correlation between ganglion cell layer and retinal

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CORRELATION BETWEEN GANGLION CELL LAYER AND RETINAL NERVE FIBER LAYER THICKNESS WITH CONTRAST 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 Retina 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

Diabetes mellitus (DM) is one of the most common chronic illness found in the world. According to International Diabetes Federation (IDF) prediction, the number of people with DM in Indonesia will continue to increase from 9.1 million people in 2014 to 14.1 million in 2035.¹ Diabetic retinopathy (DR) is one of ocular complications caused by DM, and constitute as one of the major cause of vision impairment and blindness

worldwide. More than a third of people with DM have signs of diabetic retinopathy. The number of people with visual impairment attributable to DR also continue to increase, form 1.4 million people in 1990 to 2.6 million in 2015.^2–4

It is postulated that the hyperglycemia state caused by DM already caused multiple dysfunction on celullar level before DR could be detected clinically. Glial cell reactivity, increased extracellular

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glutamate level, oxidative stress, renin-angiotensin system induction, upregulation of Advanced Glycation Endproducts (AGEs), increased of pro apoptotic factors coupled with imbalance of retinal neuroprotective factor production all contribute to retinal neurodegenerative state through apoptosis induction.^5–8

Apoptosis of retinal ganglion cells could manifest on thinning of ganglion cell layer and Retina Nerve Fiber Layer (RNFL).^8,9 Various studies regarding the measurement of retinal layer thickness in DM patients without clinical manifestations of DR to date mention different results.^10–15

Contrast sensitivity is known to be caused by physiological response of ganglion cells. Loss of ganglion cells due to apoptosis accompanied by dysfunction of the surviving ganglion cells cause deficits in ganglion cell function that can be detected clinically through decreased contrast sensitivity.

Reduction of contrast sensitivity could manifest early, even in people with normal visual acuity. There is still controversy about the spatial frequency on contrast sensitivity that is affected by DM.^16–18

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 method. DM patients without clinical

manifestations of DR from the chronic disease management program (Prolanis) in primary health care facilities within Bandung area who are willing to take part in this study were examined further at the National Eye Center, Cicendo Eye Hospital. This study was conducted from January until March 2020.

Inclusion criteria in this study were patients with type II DM without clinical manifestations of DR, aged 40-60 years old, and have best corrected visual acuity 6/6. The exclusion criteria were intraocular pressure > 21 mmHg, any refractive media opacity, presence of any other retinal or ocular disease, history of any ocular surgery or procedure, uncontrolled hypertension, any medication history that can cause ocular toxicity such as ethambuthol, and Optical Coherence Tomography (OCT) imaging with signal strength 5 or less.

After sample size calculation, the number of sample needed in this study was 47 eyes. Sample selection was done based on consecutive admission until the required sample size was obtained.

Picture 1. Contrast Sensitivity Test CSV-1000

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Patients examination begins with history taking to collect patients identity and history. Visual acuity and refractive correction were carried out using Snellen chart 6 m apart. Patient then underwent intraocular pressure measurement using non contact tonometry and anterior segment examination using slit-lamp biomicroscopy. Contrast sensitivity was performed using CSV-1000 chart (VectorVision). OCT imaging was carried out using Cirrus HD-OCT 5000 (Carl Zeiss Meditec).

For contrast sensitivity examination, patient was seated with applied best corrected visual acuity, 2.5 meter from the chart. Chart retro- illumination must be turned on during examination. Examination was carried out one by one on each eye, and on every spatial frequency consecutively, starting from 3 cpd or line A, to 6, 12, then 18 cpd, or line B, C, then D.

Sample patch on every spatial frequency was first revealed to the patient, then the patient was asked to identify circle patch on each column which contain gratings. Three choice were given to the patient, was the patch that contain gratings located in the upper or lower line, or neither had gratings.

