Implicit Times Research Articles

Variability of Normal Values of Electroretinogram Parameters Due to Aging in Healthy Individuals.

Aim- To find normal values of implicit time and amplitudes of full-field electroretinogram and to determine their changes with age in healthy Romanian subjects. Material and Methods- The prospective study included 59 healthy subjects aged between 20 and 80 years old; in the end, we had valid ERG recordings for all tests from 54 subjects. All of the participants underwent full-field ERG, recorded with Metrovision MonPack One system. The implicit times and amplitudes were analyzed for a and b waves in dark-adapted 0.01 ERG, dark-adapted 3.0 ERG, dark-adapted oscillatory potentials, light-adapted 3.0 ERG, and 30Hz flicker ERG according to International Society for Clinical Electrophysiology of Vision (ISCEV) protocols. Results- ERG latency values were bigger in subjects above 50 years old than in younger subjects for b wave in dark adapted 0.01, dark adapted 3.0, light adapted 3.0 and dark adapted 3.0 flicker and for a wave in dark adapted 0.01 and dark adapted 3.0 ERG. There was no significant difference in latency values for dark adapted 3.0 oscillatory potentials between young and old subjects. Because of increased variability, we could not prove that observed differences for amplitudes held statistical significance. Conclusions- This study proves there is a major loss in retinal activity due to aging, most of it being caused by the rod cells delayed response. Also, oscillatory potentials do not seem to be affected by age, and could prove a valuable test to investigate for changes in patients with Diabetes mellitus.

Ocular blood flow and retinal electrogenesis in retinitis pigmentosa

to investigate correlations between changes in ocular hemodynamics revealed by color Doppler flow mapping (CDFM) and pulsed-wave (PW) Doppler imaging, one the one hand, and electrical activity of the retina, on the other, in patients with early, moderate, and severe retinitis pigmentosa (RP). A total of 20 patients (40 eyes) aged from 16 to 40 years (28.4 ± 8.2 years on average) with retinitis pigmentosa were enrolled. The control group consisted of 20 healthy volunteers of the same age range. All participants underwent full-field electroretinography (ERG), flicker ERG, and macular ERG as well as blood flow assessment in the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (SPCA) by means of CDFM and PW-Doppler. Ocular blood flow in CRA and SPCA appeared disturbed in patients with early RP. In cases of moderate and severe RP, the peak systolic velocity of CRA and SPCA blood flow was significantly decreased. Systolic and end diastolic blood flow velocities in CRA and SPCA has been shown to be directly related to full-field ERG a-wave and b-wave amplitudes, correspondingly, but negatively correlated with their implicit times. The revealed decrease in CRA and SPCA blood flow indices proves retinal and choroidal circulation deficit in patients with advanced RP. As shown, moderate blood flow changes are already present in early RP and progress as retinal photoreceptors and bipolar cells become suppressed, which may be useful for RP diagnosis and monitoring.

DNA Aptamer Raised against Advanced Glycation End Products Prevents Abnormalities in Electroretinograms of Experimental Diabetic Retinopathy

Purpose: Abnormalities in electroretinograms (ERG), such as reduced amplitudes and delayed implicit times of a- and b-wave and oscillatory potentials (OPs), are one of the earliest features of diabetic retinopathy prior to obvious vascular changes in diabetic retinas. We have previously shown that serum levels of advanced glycation end products (AGEs) are correlated with a delayed latency of OPs in type 2 diabetic rats. However, the pathological role of AGEs in ERG abnormalities remains unclear. We examined here whether high-affinity DNA aptamer directed against AGEs (AGE-aptamer) prevents ERG abnormalities in experimental type 1 diabetic retinopathy. Methods: Streptozotocin-induced diabetic rats or control rats received continuous intraperitoneal infusion of either AGE-aptamer or control aptamer via an osmotic mini pump for 16 weeks. Anthropometric, metabolic, and hemodynamic variables were measured, and an ERG was performed. Results: Although AGE-aptamer did not affect body weight, fasting and random blood glucose, HbA1c, blood pressure, or lipid parameters, it completely prevented the increase in serum AGE levels as well as the reduction of a- and b-wave and OP amplitudes in diabetic rats. Conclusion: The present study demonstrated for the first time that AGE-aptamer prevents abnormalities in ERG in experimental diabetic retinopathy probably by blocking the harmful effects of AGEs.

