Doc Ophthalmol DOI 10.1007/s10633-014-9447-9

ORIGINAL RESEARCH ARTICLE

Multifocal electroretinogram responses in Nepalese diabetic patients without retinopathy Prakash Adhikari • Subash Marasini • Raman Prasad Shah • Sagun Narayan Joshi Jeevan Kumar Shrestha



Received: 28 August 2013 / Accepted: 27 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose To determine neuroretinal function with multifocal electroretinogram (mfERG) in diabetic subjects without retinopathy. Methods Multifocal electroretinogram (mfERG) was performed in 18 eyes of 18 diabetic subjects without retinopathy and 17 eyes of 17 age and gendermatched healthy control participants. Among 18 diabetic subjects, two had type 1 and 16 had type 2 diabetes. MfERG responses were averaged by the retinal areas of six concentric rings and four quadrants, and 103 retinal locations; N1–P1 amplitude and P1implicit time were analysed. Results Average mfERG N1–P1 amplitude (in nv/deg2) of 103 retinal locations was 56.3 ± 17.2 (mean ± SD) in type 1 diabetic subjects, 47.2 ± 9.3 in type 2 diabetic subjects and 71.5 ± 12.7 in controls.

P. Adhikari (&) Visual Science and Medical Retina Laboratories, Institute of Health and Biomedical Innovation, School of Optometry and Vision Science, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4059, Australia e-mail: [email protected]

Average P1-implicit time (in ms) was 43.0 ± 1.3 in type 1 diabetic subjects, 43.9 ± 2.3 in type 2 diabetic subjects and 41.9 ± 2.1 in controls. There was significant reduction in average N1–P1 amplitude and delay in P1-implicit time in type 2 diabetic subjects in comparison to controls. mfERG amplitude did not show any significant correlation with diabetes duration and blood sugar level. However, implicit time showed a positive correlation with diabetes duration in type 2 diabetic subjects with diabetes duration C5 years. Conclusions This is the first study in a Nepalese population with diabetes using multifocal electroretinography. We present novel findings that mfERG N1–P1 amplitude is markedly reduced along with delay in P1implicit time in type 2 diabetic subjects without retinopathy. These findings indicate that there might be significant dysfunction of inner retina before the development of diabetic retinopathy in the study population, which have higher prevalence of diabetes than the global estimate and uncontrolled blood sugar level. Keywords Multifocal electroretinogram  Diabetes  Diabetic retinopathy  N1–P1 amplitude  P1-implicit time

S. Marasini Ajou University Neuroscience Postgraduate Program, Suwon, South Korea

Introduction

R. P. Shah  S. N. Joshi  J. K. Shrestha Eye Department, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal

The 2012 global estimate is that there are approximately 93 million people living with diabetic retinopathy (DR) and among them, 28 million are with vision-

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threatening DR [1]. Despite much research, there is still no effective treatment for saving vision in the late stages of DR [2]. The vision of many people with diabetes could be preserved, at least for a longer period, if the disease can be caught at early stage and treatment like better blood glucose control can be initiated. The visual function in diabetic patients may be disturbed even without any visible structural damage to the retina. Electrophysiological tests demonstrate abnormal results in diabetic patients without any ophthalmoscopic changes [3–7]. Many studies indicate that neural changes take place in the retina of a diabetic patient before vascular changes are apparent and these worsen as DR progresses [3–6]. Studies have shown that multifocal electroretinogram (mfERG) implicit time and amplitude are highly sensitive methods of assessment of local retinal function in diabetes; implicit time being early indicator of DR before amplitude is affected [7]. However, few studies on pattern ERG in diabetic patients report abnormal ERG responses in the presence of diabetic retinopathy only [8, 9] and normal or even supernormal amplitude in diabetic patients with nonproliferative DR [10]. Harrison et al. [11] recently determined that mfERG implicit time is a good predictor of diabetic retinopathy in retinas with no retinopathy. The potential of mfERG amplitude and implicit time to predict the retinal areas of future retinopathy provides clinicians an important clinical tool to screen, follow-up, and even consider early prophylactic treatment of DR [12] including protein tyrosine kinase pathway inhibitor [13], aspirin [14] and better metabolic control [15]. We were interested to measure neuroretinal function in Nepalese diabetic patients because a very high prevalence (14.6 % [16], 10.6 % [17]) of diabetes has been reported in this population in comparison to the global estimate (6.4 %) [18] owing to the lack of public awareness and poor medical services. This is the first study in diabetic population in Nepal using mfERG. It aims to compare mfERG responses (N1–P1 amplitude and P1-implicit time) in a diabetic population without DR to healthy control participants without diabetes and to correlate mfERG responses with diabetes duration and blood sugar level.