Table 1. Scoring System for CSV-1000 Patch

LogCS A

3 cpd B 6 cpd

C 12 cpd

D 18 cpd

0 0,70 0,91 0,61 0,17

1 1,00 1,21 0,91 0,47

2 1,17 1,38 1,08 0,64

3 1,34 1,55 1,25 0,81

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

7 1,93 2,14 1,84 1,40

Contrast sensitivity value in the last column which the patient can correctly

identify the circle that has grating was recorded as the log contrast sensitivity that the patient had at each spatial frequency. Ganglion cell thickness was measured using Ganglion Cell Analysis (GCA) mode from macular cube scan. This analysis measure the sum of ganglion cell layer and inner plexiform layer thickness. RNFL thickness analysis was acquired by Optic Nerve Head (ONH) and RNFL analysis mode from optic disc cube scan.

Linear regression analysis was carried out to evaluate correlation between ganglion cell layer and RNFL thickness in relation to contrast sensitivity. The data obtained was processed using Microsoft Excel and SPSS version 24.0. The data will be presented in the form of tables and graph.

RESULT

A total of 47 eyes from 32 DM patients without DR who met the inclusion criteria and did not have an exclusion category were included in this study.

Table 2. Subject Characteristics

Variable N=32

Age (years)

Median 53.00

Range (min-max) 42.00-60.00

Gender

Male 7 (21.87%)

Female 25 (78.12%)

DM Duration (years)

Median 5.00

Range (min-max) 1.00-11.00

The mean age in this study was 52.28±5.136 years. Total people with DM included in this study was 32, consisted of 7 male (21.87%) and 25 female (78.12%). The mean DM

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duration in this study was 5.62±2.558 years. 47 eyes which met the inclusion criteria underwent contrast sensitivity measurement and OCT imaging. Table 3 provides the clinical picture of contrast sensitivity and OCT imaging results of the eyes.

Table 3. Clinical Characteristics

Variable N=47

(eyes) Contrast Sensitivity 3 cpd (logCS)

Mean ± Standard Deviation 1.34±0.236 Contrast Sensitivity 6 cpd (logCS)

Mean ± Standard Deviation 0.81±0.311 Ganglion Cell Thickness (µm)

Mean ± Standard Deviation 82.17±7.963 RNFL Thickness (µm)

Mean ± Standard Deviation 98.09±9.833

The data was then analyzed using simple linear regression to provide information on association between ganglion cell layer and RNFL thickness in relation to contrast sensitivity.

Table 4. Linear Regression Analysis Result Between Ganglion Cell Layer Thickness (X) and Contrast Sensitivity (Y)

Variable P value ɑ b R²

Contrast Sensitivity 3 cpd

0.682 1.485 -0.002 0.004 Contrast

Sensitivity 6 cpd

0.008* 0.210 0.016 0.145 Contrast

Sensitivity 12 cpd

0.932 1.277 0.000 0.000 Contrast

Sensitivity 18 cpd

0.000* -0.782 0.019 0.247 Note : ɑ = constant value, b = regression coefficient,

* p < 0.05

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). This mean linear regression analysis models between these variable were feasible to use. The linear regression equation was as follows : Y = ɑ + bX. Contrast sensitivity on spatial frequency 6 and 18 cpd can be calculated based constant value (ɑ) with regression coefficient (b) in Table 4 and Table 5 and known ganglion cell layer or RNFL thickness value.

Table 5. Linear Regression Analysis Result Between RNFL Thickness (X) and Contrast Sensitivity (Y)

Variable P value ɑ b R²

0.576 1.532 -0.002 0.007

0.000* -1.551 0.032 0.836

0.245 1.766 -0.005 0.030

0.000* -1.621 0.025 0.614

Note : ɑ = constant value, b = regression coefficient,

* p < 0.05

Regression coefficient between ganglion cell layer thickness and contrast sensitivity on 6 and 18 cpd both had positive value (b = 0.016 &

0.019). Regression coefficient between RNFL thickness and contrast sensitivity on 6 and 18 cpd also both yield positive value (b = 0.032 &

0.025). The positive regression coefficient value indicates that if the thickness value of ganglion cell layer or RNFL gets lower, the lower contrast sensitivity value will be, and vice versa. The association between these variables can be seen in the graph at Picture 2.

