclusion: These findings demonstrate that the LC surface morphology exhibits changes along with the glaucomatous optic disc damage. However, the clinical appearance of LC surface in glaucomatous eyes may continue to change, even when the neural rim damage is clinically stable. These findings are probably associated with the chronic cellular events of tissue remodelling that occur in the glaucomatous optic nerve head.
PMCID: PMC1772022  PMID: 14736786
glaucoma; lamina cribrosa; morphometric analysis; optic nerve head remodelling
16.  Morphology of Astrocytes in a Glaucomatous Optic Nerve 
To establish the morphologic changes of astrocytes in the glial lamina of glaucomatous mice.
A strain of mice that expresses GFP in individual astrocytes (hGFAPpr-GFP) was crossed into the DBA/2J strain that develops glaucoma. In the resulting strain (D2.hGFAPpr-GFP) we assessed the severity of glaucoma by staining the retina for neurofilaments and counting the neurons of the retinal ganglion cell layer. We observed the morphology of astrocytes in the glial lamina of the optic nerves.
D2.hGFAPpr-GFP mice developed glaucoma in an age-dependent manner. Astrocytes in the glial lamina showed morphologic changes that correlated with the severity of glaucoma. The cells showed thickening of processes from 1.3 ± 0.28 μm in nondiseased animals to 1.71 ± 0.46 μm in eyes with moderate glaucoma and 2.1 ± 0.42 μm in those with severe glaucoma. Their spatial coverage, as determined by their convex polygon area, was reduced in eyes with severe glaucoma. The astrocytes in severely glaucomatous optic nerves also showed simplification of their processes. In 6-month-old mice with no obvious signs of degeneration in the retina, we found astrocytes with appendages growing out of primary astrocyte processes into the axon bundles. This localized hypertrophy of processes was never observed in the hGFAPpr-GFP strain.
Confirming results after optic nerve crush, astrocytes in glaucomatous optic nerves had thickened and simplified processes, and reduced spatial coverage. We also found evidence of localized sprouting of new processes in early stages of the disease, before detectable changes in ganglion cell number.
Astrocytes in the glial lamina of glaucomatous optic nerves showed morphologic changes: thickening and simplification of processes, reduced spatial coverage, and sprouting of new processes into the axon bundles.
PMCID: PMC3564449  PMID: 23322566
17.  Comparison of Optic Disc Morphology of Optic Nerve Atrophy between Compressive Optic Neuropathy and Glaucomatous Optic Neuropathy 
PLoS ONE  2014;9(11):e112403.
To compare the optic nerve head (ONH) structure between compressive optic neuropathy (CON) and glaucomatous optic neuropathy (GON), and to determine whether selected ONH quantitative parameters effectively discriminate between GON and CON, especially CON cases presenting with a glaucoma-like disc.
We prospectively assessed 34 patients with CON, 34 age-matched patients with moderate or severe GON, and 34 age-matched healthy control subjects. The quantitative parameters of ONH structure were compared using the Heidelberg Retina Tomograph 2 (HRT2) and Spectralis optical coherence tomography with an enhanced depth imaging method.
The mean and maximum cup depths of CON were significantly smaller than those with GON (P<0.001 and P<0.001, respectively). The distance between Bruch's membrane opening and anterior surface of the lamina cribrosa (BMO-anterior LC) of CON was also significantly smaller than that of glaucoma but was similar to that of the healthy group (P<0.001 and P = 0.47, respectively). Based on Moorfields regression analysis of the glaucoma classification of HRT2, 15 eyes with CON were classified with a glaucoma-like disc. The cup/disc area ratio did not differ between cases of CON with a glaucoma-like disc and cases of GON (P = 0.16), but the BMO-anterior LC and mean and maximum cup depths of CON cases with a glaucoma-like disc were smaller than those in GON (P = 0.005, P = 0.003, and P = 0.001, respectively).
Measurements of the cup depths and the LC depth had good ability to differentiate between CON with a glaucoma-like disc and glaucoma. There was no laminar remodeling detected by laminar surface position in the patients with CON compared to those with GON.
