Evaluation of the lamina cribrosa in patients with diabetes mellitus using enhanced depth imaging spectral-domain optical coherence tomography

Abstract

Purpose:

To compare the lamina cribrosa thickness and anterior lamina cribrosa depth between patients with and without diabetes mellitus and to investigate the effect of metabolic control and duration of diabetes mellitus on lamina cribrosa thickness and anterior lamina cribrosa depth using enhanced depth imaging spectral-domain optical coherence tomography.

Methods:

A total of 70 patients were enrolled in this cross-sectional study and were divided into the diabetes and control groups. Intraocular pressure, circumpapillary retinal nerve fibre layer thickness, anterior lamina cribrosa depth and lamina cribrosa thickness were compared between the groups.

Results:

In the control group, the mean intraocular pressure was 14.6 ± 3.1 (mean ± standard deviation) mmHg, mean circumpapillary retinal nerve fibre layer thickness was 105.41 ± 5.86 μm, mean anterior lamina cribrosa depth was 420.3 ± 90.2 μm and mean lamina cribrosa thickness was 248.5 ± 5.4 μm. In the diabetes group, the mean intraocular pressure was 13.9 ± 2.2 mmHg, mean circumpapillary retinal nerve fibre layer thickness was 101.37 ± 10.97 μm, mean anterior lamina cribrosa depth was 351.4 ± 58.6 μm and mean lamina cribrosa thickness was 271.6 ± 33.9 μm. Lamina cribrosa thickness was significantly higher (p < 0.001) and anterior lamina cribrosa depth was significantly lower (p = 0.003) in the diabetes group. There was no statistical difference between the groups with regard to age, spherical equivalent, axial length, circumpapillary retinal nerve fibre layer thickness and intraocular pressure (p = 0.69, 0.26, 0.47, 0.06 and 0.46, respectively). Lamina cribrosa thickness and anterior lamina cribrosa depth were not significantly correlated with duration of diabetes mellitus (lamina cribrosa thickness: r = −0.078, p = 0.643; anterior lamina cribrosa depth: r = −0.062, p = 0.710) or HbA1c levels (lamina cribrosa thickness: r = −0.078, p = 0.596; anterior lamina cribrosa depth: r = −0.228, p = 0.169).

Conclusion:

The results of this study showed that the optical coherence tomography measurement of lamina cribrosa revealed thicker and more anteriorly positioned lamina cribrosa for patients with diabetes mellitus compared with those for healthy controls.

Keywords

Diabetes mellitus enhanced depth imaging lamina cribrosa spectral-domain optical coherence tomography

Introduction

Primary open-angle glaucoma (POAG) is a chronic progressive optic neuropathy. The resultant loss of retinal ganglion cells (RGCs) and their axons leads to a characteristic acquired optic atrophy.¹ The lamina cribrosa is a mesh-like structure that surrounds and protects the RGC axons at the optic nerve head.^2–4 Deformation and displacement of the lamina cribrosa can block the axoplasmic flow within RGC axons.^5–7 Thus, the lamina cribrosa is a key site for axonal injury in glaucomatous optic neuropathy.

A histologic study has shown deformation of the posterior lamina cribrosa in monkey eyes with induced glaucoma.⁸ Deepening of the anterior lamina cribrosa, which occurs secondary to a posterior shift and/or thinning of the lamina cribrosa, causes mechanical stress on the optic nerve head. Recent advances in optical coherence tomography (OCT) have enabled visualization of the lamina cribrosa in clinical settings.⁹ OCT images of eyes with POAG have shown lamina cribrosa deformations such as increased anterior lamina cribrosa depth (ALCD) and decreased lamina cribrosa thickness (LCT).^10–12