Determination coefficient gives projection of the independent variable, or the thickness of the ganglion and RNFL cell layers ability in explaining

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

2.10% and 6.10%, whilst the determination coefficient of RNFL thickness variable against contrast sensitivity variable at 6 cpd and 18 cpd were 69.89% and 37.70%.

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(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

Data characteristics in this study comprising of age, sex, and duration of DM since first diagnosed based on the history taking. This study had 25 female subjects (78.12%), or more female subjects compared to male.

Mean age in this study was 52.28 ± 5.136 years. The subject characteristics in this study match DM characteristics in Indonesia as reported by 2018^th Riskesdas. The Riskesdas study showed most of DM patients in Indonesia were female, aged 55-64 years old.¹⁹

Mean ganglion cell layer thickness found in this study was 82.17±7.963

micrometer. Zeiss Cirrus HD-OCT 5000 asian normative database showed average thickness on ganglion cell analysis mode was 83.2±5.3 micrometer. Mean ganglion cell layer thickness in this study was found to be thinner than the asian normative database. Previous studies by Borooah et al and by Chhablani et al yield similar result, the ganglion cell layer were found to be significantly thinner in DM patients without DR compared to normal population.^6,13,20

The mean RNFL thickness found in this study was 98.09±9.833 micrometer. A study by Knight et al showed mean RNFL thickness in asian

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race as measured using Cirrus HD- OCT 5000 was 96.4±1.1 micrometer.

Our study found thinner mean ganglion cell layer compared to normative population database, but not with RNFL thickness. Zhu et al found the decreased of ganglion cell layer thickness occurred earlier than RNFL thickness in DM patients without DR.

Earlier reduction of ganglion cell layer might be attributable to ganglion cell body apoptosis induced by hyperglycemia in DM, also higher metabolic demand in macula area.^9,21,22

Regression coefficients between ganglion cell layer thickness, RNFL thickness and contrast sensitivity on spatial frequency 6 and 18 cpd all had positive value. The positive regression coefficient value indicates that if the thickness value of ganglion cell layer or RNFL gets lower, the lower contrast sensitivity value will be, and vice versa. Human contrast sensitivity were known to be closely affected by ganglion cell physiologic response.¹⁷ All of the association found in this study between ganglion cell and RNFL layer with contrast sensitivity were found on spatial frequency 6 and 18 cpd, or on low-intermediate and high spatial frequency.

To date, there is still controversy about the spatial frequency on contrast sensitivity that is affected by DM.

Studies by Safi et al and Zhu et al found that DM without DM could impaired contrast sensitivty in all spatial frequency.^23,24 A study by Heravian et al using CSV-1000 showed DM patients without DR had decreased contrast sensitivity in all spatial frequency 3, 6, and 18 cpd, but not in 12 cpd. Beszédesová et al found significant impairment of contrast

sensitivity in mild non-proliferative DR patients compared to DM patients without DR on spatial frequency 6, 12 and 18 cpd, but not on 3 cpd. Previous study on optic neuritis also demonstrated that loss of contrast sensitivity could happen in many ways, rarely including regional loss on certain spatial frequency.^25–27

Human capabilities on judging contrast sensitivity at each spatial frequency generally increases from very low spatial frequency up to 6 cpd, and then decreases from spatial frequency above 6 cpd. The visual system is known to selectively lose contrast sensitivity at high spatial frequencies. This decrease in contrast sensitivity can be influenced by optical or neuronal system.^27,28

The discrepancy of contrast sensitivity reduction on various spatial frequency found in different studies can also be influenced by research method and contrast sensitivity chart that being used. The most commonly used contrast sensitivity tests with gratings are CSV-1000 and FACT chart. Each chart has it is own advantages and disadvantages. CSV- 1000 has retro-illumination system that guarantee equal illumination on the entire chart surface. This chart also had a wide range of logCS value in each spatial frequency.^29–31

The ability of one contrast sensitivity test to describe the quality of vision depends on its accuracy.

