Boxes represent 25% to 75% (lower to upper) quartiles; lines in boxes, medians; whiskers, variability (minimum and maximum values); and open and shaded circles, individual data points. Mean pRNFL thicknesses were decreased over time in all groups. DR indicates diabetic retinopathy; NPDR, nonproliferative DR.
eFigure 1. Scatter and Box Plots of Quadrant Peripapillary Retinal Nerve Fiber Layer Thicknesses at Each Visit
eFigure 2. Estimated Reduction Slope of Mean Retinal Nerve Fiber Layer Thickness
eFigure 3. Forest Plot of Published Data on the Rate of Mean pRNFL Loss in Abnormal and Normal Eyes
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Lim HB, Shin YI, Lee MW, Park GS, Kim JY. Longitudinal Changes in the Peripapillary Retinal Nerve Fiber Layer Thickness of Patients With Type 2 Diabetes. JAMA Ophthalmol. 2019;137(10):1125–1132. doi:10.1001/jamaophthalmol.2019.2537
How does type 2 diabetes affect longitudinal changes in peripapillary retinal nerve fiber layer thickness?
In this study of 101 patients with type 2 diabetes, progressive reduction of peripapillary retinal nerve fiber layer thickness was observed in healthy controls and patients without and with diabetic retinopathy; however, type 2 diabetes was associated with a greater loss of peripapillary retinal nerve fiber layer, regardless of whether diabetic retinopathy was present.
These findings suggest that peripapillary retinal nerve fiber layer loss may occur in people with type 2 diabetes even in the absence of diabetic retinopathy progression.
Type 2 diabetes is expected to accelerate age-related peripapillary retinal nerve fiber layer (pRNFL) loss, but limited information on the rate of reduction in pRNFL thicknesses in patients with type 2 diabetes is available.
To investigate longitudinal changes in pRNFL thickness in patients with type 2 diabetes, with or without diabetic retinopathy (DR).
Design, Setting, and Participants
A total of 164 eyes of 63 healthy individuals and 101 patients with type 2 diabetes (49 patients without DR [non-DR group] and 52 patients with mild to moderate nonproliferative DR [NPDR group]) were enrolled in this prospective, longitudinal, observational study from January 2, 2013, through February 27, 2015. Participants were followed up for 3 years, and the peripapillary mean and sector RNFL thicknesses were measured at 1-year intervals. The mean rate of pRNFL loss was estimated using a linear mixed model and compared among the 3 groups. Follow-up was completed on March 16, 2018, and data were analyzed from April 2 through July 27, 2018.
Type 2 diabetes.
Main Outcomes and Measures
The rate of reduction in pRNFL thickness in patients with type 2 diabetes.
A total of 164 participants (88 women [53.7%]; mean [SD] age, 58.2 [8.7] years) were included in the study analysis. The mean (SD) age of the control group was 56.5 (9.3) years (39 women [61.9%]); the non-DR group, 59.1 (9.4) years (26 women [53.1%]); and the NPDR group, 59.4 (11.0) years (23 women [44.2%]). Mean (SD) duration of type 2 diabetes was 7.1 (4.4) years in the non-DR group and 13.2 (8.4) years in the NPDR group. The baseline mean (SD) pRNFL thickness was 96.2 (11.0) μm in the control group, 93.5 (6.4) μm in the non-DR group, and 90.4 (7.9) μm in the NPDR group. During 3 years of follow-up, these values decreased to 95.0 (9.2) μm in the control group, 90.3 (6.4) in the non-DR group, and 86.6 (7.9) μm in the NPDR group. In a linear mixed model, the estimated mean pRNFL loss was −0.92 μm/y in the non-DR group (P < .001) and −1.16 μm/y in the NPDR group (P < .001), which was 2.9-fold (95% CI, 1.1-14.8; P = .003) and 3.3-fold (95% CI, 1.4-18.0; P < .001) greater, respectively, than that of the control group (−0.35 μm/y; P = .01).
Conclusions and Relevance
Progressive reduction of pRNFL thickness was observed in healthy controls and patients with type 2 diabetes without and with DR; however, type 2 diabetes was associated with a greater loss of pRNFL regardless of whether DR was present. These findings suggest that pRNFL loss may occur in people with type 2 diabetes even in the absence of DR progression.