Subjects and methods The study was conducted over the duration of one year at a tertiary eye centre in Nepal, and purposive

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sampling method was applied to select subjects. The research adhered to the tenets of the Declaration of Helsinki and ethical clearance was obtained from the Research Ethics Committee of Tribhuvan University, Nepal. Informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. Subjects with known history of diabetes (type 1 and type 2) for at least 2 years, but without any DR according to ETDRS classification, were included in the study. Information about type and duration of diabetes was obtained by review of medical records of the subjects. Fasting blood sugar (FBS) was measured within 10 days of mfERG testing. Subjects with best corrected visual acuity (BCVA) worse than 6/9, with visible media opacity, with history of other ocular disease or surgery, with high degree of refractive error (spherical equivalent [6.00 DS of myopia and [5.00 DS of hyperopia) were excluded. Similar criteria were applied to select age and gender-matched controls without diabetes. All participants underwent complete ophthalmic evaluation including visual acuity testing with Bailey-Lovie Log MAR chart, anterior segment examination by slit lamp biomicroscopy, refraction, IOP measurement and dilated fundus examination before mfERG testing. Bailey-Lovie chart was used in place of more commonly used Snellen’s chart for more precise visual acuity measurement. The dilated fundus examination including the macula examination was performed with 20 D and 90 D Volk lens by two retina specialists (JKS and SNJ) who were masked to mfERG findings.

Multifocal electroretinogram Recording of the fast flicker mfERG was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines using RETISCAN SYSTEM (Roland Consult Electrophysiological Diagnostic System, Brandenburg, Germany). Pupils were fully dilated with 1 % tropicamide. One gold-cup electrode was used as ground (attached to the forehead) and two electrodes as reference (attached to the temple) after cleaning the skin with abrasive gel. After anaesthetizing the cornea with topical 4 % xylocaine, recording was performed with both eyes open by using contact lens electrodes (Jet electrode; LKC Technologies, Gaithersburg,

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Fig. 1 Multifocal electroretinogram (mfERG) plots showing different retinal rings (A) and quadrants (B). The rings are described in methods. ST superotemporal, IT inferotemporal, IN inferonasal and SN superonasal. The quadrants are demarcated by solid bold lines

MD), but for the purpose of analysis, the data of the right eye only were considered. The stimuli were displayed on a 2100 CRT monitor with the frame frequency of 75 Hz with RETISCAN software version 07/01 using a black-and-white pattern of 103 hexagons. Each hexagon was temporally modulated between black (\2 cd/m2) and white (120 cd/m2) with a contrast of 98 %, according to a pseudorandom binary m-sequence. The viewing distance was 28 cm which allowed a viewing angle of 30°. Presbyopic participants used appropriate correction if necessary for clear visualization of the fixation target. Occasional artefacts, such as blinks during the recording, were eliminated by the RETISCAN software and that part of the sequence was immediately repeated to record a new response free of artefacts. A standard m-sequence was recorded by dividing into eight short segments periods. MfERG N1–P1 amplitude was measured from the trough of the first negative wave (N1) to the peak of the first positive wave (P1), and P1implicit time was defined as the time at which the peak of P1 occurred [19]. Analysis of responses was done by regional averages derived from six concentric rings and four quadrants, and average response from all 103 hexagonal locations. The mfERG components were analysed among the studied cohorts along ring 1 (central hexagon, 5°), ring 2 (5°–10°), ring 3 (10°–15°), ring 4 (15°–20°), ring 5 (20°– 25°) and ring 6 (25°–30°); and superonasal (SN), inferonasal (IN), superotemporal (ST), and inferotemporal (IT) quadrants of retina (Fig. 1).