Functional evaluation using multifocal electroretinogram after selective retina therapy with a microsecond-pulsed laser.

To evaluate the changes of retinal function with multifocal electroretinogram (mfERG), and estimate the association between functional and structural changes after selective retina therapy (SRT) with microsecond-pulsed laser in comparison to continuous wave laser photocoagulation (cwPC). Selective retina therapy and cwPC were applied with 10 × 10 shots and 1/2 lesion-width on the retina in the right and left eyes of 20 healthy Chinchilla Bastard rabbits, respectively. Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), and mfERG were performed before, and on days 1, 7, and 30 after both laser treatments. The mean ratios of amplitudes and implicit times of N1 and P1 from eight hexagons covering laser-treated retinal lesions/total retina were measured. Histology was obtained after killing three rabbits at each time period to observe the anatomic changes after both laser treatments. The mean ratios of amplitudes of N1 and P1 in SRT lesions did not change significantly for 30 days after laser treatment. Only subtle reductions of the mean ratios of N1 and P1 amplitudes on day 1, thereafter the amplitudes showed the trend to recover toward baseline values. Histology and OCT revealed temporary and reversible morphologic changes after SRT, which restored to normal within 1 month. However, the mean ratios of N1 amplitudes on days 7 and 30 (P = 0.010, P < 0.001, respectively), and P1 amplitudes on days 7 and 30 (P < 0.001, P < 0.001, respectively) declined significantly in cwPC lesions compared with baseline. Disorganization and atrophic changes were identified on histology and OCT after cwPC. The results suggest that SRT preserved retinal function as well as anatomical structure after treatment.

Comparing focal and global responses on multifocal electroretinogram with retinal nerve fibre layer thickness by spectral domain optical coherence tomography in glaucoma

PurposeTo evaluate first and second order responses on multifocal electroretinogram (mfERG) and with retinal nerve fibre layer thickness (RNFL) on Cirrus spectral domain optical coherence tomography (SD-OCT) in glaucoma.MethodsPatients (old...

Multifocal electroretinography in subjects with age-related macular degeneration.

To evaluate retinal function objectively in subjects with different stages of age-related macular degeneration (AMD) using multifocal electroretinography (mfERG) and compare it with age-matched control group. A total of 42 subjects with AMD and 37 age-matched healthy control group aged over 55years were included in this prospective study. mfERG test was performed to all subjects. Average values in concentric ring analysis in four rings (ring 1, from 0° to 5° of eccentricity relative to fixation; ring 2, from 5° to 10°; ring 3, from 10° to 15°; ring 4, over 15°) and in quadrant analysis (superior nasal quadrant, superior temporal quadrant, inferior nasal quadrant and inferior temporal quadrant) were recorded. Test results were evaluated by one-way ANOVA test and independent samples t test. In mfERG concentric ring analysis, N1 amplitude, P1 amplitude and N2 amplitude were found to be lower and N1 implicit time, P1 implicit time and N2 implicit time were found to be delayed in subjects with AMD compared to control group. In quadrant analysis, N1, P1 and N2 amplitude was lower in all quadrants, whereas N1 implicit time was normal and P1 and N2 implicit times were prolonged in subjects with AMD. mfERG is a useful test in evaluating retinal function in subjects with AMD. AMD affects both photoreceptors and inner retinal function at late stages.

Flicker cone function in normal and day blind sheep: a large animal model for human achromatopsia caused by CNGA3 mutation.