Type 2 diabetes (hereafter referred to as diabetes), a global health problem, is an important cause of mortality and morbidity.1 The global prevalence of diabetes has been increasing during recent decades, from 108 million in 1980 to 422 million in 2014, and is expected to increase to 629 million (9.9% of the global population) by 2045 because of rapid increases in the prevalence of obesity and physical inactivity.2,3
Diabetic retinopathy (DR) is a major complication of diabetes, and approximately 93 million people worldwide have DR.4 Various biochemical mechanisms associated with hyperglycemia and hypoxic damage have been implicated in the progression of DR.5 Other studies6,7 have reported that neuronal damage in the retina can occur before clinically detectable microvascular changes, a phenomenon known as diabetic retinal neurodegeneration (DRN). Diabetic retinal neurodegeneration caused by neuronal apoptosis and glial cell activation affects the retinal ganglion cell layer, resulting in thinning of the ganglion cell–inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL).8-11
Peripapillary RNFL (pRNFL) thickness, which can be measured easily by spectral-domain optical coherence tomography (SD-OCT), is a reliable and important variable that can be affected by various conditions, including retinal disease, neuro-ophthalmic disease, and glaucoma.12-16 Using commercially available software, disease progression can be determined by trend analysis of pRNFL thickness; this analysis can provide important information, especially in patients with glaucoma. Previously, several trend analyses of pRNFL17-19 revealed age-related loss of pRNFL, which was accelerated by abnormal eye conditions. Diabetes leads to retinal damage due to ischemic changes and neuronal degeneration5 and is expected to accelerate age-related pRNFL loss. Considering that diabetes is a common disease and an important risk factor for glaucoma,20 information concerning changes in pRNFL thickness over time in diabetes would be helpful to physicians.
In this prospective study, we measured changes in pRNFL thickness in healthy control individuals and patients with diabetes for a 3-year period. We aimed to estimate the rate of pRNFL loss over time in patients with diabetes and compare this rate with that of a control group.
We performed a prospective, longitudinal, observational study. The study protocol was approved by the institutional review board of Chungnam National University Hospital, Daejeon, Republic of Korea, and adhered to the tenets of the Declaration of Helsinki.21 All included participants met the eligibility criteria and provided written informed consent to participate. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Patients with diabetes who visited the Retina and Vitreous Clinic of Chungnam National University Hospital for a checkup of DR were enrolled consecutively from January 2, 2013, through February 27, 2015. All patients were initially diagnosed with diabetes at the Department of Internal Medicine of Chungnam National University Hospital, and the diagnosis of diabetes was made according to the criteria of the American Diabetes Association.22 All patients exhibited a best-corrected visual acuity (BCVA) of 20/25 or better, and none had any history of ocular surgery. The exclusion criteria consisted of a history of systemic disease other than diabetes and hypertension, glaucoma, optic nerve disorder, intraocular pressure (IOP) greater than 21 mm Hg, spherical equivalent greater than +6.0 diopters (D) or less than −6.0 D, optic disc abnormalities, axial length of at least 26.0 mm, or any other optic nerve or retinal dysfunction except DR. If both eyes met the inclusion criteria, 1 eye was randomly selected.
All patients initially underwent a comprehensive ophthalmic examination, including a review of their medical history, BCVA, slitlamp examination, IOP measurement, dilated fundus examination, photography, axial length measurement using a commercially available biometer (IOLMaster; Carl Zeiss Meditec), SD-OCT (Carl Zeiss Meditec), and fluorescein angiography (HRA Spectralis instrument; Heidelberg Engineering). Diabetic retinopathy was graded according to the International Clinical Diabetic Retinopathy Disease Severity scale.23 The patients with diabetes were divided into a non-DR group and a nonproliferative DR (NPDR) group. The NPDR group consisted of patients with mild and moderate NPDR only; all patients with a higher grade of DR were excluded.
Among the participants who visited our clinic for various reasons (health screening checkup, routine check for ocular disease such as cataract, peripheral vitreous floater, etc), those who met exclusion criteria and had recorded glucose levels (fasting plasma glucose level <100 mg/dL [to convert to millimoles per liter, multiply by 0.0555] or hemoglobin A1c [HbA1c] level <5.7% [to convert to proportion of total hemoglobin, multiply by 0.01]) were enrolled in the control group. Controls had no ocular disease or prior intraocular surgery and had a normal anterior segment and fundus, BCVA of at least 20/25, IOP in the reference range, and a spherical equivalent within ±6.0 D.
All participants underwent examinations including BCVA and IOP measurement, slitlamp biomicroscopy, dilated fundus examination, photography, and SD-OCT every 12 months for 3 years. Follow-up was completed on March 16, 2018. Patients who underwent intraocular surgery, were diagnosed with macular edema, had DR grade progression exceeding mild to moderate NPDR, or were lost to follow-up were excluded from the study.
