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CORRELATION BETWEEN GANGLION CELL LAYER AND RETINAL NERVE FIBER LAYER THICKNESS WITH SENSITIVITY IN DIABETES MELITUS PATIENT WITHOUT DIABETIC RETINOPATHY

Dian Paramitasari, R Maula Rifada, Susi Heryati Ophtalmology Department, Faculty of Medicine Padjadjaran University National Eye Center Cicendo Eye Hospital

Abstract Introduction : Diabetic retinopathy is one of ocular complications caused by Diabetes Mellitus (DM). Before clinical manifestation of retinopathy diabetic could be detected, it is postulated that the hyperglycemia state already caused multiple dysfunction on celullar level. Retinal neurodegenerations on early phase of DM is difficult to detect clinically. Measuring retinal thickness and contrast sensitivity could detect these initial changes. Objective : To detect positive correlation between ganglion cell layer and Nerve Fiber Layer (RNFL) thickness in relation to contrast sensitivity. Methods : This study used cross sectional method, with 47 eyes from 32 DM patients without any sign of diabetic retinopathy that met the study criteria. Ganglion cell layer and RNFL thickness were measured using Opctical Coherence Tomography (OCT) examination, while contrast sensitivity were measured using CSV-1000 chart.The collected data were analyzed using linear regresion to detect correlation between ganglion cell layer and RNFL thickness to contrast sensitivity. Result : According to reliability analysis, the linear regression model between ganglion cell layer, RNFL thickness and contrast sensitivity on spatial frequency 6 cpd and 18 cpd were significant (p < 0.005). Positive regression coefficient were found among ganglion cell layer and RNFL thickness in relation to contrast sensitivity on spatial frequency 6 cpd and 18 cpd (b = 0.016, 0.019, 0.032, 0.025). Conclusion : Positive correlations were found between ganglion cell layer and RNFL thickness in relation to contrast sensitivity on spatial frequency 6 cpd and 18 cpd. Keywords : Diabetes Mellitus, Ganglion Cell Layer Thickness, RNFL Thickness, Contrast Sensitivity

INTRODUCTION worldwide. More than a third of Diabetes mellitus (DM) is one of people with DM have signs of diabetic the most common chronic illness retinopathy. The number of people found in the world. According to with visual impairment attributable to International Diabetes Federation DR also continue to increase, form 1.4 (IDF) prediction, the number of people million people in 1990 to 2.6 million with DM in Indonesia will continue to in 2015.2–4 increase from 9.1 million people in It is postulated that the 2014 to 14.1 million in 2035.1 Diabetic hyperglycemia state caused by DM retinopathy (DR) is one of ocular already caused multiple dysfunction complications caused by DM, and on celullar level before DR could be constitute as one of the major cause of detected clinically. Glial cell vision impairment and blindness reactivity, increased extracellular 2

glutamate level, oxidative stress, manifestations of DR from the chronic renin-angiotensin system induction, disease management program upregulation of Advanced Glycation (Prolanis) in primary health care Endproducts (AGEs), increased of pro facilities within Bandung area who are apoptotic factors coupled with willing to take part in this study were imbalance of retinal neuroprotective examined further at the National Eye factor production all contribute to Center, Cicendo Eye Hospital. This retinal neurodegenerative state study was conducted from January through apoptosis induction.5–8 until March 2020. Apoptosis of retinal ganglion cells Inclusion criteria in this study were could manifest on thinning of ganglion patients with type II DM without cell layer and Retina Nerve Fiber clinical manifestations of DR, aged Layer (RNFL).8,9 Various studies 40-60 years old, and have best regarding the measurement of retinal corrected 6/6. The layer thickness in DM patients without exclusion criteria were intraocular clinical manifestations of DR to date pressure > 21 mmHg, any refractive mention different results.10–15 media opacity, presence of any other Contrast sensitivity is known to be retinal or ocular disease, history of any caused by physiological response of ocular surgery or procedure, ganglion cells. Loss of ganglion cells uncontrolled hypertension, any due to apoptosis accompanied by medication history that can cause dysfunction of the surviving ganglion ocular toxicity such as ethambuthol, cells cause deficits in ganglion cell and Optical Coherence Tomography function that can be detected clinically (OCT) imaging with signal strength 5 through decreased contrast sensitivity. or less. Reduction of contrast sensitivity could After sample size calculation, the manifest early, even in people with number of sample needed in this study normal visual acuity. There is still was 47 eyes. Sample selection was controversy about the spatial done based on consecutive admission frequency on contrast sensitivity that until the required sample size was is affected by DM.16–18 obtained. This study aims to detect positive correlation between ganglion cell layer and Retina Nerve Fiber Layer (RNFL) thickness in relation to contrast sensitivity. Knowing the relationship between contrast sensitivity and the thickness of ganglion cell layer and RNFL are expected to help early detection of retinal disorders in DM patients before diabetic retinopathy manifestations arise.

