International Journal of Retina (IJRETINA) 2025.
Volume 8.
Number 1.
P-ISSN.
E-ISSN.
RETINAL NERVE FIBER LAYER THICKNESS ASSOCIATED WITH
SEVERITY OF DIABETIC PERIPHERAL NEUROPATHY
IN DIABETES MELLITUS TYPE 2
Mutiara Kristiani Putri1.
Muhammad Arfan1.
Herisa Rahmasari1.
Nadia Artha Dewi1.
Rulli Rosandi2.
Shahdevi Nandar Kurniawan3 Department of Ophthalmology.
Faculty of Medicine Universitas Brawijaya.
Indonesia Department of Internal Medicine.
Faculty of Medicine Universitas Brawijaya.
Indonesia Department of Neurology.
Faculty of Medicine Universitas Brawijaya.
Indonesia Abstract Introduction: To identify whether the Retinal Nerve Fiber Layer is useful in detecting severity of peripheral neurodegeneration in diabetic patients Methods: A cross-sectional study was conducted.
36 people were enrolled in this study which is divided into two groups.
18 people with type 2 diabetes mellitus (DM) with Diabetic Peripheral Neuropathy (DPN) and 18 people with type 2 DM non-DPN.
All subjects were 40-60 years old, and the best corrected visual acuity was better than 0,2 logMAR.
An Optical Coherence Tomography (OCT) examination was carried out to determine the Retinal Nerve Fiber Layer (RNFL) thickness, an Electroneuromyography (ENMG) examination and DNS-Ina Score was applied to establish a diagnosis of DPN.
Data were analyzed with independent T-test and Spearman correlation analysis.
Results: The average RNFL thickness in the DM with DPN was thinner than the RNFL thickness in the DM non-DPN group .
22 A 38.
61A9.
At temporal quadrant and nasal quadrant.
RNFL was also thinner in DM DPN group than DM non-DPN group .
78A12.
21, vs 76.
A 8.
53, p 0.
11A11.
38 vs 77.
39 A 14, p 0.
Sural and tibial amplitude .
44A2.
87 and 85A 4.
, were the most significant predictor values in determining the severity of DPN .
=0.
Average, temporal, and nasal RNFL thinning has an inverse association with DPN severity .
=-0,285.
-0,258.
and -0,.
Conclusion: RNFL was thinner at average, temporal, nasal quadrant in the DM group with DPN compared to DM non-DPN group.
RNFL thickness has an inverse association with the severity of the DPN although they were not statistically significant.
Keywords: Diabetes Mellitus.
Diabetic Peripheral Neuropathy.
Retinal Nerve Fiber Layer Cite This Article: PUTRI.
Mutiara Kristiani et al.
RETINAL NERVE FIBER LAYER THICKNESS ASSOCIATED WITH SEVERITY OF DIABETIC
PERIPHERAL NEUROPATHY IN DIABETES MELLITUS TYPE 2.
International Journal of Retina, [S.
], v.
8, n.
1, p.
ISSN 2614-8536.
Available at: <https://w.
com/index.
php/ijretina/article/view/320>.
Date accessed: 05 mar.
doi: https://doi.
org/10.
35479/ijretina.
Published by: INAVRS https://w.
org/ | International Journal of Retina https://ijretina.
with this condition, but several recent studies have INTRODUCTION Correspondence to:
Mutiara Kristiani Putri.
Universitas Brawijaya.
Indonesia, mutiarakristianiputri@gmail.
Diabetes Mellitus long-term hyperglycemia caused by insulin insufficiency or Diabetes Mellitus more common over the world.
According to the International Diabetes Federation (IDF), there will be 415 million diabetes patients globally in 2015.
2017, there were 10.
3 million Diabetes Mellitus in Indonesia, with a projected increase to 7 million by 2045.
Diabetes is known to produce a retinopathy, neuropathy, and nephropathy 1,2 Diabetic retinopathy is a discovered evidence that neuronal changes occur prior to clinical vascular abnormalities.