Recently we reported on day blindness in sheep caused by a mutation in the CNGA3 gene, thus making affected sheep a naturally occurring large animal model for therapeutic intervention in CNGA3 achromatopsia patients. The purpose of this study was to characterize flicker cone function in normal and day blind sheep, with the aim of generating a normative data base for ongoing gene therapy studies. Electoretinographic (ERG) cone responses were evoked with full-field conditions in 10 normal, 6 heterozygous carriers and 36day blind sheep. Following light adaptation (10min, 30cd/m(2)), responses were recorded at four increasing light intensities (1, 2.5, 5 and 10cds/m(2)). At each of these intensities, a single photopic flash response followed by 8 cone flicker responses (10-80Hz) was recorded. Results were used to generate a normative data base for the three groups. Differences between day blind and normal control animals were tested in two age-matched groups (n=10 per group). The normal sheep cone ERG wave is bipartite in nature, with critical flicker fusion frequency (CFF) >80Hz. In all four flash intensities, the single photopic flash a-wave and b-wave amplitudes were significantly lower (p<0.005), and implicit times significantly delayed (p<0.0001), in day blind animals. In all four flash intensities, CFF values were significantly lower (p<0.0001) in day blind sheep. Cone function is severely depressed in day blind sheep. Our results will provide a normative data base for ongoing gene therapy studies.

Anemia and retinal function in a mouse model of acute colitis

Individuals with inflammatory bowel diseases (IBD) have an elevated risk of ocular inflammation. Both the anterior and posterior eye can be affected by IBD, although posterior eye dysfunction is more likely to go undetected. Little investigative attention has been directed toward the mechanisms of ocular dysfunction with IBD; however, given the prevalence of anemia in IBD and the effects of anemia on the retina, we examined the association between retinal function (electroretinography, ERG) and the anemia induced by experimental IBD, and we tested for a potential retinal benefit of acutely attenuating anemia (via red blood cell (RBC) infusion). Colitis was induced in mice in a model involving drinking water ingestion of dextran sodium sulfate (DSS), with untreated drinking water administered to controls. A subset of the DSS mice was infused with RBCs to attenuate the severity of the anemia induced by DSS. ERG signals (a-waves, b-waves, and oscillatory potential amplitudes and implicit times) were compared between the three groups of mice to evaluate retinal function. ERG amplitudes were significantly decreased in DSS mice compared to controls, with the amplitudes demonstrating a positive correlation with hematocrit, that is, the lowest ERG amplitudes were found with the most severe cases of anemia. An acute infusion of RBCs into DSS mice provided an improvement in the oscillatory potential implicit times, but no significant improvements in other ERG parameters. Despite the association between anemia and ERG signals in DSS-induced colitis, acute RBC infusion may only partially attenuate the associated retinal dysfunction.

What monitor can replace the cathode-ray tube for visual stimulation to elicit multifocal electroretinograms?

To compare a conventional cathode-ray tube (CRT) screen to organic light-emitting diode (OLED) and liquid crystal display (LCD) screens as visual stimulators to elicit multifocal electroretinograms (mfERGs), mfERGs were recorded from seven eyes of seven healthy volunteers (21 ± 2 years). The mfERGs elicited by a conventional CRT screen (S710, Compaq Computer Co.) were compared to those elicited by a studio-grade master OLED monitor (PVM-1741, Sony, Japan) and a conventional LCD (S1721, Flexscan, Eizo Nanao Corp., Japan). The luminance changes of each monitor were measured with a photodiode. CRT, OLED, and LCD screens with a frame frequency of 60 Hz were studied. A hexagonal stimulus array with 61 stimulus elements was created on each monitor. The serial white stimuli of the OLED screen at 60 Hz did not fuse, and that of the LCD screens fused. The amplitudes of P1 and P2 of the first-order kernels of the mfERGs were not significantly different from those elicited by the CRT and OLED screens, and the P1 amplitude of the first-order kernel elicited by the LCD stimuli was significantly smaller than that elicited by the CRT in all the groups of the averaged hexagonal elements. The implicit times were approximately 10 ms longer in almost all components elicited by the LCD screen compared to those elicited by the CRT screen. The mfERGs elicited by monitors other than the CRT should be carefully interpreted, especially those elicited by LCD screens. The OLED had good performance, and we conclude that it can replace the CRT as a stimulator for mfERGs; however, a collection of normative data is recommended.

Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma.

To evaluate pattern-evoked retinal and cortical responses [pattern electroretinogram (PERG) and visual-evoked potential (VEP), respectively] after treatment with coenzyme Q10 in conjunction with vitamin E in open-angle glaucoma (OAG) patients. Forty-three OAG patients (mean age, 52.5±5.29 y; intraocular pressure <18 mm Hg with β-blocker monoterapy only) were enrolled. At baseline and after 6 and 12 months, simultaneous recordings of PERG and VEPs were obtained from 22 OAG patients who underwent treatment consisting of coenzyme Q10 and vitamin E (Coqun, 2 drops/d) in addition to β-blocker monoterapy (GC group), and from 21 OAG patients who were only treated with β-blockers (GP group). At baseline, intraocular pressure, PERG, and VEP parameters were similar in both GC and GP groups (analysis of variance, P>0.05). After 6 and 12 months, PERG and VEP response parameters of GP patients were unchanged when compared to baseline. In GC patients, PERG P50 and VEP P100 implicit times were decreased, whereas PERG P50-N95 and VEP N75-P100 amplitudes were increased (P<0.01) when compared to baseline. In the GC group, the differences in implicit times and amplitudes with respect to baseline were significantly larger (P<0.01) than those recorded in the GP group. The improvement (12 mo minus baseline) of VEP implicit time was significantly correlated with the changes of PERG P50-N95 amplitude (r=-0.66171, P=0.0008) and P50 implicit time (r=0.68364, P=0.00045) over a period of 12 months. Coenzyme Q10 associated with vitamin E administration in OAG shows a beneficial effect on the inner retinal function (PERG improvement) with consequent enhancement of the visual cortical responses (VEP improvement).

Electroretinographic characteristics in children with infantile nystagmus syndrome and early-onset retinal dystrophies.

To differentiate early-onset retinal dystrophies on the basis of electroretinogram (ERG) characteristics in children with infantile nystagmus syndrome (INS). Thirty-seven children with INS and early-onset retinal dystrophies were included, with diagnosis according to clinical and ERG findings. Three ERG protocols were used according to the child's age and 17 children were followed with 2 protocols: 27 (mean 2.1 years) were recorded with skin electrodes to flash stimulation, 16 (mean 6.5 years) with skin electrodes to full-field stimulation, and 11 (mean 12.2 years) with HK electrodes to full-field stimulation. The ERGs were compared to those of age-matched controls, with differences significant if p&lt;0.05. Clinical and electrophysiologic findings were in agreement across all of the children. In nine children with Leber congenital amaurosis, the scotopic and photopic ERGs were not recordable under all protocols. Six children with congenital stationary night blindness (CSNB) had electronegative scotopic ERG under all protocols, those with complete CSNB had absent rod ERG, and those with incomplete CSNB had reduced rod ERG. Eight children with achromatopsia had nonrecordable photopic and subnormal scotopic ERG under all protocols. The implicit times of the scotopic b-waves were prolonged. One child had blue-cone monochromatism and reduced photopic and normal S-cone ERG. Six children with cone-rod dystrophy without systemic disorder, and seven children with systemic disorder, had affected photopic and scotopic ERGs under all protocols. In children with INS, some early-onset retinal dystrophies can be differentiated through ERGs, also with skin electrodes.

Measurement of retinal function with flash-electroretinography in Chinese patients with hyperlipidemia.