METHODS This study uses cross-sectional Picture 1. Contrast Sensitivity Test method. DM patients without clinical CSV-1000

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Patients examination begins with identify the circle that has was history taking to collect patients recorded as the log contrast sensitivity identity and history. Visual acuity and that the patient had at each spatial refractive correction were carried out frequency. Ganglion cell thickness using Snellen chart 6 m apart. Patient was measured using Ganglion Cell then underwent intraocular pressure Analysis (GCA) mode from macular measurement using non contact cube scan. This analysis measure the tonometry and anterior segment sum of ganglion cell layer and inner examination using slit-lamp plexiform layer thickness. RNFL biomicroscopy. Contrast sensitivity thickness analysis was acquired by was performed using CSV-1000 chart Optic Nerve Head (ONH) and RNFL (VectorVision). OCT imaging was analysis mode from optic disc cube carried out using Cirrus HD-OCT scan. 5000 (Carl Zeiss Meditec). Linear regression analysis was For contrast sensitivity carried out to evaluate correlation examination, patient was seated with between ganglion cell layer and RNFL applied best corrected visual acuity, thickness in relation to contrast 2.5 meter from the chart. Chart retro- sensitivity. The data obtained was illumination must be turned on during processed using Microsoft Excel and examination. Examination was carried SPSS version 24.0. The data will be out one by one on each eye, and on presented in the form of tables and every spatial frequency consecutively, graph. starting from 3 cpd or line A, to 6, 12, then 18 cpd, or line B, C, then D. RESULT Sample patch on every spatial A total of 47 eyes from 32 DM frequency was first revealed to the patients without DR who met the patient, then the patient was asked to inclusion criteria and did not have an identify circle patch on each column exclusion category were included in which contain . Three choice this study. were given to the patient, was the patch that contain gratings located in Table 2. Subject Characteristics the upper or lower line, or neither had Variable N=32 Age (years) gratings. Median 53.00 Range (min-max) 42.00-60.00 Table 1. Scoring System for CSV-1000 LogCS Gender Patch A B C D Male 7 (21.87%) 3 cpd 6 cpd 12 cpd 18 cpd Female 25 (78.12%) 0 0,70 0,91 0,61 0,17 1 1,00 1,21 0,91 0,47 DM Duration (years) 2 1,17 1,38 1,08 0,64 Median 5.00 3 1,34 1,55 1,25 0,81 Range (min-max) 1.00-11.00 4 1,49 1,70 1,40 0,96 5 1,63 1,84 1,54 1,10 6 1,78 1,99 1,69 1,25 The mean age in this study was 7 1,93 2,14 1,84 1,40 52.28±5.136 years. Total people with DM included in this study was 32, Contrast sensitivity value in the last consisted of 7 male (21.87%) and 25 column which the patient can correctly female (78.12%). The mean DM 4

duration in this study was 5.62±2.558 significant (p < 0.005). This mean years. 47 eyes which met the inclusion linear regression analysis models criteria underwent contrast sensitivity between these variable were feasible measurement and OCT imaging. Table to use. The linear regression equation 3 provides the clinical picture of was as follows : Y = ɑ + bX. Contrast contrast sensitivity and OCT imaging sensitivity on spatial frequency 6 and results of the eyes. 18 cpd can be calculated based constant value (ɑ) with regression Table 3. Clinical Characteristics coefficient (b) in Table 4 and Table 5 Variable N=47 and known ganglion cell layer or (eyes) Contrast Sensitivity 3 cpd (logCS) RNFL thickness value. Mean ± Standard Deviation 1.34±0.236