Diabetes mellitus (DM) is a systemic disease characterized by hyperglycaemia secondary to insulin deficiency or insulin resistance. Increased apoptosis of RGCs and early RGC death have been reported in diabetic eyes.^13,14 It has also been reported that several proapoptotic molecules are expressed by ganglion cells in diabetic retinas.¹⁴ Experiments with animal models have shown that retrograde axonal transport in large- and medium-sized RGCs is damaged in diabetic eyes before optic nerve involvement.^15,16 Development of diabetic optic neuropathy may be attributed to increased accumulation of advanced glycation end products in cribriform plates and in the vicinity of optic nerve vessels.¹⁷ However, to date, no study has assessed the association between DM and morphological changes in the lamina cribrosa. In this study, we compared the thickness and depth of the lamina cribrosa between diabetic and non-diabetic eyes using enhanced depth imaging OCT.

Methods

Study design and subjects

This was a prospective, observational cross-sectional study with participants recruited at the Kayseri Training and Research Hospital. Those in the diabetes group were recruited from the Department of Endocrinology and Metabolic Disorders clinic and those in the control group were recruited from the outpatient clinic.

All participants were Turkish citizens of Caucasian origin. Demographic data were collected, and participants were asked about the presence of systemic diseases. One eye per subject was randomly selected if both eyes were eligible.

In the diabetes group, all participants had been diagnosed with type 2 DM using current guidelines published by the American Diabetes Association.¹⁸ They were all receiving oral antidiabetic medication or insulin therapy. Duration of DM was recorded. HbA1c measurements and ophthalmic assessments were performed on the same day. The control group included age- and sex-matched individuals with good general and ocular health. All participants in the control group had good visual acuity and no retinal disease.

Informed consent was obtained from all participants before the study commenced. The study protocol conformed to the tenets of the Declaration of Helsinki and was approved by the local medical ethics committee.

Ophthalmic examination

The study population of 70 eyes, 38 from participants with type 2 DM and 32 from control participants, was examined between July 2016 and February 2017. Each participant underwent a complete ophthalmic examination that included central corneal thickness (CCT), keratometry measured using a Scheimpflug camera (Pentacam HR; Oculus GmbH, Wetzlar, Germany), axial length (AL) of the eye measured with the IOL Master (Carl Zeiss Meditec, Dublin, CA), slit-lamp biomicroscopy, fundus examination and gonioscopy. Refraction was measured using a Tonoref II autorefractor/tonometer (Nidek Co. Ltd., Japan). The spherical equivalent (SE) was calculated as the sum of the sphere value and half the cylindrical value. Intraocular pressure (IOP) was measured using Goldmann applanation tonometry. Visual fields were assessed with the Humphrey field analyzer using the central 24-2 fields and with the Swedish Interactive Thresholding Algorithm standard strategy. Visual field reliability criteria included < 20% fixation loss and < 20% false-negative and false-positive rates. All participants undertook and passed the Glaucoma Hemifield Test (mean and pattern standard deviations within normal limits) and had no characteristic glaucomatous visual-field defects.

The circumpapillary retinal nerve fibre layer (cpRNFL) thickness measurements were obtained using the Spectralis Spectral-Domain Optical Coherence Tomography (SD-OCT). The OCT scanning circle (diameter, 3.4 mm) was manually positioned at the centre of the optic disc by experienced operators, and the average peripapillary RNFL thickness was recorded in micrometres.

Glaucoma and ocular hypertension were excluded using criteria of IOP < 21 mmHg and normal optic nerve appearance on a nonglaucomatous, standard automated perimetry visual field examination. Exclusion criteria were a history of surgery or laser treatment, any retinal disease, neurologic diseases affecting the optic disc or visual field, tilted discs or nonglaucomatous optic disc atrophy, and any significant media opacity that obscured the fundus.

Lamina cribrosa assessment

SD-OCT scans taken with a Heidelberg Spectralis SD-OCT imaging platform with an enhanced depth imaging programme (Heidelberg Engineering, Heidelberg, Germany) were used to measure LCT and ALCD of participants. Scans were excluded from the analysis if they had a quality score of < 20 or they provided an unclear image of the fundus or the border of the lamina cribrosa.