We used flash electroretinography (F-ERG) to determine if retinal function was impaired in patients with hyperlipidemia, including visual acuity and fundus morphological changes, and to identify predictors of impaired retinal function in hyperlipidemia patients. This was a prospective case-control study (Shanghai, China; February 2011 to January 2012) in 696 hyperlipidemia patients and 136 healthy controls. Exclusion criteria included best-corrected visual acuity <0.6, previous intraocular surgery, and chronic comorbidities. Each participant underwent a comprehensive series of ophthalmologic examinations, and standard F-ERG examination. Data were analyzed using t-tests and multivariate analysis. Six hundred and twenty-six hyperlipidemia patients (57.69 ± 14.01 years; 59.58% female) and 120 healthy controls (55.13 ± 14.03 years; 60% female) were included in the final analysis. After adjustment for age and gender using multivariate covariance analysis, F-ERG result revealed significantly lower response amplitudes in the hyperlipidemia group (P < 0.05), and longer implicit times (P < 0.05) than the control group. F-ERG parameters were significantly different between the two groups. Stepwise multiple linear regression analysis showed that serum LDL levels (P < 0.001), BMI (P < 0.001), duration of hyperlipidemia (P < 0.001), and serum HDL levels (P = 0.03) were negatively correlated with ΣOps. The present study suggests that the retinal function of hyperlipidemia patients was significantly lower than in healthy controls, even before the occurrence of pathological changes in the fundus.

Changes in rod and cone-driven oscillatory potentials in the aging human retina.

We recorded oscillatory potentials (OPs) to document how age impacts on rod- and cone-driven inner retina function. Dark- and light-adapted electroretinogram (ERG) luminance-response functions were recorded in healthy human subjects aged 20 to 39, 40 to 59, and 60 to 82 years. Raw ERG traces (0.1-300 Hz) were filtered (75-300 Hz) to measure OPs trough-to-peak in the time-amplitude domain. Morlet wavelet transform (MWT) allowed documenting OPs time-amplitude-frequency distribution from raw traces. Under dark adaptation, both methods revealed reduced OP amplitudes and prolonged implicit times by 40 years of age. The MWT identified a high-frequency band as the main oscillator, which frequency (150-155 Hz) was unaffected by age. Under light adaptation, most OP peaks were delayed by 40 years of age. Peak-trough measures yielded inconsistent results in relation to luminance. Contrastingly, MWT distinguished two frequency bands at all luminances: high frequency (135 ± 6 Hz) time locked to the onset of early OPs and low frequency (82 ± 7 Hz), giving rise to early and late OPs. By 60 years, there was a consistent power reduction specific to the low-frequency band. Age-related OP changes precede those seen with a- (photoreceptoral) and b-waves (postphotoreceptoral). In addition, MWT allows quantifying distinct low- and high-frequency oscillators in the human retina, which complement traditional OP analysis methods. The identification of an age-independent OP marker (light-adapted high frequency band) opens a new dimension for the screening of retinal degenerations and their impact on inner retina function.

Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX Trial)

X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100,000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found. Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. clinicaltrials.gov Identifier: NCT00100230.

Retinal Function and Morphology in the Rabbit Eye after Intravitreal Injection of the TNF Alpha Inhibitor Adalimumab

Aim: To study the effects of the tumor necrosis factor alpha inhibitor adalimumab on rabbit retina after injection into the vitreous body.Methods: Forty-eight rabbits of mixed strain (9–12 months old, weighing ≈ 3.5 kg) were randomized into four groups. Adalimumab was injected at one of two concentrations (1.25 mg or 2.5 mg) into the eyes of two groups, and balanced salt solution into the eyes of the third group. The fourth group acted as controls. Full-field electroretinography (ffERG) was performed before injection and 1 and 6 weeks post-injection. At 6 weeks post-injection the rabbits were euthanized and the sectioned retinas were studied. Retinal histology was studied with hematoxylin–eosin staining. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Müller cells.Results: No significant difference in ffERG amplitudes or implicit times was observed between the four groups at any time point. Histological and immunohistochemical findings were similar in all groups.Conclusions: Injection of adalimumab into the vitreous body of healthy rabbits, at doses up to 2.5 mg, does not appear to be toxic to the rabbit retina.