Contrast Sensitivity 6 cpd (logCS) Table 5. Linear Regression Analysis Result Mean ± Standard Deviation 1.54±0.339 Between RNFL Thickness (X) and Contrast Sensitivity (Y) Contrast Sensitivity 12 cpd (logCS) Variable P value ɑ b R2 Mean ± Standard Deviation 1.24±0.307 Contrast 0.007 Sensitivity 3 0.576 1.532 -0.002 Contrast Sensitivity 18 cpd (logCS) cpd Mean ± Standard Deviation 0.81±0.311 Contrast 0.836 Sensitivity 6 0.000* -1.551 0.032 Ganglion Cell Thickness (µm) cpd Mean ± Standard Deviation 82.17±7.963 Contrast 0.030 Sensitivity 12 0.245 1.766 -0.005 RNFL Thickness (µm) cpd Mean ± Standard Deviation 98.09±9.833 Contrast 0.614 Sensitivity 18 0.000* -1.621 0.025 cpd The data was then analyzed using Note : ɑ = constant value, b = regression coefficient, simple linear regression to provide * p < 0.05 information on association between ganglion cell layer and RNFL Regression coefficient between thickness in relation to contrast ganglion cell layer thickness and sensitivity. contrast sensitivity on 6 and 18 cpd both had positive value (b = 0.016 & Table 4. Linear Regression Analysis Result 0.019). Regression coefficient Between Ganglion Cell Layer Thickness between RNFL thickness and contrast (X) and Contrast Sensitivity (Y) Variable P value ɑ b R2 sensitivity on 6 and 18 cpd also both Contrast 0.682 1.485 -0.002 0.004 yield positive value (b = 0.032 & Sensitivity 3 cpd Contrast 0.008* 0.210 0.016 0.145 0.025). The positive regression Sensitivity 6 cpd coefficient value indicates that if the Contrast 0.932 1.277 0.000 0.000 Sensitivity 12 cpd thickness value of ganglion cell layer Contrast 0.000* -0.782 0.019 0.247 or RNFL gets lower, the lower contrast Sensitivity 18 cpd sensitivity value will be, and vice Note : ɑ = constant value, b = regression coefficient, * p < 0.05 versa. The association between these variables can be seen in the graph at According to reliability analysis, Picture 2. the linear regression model between Determination coefficient gives ganglion cell layer, RNFL thickness projection of the independent variable, and contrast sensitivity on spatial or the thickness of the ganglion and frequency 6 cpd and 18 cpd were RNFL cell layers ability in explaining 5

the dependent variable, or contrast 2.10% and 6.10%, whilst the sensitivity. The determination determination coefficient of RNFL coefficient can be calculated from R2 thickness variable against contrast value. The determination coefficient sensitivity variable at 6 cpd and 18 cpd of ganglion cell layer thickness were 69.89% and 37.70%. variable against contrast sensitivity variable at 6 cpd and 18 cpd were

(A) (B)

(C) (D) Picture 2. Graph showing association between ganglion cell layer thickness and contrast sensitivity on spatial frequency 6 cpd (A) as well as 18 cpd (B), along with association between RNFL thickness and contrast sensitivity on spatial frequency 6 cpd (C) also 18 cpd (D)

DISCUSSION micrometer. Zeiss Cirrus HD-OCT Data characteristics in this study 5000 asian normative database showed comprising of age, sex, and duration of average thickness on ganglion cell DM since first diagnosed based on the analysis mode was 83.2±5.3 history taking. This study had 25 micrometer. Mean ganglion cell layer female subjects (78.12%), or more thickness in this study was found to be female subjects compared to male. thinner than the asian normative Mean age in this study was 52.28 ± database. Previous studies by Borooah 5.136 years. The subject et al and by Chhablani et al yield characteristics in this study match DM similar result, the ganglion cell layer characteristics in Indonesia as reported were found to be significantly thinner by 2018th Riskesdas. The Riskesdas in DM patients without DR compared study showed most of DM patients in to normal population.6,13,20 Indonesia were female, aged 55-64 The mean RNFL thickness found in years old.19 this study was 98.09±9.833 Mean ganglion cell layer thickness micrometer. A study by Knight et al found in this study was 82.17±7.963 showed mean RNFL thickness in asian 6

