Administration of Nicotine Can Inhibit Myopic Growth in Animal Models.

Purpose: While previously investigating the mechanism by which atropine inhibits ocular growth, we observed that stimulation of nicotinic receptors can inhibit experimental myopia. This study expands on that preliminary finding and investigates the safety and efficacy of nicotinic stimulation in the inhibition of ocular growth. Methods: Nicotine's ability to inhibit form-deprivation myopia (FDM), following intravitreal injection (9 chicks per group) or topical application (6 chicks per group), was investigated over three doses. The ability of nicotine to inhibit lens-induced myopia (LIM) was also tested (in 12 chicks). For ocular safety, following 4 weeks of topical treatment with nicotine (n = 10), pupillary reflex, intraocular pressure, corneal curvature/thickness, lens thickness, retinal health (retinal thickness/cell apoptosis), as well as retinal function (electroretinogram recordings) were assessed. We also examined the effects of nicotine on non-ocular autonomic functions in both chicks (n = 5) and mice (n = 5). Results: Nicotine was observed to significantly inhibit the development of FDM in chicks when administered as an intravitreal injection (P < 0.05) or topical eye drops (P < 0.05), albeit not in a dose-dependent manner. Nicotine also inhibited LIM (P < 0.05) to a similar degree to that seen for FDM. Although ocular health was (for the most part) unaffected by nicotine, the highest topical dose induced a temporary reduction in cardiorespiratory output (P < 0.05). Conclusions: Nicotine, administered as an intravitreal injection or topical eye drop, significantly inhibits the development of experimental myopia. Although the anti-myopic effects observed presently are interesting, the well-reported side effects (expanded on presently) and addictive properties of nicotine would preclude its clinical use.

Acute Effects of Oral Caffeine Intake on Human Global-Flash mfERG Responses: A Placebo-Controlled, Double-Masked, Balanced Crossover Study.

Purpose: To determine the acute effect of caffeine intake on the retinal responses as measured with a global-flash multifocal electroretinogram (gfmERG) protocol at different contrast levels. Methods: Twenty-four young adults (age = 23.3 ± 2.4 years) participated in this placebo-controlled, double-masked, balanced crossover study. On two different days, participants orally ingested caffeine (300 mg) or placebo, and retinal responses were recorded 90 minutes later using a gfmERG at three contrast levels (95%, 50%, and 29%). The amplitude response density and peak time of the direct and induced components (direct component [DC] and induced component [IC], respectively) were extracted for five different eccentricities (1.3°, 5.0°, 9.6°, 15.2°, and 21.9°). Axial length, spherical equivalent refraction, habitual caffeine intake, and body weight were considered as continuous covariates. Results: Increased IC amplitude response density was found after caffeine ingestion in comparison to placebo (P = 0.021, ƞp2 = 0.23), specifically for the 95% and 50% stimulus contrasts (P = 0.024 and 0.018, respectively). This effect of caffeine on IC amplitude response density was independent of the retinal eccentricity (P = 0.556). Caffeine had no effect on DC amplitude response density or DC and IC peak times. Conclusions: Our results show that oral caffeine intake increases the inner electro-retinal activity in young adults when viewing stimuli of high- (95%) to medium-contrast (50%). Given the increasing evidence that the inner retinal function is involved in the emmetropization process, these results may suggest that caffeine or its derivatives could potentially play a role in the mechanisms involved in eye growth.

The Effect of High-Dose Erythropoietin Perinatally on Retinal Function in School-Aged Children Born Extremely or Very Preterm.

