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Study of visual evoked potentials in patients with type 2 diabetes mellitus and diabetic retinopathy.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by abnormal glucose homeostasis, in the context of insulin resistance and relative insulin deficiency. [1] T2DM is a global epidemic its prevalence is rapidly increasing all over the globe. [2] The International Diabetes Federation estimates the total number of diabetic patients to rise to 69.9 million by the year 2025. [3] With an increasing trend in the incidence of diabetes reported, there is also an increase in complications of T2DM due to damage and dysfunction of the organs such as the eye. [4]

Diabetes is a major cause of blindness. [5] Diabetic retinopathy (DR) is a complication of T2DM, which is the sixth common cause of blindness in India, [6] the overall prevalence being 17.6% in the Indian population. [7] There is enough evidence to show that at least 90% of these new cases could be reduced if there were proper and vigilant treatment and monitoring of the eyes. [8] During the initial stage of DR, most people do not notice any change in their vision. [9] Hence, it is beneficial for the patient to have any changes in the function of the retina identified early enough, to effect early treatment.

A measure of visual function in patients with diabetes can be performed using visually evoked potentials (VEPs), which are electrical potential differences occurring in the visual areas of the occipital cortex, in response to visual stimuli and are recorded from the scalp.

Patients with T2DM and with DR have shown abnormalities in VEP recordings, relating to increase in implicit time/latency. [10,11]

With this information, our study makes an attempt to document and interpret the changes in the VEP waveforms such as latency and amplitude of P100, occurring in the patients with T2DM, and in patients having DR.

MATERIALS AND METHODS

This study is an analytical case-control study which was conducted on patients who attended the outpatient of the Department of Ophthalmology of the SRM Medical College Hospital and Research Centre, Kattankulathur - 603 203, India, from September 2011 till August 2012 for 1 year. The study was conducted in accordance with the ethical guidelines for biomedical research on human subjects by the Central Ethics Committee on Human Research and those as contained in the "Declaration of Helsinky". The study was approved by the Institutional Ethical Committee on Human Subjects' Research.

In the present study, a total of 111 patients were studied. They included 17 male and 20 female patients with T2DM of age group 40-70 years grouped as Group A; 37 male and female patients with DR of age group 40-70 years grouped as Group B; healthy male and female controls in the age group 40-70 years grouped as Group C which is the inclusion criteria. Both cases and controls were given an explanatory note, explaining the purpose of the study and the right to deny participation following which due consent on the patient consent form was obtained from each patient before inducting them in the study. Smokers, alcoholics, patients having optic neuropathy, epilepsy, those who had undergone ocular surgery, were excluded from the study.

Personal details of all the participants such as name, age, sex, ethnicity, address, and contact phone number, and relevant medical history were entered in a questionnaire from those who agreed to the study.

A retinal examination was done using direct ophthalmoscope after dilatation of pupils, to document absence or presence of DR to group them as Group A and B, respectively.

The Medicaid Neurostim EMG EP machine was used to record VEPs on each patient. The patients were first explained about the test. They were asked to wash the hair with shampoo the night before the test and not to apply oil on their head. If the patient usually wears glasses, they were asked to be worn during the test. The patients were asked to maintain accurate visual fixation throughout the test.

The test was performed as per the ISCEV guidelines according to the instrument instruction manual. A constant distance of 100 cm was maintained between the TV screen and the patient. VEPs were recorded through pattern-reversal stimulation with mid-size checks (24-32') using a checkerboard. Skin electrodes were used for recording VEPs. These included three scalp electrodes, i.e., Frontal, Occipital, and grounding. The aim was to achieve maximal stimulation of the foveal and parafoveal fibers at 75% contrast and a reversal rate of 1.2 Hz. Uniform illumination was maintained in the laboratory, and the electrode impedance was kept at less than 5 kQ. An average of 100 sweeps of stimuli was given to each eye. This was repeated twice, and the average of the two was superimposed to demonstrate reproducibility. Any difference of more than 3 m sec in the latencies between trials was not included in the study. The evoked responses were averaged and analyzed by the Medicaid Neurostim EP machine. The peak P100 latencies and amplitudes were recorded, and a printout of the test report was taken.