We performed SD-OCT with a commercially available instrument (Cirrus HD-OCT; Carl Zeiss Meditec) using a 512 × 128 macular cube combination scan and a 200 × 200 optic disc cube scan. Central macular thickness was measured using a 512 × 128 macular cube combination scan. During the macular cube scan, we also measured the mean GC-IPL thickness using a ganglion cell analysis algorithm. A 200 × 200 scan mode optic disc cube was used to image the optic disc and the pRNFL over a 6 × 6-mm optic nerve head. The pRNFL thicknesses of the 4 quadrant sectors (superior, inferior, nasal, and temporal) were then measured. Optic nerve head variables, including the rim area, disc area, and mean cup-disc ratio, were also determined.
Two scans were performed for all participants by an experienced examiner, and we selected the best scan among those showing a signal strength of at least 7. We excluded the data of patients with a signal strength of less than 7, other image quality problems such as motion or off-centered scan, or missing data due to floaters, vignetting, or cataract on the SD-OCT scan.
Data were analyzed from April 2 through July 27, 2018. All statistical analyses were performed using SPSS for Windows statistical software, version 21.0 (SPSS, Inc) and R Studio, version 1.1.453 (R Development Core Team). Snellen BCVA results were converted into logMAR values. Continuous variables are presented as mean (SD). A 2-tailed P < .05 denoted statistical significance.
Baseline demographics and OCT measurements, including central macular thickness, mean GC-IPL thickness, optic nerve head variables, and pRNFL thickness, were compared using 1-way analysis of variance (ANOVA) with Bonferroni correction and the χ2 test; the pRNFL thickness was also compared among visits. Repeated-measures ANOVA was used to analyze longitudinal changes in RNFL thickness in each group. Linear mixed-effects models were fitted to calculate and compare the rate of reduction in pRNFL thickness over time among the 3 groups. Age, sex, duration of diabetes, HbA1c level, spherical equivalent, BCVA, axial length, IOP, baseline pRNFL thickness, follow-up duration, and interaction between group and follow-up duration were included as fixed effects, and the participant levels were included as the random intercept. In addition, univariate and multivariate linear mixed models were fitted to identify factors associated with longitudinal changes in pRNFL thickness. These variables were first fitted in a univariate model, and variables significant at P < .05 were then included in multivariate analysis to determine the independence of the effects.
A total of 122 patients with diabetes and 82 healthy control individuals were initially included in this study; 40 individuals were excluded owing to loss to follow-up (n = 24), progression of DR (n = 9), intraocular surgery (n = 4), or diabetic macular edema (n = 3). As a result, a total of 164 participants (76 men [46.3%] and 88 women [53.7%]; mean [SD] age, 58.2 [8.7] years), including 101 patients (49 in the non-DR group and 52 in the NPDR group) and 63 control individuals, were finally enrolled.
The mean age of the control group was 56.5 (9.3) years (39 women [61.9%]); the non-DR group, 59.1 (9.4) years (26 women [53.1%]); and the NPDR group, 59.4 (11.0) years (23 women [44.2%]) (P = .12) (Table 1). The mean duration of diabetes was 7.1 (4.4) years for the non-DR group and 13.2 (8.4) years for the NPDR group (P < .001). The baseline mean GC-IPL thicknesses of the non-DR group (81.1 [4.5] μm; P = .049) and the NPDR group (79.7 [6.7] μm; P = .002) were lower than that of the control group (84.2 [6.2] μm). The baseline mean RNFL thickness of the control group was 96.2 (11.0) μm; the non-DR group, 93.5 (6.4) μm; and the pNPDR group, 90.4 (7.9) μm.
At 3 years of follow-up, the mean baseline RNFL thickness was significantly decreased in the control group to 95.0 (9.2) μm (P = .04); in the non-DR group, to 90.3 (6.4) μm (P < .001); and in the NPDR group, to 86.6 (7.9) μm (P < .001) (Table 2 and Figure). The RNFL thicknesses of the superior (eFigure 1A in the Supplement) and inferior (eFigure 1C in the Supplement) segments showed reduction over time in all groups. In the nasal (eFigure 1B in the Supplement) and temporal (eFigure 1D in the Supplement) segments, the non-DR group (nasal, from 68.0 [8.8] to 65.4 [10.2] μm [P = .005]; temporal, from 69.5 [9.6] to 67.3 [10.0] μm [P = .002]) and NPDR group (nasal, from 65.1 [10.9] to 62.4 [9.8] μm [P = .001]; temporal, from 69.2 [9.3] to 66.5 [9.0] μm [P < .001]) showed changes in thickness.
When comparing the 3 groups at each visit, differences were initially found in the mean, superior, and inferior segment thickness. At the 3-year visit, significant differences were found in the mean and individual segment thicknesses. Detailed values at each visit are shown in Table 2.