Statistical analysis SigmaPlot software package was used for data analysis. Data were described as mean ± SD and 95 % confidence interval; p \ 0.05 was considered statistically significant. Mean was used to describe data as the data distribution was symmetrical. Oneway repeated measures ANOVA (parametric test) was applied to compute the differences in the mfERG responses between the diabetic and control subjects as we assumed that our data were normally distributed. Post-hoc analysis was done with Holm-Sidak method for pairwise multiple comparisons of ERG responses in different rings and quadrants between patients and controls. The correlation of mfERG amplitude and implicit time with diabetes duration and blood sugar level was calculated with Pearson’s Correlation. Multiple linear regression analysis was used to determine if age, diabetes duration, and FBS would predict average N1–P1 amplitude and P1-implicit time in type 2 diabetes.

Results Multifocal electroretinogram (mfERG) data of 18 right eyes of 18 diabetic subjects without retinopathy and 17 right eyes of 17 age and gender-matched healthy control participants were considered for analysis. Two diabetic subjects had type 1 diabetes, and the remaining 16 had type 2 diabetes. The mean age of diabetic

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Fig. 2 Multifocal electroretinogram (mfERG) responses from 103 retinal locations of a diabetic patient (A) and a control subject (B). Note that amplitudes are greater in the control than in the diabetic subject in most of the locations

subjects was 49.1 ± 12.6 years and that of normal controls was 50.3 ± 14.0 years. Out of 16 type 2 diabetic subjects, 50 % (8) were male and 50 % (8) were female and out of 17 controls, 58.8 % (10) were male and 41.2 % (7) were female. The age (p = 0.145) and gender (p = 0.432) were not statistically different among study groups. In diabetic subjects, the mean duration of diabetes was 6.3 ± 4.0 years and the mean fasting blood glucose level was 154.4 ± 31.3 mg/dL (1 mg/dL = 0.0555 mmol/L). Multifocal ERG findings Type 2 diabetic subjects showed reduced average mfERG N1–P1 amplitude and delayed P1-implicit time in comparison to controls. The results are discussed in detail below. The statistics were calculated on type 2 diabetes, and control group only as the sample size (n = 2) for type 1 diabetes group was very small. MfERG amplitude in 103 retinal locations for a type 2 diabetic subject and a control subject is shown in Fig. 2. N1–P1 amplitude Average mfERG N1–P1 amplitude of all (103) hexagonal locations was 56.3 ± 17.2 and 47.2 ± 9.3 nv/deg2 in type 1 and type 2 diabetic subjects; and 71.5 ± 12.7 nv/deg2 in controls (Table 1). Average mfERG N1–P1 amplitude of 103 retinal locations was significantly reduced in type 2

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diabetic subjects compared to controls (p \ 0.001). We found that N1–P1 amplitude in various rings and quadrants of retina was significantly different between study groups (p \ 0.001). Post hoc analysis revealed that the reduction in amplitude was statistically significant in rings 1, 2, 3 and in IT quadrant in type 2 diabetic subjects. P1-implicit time Average mfERG P1-implicit time of 103 retinal locations was 43.0 ± 1.3 and 43.9 ± 2.3 ms in type 1 and type 2 diabetic subjects; and 41.9 ± 2.1 ms in controls (Table 2). Average P1-implicit time was significantly delayed in type 2 diabetic subjects compared to controls (p \ 0.010). Post-hoc analysis on comparing P1-implicit time in different rings and quadrants of retina showed that rings 1 and 6; and SN and IT quadrants only showed statistically significant delay in P1-implicit time in type 2 diabetic subjects compared to controls. Association of N1–P1 amplitude and P1-implicit time with diabetes duration and blood sugar level Pearson’s correlation was calculated to find the association of mfERG amplitude and implicit time with diabetes duration and blood sugar level in type 2 diabetes group (Table 3).