It is also stated that peripheral neuropathy can cause changes in the thickness of the retinal nerve fiber layer (RNFL).
This can happened even before the retina suffers microvascular injury.
The retinal nerve fiber layer (RNFL) may be one of the objective indicators of a neurodegenerative state similar to that occurring in patients with diabetic peripheral neuropathy based on this evidence, which suggests that thinning of the RNFL occurs prior to vascular changes.
This study also explores the understanding of the underlying pathophysiological relationship between these two relationship between diabetic retinopathy and diabetic peripheral neuropathy.
Therefore, the complication of the eye caused by the most frequent purpose of this study was to determine the type of diabetes mellitus.
this complication can relationship between retinal nerve fiber layer result in permanent vision loss.
Diabetic retinopathy thickness and the severity of diabetic peripheral is a known cause of blindness in persons of working neuropathy in type 2 diabetes mellitus patients According to statistics, 93 million individuals worldwide suffer from diabetic retinopathy, with the number expected to rise to 224 million by 2040.
Early components in the prevention and treatment of this 3 Diabetic peripheral neuropathy (DPN) is METHODS A cross-sectional study was used in this study.
The data for this study Endocrinology, was collected from the Neurology.
Ophthalmology Polyclinics at Dr.
Saiful Anwar General Hospital from March to December 2022.
The participants in this another microvascular consequence that affects study were Type 2 Diabetes Mellitus outpatients at 30-50% of diabetic patients.
It is caused by the Endocrinology and Neurology polyclinic of Dr.
Saiful Anwar General Hospital (Diagnosed by which causes nerve ischemia.
Diabetes.
The Retinal endocrinologist with HbA1c > 6.
5%).
All patients are Nerve Fiber Layer (RNFL) can be assessed using 40-60 years old age, no other ocular or systemic Optical Coherence Tomography (OCT), which is disease detected that can caused retinopathy and impacted by diabetes and is associated with the other caused of peripheral neuropathy.
According to development of Diabetic Peripheral Neuropathy the estimation results, this study is more appropriate (DPN).
to use the Lemeshow formula, which is adjusted to The relationship between these two issues is particularly important for various reasons, including pathophysiological and clinical involvement.
Many studies have focused on vascular changes associated the study design and no treatment is performed in each group, so that a minimum number of samples is obtained in each group.
The sample in both groups (DM with and without DPN) was 18.
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The Diabetic Peripheral Neuropathy group and the inferior quadrant, 76.
33 micrometers in the temporal group without Diabetic Peripheral Neuropathy are quadrant, and 77.
39 micrometers in the nasal The The average RNFL thickness in DM patients independent variable of this study is the thickness of with DPN was 100.
22 micrometers for each quadrant, the retinal nerve fiber layer.
Retinal Nerve Fiber Layer particularly the superior quadrant was 125.
Thickness was examined using OCT ( Cirrus 5000, micrometers, the inferior was 128.
28 micrometers.
Carl Zeiss Meditec.
Jena.
German.
DPN was the temporal was 71.
78 micrometers, and the nasal diagnosed by neurologist with Electro Neuro 11 micrometers.
Myography (USA Cadwell Sierra Summit ENMG) and DNS-Ina Questioner.
The severity of DPN using Consensus Development Conference of Standardized Measured in Diabetic Neuropathy.
Ethics of Health Study RSUD Dr.
Saiful Anwar Malang Number In the nerve conduction study, the sural nerve amplitude (SNAP) was found to be 17.
66 microvolts in the DM group without DPN and 5.
72 microvolts in the DM group with DPN.
The distal sural latency was 400/107/K.
3/302/2021 was given.
found to be 0.
87 ms in the non-DPN DM group and RESULTS conduction was found to be 113.
72 m/s in the DM 37 ms in the DM group with DPN.
The sural nerve The DM group with DPN had a greater mean age group without DPN and 104.
72 m/s.
The amplitude than the DM group without DPN .
years and 48 of the tibial nerve (CMAP) was measured in the DM years, respectivel.