PURPOSE: To investigate the long-term effects of high-dose recombinant human erythropoietin (rhEPO) administered during the perinatal period on retinal and visual function in children born extremely or very preterm. DESIGN: Randomized, double-blind clinical trial follow-up plus cohort study. METHODS:  Setting: Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland. STUDY POPULATION: Extremely or very preterm-born children aged 7 to 15 years, previously randomized to receive either high-dose rhEPO or placebo in the perinatal period. INCLUSION CRITERIA: participation in an ongoing neuropediatric study (EpoKids), written informed consent. EXCLUSION CRITERIA: previous ocular trauma or surgery; retinal or developmental disease unrelated to prematurity. Healthy control (HC) children of comparable age were recruited. INCLUSION CRITERIA: term birth, informed consent. EXCLUSION CRITERIA: any ocular/visual abnormality, high refractive error. Intervention status (rhEPO/placebo) was unknown to examiners and subjects at examination, with examiners unblinded only after completion of all analyses. OBSERVATION PROCEDURES: The electroretinogram (ERG) was performed with the RETeval device (LKC Technologies, Inc). Ophthalmological and orthoptic examinations excluded comorbidity in the prematurely born cohort and ocular diseases in the HC group. MAIN OUTCOME MEASURES: Scotopic and photopic ERG response amplitudes and peak times (6 amplitudes; 6 peak times). Secondary outcomes were habitual visual acuity and color discrimination performance (for descriptive summary only). RESULTS: No differences in ERG parameters between EPO (n = 52; 104 eyes) and placebo (n = 35; 70 eyes) subgroups were observed (all corrected P > .05). Two cone system-mediated peak times were slightly slower in the placebo than HC (n = 52; 104 eyes) subgroup (coefficient/95% confidence interval = 0.53/0.21-0.85 and 0.36/0.13-0.60; P = .012 and .022); a predominantly rod system-mediated peak time was slightly faster in the EPO than the HC subgroup (coefficient/95% confidence interval = -4.33/-6.88 to -1.78; P = .011). Secondary outcomes were comparable across subgroups. CONCLUSIONS: Administration of high-dose rhEPO to infants born extremely or very preterm during the perinatal period has no measurable effects on retinal function in childhood compared to placebo. Premature birth may cause small, likely clinically insignificant effects on retinal function in childhood, which may be partially mitigated by administration of rhEPO during the perinatal period.

Effects of D-serine treatment on outer retinal function.

The role of the N-Methyl-D-Aspartate Receptor (NMDAR) in the outer retina is unclear despite expression of the NMDAR-complex and its subunits in the outer retina. The flash-electroretinogram (fERG) offers a non-invasive measurement of the retinal field potentials of the outer retina that can serve to clarify NMDAR contribution to early retinal processing. The role of the NMDAR in retinal function was assessed using a genetic mouse model for NMDAR hypofunction (SR-/-), where the absence of the enzyme serine racemase (SR) results in an 85% reduction of retinal D-serine. NMDAR hypo- and hyperfunction in the retina results in alterations in the components of the fERG. The fERG was examined after application of exogenous D-serine to the eye in order to determine whether pre- and post-topical delivery of D-serine would alter the fERG in SR-/- mice and their littermate WT controls. Amplitude and implicit time of the low-frequency components, the a- and b-wave, were conducted. Reduced NMDAR function resulted in a statistically significantly delayed a-wave and reduced b-wave in SR-/- animals. The effect of NMDAR deprivation was more prominent in male SR-/- mice. A hyperfunction of the NMDAR, through exogenous topical delivery of 5 mM D-serine, in WT mice caused a significantly delayed a-wave implicit time and reduced b-wave amplitude. These changes were not observed in female WT mice. There were temporal delays in the a-wave and amplitude and a decrease in the b-wave amplitude and implicit time in both hypo- and NMDAR hyperfunctional male mice. These results suggest that NMDAR and D-serine are involved in the retinal field potentials of the outer retina that interact based on the animal's sex. This implicates the involvement of gonadal hormones and D-serine in retinal functional integrity.

Non-invasive evaluation of toxicity in vitreoretinal domain following insertion of sustained release methotrexate micro-implant.