Doc Ophthalmol Table 1 Mean N1–P1 amplitudes (nV/deg2) for 6 rings and 4 quadrants of retina Area of retina

Type 1 diabetic subjects

Type 2 diabetic subjects

Controls

p value 

Ring 1

67.7 ± 19.3

87.7 ± 22.7

145.4 ± 47.9

\0.001

Ring 2

67.9 ± 28.9

62.5 ± 17.3

92.3 ± 11.2

\0.001

Ring 3 Ring 4

61.6 ± 33.0 56.9 ± 10.7

46.9 ± 12.3 35.2 ± 7.9

67.3 ± 12.3 49.8 ± 6.3

0.013 0.609

Ring 5

44.9 ± 6.0

26.7 ± 7.1

40.3 ± 7.8

0.835

Ring 6

39.1 ± 4.8

24.1 ± 7.1

33.7 ± 5.7

1.000

SN quadrant

46.8 ± 7.4

29.8 ± 6.9

47.9 ± 5.1

0.121

IN quadrant

45.1 ± 4.9

29.2 ± 8.4

47.3 ± 5.2

0.055

ST quadrant

49.0 ± 14.5

30.9 ± 9.0

47.3 ± 5.4

0.253

IT quadrant

47.8 ± 18.3

28.4 ± 8.9

47.6 ± 5.3

0.036

Average of 103 locations

56.3 ± 17.2

47.2 ± 9.3

71.5 ± 12.7

 

\0.001

Between type 2 diabetic subjects and controls

Table 2 Mean P1-implicit times (ms) for 6 rings and four quadrants of retina

Table 3 Correlation of P1-implicit time with diabetes duration in type 2 diabetic subjects

Area of retina

Areas of retina

Correlation (r)

Ring 1

0.210

0.435

Ring 2 Ring 3

0.113 0.538

0.676 0.032

Ring 4

0.396

\0.001

Ring 5

0.417

\0.001

Ring 6

0.355

\0.001

Type 1 diabetic subjects

Type 2 diabetic subjects

Controls

p value 

Ring 1

43.7 ± 3.5

45.7 ± 2.0

43.0 ± 2.5

0.001

Ring 2

42.7 ± 2.1

45.0 ± 2.2

42.0 ± 2.3

0.058

Ring 3

42.7 ± 2.1

44.2 ± 2.1

41.5 ± 1.9

0.986

Ring 4

42.2 ± 1.3

44.9 ± 1.8

41.8 ± 1.8

1.000

Ring 5

43.1 ± 0.0

44.6 ± 1.7

41.5 ± 2.5

0.453

Ring 6

43.6 ± 0.7

45.2 ± 1.4

41.3 ± 2.6

0.001

SN quadrant

43.1 ± 0.0

44.6 ± 1.6

41.5 ± 2.7

0.013

IN quadrant

43.2 ± 1.3

44.7 ± 1.4

41.5 ± 3.2

0.633

ST quadrant IT quadrant

43.6 ± 0.7 43.6 ± 0.7

44.8 ± 2.0 44.7 ± 2.0

41.4 ± 2.0 41.4 ± 3.2

0.248 0.002

Average of 103 locations

43.0 ± 1.3

43.9 ± 2.3

41.9 ± 2.1

0.010

 

Between type 2 diabetic subjects and controls

The subjects were divided into two subgroups; first with diabetes duration \5 years and second with diabetes duration C5 years (Figs. 3, 4). Average N1– P1 amplitude of 103 retinal locations showed a trend of decrease with increasing diabetes duration (r = -0.587, p = 0.075) (Fig. 3B) in the subjects with diabetes duration C5 years, but the association was not statistically significant. N1–P1 amplitude in retinal rings and quadrants showed similar, but not significant association with diabetes duration. The subjects with diabetes duration C5 years showed a significant