RESULTS

In our study, three groups were studied, the sample size of each being 37, corresponding to an odds ratio of 4. (Sample size determination by Kelsey-Fleiss/Fleiss with CC Kelsey et al. Methods in Observational Epidemiology, Second Edition Tables 12-15; and Fleiss, statistical methods for rates and proportions, formulas. 3.18 and 3.19, CC=Continuity Correlation Factor). The collected data were entered in the MS Excel spreadsheet. Statistical analysis was done using - analysis of variance (ANOVA) one-way, which included that for latency and amplitude of P100 and multiple comparisons and post-hoc test. The descriptive tables for age are given in Table 1, and descriptive tables for gender in Table 2. The mean standard deviation, maximum, minimum, standard error, and confidence bounds for the latency and amplitude of P100 for both eyes of the three groups are given in Tables 3 and 4. The comparative analysis was made using one-way multivariate ANOVA on three groups, and the results are given in Table 5. The post-hoc test results are given in Table 6.

It can be seen that the mean value of P100 latency in the group with DR for right eye (RE) is 134.4327 ms (confidence interval [CI]: 133.52, 135.34), and for left eye (LE) is 134.6937 ms (CI: 134.01, 135.37) which indicates maximum increase in the P100 latency among the 3 study groups. The mean value of P100 latency in the control group with RE is 102.5773 ms (CI: 101.10, 103.16), LE-102.4790 ms (CI: 102.0, 102.96 ms). The mean value of P100 latency in the group with T2DM for RE is 124.3817 ms (CI: 123.19, ms)

and for LE is 125.7677 ms (CI: 124.89, 126.64 ms). The mean value of P100 amplitude in the three groups is the same, that is, for RE is 10.6333 mV (CI: 10.45, 10.48 mV) and for LE is 10.3667 mV (CI: 10.18, 10.54 mV). Since the p values of all combinations are <0.05, the latency values of both eyes of all three groups are different. It is maximum is Group B and minimum in Group C. The insignificant p values (P>0.05) establish that the P100 amplitude values of both eyes do not differ from one another (Table 7).

DISCUSSION

We have found in our study that the P100 latencies of VEP were significantly prolonged in patients with T2DM when compared to the control group indicating that neuronal damage occurs before any visible changes in the retina are seen. The P100 latencies were significantly prolonged in T2DM patients with DR when compared with the patients with T2DM without DR indicating that the magnitude of neuronal damage is more in T2DM patients having DR than those who did not. However, the P100 amplitudes were not affected significantly in T2DM or the DR groups.

Earlier studies of VEPs in diabetic patients have established the prevalence of abnormalities in VEPs of diabetic patients of both sexes in comparison with a control population. [12-14] Studies with pattern-reversal VEPs have shown abnormalities as an increase in latency of P100 in patients with T2DM with and without retinopathy. [15-17] There is prolonged P100 latency reported in patients with diabetes some of whom had DR. [13] Prolongation of latency has also been reported in diabetic patients who did not have retinopathy. [18,19] It has also been reported that the VEP abnormalities did not correlate with the level of retinopathy. [20] It has been shown that VEP can detect early retinal dysfunction in diabetics having no features of retinopathy and so it can be a method to detect early alterations reflecting preclinical microvascular or neurodegenerative changes inside or upstream the retina in patients without DR. [21]

The limitation of our study is that since the study groups were a section of the patients and patients who came to the outpatient in the Department of Ophthalmology, they do not truly reflect the exact prevalence in the community. Hence, a larger study sample has to be studied for better understanding and validation of the test. Further follow-up study is required, to throw more light on the time taken for the T2DM patients to manifest the earliest detectable neurophysiological variations.

CONCLUSION

DR is a serious sight-threatening complication of T2DM and early detection of changes in the visual function using electrophysiology before the florid manifestation of DR is useful to detect and treat this otherwise irreversible blindness.