PURPOSE: To evaluate the safety and toxicity profile of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based sustained release methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes using non-invasive testing that included electroretinography (ERG), ultrasound biomicroscopy (US), slit-lamp biomicroscopy (SLB), funduscopy, and intraocular pressure (IOP). METHODS: PLGA-coated CS-based micro-implants containing 400 µg of MTX and placebo (without drug) micro-implants were surgically-implanted in the vitreous of the right and the left eyes, respectively, in each of the thirty New Zealand rabbits. ERG, US, SLB, funduscopy, and IOP were assessed in both eyes at pre-determined time points (days: 1, 3, 7, 14, 28 and 56). The safety of micro-implants was assessed by analyzing the ERG data using different statistical models, to quantify and compare the functional integrity of the retina. Further, US, funduscopy, SLB and IOP determined the condition of the retina, the micro-implant and associated intraocular features. RESULTS: Statistical analyses of the ERG data showed unchanged functional integrity of retina between eyes with the PLGA-coated CS-based MTX micro-implant and the placebo micro-implant. US analysis showed that micro-implants were stationary throughout the study. SLB, funduscopy and IOP further confirmed that there were no abnormalities in the intraocular physiology. CONCLUSION: The findings from ERG, US, SLB, funduscopy, and IOP showed no detectable adverse effects caused by our biodegradable micro-implants. These non-invasive techniques appeared to show lack of significant ocular toxicity over time in spite of degradation and changes in morphology of the micro-implants following intraocular implantation.

Repurposing bortezomib for choroidal neovascularization treatment via antagonizing VEGF-A and PDGF-D mediated signaling.

Neovascular age-related macular degeneration (neoAMD) is the leading cause of blindness in AMD and manifests as choroidal neovascularization (CNV). Anti-vascular endothelial growth factor (VEGF) therapies are the mainstay treatments but with limited efficacy and cause detrimental effects on the retina after long-term application. These disadvantages warrant alternative strategy. Herein, we examined the effect on CNV by intravitreal injection of bortezomib, a reversible proteasome inhibitor, and further dissected the mechanism. Krypton red Laser was used to create CNV model in mice. The angiogenesis volume was assessed in choroidal flat-mount with isolectin GS-IB4 labeling and the leakage was examined with fluorescein fundus angiography. Injection of Borsub inhibited angiogenesis in the CNV model which was dose-dependent; the injection significantly inhibited leakage as well. Furthermore, Borsub injection reduced the contents of VEGF-A, macrophage chemotactic factor 1 (MCP-1), and platelet-derived growth factor (PDGF)-D but not PDGF-B, examined by enzyme-linked immunosorbent assay, in choroid/retinal pigment epithelium (RPE) tissue. These injections also reduced phospho-VEGFR-2 and phospho-PDGFRß in choroid/RPE tissue examined by immunoblotting. Moreover, Borsub inhibited the recruitment of mural cells or macrophages to laser-injured spots. Injection of Borsub indicated negative effect on scotopic and photopic responses recorded by electroretinogram. Altogether, intravitreal injection of Borsub significantly reduced CNV by antagonizing VEGF-A/Flk-1 and PDGF-D/PDGFRß pathways without impacting electroretinography parameters. Thus, Borsub may offer an invaluable therapy for the prevention and treatment of neoAMD.

Is intravitreal topotecan toxic to retinal function?

BACKGROUND: Intravitreal injections of topotecan are used in the management of retinoblastoma with vitreous seeds. This study evaluated whether intravitreal topotecan was associated with retinal toxicity. METHODS: Retrospective cohort study of patients with retinoblastoma who were treated with intravitreal topotecan at Memorial Sloan Kettering Cancer Center between December 2014 and May 2019. Electroretinogram (ERG) responses under anaesthesia were measured immediately before treatment with intravitreal topotecan and at the next visitor approximately one-month. Ocular toxicity was defined by a decrease in the ERG response at 30 Hz at follow-up. RESULTS: Ocular toxicity was evaluated by ERG on 50 evaluable injections administered to 28 eyes. 22 (44.0%) injections were performed with concurrent intravitreal melphalan. The median time to ERG measurement following an injection was 27 days. By using a paired t-test, intravitreal topotecan combined with melphalan (n=22) at a dose of 25 µg or 30 µg was associated with a significant decrease in ERG amplitude at follow-up (p=0.046, 95% CI -20.4 µV to -0.2 µV). Among eyes that only received topotecan (n=28) at doses of 20 µg or 30 µg, there was not a significant difference in ERG amplitude measured (p=0.85, 95% CI -7.0 µV to 5.8 µV). CONCLUSION: Intravitreal topotecan combined with intravitreal melphalan was associated with a decrease in ERG amplitude; there was not a significant decrease in ERG amplitude observed in patients who received topotecan alone. These findings suggest that intravitreal topotecan injections at doses of 20 µg or 30 µg are not associated with retinal toxicity in patients with retinoblastoma.