The method for enhanced depth imaging of the optic nerve head with an SD-OCT device is published elsewhere.¹⁹ Briefly, the SD-OCT device was set to image a 15° × 10° rectangle centred on the optic disc. This rectangle was divided into approximately 65 sections, each comprising an average of 100 OCT frames. From these horizontal B scans, we selected three frames (centre, midsuperior, and midinferior) that passed through the optic nerve head, and parameters were measured in each of these frames. During measurement, the centre of lamina cribrosa plate was used for thickness.

Figure 1 depicts OCT images of lamina cribrosa borders and Bruch’s membrane opening in a participant with DM and a control. The Bruch’s membrane opening is defined as the line that connects both ends of Bruch’s membrane. Distances were measured on the line perpendicular to the reference line. Parameters were measured as close as possible to the vertical centre of the optic nerve head. When a vessel trunk made the measurement impossible, measurements were recorded at the temporal side. Anterior and posterior borders of the highly reflective region at the vertical centre of the optic nerve head in horizontal SD-OCT cross-sections were defined as lamina cribrosa borders, and the distance between them was defined as LCT.

Figure 1.

Optical coherence tomographic (OCT) images of a 58-year-old patient in the diabetes group and a 56-year-old in the control group. (Top) The right eye of the patient with diabetes: lamina cribrosa thickness = 278 µm; anterior lamina cribrosa depth = 371 µm. (Bottom) The right eye of the control: lamina cribrosa thickness = 245 µm; anterior lamina cribrosa depth = 473 µm.

Adjustment of contrast settings aided in the identification of images that provided the clearest visualization of the lamina cribrosa. ALCD was defined as the distance between the Bruch’s membrane opening and the anterior border of the lamina cribrosa. Measurements were obtained using HEYEX software 6.0 (Heidelberg Engineering Inc., Heidelberg, Germany). All images were independently analysed by two examiners (S.A. and B.K.), who determined LCT and ALCD twice. Thus, each LCT and ALCD value was calculated four times, and the mean was used in the primary analysis. Prior to the primary analysis, reproducibility of the LCT and ALCD measurements was tested by calculating interexaminer and intraexaminer intraclass correlation coefficients using 15 randomly selected images.

Two ophthalmologists measured all parameters on these images and masked inter- and intraobserver reproducibility of measurements was evaluated, and comparison revealed a Spearman correlation coefficient of >0.90.

Statistical analyses

Baseline characteristics of the members of the diabetes and control groups were compared. The Shapiro–Wilk test was used to test normality before using parametric tests. Parametric data were compared using Student’s t-test, and non-parametric data were compared using the Mann–Whitney U test. The chi-square test was used to compare categorical data. The Pearson correlation coefficient was used when two variables were measured, and the Spearman correlation coefficient was used when variables were non-parametric. The analysis of covariance (ANCOVA) test was used to account for the effects of age, sex and AL values on significant differences between the groups. Age, sex and AL values were set as covariates in the ANCOVA test. Logarithmic transformation was used to convert non-parametric data to parametric data where needed. A p-value of <0.05 was considered significant. Statistical analyses were performed using SPSS version 21.0 (SPSS, Inc., Chicago, IL, USA).

Results

The study included 32 eyes from 32 healthy controls (23 women, 9 men) and 38 eyes from 38 participants with DM (28 women, 10 men). The mean ± standard deviation age of the included subjects was 58.6 ± 7.7 years and 59.1 ± 7.4 years for the control and diabetes groups, respectively (p = 0.696). Gender distribution was similar between the groups (p = 0.473). In the diabetes group, mean HbA1c at the time of the study was 7.24% ± 1.5%, and mean duration of DM was 8.2 ± 5.2 years.

Table 1 shows the results of Goldmann applanation tonometry, Pentacam, enhanced depth imaging OCT, and biometric parameters of the studied eyes.