Accuracy is the result of validity and reliability tests measurements.

Pomerance et al found a good test- retest reliability for CSV-1000 in glaucoma patients. CSV-1000 reliability was stated to be better than the Pelli-Robson test or other grating test such as Vistech. Richman et al also

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found that among other grating tests such as Vistech and FACT, the CSV- 1000 had the best reliability. A study by Kelly et al which aims to determine the reliability of the CSV-1000 in people with normal vision found that the CSV-1000 reliability is not as good as those found by Pomerance et al.

This study also assessed the reliabilty at each spatial frequency, and found the best reliability score at 6 and 18 cpd.^32–34

According to coefficient determination calculation, the ability of ganglion cell thickness variable in describing the variance of contrast sensitivity at 6 and 18 cpd were 2.10%

and 6.10% respectively. In the meantime, the RNFL thickness variable could explain the variance of contrast sensitivity at 6 and 18 cpd as much as 69.89% and 37.70%.

Other factors that could contribute to contrast sensitivity include refractive media opacity, other retinal and optic nerve abnormalities, glaucoma, and high refractive error.¹⁷ This study has excluded refractive media opacity, other retinal anormalities, high intraocular pressure, and also myopia above 6 dioptre. Other factors that has the capability to affect contrast sensitivity include variance in pupil diameter, vitreous body consistency, examination room illumination level, and presence of glare.^17,35 This study has attempted to control the uniform room illumination state by performing a contrast sensitivity test in the same dim room between patients, and control glare by providing room adaptation for 20 minutes before the examination. Previous study also found several risk factors that affect contrast sensitivity in DM patients,

namely older age and higher systolic blood pressure.²⁵ RNFL thickness variable could explain the variance of contrast sensitivity at 6 cpd as much as 69.89%, or in other words, this study shows great influence of RNFL thickness on contrast sensitivity value at low-intermediate spatial frequency.

The human ability to perceive contrast is the result of complex mechanism from various cell types and layers in the retina, that currently combined by OCT machines into a single layer.

Human visual system consist of multiple channels that respond and transmit different spatial frequencies.

Receptive area, on-off system, and lateral inhibition all are physiological mechanism that may contribute ro different spatial frequency channels.

Various ganglion cell types that the human had are known to contribute to different visual channels, such as M and P ganglion cells, also central

“ON” and central “OF” ganglion cells.

M ganglion cells are known to have a greater receptive area compared to P ganglion cells. Low spatial frequency will stimulate neurons with large receptive areas, and high spatial frequencies will stimulate neurons with smaller receptive areas. The human retina consist of more M ganglion cells in the periphery and P ganglion cells in the macular area.17,28,36–38

One of the limititations in this study is utilization of consecutive sampling technique, therefore the subjects were not randomized. Several other factors that are known to affect contrast sensitivity may also contribute to the obtained results. The data collection in this study was also only carried out in one visit, so it may not be able to maximally provide the information on

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progresivity of ganglion cell layer and RNFL thinning and their relation to contrast sensitivity.

CONCLUSION

Positive correlations were found between ganglion cell layer thickness in relation to contrast sensitivity on spatial frequency 6 cpd and 18 cpd.

Positive correlations were also found between RNFL thickness and contrast sensitivity on spatial frequency 6 cpd and 18 cpd.

Further study needs to be done with randomized sampling, and with periodic examination of ganglion cell layer and RNFL thickness alongside contrast sensitivity test to provide more excellent progressivity relationship between those variables.

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