Differences in neuroretinal function between adult males and females.

To determine whether neuroretinal function differs in healthy adult males and females younger and older than 50 years. This study included one eye from each of 50 normal subjects (29 females and 21 males). Neuroretinal function was assessed using first-order P1 implicit times (ITs) and N1-P1 amplitudes (AMPs) obtained from photopic multifocal electroretinograms. To assess local differences, retinal maps of local IT and (separately) AMP averages were constructed for each subject group. To examine global differences, each subject's 103 ITs and (separately) AMPs were also averaged to create whole-eye averages. Subsequently, retinal maps and whole-eye averages of one subject group were compared with those of another. In subjects younger than 50 years, neuroretinal function differed significantly between the males and females: local ITs were significantly shorter at 83 of 103 tested retinal locations, and whole-eye IT averages were shorter (p = 0.015) in the males compared with the females. In contrast, no analysis indicated that the males and females older than 50 years were significantly different. A subanalysis showed that the females who reported a hysterectomy (n = 5) had the longest whole-eye ITs of all subject groups (p ≤ 0.0013). In the females who did not report a hysterectomy, neuroretinal function was worse in the females older than 50 years compared with the females younger than 50 years: local ITs were significantly longer at 62 of 103 retinal locations tested, and whole-eye IT averages tended to be greater (p = 0.04). Conversely, ITs were not statistically different between the younger and older males. N1-P1 amplitudes did not differ between the sexes. Multifocal electroretinogram IT differs between males and females, depending on the age group and hysterectomy status.

Detection of early age-related macular degeneration using novel functional parameters of the focal cone electroretinogram.

The focal cone electroretinogram is a sensitive marker for macular disease, but have we unlocked its full potential? Typically assessment of waveform parameters is subjective and focuses on a small number of locations (e.g. the a-wave). This study evaluated the discriminatory and diagnostic potential of 4 conventional and 15 novel, objectively determined, parameters in patients with early Age-related Macular Degeneration. Focal cone electroretinograms were recorded in 54 participants with early Age-related Macular Degeneration (72.9±8.2 years) and 54 healthy controls (69±7.7 years). Conventional a and b wave amplitudes and implicit times were measured and compared to novel parameters derived from both the 1st and 2nd derivatives and the frequency-domain power spectrum of the electroretinogram.Statistically significant differences between groups were shown for all conventional parameters, the majority of 1st and 2nd derivative parameters and the power spectrum at 25 and 30 Hz. Receiver operating characteristics showed that both conventional and 1st and 2nd derivative implicit times had provided the best diagnostic potential. A regression model showed a small improvement over any individual parameter investigated. The non-conventional parameters enhanced the objective evaluation of the focal electroretinogram, especially when the amplitude was low. Furthermore, the novel parameters described here allow the implicit time of the electroretinogram to be probed at points other than the peaks of the a and b waves. Consequently these novel analysis techniques could prove valuable in future electrophysiological investigation, detection and monitoring of Age-related Macular Degeneration.

Rodent Hyperglycemia-Induced Inner Retinal Deficits are Mirrored in Human Diabetes.