VEP is a useful tool in detecting early dysfunction due to retinal ganglion cell damage in diabetics before signs of DR are actually detected in the patients. The ideal parameter of VEP is latency of P100. The present study has shown that P100 latency was significantly prolonged in patients with T2DM and patients with DR, when compared to controls and highlighted the importance of VEP as a valuable non-invasive test to detect early neuronal changes in the pre-retinopathy stage in T2DM patients. Thus, VEP can be recommended as an early investigation in T2DM before the occurrence of retinopathy to monitor the early effects of diabetes on visual function thus helping to prevent blindness.

REFERENCES

[1.] Kumar V, Fausto N, Abbas AK, Cotran RS, Robbins SL. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, PA: Saunders; 2005. p. 1194-5.

[2.] Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of type 2 diabetes: Indian scenario. Indian J Med Res. 2007;125(3):217-30.

[3.] Kertes PJ, Johnson TM, editors. Evidence Based Eye Care. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.

[4.] American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32 Suppl 1:S62-7.

[5.] World Health Organization. Global Report on Diabetes. Geneva: WHO; 2016.

[6.] Sicree R, Shaw J, Zimmet P. Diabetes and impaired glucose tolerance. In: Gan D, editor. Diabetes Atlas. International Diabetes Federation. 3 (rd) ed. Belgium: International Diabetes Federation; 2006. p. 15-103.

[7.] Rema M, Premkumar S, Anitha B, Deepa R, Pradeepa R, Mohan V. Prevalence of diabetic retinopathy in urban India: The Chennai Urban Rural Epidemiology Study (CURES) eye study, I. Invest Ophthalmol Vis Sci. 2005;46(7):2328-33.

[8.] Tapp RJ, Shaw JE, Harper CA, de Courten MP, Balkau B, McCarty DJ, et al. The prevalence of and factors associated with diabetic retinopathy in the Australian population. Diabetes Care. 2003;26(6):1731-7.

[9.] Bek T, Hammes HP, Porta M, editors. clinical presentations and pathological correlates of retinopathy. Experimental Approaches to Diabetic Retinopathy. Front Diabetes. Vol. 20. Basel: Karger; 2010. p. 1-19.

[10.] Anastasi M, Lodato G, Cillino S. VECPs and optic disc damage in diabetes. Doc Ophthalmol. 1987;66:331-6.

[11.] Collier A, Reid W, McInnes A, Cull RE, Ewing DJ, Clarke BF. Somatosensory and visual evoked potentials in insulin-dependent diabetics with mild peripheral neuropathy. Diabetes Res Clin Pract. 1988;5(3):171-5.

[12.] Wolff BE, Bearse MA Jr, Schneck ME, Barez S, Adams AJ. Multifocal VEP (mfVEP) reveals abnormal neuronal delays in diabetes. Doc Ophthalmol. 2010;121(3):189-96.

[13.] Algan M, Ziegler O, Gehin P, Got I, Raspiller A, Weber M, et al. Visual evoked potentials in diabetic patients. Diabetes Care. 1989;12(3):227-9.

[14.] Ewing FM, Deary IJ, Strachan MW, Frier BM. Seeing beyond retinopathy in diabetes: Electrophysiological and psychophysical abnormalities and alterations in vision. Endocr Rev. 1998;19(4):462-76.

[15.] Alessandrini M, Paris V, Bruno E, Giacomini PG. Impaired saccadic eye movement in diabetic patients: The relationship with visual pathways function. Doc Ophthalmol. 1999;99(1):11-20.

[16.] Comi G. Evoked potentials in diabetes mellitus. Clin Neurosci. 1997;4(6):374-9.

[17.] Regan D. Human Brain Electrophysiology: Evoked Potentials and Evoked Magnetic Fields in Science and Medicine. New York: Elsevier; 1989. p. 672.

[18.] Mariani E, Moreo G, Colucci GB. Study of visual evoked potentials in diabetics without retinopathy: Correlations with clinical findings and polyneuropathy. Acta Neurol Scand. 1990;81(4):337-40.

[19.] Yaltkaya K, Balkan S, Baysal AI. Visual evoked potentials in diabetes mellitus. Acta Neurol Scand. 1988;77(3):239-41.