The average HbA1C in DM group without DPN to be 13.
07 microvolts and 6.
patients with DPN was 8.
47, whereas the average microvolts in the DM group with DPN, the distal HbA1C in DM patients without DPN was 8.
Visual tibial latency in the DM group without DPN was 4.
acuity was variable in the DM without DPN group, ms and 4.
96 ms in the DM group with DPN, while with an average visual acuity of 0.
19 logMAR and 0.
the tibial nerve conduction velocity in the DM group logMAR in the DM with DPN group.
DM patients without DPN was 57.
22 m/s and 47.
11 m/s in the DM without DPN had an average RNFL of 102.
group with DPN.
Table 1 shows the descriptive data of micrometers, with 122.
22 micrometers the respondents.
quadrant, 123.
50 micrometers in the Table 1.
Data distribution 95% CI
Variable Group
Mean
DM non DPN
DM DPN
DM non DPN
Lower
Bound
Upper
Bound
Minimum
Maximum
DM DPN
DM non DPN
DM DPN
Visual Acuity DM non DPN Published by: INAVRS https://w.
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Age
HbA1c
Duration DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
Sural amplitudo
DM non DPN
DM DPN
Sural distal
DM non DPN
DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
DM non DPN
DM DPN
RNFL (Averag.
RNFL (Superio.
RNFL (Inferio.
RNFL (Tempora.
RNFL (Nasa.
Sural conduction velocity .
Tibia amplitudo .
Tibia distal latency .
Tibia conduction velocity .
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Furthermore, in this study, the gender distribution that the data utilized has a normally distributed in the DM group with DPN was 8 males .
67%) and distribution, so the correlation test used parametric 10 females .
56%), whereas the DM group without statistics, specifically the Independent T Test.
DPN was 12 males .
67%) and 6 females .
33%).
Whereas the p value for visual acuity variables, distal With a total of 20 men .
6%) and 16 women sural delay, and tibial conduction velocity is 0.
The .
4%).
Table 2 shows the results of a thickness comparison test between DM with DPN and DM assessment using the RNFL and ENMG to estimate without DPN employs nonparametric statistics, the amplitude, latency, and conduction velocity .
particularly the Mann Whitney test and Spearman's of both sensory and motor nerves.
The normality test Table 3 shows the results of the results for Age.
HbA1c.
Duration, and RNFL comparison test for each variable.
ENMG parameters had a p value > 0.
05, indicating Table 2.
Respondents Characteristic Variable Groups DM non DPN
Characteristic Female Male
Female Male
Mild
Moderate Severe Gender
DM DPN
DM non DPN
DNS score
DM DPN
Severity DM DPN Published by: INAVRS https://w.
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Table 3.
Comparison Test in Variables Groups (MeanAS.
Variable DM DPNv.
DM non DPNv.
Age 88A6.
66A5.
HbA1c 22A1.
47A1.
Score 00A0.
0A1.
000 *mw Duration 47A2.
97A2.
Visual acuity 19A0.
010 *mw Sural amplitudo .
66A6.
44A20.
Sural distal latency .
87A0.
37A1.
Sural conduction velocity .
72A43.
72A48.
Tibia amplitudo .
07A3.
85A4.
Tibia distal latency .
79A1.
96A1.
Tibia conduction velocity .
22A4.
11A18.
*p<0,05 .
tatistically significan.
mw= mann whitney There are significant differences in age.
DNS score, visual acuity, sural amplitude, tibia amplitude, and tibia conduction velocity, as shown in Table 3.
While the average RNFL, superior RNFL, inferior RNFL, temporal RNFL, and nasal RNFL results in both groups were negligible .
>0.
, they are summarized in Table 4.
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Figure 1.
RNFL thickness in DM with and without DPN Table 5.
Correlation between the severity of DPN with RNFL thickness SeverityIeAverage RNFL
SeverityIeSuperior RNFL
SeverityIeInferior RNFL
0,427
SeverityIeTemporal RNFL SeverityIeNasal RNFL Because the correlation test for all types of RNFL had a p-value more than 0.