Case Report: Long-term Structural and Functional Effects of Ethambutol Optic Neuropathy.

SIGNIFICANCE: This case report demonstrates reduction in the retinal nerve fiber layer (RNFL) thickness and an abnormal electroretinogram after toxic optic neuropathy from ethambutol, more than 1 year after improvements in visual acuity (VA) and visual fields (VFs) were seen. Although many studies have described complications of ethambutol, continuing reduction in RNFL thickness 2 years after discontinuation has not been described elsewhere. PURPOSE: It is well known that ethambutol can cause optic nerve toxicity, visual impairment, and VF loss. Visual acuity can be regained after stopping the drug; however, the amount and time frame are variable. There are few data on long-term follow-up of these cases to direct clinicians how to proceed once VA has stabilized. Here we present a case with 2 years of follow-up for a patient with ethambutol toxicity, showing the condition change even after VA becomes normal. CASE REPORT: A 61-year-old man presented shortly after discontinuing ethambutol for Mycobacterium avium complex. Visual acuity values were 20/70 in the right eye and 20/125 in the left eye with cecocentral VF scotomas. Optical coherence tomography showed normal RNFL. Visual-evoked potentials were significantly reduced and delayed. Over the course of 2 years, the patient became asymptomatic as VA and VF returned to normal and visual-evoked potential improved. However, the optical coherence tomography RNFL was reduced from each visit to the next, and the electroretinogram showed decreased scotopic and photopic amplitudes. CONCLUSIONS: Signs of ethambutol toxicity may remain or worsen years after discontinuation, even in the absence of patient symptoms and with normal VA and VF.

Electrophysiological and SD-OCT findings in patients receiving chloroquine therapy in relation to cumulative dosage and duration of treatment.

PURPOSE: Assessment of multifocal ERG (mfERG) changes in patients treated with chloroquine and their correlation with morphological abnormalities, detected by spectral-domain optical coherence tomography in relation to cumulative dosage. METHODS: Data from 37 eyes of 20 patients were retrospectively collected, and one randomly selected eye per patient was considered for statistical analysis. Eyes were divided into three groups according to mfERG and visual acuity findings: normal, early and advanced maculopathy. Functional measures of the first three mfERG rings were compared with retinal thickness measures of the corresponding OCT ETDRS circles. Data on cumulative dose and duration of therapy were also evaluated. RESULTS: The mean mfERG values progressively decreased according to the stage of the disease. In particular in the early maculopathy group, amplitudes were significantly reduced in all the three central rings. The mean ring ratio R1/R2 was abnormal only in the early maculopathy group. OCT thickness measures were significantly lower in all the three ETDRS circles in the advanced maculopathy group, and in the paracentral circle in the early maculopathy group. Considering all the eyes, there was a statistically significant correlation between functional and morphological values (p < 0.001). High chloroquine cumulative dosages were always associated with retinal toxic effects, whereas lower cumulative dosages generated different levels of toxicity. CONCLUSIONS: This study shows a strong association between mfERG ring values and the corresponding OCT thickness measures; however, mfERG may enhance early detection of functional changes in patients treated with chloroquine, especially in ambiguous cases. At low chloroquine cumulative dosages, different subjects might have different susceptibilities to the drug.

Electroretinographic abnormalities associated with pregabalin: a case report.