PMCID: PMC4223062  PMID: 25375855
18.  Deformation of the lamina cribrosa by elevated intraocular pressure. 
The purpose of this study was to determine the mechanical response of the lamina cribrosa (LC) to elevated intraocular pressure (IOP) so as to identify possible mechanisms of optic nerve damage in early glaucoma. Ten pairs of normal human eyes were fixed after 24 hours' exposure to 50 mm Hg pressure (experimental eyes) or 5 mm Hg pressure (contralateral control eyes). Photomicrographs of the central region of the optic nerve head (ONH) were taken to examine the LC morphologically and to measure the dimensions of the LC. It was found that elevated IOP caused the LC to deflect posteriorly without affecting its thickness. The majority of the posterior displacement in the LC occurred near the periphery of the ONH. This shape change is consistent with a model of force distribution within the LC in which shear stresses are dominant; such stresses are maximal at the periphery and minimal at the centre of the ONH. These findings support a model in which mechanical forces, specifically shearing stresses within the peripheral lamina, play a direct role in the pathology of glaucomatous optic neuropathy.
PMCID: PMC504892  PMID: 7918293
19.  Transforming growth factor β isoforms in human optic nerve heads 
AIM—To determine if the isoforms of transforming growth factor β (TGF-β) are present in fetal, normal adult, and glaucomatous optic nerve heads.
METHODS—To localise cells synthesising TGF-β, optic nerve heads were stained using antibodies to TGF-β1, TGF-β2, and TGF-β3. To demonstrate synthesis, human optic nerve heads from fetal, glaucomatous, and normal age matched subjects were explanted, cultured overnight, and the culture supernatant was assayed for the presence of TGF-β1 and TGF-β2 by bioassay. In addition, semiquantitative RT-PCR was performed to determine the gene expression pattern of TGF-β2.
RESULTS—Immunohistochemistry of glaucomatous samples revealed the presence of intense staining for TGF-β2 primarily in astrocytes, whereas TGF-β1 was localised to blood vessels. No TGF-β3 immunoreactivity was observed. There was little or no expression of TGF-β in normal optic nerve heads. Optic nerve heads from glaucomatous eyes released 70-100-fold more TGF-β2 than normal age matched optic nerve heads. Fetal optic nerve heads released 90-100-fold more TGF-β2 than normal adult optic nerve heads. TGF-β1 was undetectable by bioassay in all samples tested. There was no apparent increase in TGF-β2 gene expression in glaucomatous and fetal eyes, suggesting post-transcriptional regulatory mechanisms.
CONCLUSIONS—These results demonstrate that TGF-β2 is produced in high levels in the fetal and glaucomatous optic nerve heads, perhaps by a mechanism of post-transcriptional regulation. TGF-β may be important during development of the optic nerve head and, in glaucoma, TGF-β2 may be a mediator of astrocyte reactivation and extracellular matrix remodelling in the lamina cribrosa.

 Keywords: astrocytes; glaucoma; optic nerve head; transforming growth factor β
PMCID: PMC1722920  PMID: 10396201
20.  Longitudinal Change Detected by Spectral Domain Optical Coherence Tomography in the Optic Nerve Head and Peripapillary Retina in Experimental Glaucoma 
Longitudinal spectral domain OCT imaging is capable of detecting deep optic nerve head changes, in particular posterior displacement of the anterior lamina cribrosa surface, in a nonhuman primate experimental model of glaucoma.
To investigate whether longitudinal changes deep within the optic nerve head (ONH) are detectable by spectral domain optical coherence tomography (SDOCT) in experimental glaucoma (EG) and whether these changes are detectable at the onset of Heidelberg Retina Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany)–defined surface topography depression.
Longitudinal SDOCT imaging (Spectralis; Heidelberg Engineering) was performed in both eyes of nine rhesus macaques every 1 to 3 weeks. One eye of each underwent trabecular laser-induced IOP elevation. Four masked operators delineated internal limiting membrane (ILM), retinal nerve fiber layer (RNFL), Bruch's membrane/retinal pigment epithelium (BM/RPE), neural canal opening (NCO), and anterior lamina cribrosa surface (ALCS) by using custom software. Longitudinal changes were assessed and compared between the EG and control (nonlasered) eyes at the onset of HRT-detected surface depression (follow-up 1; [FU1]) and at the most recent image (follow-up 2; [FU2]).