[20.] Bartek L, Gat'kova A, Rybka J, Kalita Z, Smecka Z. Visual evoked potentials in diabetics. Cesk Oftalmol. 1989;45(3):192-6.

(21.) Han Y, Schneck ME, Bearse MA Jr, Barez S, Jacobsen CH, Jewell NP, et al. Formulation and evaluation of a predictive model to identify the sites of future diabetic retinopathy. Invest Ophthalmol Vis Sci. 2004;45(11):4106-12.

Rachula Daniel (1), Saravanan Ayyavoo (1), Bagavan Dass (2)

(1) Department of Physiology, SRM Medical College and Research Centre, SRM University, Kattankulathur, Kancheepuram, Tamil Nadu, India, (2) Department of Statistics, School of Public Health, SRM University, Kattankulathur, Kancheepuram, Tamil Nadu, India

Correspondence to: Rachula Daniel, E-mail: rachuladaniel@gmail.com

Received: August 08, 2016; Accepted: August 24, 2016

DOI: 10.5455/njppp.2017.7.0824424082016
Table 1: Two-way table for age and groups

Age code                                  Group
                    Patients with type 2  Patients with type 2
                    diabetes mellitus     diabetic retinopathy

40-50
 Count                4                     4
 % within age code   33.3                  33.3
 % within group      10.8                  10.8
51-60
 Count                7                     7
 % within age code   33.3                  33.3
 % within group      18.9                  18.9
61-70
 Count               21                    21
 % within age code   33.3                  33.3
 % within group      56.8                  56.8
71-80
 Count                5                     5
 % within age code   33.3                  33.3
 % within group      13.5                  13.5
Total
 Count               37                    37
 % within age code   33.3                  33.3
 % within group     100.0                 100.0

Age code            Group            Total
                    Controls
                    (control group)

40-50
 Count                4               12
 % within age code   33.3            100.0
 % within group      10.8             10.8
51-60
 Count                7               21
 % within age code   33.3            100.0
 % within group      18.9             18.9
61-70
 Count               21               63
 % within age code   33.3            100.0
 % within group      56.8             56.8
71-80
 Count                5               15
 % within age code   33.3            100.0
 % within group      13.5             13.5
Total
 Count               37              111
 % within age code   33.3            100.0
 % within group     100.0            100.0

Table 2: Two-way table for gender and different groups

Group                                   Gender          Total
                                        Male    Female

Patients with type 2 diabetes mellitus
 Count                                  17      20       37
 % within group                         45.9    54.1    100.0
 % within gender                        32.1    34.5     33.3
Patients with diabetic retinopathy
 Count                                  18      19       37
 % within group                         48.6    51.4    100.0
 % within gender                        34.0    32.8     33.3
Controls (control group)
 Count                                  18      19       37
 % within group                         48.6    51.4    100.0
 % within gender                        34.0    32.8     33.3

Table 3: The descriptive statistics for amplitude of RE and LE of P100
for three groups

Variable      N    Mean     Standard deviation  Standard error

Amplitude RE
 Group A      37   10.6333  0.49013             0.08949
 Group B      37   10.6333  0.49013             0.08949
 Control      37   10.6333  0.49013             0.08949
Total         111  10.6333  0.48459             0.05108
Amplitude LE
 Group A      37   10.3667  0.49013             0.08949
 Group B      37   10.3667  0.49013             0.08949
 Control      37   10.3667  0.49013             0.08949
Total         111  10.3667  0.48459             0.05108

Variable       95% confidence interval for mean   Minimum   Maximum
               Lower bound   Upper bound

Amplitude RE
 Group A       10.4503       10.8164              10.00     11.00
 Group B       10.4503       10.8164              10.00     11.00
 Control       10.4503       10.8164              10.00     11.00
Total          10.5318       10.7348              10.00     11.00
Amplitude LE
 Group A       10.1836       10.5497              10.00     11.00
 Group B       10.1836       10.5497              10.00     11.00
 Control       10.1836       10.5497              10.00     11.00
Total          10.2652       10.4682              10.00     11.00