PURPOSE: Pregabalin binds to the α2-δ1/α2-δ2 subunits of the voltage-gated L-type calcium channel (LTCC), which is expressed in rod/cone photoreceptor terminals. The purpose of this report was to describe electroretinographic abnormalities associated with pregabalin treatment. CASE PRESENTATION: This is an observational case report. A 49-year-old female reported photophobia and night blindness in her left eye after 10 months of pregabalin administration. One month after the symptoms, ophthalmic examinations were performed, which revealed good visual acuity and no remarkable fundus findings. However, full-field electroretinography (ERG) of the left eye revealed a decreased b-wave in rod ERG, a slightly decreased a-wave and severely decreased b-wave (negative ERG) in bright flash ERG, decreased a- and b-waves in cone ERG, and decreased b-waves in 30-Hz flicker ERG. These findings are similar to those seen in incomplete congenital stationary night blindness, whereas the right eye ERG showed normal responses, except for a square a-wave in cone ERG. The ERG gradually improved from 1 to 12 months after discontinuing pregabalin. Finally, b-waves in bright flash ERG and cone ERG responses largely recovered, but b-waves in rod ERG and a-waves in bright flash ERG only partially recovered in the left eye. The square a-wave recovered to normal in the right eye. CONCLUSIONS: This is the first report to indicate that ERG abnormalities might be associated with pregabalin treatment. Our results suggest that pregabalin may affect LTCC function via the α2-δ1/α2-δ2 subunits, which leads to defective synaptic transmission from rod/cone photoreceptors to bipolar cells.

Effect of stopping hydroxychloroquine therapy on the multifocal electroretinogram in patients with rheumatic disorders.

OBJECTIVE: To report the effect of hydroxychloroquine therapy cessation on the multifocal electroretinogram (mfERG) in a case series of patients with rheumatic disease suspected to have retinopathy. METHODS: Comprehensive data were retrospectively reviewed on 14 patients from a total of 50 cases who discontinued hydroxychloroquine due to suspected toxicity. Patients were followed for 4 years after the cessation of therapy. mfERG testing had been part of original screening for hydroxychloroquine retinopathy and was continued after therapy cessation at 6-month intervals. Descriptive statistics, independent sample t test, and one-way analysis of variance with repeated measures and post hoc analysis were conducted to determine patients' clinical characteristics and changes in the mfERG after therapy cessation, respectively. RESULTS: All 14 patients were female; 12 were treated for rheumatoid arthritis and 2 for systemic lupus erythematosus. Three groups were identified: (i) 9 patients in whom the responses of the mfERG recovered to within normative values after cessation of hydroxychloroquine therapy, (ii) 3 who experienced limited recoveries, and (iii) 1 patient whose mfERG response was unchanged. There was no significant difference (p > 0.05) in the clinical characteristics of these patients. However, the proportional reduction of mfERG ring 1, 2, and 3 amplitudes from age normal responses at the time of discontinuation of drug use for the first and second groups of patients was significantly different, with more reduction in group 2 (p < 0.05). CONCLUSION: Early detection of hydroxychloroquine retinopathy through screening and subsequent therapy discontinuation could result in recovery of the mfERG ring amplitude response and preservation of visual function.

Subcutaneous delivery of tauroursodeoxycholic acid rescues the cone photoreceptors in degenerative retina: A promising therapeutic molecule for retinopathy.

Inherited retinal degeneration (RD) comprises a heterogeneous group of retinopathies that rank among the main causes of blindness. Tauroursodeoxycholic acid (TUDCA) is taurine conjugate hydrophilic bile acid that demonstrates profound protective effects against a series of neurodegenerative diseases related to oxidative stress. This study sought to evaluate the TUDCA induced effects of on a pharmacologically induced RD animal model by electroretinogram (ERG) examination, behavior tests, morphological analysis and immunochemistry assay. Massive photoreceptor degeneration in mice retina was induced by an intraperitoneal administration of N-methyl-N-nitrosourea(MNU). Subcutaneous delivery of TUDCA inhibits effectively the photoreceptor loss and visual impairments in the MNU administered mice. In the retinal flat-mounts of TUDCA treated mice, the cone photoreceptors were efficiently preserved. Furthermore, the multi-electrodes array (MEA) was used to detect the firing activities of retinal ganglion cells within the inner retinal circuits. TUDCA therapy could restrain the spontaneous firing response, enhance the light induced firing response, and preserve the basic configurations of ON-OFF signal pathway in degenerative retinas. Our MEA assay provided an example to evaluate the potency of pharmacological compounds on retinal plasticity. TUDCA affords these protective effects by modulating apoptosis and alleviating oxidative stress in the degenerative retina. In conclusion, TUDCA therapy can ameliorate the photoreceptor degeneration and rectify the abnormities in visual signal transmission. These findings suggest that TUDCA might act as a potential medication for these retinopathies with progressive photoreceptor degeneration.