The estimated rate of reduction in RNFL thickness in the control group was −0.35 μm/y; in the non-DR group, −0.92 μm/y; and in the NPDR group, −1.16 μm/y (Table 3 and eFigure 2 in the Supplement). In comparison among the 3 groups, the rates of reduction of all RNFL thickness variables in the non-DR (2.9-fold [95% CI, 1.1-14.8] P = .003) and NPDR (3.3-fold [95% CI, 1.4-18.0]; P < .001) groups were faster than those of the control group except in the temporal segment. However, no difference between the non-DR and NPDR groups was identified.
Using a univariate linear mixed model, age (estimate, −1.73 [95% CI, −3.16 to −0.31] μm/y; P = .02), duration of diabetes (estimate, −0.76 [95% CI, −1.11 to −0.32] μm/y; P = .002), baseline mean pRNFL thickness (estimate, 11.1 [95% CI, 10.7-11.6] μm/y; P < .001), and follow-up duration (estimate, −0.88 [95% CI, −1.03 to −0.73] μm/y; P < .001) were associated with longitudinal changes in the mean RNFL thickness (Table 4). In multivariate linear mixed models including variables significant at P < .05 in the univariate analyses, the duration of diabetes (estimate, −0.64 [95% CI, −0.95 to −0.21]; P = .01), baseline mean RNFL thickness (estimate, 10.98 [95% CI, 10.51 to 11.45]; P < .001), and follow-up duration (estimate, −0.87 [95% CI, −1.02 to −0.72]; P < .001) remained as significant factors.
In this study, the pRNFL thickness of patients with diabetes with or without DR was evaluated longitudinally. In the analysis of 101 patients with diabetes and 63 control individuals followed up for 3 years, pRNFL thickness was reduced over time in all groups. The rate of reduction in pRNFL thickness of the non-DR and NPDR groups was 2.9-fold and 3.3-fold faster, respectively, than that of the healthy control group. Thus, diabetes, regardless of DR, was an important factor in the age-related reduction in pRNFL thickness.
In the retina, neuronal, glial, and vascular cells are closely connected in the neurovascular unit to maintain the homeostasis necessary for normal neuroretinal function, such as of the blood-retinal barrier and neural signaling.5,24 This connection explains why retinal microvascular changes, both structural and functional, occur in parallel with neuronal changes. Neurodegeneration in patients with diabetes manifests structurally as inner retinal thinning, neural apoptosis, and reactive gliosis and functionally as abnormalities on electroretinography, loss of dark adaptation and contrast sensitivity, color vision disturbance, and abnormal microperimetry findings.25-29 Previous studies reported that retinal ganglion and amacrine cells were the first neurons in which diabetes–induced apoptosis was detected, and this led to a reduced thickness of the inner retinal layers, including the GC-IPL and the pRNFL.6,30
Numerous cross-sectional studies5-7,9-11,25 have reported that inner retinal thinning occurs in patients with diabetes without DR. One longitudinal study8 reported that the GC-IPL and RNFL thicknesses in the macular area, as measured by time-domain OCT with an open-source program (Iowa Reference Algorithms; Retinal Image Analysis Laboratory, Iowa Institute for Biomedical Imaging), were progressively reduced in 45 patients with diabetes with minimal to no DR. Although time-domain OCT has low resolution, and inner retinal layers were measured in different areas among studies, these results were nonetheless consistent with our findings; together findings of inner retinal thinning in patients with no DR suggest that DRN is an early event in the pathogenesis of DR that may precede retinal microvascular changes.
In patients with diabetes, the progression of neuronal degeneration is associated with multiple factors, including metabolic and ischemic effects. Hyperglycemia triggers metabolic processes, including protein and lipid glycosylation and the production of oxidative species, which are thought to cause nerve damage. Ischemic changes and decreased neurovascular flow have also been reported to be associated with areas of neuropathy.31 In the present study, pRNFL thickness in the non-DR group did not differ from that in the NPDR group at the initial visit. However, differences between the 2 groups were observed in mean and inferior segment thickness after 3 years, possibly due to greater accumulation of metabolic and ischemic damage in the NPDR group.
In the present study, the rate of reduction in RNFL thickness in the NPDR group was higher than that in the non-DR group. However, the difference between the 2 groups was not significant. Several potential factors may explain these results. First, other forms of pathogenesis occurring during DR, such as breakdown of the blood-retinal barrier and inflammation,5,6,29 might have diminished the reduction in thickness. Although we excluded all cases of macular edema in the present study, subclinical retinal edema in the peripapillary area may not have been detected by SD-OCT. Second, although the RNFL thickness in patients with diabetes decreases with the severity of DR,32,33 the influence of ischemic injury on the RNFL thickness reduction rate in the early stage of DR might be smaller than that of DRN. Finally, the difference may have not been detected because of insufficient statistical power to differentiate the reduction rates of the 2 groups.