Mean IOP in EG eyes was 7.1 to 24.6 mm Hg at FU1 and 13.5 to 31.9 mm Hg at FU2. In control eyes, the mean IOP was 7.2 to 12.6 mm Hg (FU1) and 8.9 to 16.0 mm Hg (FU2). At FU1, neuroretinal rim decreased and ALCS depth increased significantly (paired t-test, P < 0.01); no change in RNFL thickness was detected. At FU2, however, significant prelaminar tissue thinning, posterior displacement of NCO, and RNFL thinning were observed.
Longitudinal SDOCT imaging can detect deep ONH changes in EG eyes, the earliest of which are present at the onset of HRT-detected ONH surface height depression. These parameters represent realistic targets for SDOCT detection of glaucomatous progression in human subjects.
PMCID: PMC3101662  PMID: 21217108
21.  Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma 
PLoS Genetics  2012;8(5):e1002611.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Author Summary
Glaucoma is a major eye disease in the elderly and is the second leading cause of blindness worldwide. The numerous familial glaucoma cases, as well as evidence from epidemiological and twin studies, strongly support a genetic component in developing glaucoma. However, it has proven difficult to identify the specific genes involved. Intraocular pressure (IOP) is the major risk factor for glaucoma and the only target for the current glaucoma therapy. IOP has been shown to be highly heritable. We investigated the role of common genetic variants in IOP by performing a genome-wide association study. Discovery analyses in 11,972 participants and subsequent replication analyses in a further 7,482 participants yielded two common genetic variants that were associated with IOP. The first (rs11656696) is located in GAS7 at chromosome 17, the second (rs7555523) in TMCO1 at chromosome 1. Both variants were associated with glaucoma in a meta-analysis of 4 case-control studies. GAS7 and TMCO1 are expressed in the ocular tissues that are involved in glaucoma. Both genes functionally interact with the known glaucoma disease genes. These data suggest that we have identified two genes involved in IOP regulation and glaucomatous neuropathy.
PMCID: PMC3342933  PMID: 22570627
22.  Accelerated Aging in Glaucoma: Immunohistochemical Assessment of Advanced Glycation End Products in the Human Retina and Optic Nerve Head 
This study aimed to determine the association between advanced glycation end products (AGEs) and glaucoma based on the known synergism between oxidative stress with AGEs and the evidence of oxidative stress during glaucomatous neurodegeneration.
The extent and cellular localization of immunolabeling for AGEs and their receptor, RAGE, were determined in histologic sections of the retina and optic nerve head obtained from 38 donor eyes with glaucoma and 30 eyes from age-matched donors without glaucoma.
The extent of AGE and RAGE immunolabeling was greater in older than in younger donor eyes. However, compared with age-matched controls, an enhanced accumulation of AGEs and an up-regulation of RAGE were detectable in the glaucomatous retina and optic nerve head. Although some retinal ganglion cells (RGCs) and glia exhibited intracellular immunolabeling for AGEs, increased AGE immunolabeling in glaucomatous eyes was predominantly extracellular and included laminar cribriform plates in the optic nerve head. Some RAGE immunolabeling was detectable on RGCs; however, increased RAGE immunolabeling in glaucomatous eyes was predominant on glial cells, primarily Müller cells.
Given that the generation of AGEs is an age-dependent event, increased AGE accumulation in glaucomatous tissues supports that an accelerated aging process accompanies neurodegeneration in glaucomatous eyes. One of the potential consequences of AGE accumulation in glaucomatous eyes appears to be its contribution to increased rigidity of the lamina cribrosa. The presence of RAGE on RGCs and glia also makes them susceptible to AGE-mediated events through receptor-mediated signaling, which may promote cell death or dysfunction during glaucomatous neurodegeneration.
PMCID: PMC2492883  PMID: 17325164
23.  Premise and Prediction – How Optic Nerve Head Biomechanics Underlies the Susceptibility and Clinical Behavior of the Aged Optic Nerve Head 
Journal of glaucoma  2008;17(4):318-328.