Table 1.

Ocular characteristics of study participants.

Parameters	Study group			Control group			p
Parameters	Mean ± SD	Median	Range	Mean ± SD	Median	Range	p
Spherical equivalent (D)	0.15 ± 1.43	0.06	−4.62 to 4.00	−0.25 ± 1.81	−0.12	−5.00 to 2.87	0.26
Axial length (mm)	23.51 ± 0.94	23.50	22.05 to 25.45	23.66 ± 0.63	23.72	22.70 to 25.14	0.47
Keratometry (mm)	7.69 ± 0.26	7.64	7.29 to 8.48	7.72 ± 0.28	7.67	7.13 to 8.50	0.61
Central corneal thickness (mm)	544.72 ± 31.45	544.50	465 to 624	538.59 ± 36.65	534	464 to 607	0.37
Intraocular pressure (mmHg)	13.97 ± 2.22	14	10 to 20	14.63 ± 3.17	15	10 to 20	0.46
cpRNFL thickness (μm)	101.37 ± 10.97	102	85 to 129	105.41 ± 5.86	106	94 to 114	0.06
LCT (μm)	271.61 ± 33.96	274.50	168 to 334	248.50 ± 5.40	250	235 to 258	< 0.001
ALCD (μm)	351.45 ± 58.61	348	258 to 479	420.32 ± 90.26	423.50	241 to 554	0.003

cpRNFL: circumpapillary retinal nerve fibre layer; LCT: lamina cribrosa thickness; ALCD: anterior lamina cribrosa depth.

Intraexaminer intraclass correlation coefficient values [95% confidence intervals (CIs)] for LCT and ALCD were 0.895 (0.751–0.969) and 0.974 (0.916–0.992), respectively. Interexaminer intraclass correlation coefficients (95% CIs) for LCT and ALCD were 0.849 (0.761–0.979) and 0.943 (0.816–0.972), respectively.

LCT was significantly higher (271.6 ± 33.9 μm vs 248.5 ± 5.4 μm, p < 0.001) and ALCD was significantly lower (351.4 ± 58.6 μm vs 420.3 ± 90.2 μm, p = 0.003) in participants with DM than in control subjects (Figure 2).

Figure 2.

Comparison of lamina cribrosa thickness (LCT) and anterior lamina cribrosa depth (ALCD) in patients with diabetes and healthy controls. LCT was 271.6 ± 33.9 μm in the diabetes group and 248.5 ± 5.4 μm in the control group. ALCD was 351.4 ± 58.6 μm in the diabetes group and 420.3 ± 90.2 μm in the control group. LCT was significantly higher (p < 0.001) and ALCD was significantly lower (p = 0.003) in patients with diabetes mellitus than in healthy controls.

The effects of possible confounding factors (age, sex and AL) on the differences in LCT and ALCD measurements between the two groups were investigated using an ANCOVA test, after logarithmic transformation of non-parametric data to parametric data. None of the potential confounders had a significant effect on the initial statistical comparisons. The statistical significances of age, sex and AL after ANCOVA test were 0.196, 0.799 and 0.342, respectively, for LCT, and 0.144, 0.176 and 0.998, respectively, for ALCD.

Mean SE, AL, CCT, IOP, cpRNFL thickness and keratometry measurements did not show any significant differences between the two groups (p = 0.26 for SE, p = 0.47 for AL, p = 0.37 for CCT, p = 0.46 for IOP, p = 0.06 for cpRNFL thickness and p = 0.61 for keratometry).

Correlation analyses in the diabetic group showed that LCT and ALCD were not significantly correlated to duration of DM (r = −0.078, p = 0.643 for LCT; r = −0.062, p = 0.710 for ALCD) or HbA1c levels (r = −0.078, p = 0.596 for LCT; r = −0.228, p = 0.169 for ALCD; Figure 3).