race as measured using Cirrus HD- sensitivity in mild non-proliferative OCT 5000 was 96.4±1.1 micrometer. DR patients compared to DM patients Our study found thinner mean without DR on spatial frequency 6, 12 ganglion cell layer compared to and 18 cpd, but not on 3 cpd. Previous normative population database, but not study on optic neuritis also with RNFL thickness. Zhu et al found demonstrated that loss of contrast the decreased of ganglion cell layer sensitivity could happen in many thickness occurred earlier than RNFL ways, rarely including regional loss on thickness in DM patients without DR. certain spatial frequency.25–27 Earlier reduction of ganglion cell layer Human capabilities on judging might be attributable to ganglion cell contrast sensitivity at each spatial body apoptosis induced by frequency generally increases from hyperglycemia in DM, also higher very low spatial frequency up to 6 cpd, metabolic demand in macula and then decreases from spatial area.9,21,22 frequency above 6 cpd. The visual Regression coefficients between system is known to selectively lose ganglion cell layer thickness, RNFL contrast sensitivity at high spatial thickness and contrast sensitivity on frequencies. This decrease in contrast spatial frequency 6 and 18 cpd all had sensitivity can be influenced by optical positive value. The positive regression or neuronal system.27,28 coefficient value indicates that if the The discrepancy of contrast thickness value of ganglion cell layer sensitivity reduction on various spatial or RNFL gets lower, the lower contrast frequency found in different studies sensitivity value will be, and vice can also be influenced by research versa. Human contrast sensitivity were method and contrast sensitivity chart known to be closely affected by that being used. The most commonly ganglion cell physiologic response.17 used contrast sensitivity tests with All of the association found in this gratings are CSV-1000 and FACT study between ganglion cell and chart. Each chart has it is own RNFL layer with contrast sensitivity advantages and disadvantages. CSV- were found on spatial frequency 6 and 1000 has retro-illumination system 18 cpd, or on low-intermediate and that guarantee equal illumination on high spatial frequency. the entire chart surface. This chart also To date, there is still controversy had a wide range of logCS value in about the spatial frequency on contrast each spatial frequency.29–31 sensitivity that is affected by DM. The ability of one contrast Studies by Safi et al and Zhu et al sensitivity test to describe the quality found that DM without DM could of vision depends on its accuracy. impaired contrast sensitivty in all Accuracy is the result of validity and spatial frequency.23,24 A study by reliability tests measurements. Heravian et al using CSV-1000 Pomerance et al found a good test- showed DM patients without DR had retest reliability for CSV-1000 in decreased contrast sensitivity in all patients. CSV-1000 spatial frequency 3, 6, and 18 cpd, but reliability was stated to be better than not in 12 cpd. Beszédesová et al found the Pelli-Robson test or other grating significant impairment of contrast test such as Vistech. Richman et al also 7

found that among other grating tests namely older age and higher systolic such as Vistech and FACT, the CSV- blood pressure.25 RNFL thickness 1000 had the best reliability. A study variable could explain the variance of by Kelly et al which aims to determine contrast sensitivity at 6 cpd as much as the reliability of the CSV-1000 in 69.89%, or in other words, this study people with normal vision found that shows great influence of RNFL the CSV-1000 reliability is not as good thickness on contrast sensitivity value as those found by Pomerance et al. at low-intermediate spatial frequency. This study also assessed the reliabilty The human ability to perceive contrast at each spatial frequency, and found is the result of complex mechanism the best reliability score at 6 and 18 from various cell types and layers in cpd.32–34 the retina, that currently combined by According to coefficient OCT machines into a single layer. determination calculation, the ability Human consist of of ganglion cell thickness variable in multiple channels that respond and describing the variance of contrast transmit different spatial frequencies. sensitivity at 6 and 18 cpd were 2.10% Receptive area, on-off system, and and 6.10% respectively. In the all are physiological meantime, the RNFL thickness mechanism that may contribute ro variable could explain the variance of different spatial frequency channels. contrast sensitivity at 6 and 18 cpd as Various ganglion cell types that the much as 69.89% and 37.70%. human had are known to contribute to Other factors that could contribute different visual channels, such as M to contrast sensitivity include and P ganglion cells, also central refractive media opacity, other retinal “ON” and central “OF” ganglion cells. and optic nerve abnormalities, M ganglion cells are known to have glaucoma, and high refractive error.17 a greater receptive area compared to P This study has excluded refractive ganglion cells. Low spatial frequency media opacity, other retinal will stimulate neurons with large anormalities, high intraocular receptive areas, and high spatial pressure, and also myopia above 6 frequencies will stimulate neurons dioptre. Other factors that has the with smaller receptive areas. The capability to affect contrast sensitivity human retina consist of more M include variance in pupil diameter, ganglion cells in the periphery and P vitreous body consistency, ganglion cells in the macular examination room illumination level, area.17,28,36–38 and presence of glare.17,35 This study One of the limititations in this study has attempted to control the uniform is utilization of consecutive sampling room illumination state by performing technique, therefore the subjects were a contrast sensitivity test in the same not randomized. Several other factors dim room between patients, and that are known to affect contrast control glare by providing room sensitivity may also contribute to the for 20 minutes before the obtained results. The data collection in examination. Previous study also this study was also only carried out in found several risk factors that affect one visit, so it may not be able to contrast sensitivity in DM patients, maximally provide the information on 8

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