Hand-held, dilation-free, electroretinography in children under 3 years of age treated with vigabatrin.

PURPOSE: The anti-epileptic drug vigabatrin is associated with reduction in light-adapted 30-Hz flicker electroretinogram (ERG) amplitude. Ophthalmological assessments, including ERGs, monitor retinal health during vigabatrin treatment. RETeval™ is a hand-held ERG device adapted for dilation-free ERG assessment. To evaluate the usefulness of RETeval™ for vigabatrin ERG assessment, we evaluated intra-visit reliability and clinical feasibility of RETeval™ ERG assessment in children under 3 years of age undergoing vigabatrin treatment. METHODS: In this prospective study, children underwent 30-Hz flicker ERG assessment with RETeval™ before routine vigabatrin monitoring including sedated-ERG using the Espion E2 Colour Dome. Intraclass correlation coefficient (ICC) statistics identified the degree of intra-visit reliability from two repeated measurements of the same participant within one testing session. The omega squared (ω2) statistic identified the level of association between RETeval™ and Espion light-adapted 30-Hz flicker responses. RESULTS: Nine children completed RETeval™ ERG testing. The intra-visit ICCs for the RETeval™ 30-Hz flicker amplitude (µV) were high: 0.81 (right eye) and 0.86 (left eye), while the implicit times (ms) were 0.79 (right eye) and 0.42 (left eye). The RETeval™ 30-Hz flicker amplitude was positively associated with the Espion 30-Hz flicker response (ω2 = 0.71). The Bland-Altman plot showed no bias in the mean difference of amplitudes between the two systems. CONCLUSION: This is the first study to assess the utility of RETeval™ device in children under 3 years of age undergoing vigabatrin treatment. RETeval™ demonstrated high intra-visit reliability with responses consistent with the standard Espion ERG. RETeval™ may be beneficial for assessment of retinal toxicity in young children treated with vigabatrin.

Corosolic acid: antiangiogenic activity and safety of intravitreal injection in rats eyes.

PURPOSE: Investigate the potential application of corosolic acid (CA) in the treatment of diseases causing retinal neovascularization. METHODS: CA cytotoxicity effect was evaluated in ARPE-19 cells by sulforhodamine B colorimetric method, and antiangiogenic activity was studied using chorioallantoic membrane (CAM) assay. An amount of 0.01 mL of CA formulations at 5, 10 and 25 µM was injected in the right eyes of Wistar rats, and the contralateral eyes received the vehicle to verify the safety of ophthalmic use. Electroretinography (ERG) was performed before, 7 and 15 days after CA administration. Animals were killed on the 15th day, and the histological analysis of retina was carried out under light microscopy. RESULTS: CA did not present cytotoxicity at concentrations below 35.5 µM after 48 h of treatment. The antiangiogenic activity was confirmed by CAM assay, since CA (range from 5 to 25 µM) induced a significant reduction in vascularity without any signs of toxicity. ERG recordings and histological evaluation did not show any signs of retinal toxicity. CONCLUSIONS: CA was effective in reducing vascularity in a CAM model and was found to be safe for potential ophthalmic use.

Revealing a retinal facilitatory effect with the multifocal ERG.