05, it can be to the gender distribution, there were 12 men relationship between the severity of DPN and the and 6 women in the DM without DPN group and thickness of RNFL.
Likewise, age.
HbA1C, and 8 men and 10 women in the DM with DPN duration all exhibited p values more than 0.
Women were shown to have increased neuropathic pain, paresthesias, and loss of Total of 36 samples were obtained.
According DISCUSSION relationship between age.
HbA1C, duration, and sensation in the lower extremities.
RNFL thickness.
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There was a disparity in the number of gender edema and elevated extracellular fluid levels.
5,13,14
comparisons in this study because the samples were According to previous study, the neurodegenerative taken based on inclusion criteria that excluded the proportion of gender.
Gender impacts RNFL thickness is primary due to DM and secondary as an thickness, according to study journals, where it is Edema and increasing extracellular fluid discovered that RNFL thickness in women is thicker levels cause damage to the blood retinal barrier and, than RNFL thickness in males, which is impacted by as a result, to the retinal ganglion.
15 In diabetic the hormone estrogen, which has a protective effect neuropathy, metabolic abnormalities and oxidative on RNFL thickness.
Because estrogen administration stress cause the beginning and progression of nerve preserves RGC and RNFL, the neuroprotective effect 16 The polyol pathway's metabolism is the of estrogen is thought to be mediated via estrogen receptors on Retinal Ganglion Cells (RGC) in animal Postmenopausal women who received estrogen hormone therapy had thicker RNFLs than women who did not get indicating that estrogen exposure can protect the RNFL and slow the aging process of the optic nerve.
6,7,8
The average age of the women in this study was 8 whereas Suryana et al discovered that the average age of menopause for Indonesian women was 50 years, implying that the average sample from this study would enter menopause.
9 The difference on ganglion cell and RNFL main pathway that connects diabetes mellitus to diabetic peripheral neuropathy.
aldose reductase is predominantly found in Schwann cells in peripheral nerves, indicating that the polyol pathway is the main route of diabetic peripheral neuropathy Furthermore, reactive oxygen species (ROS) created by the cytosol will cause mitochondrial overactivation, which will work in the hexosamine pathway.
The dynamics of mitochondrial function alterations may possibly contribute to the neurodegenerative process of diabetic peripheral neuropathy.
Nerve conduction in RNFL thickness between men and women can be considered to be 1 micrometer, and some study amplitude, increased latency, and a decrease in claim that men have an RNFL thickness of 0.
nerve conduction velocity.
Neurodegeneration is micrometers when compared to women.
The thought to occur not just in the peripheral nerves, average RNFL thickness was found to be lower in but also in the central nervous system.
There was a the DM group with DPN when compared to the DM substantial difference in lengthening the latency group without DPN, which is consistent with and decreasing the amplitude of N75-P100 on previous study by Buno et al and Srinivasan et al.
VEP assessment in recent studies.
which found a concentrated neuropathic effect in the peripapillary nerve fiber layer due to neuronal degeneration that occurs before microvascular
11,12
We assessed RNFL thickness in diabetes patients and controls, .
-60year.
The global thickness of RNFL was observed to be lower in the DM group with DPN.
According to Altman C and colleagues' study, diabetic retinopathy is a mix of microvascular anomalies and neurodegenerative effects on retinal ganglion cells.
According to study, the neurological effects of diabetes may occur before microvascular injury to the blood-retinal barrier and subsequent retinal ganglion injury as a result of 17,18 earlier study indicated global RNFL thinning when compared to the DM group with DPN and DM without DPN, albeit this was not statistically significant.
similar investigation.
Sohn EH and colleagues discovered that patients with diabetes but no diabetic retinopathy had thinner RNFL layers than Published by: INAVRS https://w.
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age-matched controls.
The study also found that thinning was observed over four years, and was occurring in the axon is higher, worsening the effects of the neurodegenerative disease.
independent of age, sex, and levels of glycosylated It can therefore be assumed that retinal nerve degeneration may precede the development of diabetic retinopathy.