Figure 3.

Correlation of HbA1c and duration of diabetes mellitus (DM) with lamina cribrosa thickness (LCT) and anterior lamina cribrosa depth (ALCD). In the diabetes group, LCT and ALCD were not associated with DM duration (r = −0.078, p = 0.643 for LCT; r = −0.062, p = 0.710 for ALCD) or metabolic control (r = −0.078, p = 0.596 for LCT; r = −0.228, p = 0.169 for ALCD).

The diabetes group was subdivided into two groups according to disease duration. There were 20 participants with disease duration of ⩽8 years and 18 with disease duration of >8 years. Differences in LCT and ALCD measurements between these groups were not significant (p = 0.174 and p = 0.447, respectively). Similarly, the diabetes group was subdivided into two groups according to HbA1c levels. Mean ± standard deviation for HbA1c levels for the two groups were 6.17 ± 0.40 (n = 19) and 8.31 ± 1.62 (n = 19). LCT and ALCD measures did not differ significantly between the groups (p = 0.682 and p = 0.599, respectively).

Discussion

Worldwide, DM and glaucoma are two major causes of vision loss.²⁰ The relationship between DM and glaucoma is not well understood and is currently the subject of much debate. With contradictory study outcomes over the last few decades, possible interaction mechanisms between DM and glaucoma and the associated risks are currently unclear. Some population-based studies have shown that patients with DM are at increased risk of developing glaucoma and experiencing severe glaucoma.^21,22 However, other studies have found no such association.^23,24 There is a need for more extensive, in-depth studies.

It has been suggested that because DM causes microvascular damage and vascular dysregulation of the retina and the optic disc, it increases the susceptibility of the optic nerve head to damage.^25,26 In contrast, some studies have found that DM inhibits the development of glaucoma.^27,28 The Ocular Hypertension Treatment Study found that of the 191 participants who reported a history of DM at baseline, 6 (3.1%) developed POAG compared to 119 (8.3%) of the 1427 participants who had no history of DM.²⁷ The univariate hazard ratio for DM was 0.40, and multivariate hazard ratio was 0.37.²⁷ After publication of the Ocular Hypertension Treatment Study report, the correlation between DM and glaucoma was questioned,²⁹ or even denied.^30,31

Our recent study using Heidelberg retina tomography III found that the rim area and rim volume were significantly increased in patients with POAG and DM compared to those without DM, suggesting a protective effect of DM against glaucomatous optic nerve damage.²⁸ Short-term hyperglycaemia protects retinal neurons, including RGCs, against ischaemic injury³² and RGCs and optic nerve axons against ocular hypertension injury, as reported in rats with diabetes that experienced less nerve fibre loss under high IOP stress.³³ It has also been reported that hyperglycaemia protected axons from tumour necrosis factor-induced optic nerve degeneration.³⁴

In 2009, Quigley hypothesized that DM was neuroprotective because the diabetic breakdown of the blood–retina barrier led to leakage of neuroprotective vascular endothelial growth factor³⁵ and induced a preischaemic survival mechanism.³⁶ Diabetic glycation of connective tissue also reinforces the lamina cribrosa and protects the nerve fibres.^37,38

This study investigated whether DM affected OCT measurements of the lamina cribrosa and whether glycaemic control had any further impact. This was the first study to investigate the effects of DM and glycaemic control on the lamina cribrosa. It revealed a thicker and more anteriorly positioned lamina cribrosa in participants with DM than in healthy subjects. These findings support the neuroprotective effect of DM on glaucomatous optic neuropathy and suggest that LCT and lamina cribrosa position mediates this protective effect.

The eyes of patients with DM have more cross-linking of collagen through the process of glycation.³⁹ This could increase the stiffness of the cornea and sclera, reducing the strain at the optic nerve head and reinforcing the lamina cribrosa against IOP-induced stress. Through this mechanism, the eyes of patients with DM could more effectively resist the damaging effects of IOP.