To evaluate the utility of low luminance stimuli to functionally probe inner retinal rod pathways in the context of diabetes mellitus in both rat and human subjects. Inner retinal dysfunction was assessed using oscillatory potential (OP) delays in diabetic rats. Scotopic electroretinograms (ERGs) in response to a series of increasing flash luminances were recorded from streptozotocin (STZ)-treated and control Sprague-Dawley rats after 7, 14, 20, and 29 weeks of hyperglycemia. We then evaluated OP delays in human diabetic subjects with (DR) and without (DM) diabetic retinopathy using the International Society for Clinical Electrophysiology in Vision (ISCEV) standard scotopic protocol and two additional dim test flashes. Beginning 7 weeks after STZ, OP implicit times in diabetic rats were progressively delayed in response to dim, but not bright stimuli. In many diabetic subjects the standard ISCEV dim flash failed to illicit measureable OPs. However, OPs became measurable using a brighter, nonstandard dim flash (Test Flash 1, -1.43 log cd s/m2), and exhibited prolonged implicit times in the DM group compared with control subjects (CTRL). Delays in scotopic OP implicit times are an early response to hyperglycemia in diabetic rats. A similar, inner retinal, rod-driven response was detected in diabetic human subjects without diabetic retinopathy, only when a nonstandard ISCEV flash intensity was employed during ERG testing. The addition of a dim stimulus to standard ISCEV flashes with assessment of OP latency during ERG testing may provide a detection method for early retinal dysfunction in diabetic patients.

Localizing Functional Damage in the Neural Retina of Adolescents and Young Adults With Type 1 Diabetes

It is unknown which regions of the retina are most susceptible to damage by diabetes mellitus. We hypothesized that the standard and slow-flash (sf-) multifocal electroretinogram (mfERG) will localize retinal regions of greatest vulnerability. A total of 55 adolescents and young adults with type 1 diabetes and without diabetic retinopathy (DR) or with mild nonproliferative DR and 54 typically-developing, age-similar control participants underwent mfERG and sf-mfERG testing. The amplitude and implicit time of the first order response of the standard mfERG and of three multifocal oscillatory potentials (mfOPs) of the sf-mfERG were compared between groups at the level of hexagons, quadrants, and rings using separate mixed model ANOVAs. Spatial mapping of the P values from post hoc pairwise comparisons illustrated patterns of retinal dysfunction. Delays in mfERG implicit times were evident across the tested retinal areas in the diabetes group. Delays in sf-mfERG implicit times were found at different eccentricities for each mfOP in the diabetes group. The greatest delays were noted in the periphery for mfOP1, in the midperiphery for mfOP2, and in the macular region for mfOP3. There were no significant group differences in amplitude for the mfERG and sf-mfERG protocols. Delays in mfERG and sf-mfERG responses suggest that the inner retina is particularly vulnerable to diabetes. Localizing regions of early dysfunction will help guide future studies to examine early structural damage associated with DR.

Electroretinograms and level of aqueous vascular endothelial growth factor in eyes with hemicentral retinal vein occlusion or branch retinal vein occlusion

Hemicentral retinal vein occlusion (hCRVO) is a disease related to CRVO but not to branch retinal vein occlusion (BRVO). We reported a significant correlation between aqueous vascular endothelial growth factor (VEGF) levels and the implicit time of 30-Hz flicker electroretinogram (ERG) in CRVO eyes. The purpose of this study was to compare aqueous VEGF levels and ERG components between hCRVO and BRVO eyes. The medical records of patients with macular edema secondary to hCRVO (12 eyes) or BRVO (16 eyes) and received an intravitreal injection of bevacizumab (IVB) at the Nagoya University Hospital from July 2009 to May 2013 were reviewed. Full-field ERGs were recorded before the IVB. Aqueous humor was collected just before the IVB to measure VEGF concentration. Differences in aqueous VEGF level and ERG components between hCRVO and BRVO eyes were determined. Mean aqueous VEGF concentration in hCRVO eyes was significantly higher than that in BRVO eyes (504 vs. 148 pg/ml, P < 0.05). The implicit time of 30-Hz flicker ERG was significantly longer in hCRVO than in BRVO eyes (33.5 vs. 29.8 ms, P < 0.01). The significant difference in VEGF levels in aqueous and implicit times of 30-Hz flicker ERG suggest that retinal ischemia is more manifest in hCRVO than in BRVO eyes.