Several studies have analyzed changes in pRNFL thickness over time in normal and abnormal eyes.18,34-38 Among patients with glaucoma, mean thickness reduction rates of −1.43 μm/y (progressor group) were reported by Lee et al34; −1.26 μm/y (progressor group), by Shin et al35; −1.28 μm/y (before disc hemorrhage), by Akagi et al36; −1.31 μm/y (pseudoexfoliation), by Lee et al37; −0.98 μm/y, by Hammel et al18; and −0.87 μm/y, by Liu et al38 (eFigure 3 in the Supplement). Lee et al39 reported that the thickness reduction rate in patients with high myopia (−1.69 μm/y) was faster than that in the control group (−0.63 μm/y) in the sixth decade of life. Among healthy individuals, Patel et al40 reported pRNFL loss rates of −0.23 μm/y; Celebi et al,41 −0.37 μm/y; Leung et al,17 −0.54 μm/y; and Wu et al,42 −0.52 μm/y. Compared with these previous studies, the rate of pRNFL loss in our control group (−0.35 μm/y) was consistent with those of previous studies, and the reduction rates in the non-DR and NPDR groups (−0.92 and −1.16 μm/y, respectively) were similar to those of the patients with glaucoma.
In the present study, changes in pRNFL thicknesses were correlated with the duration of diabetes, which was also reported in a previous study.8 Lee et al39 reported that eyes with high myopia showed a greater reduction in pRNFL for 2 years when compared with healthy eyes. In the present study, no association was found between axial length and changes in pRNFL thickness, possibly because patients with high myopia were excluded. In addition, the baseline mean pRNFL thickness was associated with changes in mean pRNFL thickness, as also reported by previous studies.17,19,43
The present study had several strengths, besides its prospective design; first, we determined the rate of RNFL loss in patients with diabetes and controls. In addition, we assessed in detail how the differences in pRNFL thickness among the 3 groups progressed for 3 years. Our results suggest that the pRNFL status as well as DR status should be checked periodically. In addition, if the patients with diabetes were young, total RNFL reduction in a lifetime would be greater than that in older patients. Second, if patients with diabetes have a disease causing pRNFL reduction, including glaucoma or optic neuropathy, the reduction rate may be accelerated. Therefore, we believe that physicians should be aware of these points and consider reductions in the pRNFL in the treatment of these patients.
This study also had several limitations. First, we could not obtain longitudinal data on blood glucose levels. Although initial HbA1c levels in this study were not correlated with changes in pRNFL thickness, and a previous study8 reported no association between serial HbA1c levels and the progression of DRN, changes in HbA1c levels might affect the rate of pRNFL loss. Second, although we excluded patients with an RNFL defect, glaucomatous optic disc, and history of IOP greater than 21 mm Hg and we carefully checked the RNFL defect and SD-OCT findings, visual field testing was not performed and a glaucoma specialist was not involved in this study, so we may have enrolled patients with preperimetric glaucoma. Finally, we could not analyze the association of functional changes and DRN.
In this prospective, longitudinal observational study, we believe our findings confirmed that pRNFL thickness in healthy controls and patients with diabetes without and with DR showed reductions over time, and that diabetes was associated with accelerated pRNFL loss, regardless of whether or not DR progressed. These results suggest that DRN may precede the microvascular abnormalities associated with DR progression, suggesting that DRN may be a component in the pathogenesis of the pRNFL reductions seen in patients with diabetes. Our study’s findings suggest that physicians should consider these findings in cases of glaucoma or neurological disease in which pRNFL observation is undertaken.
Accepted for Publication: May 19, 2019.
Corresponding Author: Jung Yeul Kim, MD, PhD, Department of Ophthalmology, Chungnam National University Hospital, 640 Daesa-dong, Jung-gu, Daejeon 35015, Republic of Korea (firstname.lastname@example.org).
Published Online: July 25, 2019. doi:10.1001/jamaophthalmol.2019.2537
Author Contributions: Dr Lim had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lim, Lee, Park, Kim.
Acquisition, analysis, or interpretation of data: Lim, Shin, Park, Kim.
Drafting of the manuscript: Lim, Park, Kim.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: All authors.
Administrative, technical, or material support: Lim, Lee, Kim.
Supervision: Lim, Lee, Kim.
Conflict of Interest Disclosures: None reported.