Our study demonstrated no statistically significant difference between the duration of DM or HbA1c levels and lamina cribrosa OCT measurements.

This result led us to consider whether disease duration and level of glycaemic control had any impact on lamina cribrosa measurements. These findings highlight the need for longitudinal and prospective studies about the impact of disease duration and metabolic control on lamina cribrosa OCT measurements in patients with DM.

This study has several limitations. It was a cross-sectional, single hospital-based study with a small number of participants. As OCT depends on light waves, the contrast of the signals in deeper tissue is lower, even when using enhanced depth imaging. Therefore, identifying the deeper border of the lamina cribrosa was relatively subjective in excluded few individuals. For more sophisticated analysis, a prospective study with a larger number of participants and the ability to conduct deeper tissue imaging will be necessary.

Within the constraints of our study, we have concluded that DM may have a protective effect over glaucomatous optic nerve damage and that this effect is associated with the thickness and position of the lamina cribrosa. However, this finding will need to be verified by more extensive, longitudinal studies.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Ethical approval

All procedures performed were in accordance with the ethical standards of the Kayseri Training and Research Hospital research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Informed consent

Informed consent was obtained from all individual participants included in the study.

ORCID iD

Bekir Küçük

References

Weinreb

Khaw

PT.

Primary open-angle glaucoma. Lancet 2004; 363: 1711–1720.

Wilczek

The lamina cribrosa and its nature. Br J Ophthalmol 1947; 31: 551–565.

Radius

Gonzales

Anatomy of the lamina cribrosa in human eyes. Arch Ophthalmol 1981; 99: 2159–2162.

Anderson

DR.

Ultrastructure of human and monkey lamina cribrosa and optic nerve head. Arch Ophthalmol 1969; 82: 800–814.

Gaasterland

Tanishima

Kuwabara

et al . Axoplasmic flow during chronic experimental glaucoma. 1. Light and electron microscopic studies of the monkey optic nerve head during development of glaucomatous cupping. Invest Ophthalmol Vis Sci 1971; 17: 838–846.

Takihara

Inatani

Eto

et al . In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS. Proc Natl Acad Sci USA 2015; 112: 10515–10520.

Minckler

Bunt

Johanson

GW.

Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci 1977; 16: 426–441.

Yang

Williams

Downs

et al . Posterior (outward) migration of the lamina cribrosa and early cupping in monkey experimental glaucoma. Invest Ophthalmol Vis Sci 2011; 52: 7109–7121.

Lee

Kim

T-W

Weinreb

et al . Visualization of the lamina cribrosa using enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2011; 152: 87–95.e1.

10.

Park

HYL

Jeon

Park

CK.

Enhanced depth imaging detects lamina cribrosa thickness differences in normal tension glaucoma and primary open-angle glaucoma. Ophthalmology 2012; 119: 10–20.

11.

Park

Brumm

Furlanetto

et al . Lamina cribrosa depth in different stages of glaucoma. Invest Ophthalmol Vis Sci 2015; 56: 2059–2064.

12.

Prata

Lopes

Prado

et al . In vivo analysis of glaucoma-related features within the optic nerve head using enhanced depth imaging optical coherence tomography. PLoS ONE 2017; 12: e0180128.

13.

Hammes

Federoff

Brownlee

Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes. Mol Med 1995; 1: 527–534.

14.

Abu-El-Asrar

Dralands

Missotten

et al . Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthalmol Vis Sci 2004; 45: 2760–2766.

15.

Zhang

Ino-ue

Dong

et al . Retrograde axonal transport impairment of large- and medium-sized retinal ganglion cells in diabetic rat. Curr Eye Res 2000; 20: 131–136.

16.

Ino-Ue

Zhang

Naka

et al . Polyol metabolism of retrograde axonal transport in diabetic rat large optic nerve fiber. Invest Ophthalmol Vis Sci 2000; 41: 4055–4058.

