Study of visual evoked potentials in patients with type 2 diabetes mellitus and diabetic retinopathy.
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.  T2DM is a global epidemic its prevalence is rapidly increasing all over the globe.  The International Diabetes Federation estimates the total number of diabetic patients to rise to 69.9 million by the year 2025.  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. 
Diabetes is a major cause of blindness.  Diabetic retinopathy (DR) is a complication of T2DM, which is the sixth common cause of blindness in India,  the overall prevalence being 17.6% in the Indian population.  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.  During the initial stage of DR, most people do not notice any change in their vision.  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.
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).
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.  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.  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. 
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.
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.
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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: firstname.lastname@example.org
Received: August 08, 2016; Accepted: August 24, 2016
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|
|Date:||Feb 1, 2017|
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