PURPOSE: We have previously shown that the amplitude of the mfERG response obtained to a single (large) hexagon is significantly smaller than that obtained when summating all the mfERG responses evoked to an array of 7-61 hexagons covering the same retinal area. The purpose of this study was to confirm our initial findings in normal subjects of different ages and in selected patients. METHODS: Binocular mfERGs (1, 7, 19, 37 and 61 hexagon arrays; Espion V6.0.54 Diagnosys LLC) were recorded from 40 normal subjects (25 aged 18-25, and 15 aged 3-12). Individual mfERG waveforms evoked in response to the multi-hexagon arrays (7, 19, 37 and 61) were summated, and the amplitude of the resulting composite mfERG waveform was compared to that measured in the response evoked to the single (large) hexagon stimulus to yield the amplitude ratio (i.e., 7:1 X100, 19:1X100, etc.). RESULTS: In normal subjects, the 7:1 ratio was 119.5 ± 9.2%, a value that gradually decreased to reach 109.4 ± 20.6% with the 61:1 ratio and a finding that was similar across all ages. CONCLUSION: The present study indicates a significant enhancement in amplitude of the summed mfERG composite waveform evoked to the 7 hexagon stimulus array (and to a lesser extent to the 19, 37 and 61 stimuli) compared to the 1 hexagon array, possibly mediated through the retinal lateral pathway (horizontal or amacrine cells), a claim that awaits confirmation. Preliminary results obtained from patients treated with Plaquenil suggest that this new method of mfERG analysis might probe a feature of macular function different from that investigated with the more usual method of mfERG ring ratio.

The Effect of Atropine on Human Global Flash mfERG Responses to Retinal Defocus.

Purpose: To investigate the action of atropine on global flash multifocal electroretinogram (gmfERG) responses to retinal defocus. Method: gmfERG recordings were made monocularly in 19 healthy adults under three lens-imposed defocus conditions (2 diopters myopic, 2 diopters hyperopic, and no defocus) before and 24 hours after instillation of 1 drop of 0.1% atropine. Signals reflecting activity from the outer and inner retina (direct [DC] and induced [IC] components respectively) were analyzed. Responses were grouped into either a central (0°-6°) or peripheral (6°-24°) retinal zone. The gmfERG responses were compared relative to the no defocus, no atropine condition. Results: Within the central zone, atropine had no effect on the amplitudes and peak times of DC or IC responses to defocus. For IC responses in the peripheral zone, there was a significant interaction effect of atropine and defocus (F2,36 = 6.050, P = 0.011) with greater post-atropine amplitudes under myopic defocus (mean increase = 15.5%, 95% confidence interval [CI] = 5.6%-25.4%, P = 0.004). Atropine also had a significant main effect of increasing IC peak times (F1,18 = 9.722, P = 0.006). For DC responses, atropine had a significant main effect of increasing DC amplitudes (F1,18 = 7.821, P = 0.012) and peak times (F1,18 = 15.406, P = 0.001) regardless of sign of defocus. Conclusions: Our results imply that atropine acts in the inner layers of the peripheral retina to affect neuronal responses to myopic defocus, raising the possibility that atropine may potentiate the effects of myopic defocus in inhibiting eye growth.

Little effect of 0.01% atropine eye drops as used in myopia prevention on the pattern electroretinogram.