We propose that age-related alterations in optic nerve head (ONH) biomechanics underlie the clinical behavior and increased susceptibility of the aged ONH to glaucomatous damage. The literature which suggests that the aged ONH is more susceptible to glaucomatous damage at all levels of intraocular pressure is reviewed. The relevant biomechanics of the aged ONH are discussed and a biomechanical explanation for why, on average, the stiffened peripapillary scleral and lamina cribrosa connective tissues of the aged eye should lead to a shallow (senile sclerotic) form of cupping is proposed. A logic for why age-related axon loss and the optic neuropathy of glaucoma in the aged eye may overlap is discussed. Finally, we argue for a need to characterize all forms of clinical cupping into prelaminar and laminar components so as to add precision to the discussion of clinical cupping which does not currently exist. Such characterization may lead to the early detection of ONH axonal and connective tissue pathology in ocular hypertension and eventually aid in the assessment of etiology in all forms of optic neuropathy including those that may be purely age-related.
PMCID: PMC2777521  PMID: 18552618
24.  The role of cerebrospinal fluid pressure in glaucoma and other ophthalmic diseases: A review 
Saudi Journal of Ophthalmology  2013;27(2):97-106.
Glaucoma is one of the most common causes of blindness in the world. Well-known risk factors include age, race, a positive family history and elevated intraocular pressures. A newly proposed risk factor is decreased cerebrospinal fluid pressure (CSFP). This concept is based on the notion that a pressure differential exists across the lamina cribrosa, which separates the intraocular space from the subarachnoid fluid space. In this construct, an increased translaminar pressure difference will occur with a relative increase in elevated intraocular pressure or a reduction in CSFP. This net change in pressure is proposed to act on the tissues within the optic nerve head, potentially contributing to glaucomatous optic neuropathy. Similarly, patients with ocular hypertension who have elevated CSFPs, would enjoy a relatively protective effect from glaucomatous damage. This review will focus on the current literature pertaining to the role of CSFP in glaucoma. Additionally, the authors examine the relationship between glaucoma and other known CSFP-related ophthalmic disorders.
PMCID: PMC3809480  PMID: 24227969
Cerebrospinal fluid pressure; Translaminar pressure; Glaucoma; Papilledema; Idiopathic intracranial hypertension; Microgravity
25.  Laser scanning tomography of the optic nerve head in ocular hypertension and glaucoma 
BACKGROUND—This study evaluated the ability of laser scanning tomography to distinguish between normal and glaucomatous optic nerve heads, and between glaucomatous subjects with and without field loss.
METHODS—57 subjects were classified into three diagnostic groups: subjects with elevated intraocular pressure, normal optic nerve heads, and normal visual fields (n=10); subjects with glaucomatous optic neuropathy and normal visual fields (n=30); and subjects with glaucomatous optic neuropathy and repeatable visual field abnormality (n=17). Three 10 degree image series were acquired on each subject using the Heidelberg retina tomograph (HRT). From the 14 HRT stereometric variables, three were selected a priori for evaluation: (1) volume above reference (neuroretinal rim volume), (2) third moment in contour (cup shape), and (3) height variation contour (variation in relative nerve fibre layer height at the disc margin). Data were analysed using analysis of covariance, with age as the covariate.
RESULTS—Volume above reference, third moment in contour, and mean height contour were significantly different between each of the three diagnostic groups (p<0.001). Height variation contour showed no significant difference among the three diagnostic groups (p=0.906).
CONCLUSIONS—The HRT variables measuring rim volume, cup shape, and mean nerve fibre layer height distinguished between (1) subjects with elevated intraocular pressures and normal nerve heads, and glaucomatous optic nerve heads, and (2) glaucomatous optic nerve heads with and without repeatable visual field abnormality. This study did not directly assess the ability of the HRT to identify patients at risk of developing glaucoma. It is hypothesised that the greatest potential benefit of laser scanning tomography will be in the documentation of change within an individual over time.

PMCID: PMC1722035  PMID: 9486029

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