p value

SN quadrant

0.318

0.230

IN quadrant

0.507

0.045

ST quadrant

0.402

0.123

IT quadrant

0.422

0.104

Average of 103 locations

0.408

0.117

positive correlation (r = 0.856, p = 0.002) between P1-implicit time and diabetes duration (Fig. 3D). P1implicit time in retinal rings and quadrants showed a significant positive correlation with diabetes duration in ring 3, 4, 5 and 6; and IN quadrant (Table 3). Both average N1–P1 amplitude and P1-implicit time did not show any correlation with fasting blood sugar (Fig. 4). Multiple linear regression showed average N1–P1 amplitude can be predicted by the equations, ‘‘Amplitude = 15.99 ? 0.55 (Age) - 4.21 (Diabetes Duration) ? 0.10 (FBS)’’ for subjects with diabetes duration \5 years [R2 = 0.63, F(3,2) = 1.14, p = 0.498] and ‘‘Amplitude = 101.68 - 0.44 (Age) - 1.23 (Diabetes Duration) - 0.12 (FBS)’’ for subjects with diabetes duration C5 years [R2 = 0.68, F(3,6) = 4.33,

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Fig. 3 Correlation of average N1–P1 amplitude and average P1-implicit time with diabetes duration in type 2 diabetic subjects. Panel A and B show the correlation of amplitude with diabetes duration in subjects with diabetes duration \5 years

(triangles) and C5 years (squares). Panel C and D show the correlation of implicit time with diabetes duration in subjects with diabetes duration \5 years (triangles) and C5 years (squares)

Fig. 4 Correlation of average N1–P1 amplitude and average P1-implicit time with fasting blood sugar (FBS) in type 2 diabetic subjects. Panel A and B show the correlation of amplitude with FBS in subjects with diabetes duration \5 years

(triangles) and C5 years (squares). Panel C and D show the correlation of implicit time with FBS in subjects with diabetes duration \5 years (triangles) and C5 years (squares)

p = 0.060]. Average P1-implicit time can be predicted by the equations, ‘‘Implicit Time = 43.88 ? 0.002 (Age) ? 1.43 (Diabetes Duration) - 0.02 (FBS)’’ for subjects with diabetes duration \5 years [R2 = 0.47, F(3,2) = 0.609, p = 0.670] and ‘‘Implicit Time = 43.70 ? 0.02 (Age) ? 0.44 (Diabetes Duration) - 0.02 (FBS)’’ for subjects with diabetes duration C5 years [R2 = 0.91, F(3,6) = 19.58, p = 0.002]. The results of regression indicated that the effect of the variables was significant only on implicit time for subjects with diabetes duration C5 years and among the variables, diabetes duration and FBS had significant partial effects on the full model.

Multifocal electroretinogram (mfERG) has been shown to be capable of detecting the neural changes that occur in retina of diabetic patients before any vascular changes are visible. The results of the present study demonstrate on average reduced fast flicker mfERG N1–P1 amplitude and delayed P1-implicit time in type 2 diabetic patients without diabetic retinopathy in comparison to normal control participants. The results of the present study are consistent with studies by Fortune et al. [7], Han et al. [20] and Bearse et al. [12], and this study also presents novel findings regarding reduced mfERG N1–P1 amplitudes in diabetes. In the studies by Fortune et al. [7], Han et al. [20], and Bearse et al. [12], it was shown that implicit time is more affected in diabetes patients and is the better predictor of future retinopathy than the amplitude. Han et al. showed that up to 50 % of implicit times were delayed significantly in mfERG of diabetic subjects without retinopathy, and Schneck et al. [21] also found that 17 % of implicit times were abnormal in retinal areas that did not have retinopathy. In contrary to these studies, we found that both mfERG amplitude and implicit time are affected in type 2

Discussion People with diabetes are at increased risk of eye complications, and most people with diabetes will get some form of retinopathy. Considering the huge strides made in the treatment of diabetic retinopathy, the earlier the retinopathy is diagnosed, the less sight threatening damage to the eye may occur.