PURPOSE: Daily administration of 0.01% atropine eye drops is a promising approach for myopia control. The mechanism of action is believed to involve the dopaminergic system of the retina, triggering an increased release of dopamine. Previous studies in psychiatric condition such as major depression suggest that pattern electroretinogram (PERG) amplitudes are modulated by changes in retinal dopamine. It is thus plausible that atropine eye drops could have an effect on PERG amplitudes. The present study was designed to test this, assessing the difference in amplitude between contrast levels and the ratio of amplitudes between check sizes as primary endpoints. METHODS: We included 14 participants with no more than ± 2 diopters of ametropia and visual acuity of at least 1.0. One eye was chosen randomly in each participant for atropine application (14 days, one drop of 0.01% atropine solution once daily before bedtime). We recorded two sets of steady-state PERG recordings: one with different contrasts (25% and 98%) and one with different check sizes (0.8° and 17°). Near-point distance, near visual acuity, and pupil diameter were measured additionally. RESULTS: The recordings to different contrasts did not show atropine-related changes of PERG amplitude. A small increase by 6% of the amplitude difference between contrast levels with atropine application was not significant (p = 0.08). Raw amplitudes in the check size condition increased with atropine by 17% (p < 0.01) and 10% (p < 0.03) for small and large checks, respectively, without a significant concomitant effect on the amplitude ratio. Pupil size was significantly affected (median increase 0.5 mm, p < 0.002). However, neither of the experimental conditions was associated with a significant correlation between pupil size and PERG effects. CONCLUSION: The effects on PERG primary endpoints after the 14-day period of atropine administration were small, especially compared to effect sizes in major depression, and statistically insignificant. Effects on raw amplitude were inconsistent. The present results suggest that retinal processing as reflected by PERG does not sizably change following a treatment regimen with atropine that is typical for myopia control.

Availability of multistep light stimulus method for evaluation of visual dysfunctions.

In the field of drug safety research, electroretinography (ERG) is commonly conducted according to the international standard method propounded by the International Society for Clinical Electrophysiology of Vision (ISCEV) in recent years. However, various ERG methods other than the ISCEV standard method are also utilized depending on the intended purpose of the evaluation. In this study, we investigated the availability of a multistep light stimulus method for evaluation of rod function in Long-Evans rats using sildenafil, which is known to inhibit phosphodiesterase 6 (PDE6) in phototransduction and induce visual dysfunctions in humans. Sildenafil was orally administered to female Long-Evans rats at doses of 15, 50, and 150 mg/kg, and ERG was recorded at 1.5 h after treatment. In addition to a - 2.0 log cd·s/m2 stimulus corresponding to dark-adapted 0.01 ERG in the ISCEV standard method, light stimulus intensities of -4.5, -4.0, -3.0, -1.0, 0.0, and +1.0 log cd·s/m2 were applied for multistep ERG recording. The amplitude and implicit time of the a-wave were decreased and prolonged, respectively, at doses of ≥50 mg/kg. The amplitude and implicit time of the b-wave were decreased and prolonged, respectively, at all doses. However, the b-wave at 15 mg/kg was only diminished or attenuated at ≤ - 3.0 log cd·s/m2, as weaker stimuli than dark-adapted 0.01 ERG in the ISCEV standard protocol. These findings suggest that sildenafil triggers visual dysfunctions through PDE6 inhibition, and indicate that the multistep light stimulus method is highly sensitive for detection of phototransduction abnormalities in retinal rod cells.

Clinical display of mfERG data.

PURPOSE: Many mfERG displays show normal responses that are larger at the center than peripherally, and the typical linear display of signals is inaccurate with respect to the retinal location of the signals. Printouts do not always indicate retinal or field view, they sometimes emphasize 3-D topographic plots which are not always representative of physiologic signals, and they show ring response densities which are different in every ring and hard to interpret without norms. These problems limit the clinical usefulness of the mfERG and limit communication in the literature. We share our Stanford Display to illustrate possible solutions to these problems. METHODS: We have changed the scaling factor for our mfERG unit to produce a trace array with near equal signals everywhere. We display responses is a spatially scaled array, in a retinal view, so that signals appear in their correct anatomic locations relative to a fundus image. The 3-D display is minimized on the page of signal analysis, and we emphasize ring response averages rather than ring response densities. RESULTS: The new scaling and trace array display greatly facilitate the analysis of retinal disease. Regions of loss are easily recognized in their fundus location. Ring ratios based upon response amplitudes all have a normal value of 1.0 which simplifies analysis. A case of early hydroxychloroquine retinopathy demonstrates the use of this Stanford display. CONCLUSIONS: Recognition of these recording and display options may help mfERG users to maximize the value of the test. Proper scaling of the mfERG stimulus array facilitates localization of retinal disease and simplifies ring response analysis. Different laboratories will have different priorities for signal analysis, but mfERG displays should always indicate the eccentricity of responses, and the use of a retina or field view.