19,20
This occurrence differs from a prior study by Bonifacio, who found thinning in the superior, inferior, and overall quadrants in the DM group with DPN but no difference in temporal quadrant RNFL thickness between the two groups.
When the RNFL thickness was examined by quadrant, it was discovered that the superior and inferior quadrants of the DM group with DPN had a greater thickness than the superior and inferior quadrant RNFL in the DM group without DPN.
Despite the fact that these two parameters are not statistically significant.
The difference in the Because few DM patients with DPN who had undergone cataract surgery and intraocular lens investigation, the visual acuity in the DM without DPN group in this study was significantly lower than that in the DM group with DPN and the average visual acuity with correction for the DM without DPN group was lower than that of the DM group with DPN because numerous patients in this group started to develop cataracts or lens clouding in the early or immature stages.
This is supported by study by Harding et al.
, which shows that peripheral neuropathy plays a separate role in the development of cataracts.
results of this study is that the density of the retinal A significant clinical aspect of DPN is the nerve fibers in each peripapillary area is different, so presence of neuronal atrophy, which happens several previous studies stated that RNFL thinning concurrently with axonal atrophy and causes also occurs in the superior and inferior quadrants damage to the axons.
This is supported by the and that the inner retinal layer is responsible for the overall retinal thickness.
The most likely cause of deficiencies include delayed nerve conduction, retinal thickness is damage to the blood-retinal decreased amplitude, and extended latency are The RNFL thickness in the peripapillary area brought on by the distal axon's atrophy.
changes more than the GCC thickness in the macular Uncontrolled hyperglycemia damages nerves by 21,22 Functional currently unidentified methods, increasing the activity of the polyol pathway by accumulating While the RNFL thickness of the temporal and sorbitol and fructose in them.
Along with this, there nasal quadrants of the DM with the DPN group was is a reduction in myo-inositol absorption, inhibition lower than the RNFL thickness of the temporal and nasal quadrants of the DM without the DPN group, retention, edema, swelling of the myelin, axoglial this was not statistically significant.
The findings in disjunction, and nerve degeneration.
It has been this study differ from previous studies in that RNFL hypothesized that diabetes may produce diabetic thickness decreased significantly in the superior and inferior quadrants while there was no difference in myelinopathy given the fact that conduction temporal RNFL thickness, 23 which may be due to the velocity, distal latency, and sural nerve amplitude in peripapillary area having higher axon density than diabetic patients all varied considerably by age and the macular area.
The progression of the disease in Although axonopathy was the primary DM patients with DPN varies widely and does not disease overall and one-third of the nerves follow a predictable pattern, and the risk of ischemia displayed demyelination, this finding also reflects Na /K -adenosine triphosphate with Na Published by: INAVRS https://w.
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results from clinical and pathological studies where straightforward instruments, simple to use, and both processes were documented.
26,17
The correlation between DNS and Children typically have a somewhat larger SNAP nerve conduction studies is significant, according amplitude due to their lower skin impedance.
to a study that compared various questionnaires Studies on nerve conduction show a little slowdown to detect complications of diabetic neuropathy.
after the age of 60.
A number of morphological and functional aspects of the peripheral nervous system are crucial in the early diagnosis of diabetic are significantly impacted by aging, including neuropathy, and they come to the conclusion muscle strength, sensory discrimination, autonomic that Type 2 Diabetes Mellitus response, and endoneural blood flow.
Aging also have electrophysiological changes indicative of has an impact on the peripheral nervous system's peripheral neuropathy prior to the clinical 27,28 Therefore, nerve conduction investigations The patients' manifestation of the condition.
Doctors can mean age in this study was 54.
89 years, which assist prevent long-term problems of diabetes suggests that the patient's age had no discernible mellitus, such as diabetic ulcers and amputations, impact on the SNAP amplitude values we found.
by early identifying peripheral neuropathy in 29,30 Type 2 Diabetes Mellitus patients.
electrophysiological properties.