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diabetic patients. Though it has been mentioned in the literature that high interindividual variability of mfERG N1–P1 amplitude (standard deviation, SD ranging from 57 to 98 nV/deg2 in normal eyes) makes this parameter a poorer predictor of diabetic retinopathy than P1-implicit time [7], our study population had quite less interindividual variability of amplitudes in diabetic (SD, 9.3 nv/deg2) as well as control subjects (SD, 12.7 nv/deg2) in comparison to previous studies. The explanation given for minimally reduced amplitude, but significantly delayed implicit time in the previous studies is that the function of the photoreceptors and the inner retina including bipolar cells, which are the primary generators of N1–P1 amplitudes, may be impaired in diabetic patients without retinopathy, but it is not completely abolished [22, 23]. Reduced amplitude in our study population indicate that this population, that has greater prevalence of diabetes and uncontrolled blood sugar level, might have marked dysfunction of the photoreceptors and bipolar cells before the onset of any clinical retinopathy. It was interesting to observe that N1–P1 amplitude was reduced in ring 1 in both diabetic groups indicating even the macula is affected before any clinical retinopathy occurs. It can be inferred that though visual acuity was normal in our diabetic subjects, the quality of vision might have been affected and the measurement of contrast sensitivity and colour vision can be important to know macular function in diabetic subjects. mfERG implicit time has been reported to increase in type 1 diabetes without clinical retinopathy, amplitude being unaffected [24, 25]. We found that both amplitude and implicit time are normal in type 1 diabetes with no clinical retinopathy. Moreover, no notable difference in mfERG responses was observed between two diabetic groups. These results are not conclusive because of very small sample size in type 1 diabetic group. There are variable results on association of diabetes duration and blood sugar level with ERG response. Shimada et al. [26] who used global flash stimulus rather than multifocal demonstrated a marginal propensity for ERG amplitudes to be associated with longer histories of diabetes. However, Kim et al. [27] showed that the duration of diabetes and glycemic control status did not correlate with the local mfERG responses. In our study, neither average N1–P1

amplitude nor average P1-implicit time showed any significant correlation with fasting blood sugar level. Average N1–P1 amplitude was not correlated with diabetes duration, but average P1-implicit time showed positive correlation with diabetes duration in type 2 diabetic subjects with diabetes duration C5 years, suggesting that P1-implicit time is delayed with increasing diabetes duration, 5 years after a person acquires diabetes. Moreover, P1-implicit time was positively correlated with diabetes duration in three rings and one quadrant of retina. The study had few limitations. Visual acuity was measured with Bailey-Lovie Log MAR chart, but not with ETDRS chart due to unavailability of the chart in the research site. However, ETDRS chart is known to give better visual acuity score than Bailey-Lovie Log MAR chart [28] and thus our inclusion criteria were not affected due to the choice of the chart as the visual acuity was better than 6/9 in all subjects. HbA1c could have been a more accurate measure than FBS to assess overall diabetes control of diabetic subjects over a long duration, but we measured FBS as we wanted to know the blood sugar level close to ERG testing time. This is probably the reason for the lack of correlation between P1-implicit time and blood sugar level. The information of diabetes duration might not have been fully reliable as it was obtained from the medical records of patients and this could have affected our results to some extent. Though adult male type 2 diabetic subjects without retinopathy show more abnormal mfERG responses than their female counterparts [29], we could not do the separate analysis for males and females in our study due to small sample size. Conclusion We demonstrate reduced mfERG N1–P1 amplitude and delayed P1-implicit time in Nepalese diabetic patients without retinopathy. Diabetes duration and fasting blood glucose have significant influence on implicit time, but not on amplitude. Our findings may be population specific, and further longitudinal studies are needed to determine whether those patients develop more severe forms of diabetic retinopathy. Acknowledgments The authors would like to thank Beatrix Feigl for comments on a manuscript draft.

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Multifocal electroretinogram responses in Nepalese diabetic patients without retinopathy.

To determine neuroretinal function with multifocal electroretinogram (mfERG) in diabetic subjects without retinopathy...
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