RE: Right eye, LE: Left eye

Table 4: The descriptive statistics of latency of RE and LE of P100 for
three groups

Variable     N    Mean       Standard deviation  Standard error

Latency RE
 Group A     37   124.3817   3.18702            0.58187
 Group B     37   134.4327   2.43577            0.44471
 Control     37   102.5773   1.55789            0.28443
Total       111  120.4639   13.59491            1.43303
Latency LE
 Group A     37   125.7677   2.34555            0.42824
 Group B     37   134.6937   1.82535            0.33326
 Control     37   102.4790   1.28157            0.23398
Total       111  120.9801   13.78079            1.45262

Variable    95% confidence interval for mean   Minimum   Maximum
            Lower bound   Upper bound

Latency RE
 Group A    123.1916      125.5717             120.14    129.88
 Group B    133.5231      135.3422             130.08    139.57
 Control    101.9956      103.1591             100.05    104.98
Total       117.6165      123.3113             100.05    139.57
Latency LE
 Group A    124.8918      126.6435             121.24    129.92
 Group B    134.0121      135.3753             130.29    138.74
 Control    102.0005      102.9575             100.01    104.58
Total       118.0938      123.8664             100.01    138.74

RE: Right eye, LE: Left eye

Table 5: Analysis of variance table for latency values of RE and LE

Variable          Sum of         Df   Mean square  F         Significant
                  squares

Latency RE
 Between groups   15912.138       2   7956.069     1288.987  0.000
 Within groups      536.994      87      6.172
Total             16449.132      89
Latency LE
 Between groups   16598.202       2   8299.101     2376.619  0.000
 Within groups      303.802      87      3.492
Total             16902.004      89

RE: Right eye, LE: Left eye

Table 6: The results of post-hoc tests for latency values of both eyes

Dependent variable  (I) Group   (J) Group  Mean difference (I-J)

Latency RE          Group A     Group B    -10.05100 (*)
                                Control     21.80433 (*)
                    Group B     Group A     10.05100 (*)
                                Control     31.85533 (*)
                    Control     Group A    -21.80433 (*)
                                Group B    -31.85533 (*)
Latency LE          Group A     Group B     -8.92600 (*)
                                Control     23.28867 (*)
                    Group B     Group A      8.92600 (*)
                                Control     32.21467 (*)
                    Control     Group A    -23.28867 (*)
                                Group B    -32.21467 (*)

Dependent variable  Standard  Significant  95% confidence interval
                    error                  Lower bound  Upper bound

Latency RE          0.64147   0.000        -11.6486      -8.4534
                    0.64147   0.000         20.2067      23.4019
                    0.64147   0.000          8.4534      11.6486
                    0.64147   0.000         30.2577      33.4529
                    0.64147   0.000        -23.4019     -20.2067
                    0.64147   0.000        -33.4529     -30.2577
Latency LE          0.48249   0.000        -10.1276      -7.7244
                    0.48249   0.000         22.0870      24.4903
                    0.48249   0.000          7.7244      10.1276
                    0.48249   0.000         31.0130      33.4163
                    0.48249   0.000        -24.4903     -22.0870
                    0.48249   0.000        -33.4163     -31.0130

RE: Right eye, LE: Left eye, (*): < 0.05

Table 7: Analysis of variance table for amplitude values of RE and LE

Variable       Sum of   Df  Mean    F       Significant
               squares      square

Amplitude RE
 Between        0.000    2  0.000   0.000   1.000
 groups
 Within        20.900   87  0.240
 groups
Total          20.900   89
Amplitude LE
 Between        0.000    2  0.000   0.000   1.000
 groups
 Within        20.900   87  0.240
 groups
Total          20.900   89

RE: Right eye, LE: Left eye
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Title Annotation:RESEARCH ARTICLE
Author:Daniel, Rachula; Ayyavoo, Saravanan; Dass, Bagavan
Publication:National Journal of Physiology, Pharmacy and Pharmacology
Article Type:Report
Date:Feb 1, 2017
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