Similar results were observed in the nerve In a recent study, it was discovered that when conduction velocity of the DPN group, which was the diagnosis of DPN is made, there is a discovered to have decreased in comparison to the DM group without DPN.
In line with study by ophthalmological results.
According to a number Sepat et al.
, 2020, subjects with diabetes of studies, diabetic peripheral neuropathy affects experienced a significant decrease in amplitude the thickness of the RNFL, which is made up of and nerve conduction velocity in the sural, the inner neural layer of ganglion cell axons median, and also ulnar nerves.
The decrease without myelin sheaths.
In this study, there was also occurred in the tibial nerve conduction RNFL, velocity parameter in DM with DPN.
Diabetes global/average thinning.
Although this difference related nutritional and metabolic alterations was not statistically significant overall, thicker that affect axoplasmic transport in peripheral RNFL was seen in the superior and inferior nerves and prevent distal axons from receiving quadrants in the DM group with DPN.
In contrast enough nutrition might result in abnormalities of to the study presented by Fawzy et al, where the these electrophysiological parameters, which superior quadrant is thinner than the other can lead to a process of neurodegeneration.
quadrants, this one does not.
35 In this study, it 31,32 Comparing the DNS score distribution was discovered that the HbA1c level had no between the DM with DPN group and the discernible impact on RNFL thickness in either the DM without DPN group, it was discovered that DM group with DPN or the DM group without the DM with DPN group had a higher DNS score DPN.
A similar study, proposed by Srinivasan et Depending on how severely the , also peripheral nerve fibers have been damaged, consistent with these findings.
11 The distribution clinical symptoms will vary.
33 The DNS and of Diabetic Peripheral Neuropathy severity in this DNE developed by Meijer were found to be study was imbalanced, with 3 DPN patients produced results that were broadly Published by: INAVRS https://w.
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having severe severity, 5 having moderate negative correlation between the severity of DPN severity, and 10 having mild severity.
The results and Retinal Nerve Fiber Layer Thickness, this of this study are in contrast to those of a study indicates the progression of the disease in DM done in 2019 by Nurlaela et al, which found that patients with DPN varies widely and does not follow most DPN damage at Dr.
Saiful Anwar Hospital is a predictable pattern, and the risk of ischemia severe severity.
This is because patients with occurring in the axon is higher, worsening the effects of the neurodegenerative disease.
Further macrovascular or other microvascular problems.
research with a proportional amount of sample in such as Diabetic Retinopathy.
Kidney Failure, each severity group is needed to get statistically Coronary Heart Disease.
Stroke, and others that signification correlative results.
Regular follow-up to will not be included in this study.
36 Early diabetes measure the retinal nerve fiber layer thickness is DPN retinopathy will see an increase in RNFL thickness volume first due to the rise in RNFL thickness on the superior and inferior.
This is supported by the theory of activation of microglia cells like Muller cells, where Diabetes induces hypertrophy and activation of Muller cells which will increase the secretion of cytokines and pro-inflammatory molecules from damaged cells to start the needed to look for progressivity thinning of RNFL and stronger correlation.
Thinning of RNFL in T2DM with DPN is an early change of anatomical structure in OCT examination.
This newness hopefully increases the awareness of diabetic retinopathy Multidisciplinary regular checks up, and comprehensive therapy is recommended to minimize further damage to Diabetes Mellitus.
regeneration process, manifesting as thickening of the RNFL in the initial phase and in the process axonal degeneration then the thickness of the RNFL will thin due to dysfunction of nerve fiber 37 In order to demonstrate clinically that neurodegenerative changes in the peripheral nerves are followed by structural changes of the RNFL, this study compares the thickness of the RNFL between groups of diabetic patients with DPN and DM patients without DPN before the development of diabetic retinopathy.
It also examines the relationship between the severity of DPN and RNFL thickness, which has not been Unfortunately unproportional amount of samples in T2DM with DPN Group 2 was limitation on this study.
REFERENCES