17.

Amano

Kaji

Oshika

et al . Advanced glycation end products in human optic nerve head. Br J Ophthalmol 2001; 85: 52–55.

18.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2004; 27(Suppl. 1): S5–S10.

19.

Spaide

Koizumi

Pozonni

MC.

Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008; 146: 496–500.

20.

Primus

Harris

Siesky

et al . Diabetes: a risk factor for glaucoma? Br J Ophthalmol 2011; 95: 1621–1622.

21.

Klein

Jensen

SC.

Open-angle glaucoma and older-onset diabetes. The Beaver Dam eye study. Ophthalmology 1994; 101: 1173–1177.

22.

Dielemans

de Jong

Stolk

et al . Primary open-angle glaucoma, intraocular pressure, and diabetes mellitus in the general elderly population. The Rotterdam Study. Ophthalmology 1996; 103: 1271–1275.

23.

Tielsch

Katz

Sommer

et al . Hypertension, perfusion pressure, and primary open-angle glaucoma. A population based assessment. Arch Ophthalmol 1995; 113: 216–221.

24.

Quigley

West

Rodriguez

et al . The prevalence of glaucoma in a population-based study of Hispanic subjects: proyecto VER. Arch Ophthalmol 2001; 119: 1819–1826.

25.

Nakamura

Kanamori

Negi

Diabetes mellitus as a risk factor for glaucomatous optic neuropathy. Ophthalmologica 2005; 219: 1–10.

26.

Kanamori

Nakamura

Mukuno

et al . Diabetes has an additive effect on neural apoptosis in rat retina with chronically elevated intraocular pressure. Curr Eye Res 2004; 28: 47–54.

27.

Gordon

Beiser

Brandt

et al . The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 714–720.

28.

Akkaya

Can

Öztürk

Comparison of optic nerve head topographic parameters in patients with primary open-angle glaucoma with and without diabetes mellitus. J Glaucoma 2016; 25: 49–53.

29.

Worley

Grimmer-Somers

Risk factors for glaucoma: what do they really mean?

Aust J Prim Health 2011; 17: 233–239.

30.

Tan

Wong

Fong

et al . Diabetes, metabolic abnormalities, and glaucoma. Arch Ophthalmol 2009; 127: 1354–1361.

31.

De Voogd

Ikram

Wolf

et al . Is diabetes mellitus a risk factor for open-angle glaucoma? The Rotterdam Study. Ophthalmology 2006; 113: 1827–1831.

32.

Casson

Chidlow

Wood

et al . The effect of hyperglycemia on experimental retinal ischemia. Arch Ophthalmol 2004; 122: 361–366.

33.

Ebneter

Chidlow

Wood

et al . Protection of retinal ganglion cells and the optic nerve during short-term hyperglycemia in experimental glaucoma. Arch Ophthalmol 2011; 129: 1337–1344.

34.

Sase

Kitaoka

Munemasa

et al . Axonal protection by short-term hyperglycemia with involvement of autophagy in TNF-induced optic nerve degeneration. Front Cell Neurosci 2015; 9: 425.

35.

Rosenstein

Krum

Ruhrberg

VEGF in the nervous system. Organogenesis 2010; 6: 107–114.

36.

Fernandez

Pasquini

Dorfman

et al . Ischemic conditioning protects from axoglial alterations of the optic pathway induced by experimental diabetes in rats. PLoS ONE 2012; 7: e51966.

37.

Terai

Spoerl

Haustein

et al . Diabetes mellitus affects biomechanical properties of the optic nerve head in the rat. Ophthalmic Res 2012; 47: 189–194.

38.

Quigley

HA.

Can diabetes be good for glaucoma? Why can’t we believe our own eyes (or data?)

Arch Ophthalmol 2009; 127: 227–229.

39.

Goh

S-Y

Cooper

ME.

The role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab 2008; 93: 1143–1152.