Transcorneal Electrical Stimulation Research Articles

Transcorneal electrical stimulation reduces the annual rate of visual field decline in retinitis pigmentosa

AbstractPurposeIn retinitis pigmentosa (RP) the visual field area (VFA) declines exponentially. We investigated whether the annual decline rate (ADR) can be slowed by transcorneal electrical stimulation (TcES).MethodsWe conducted an a posteriori analysis of data from 51 adult patients with RP who participated in an interventional, randomized, single‐masked study (clinicaltrials.gov: NCT01837901; Schatz et al., 2017, IOVS 58(1)). Patients were randomized into 3 groups stimulated with 0 mA (sham stimulation), 150% or 200% of their phosphene threshold, respectively. Over one year, TcES was applied monocularly, 30 min per week with biphasic current pulses (OkuStim, 5 ms each phase, 20 Hz, 0.2 to 1.0 mA). VFA were repeatedly assessed in both eyes (Octopus 900, target V4e). VFA values were normalized to percentage of baseline value, transformed into the natural logarithm, averaged within groups, and subjected to a weighted linear regression analysis. ADR was calculated from the slope of best fit line for both eyes in the sham group (n = 20) and in the treated group (n = 31, 150% and 200% groups pooled).ResultsIn the sham group, for the stimulated eyes the ADR was 8.0% (F‐test for slope: p = 0.011) while for the non‐stimulated eyes it was 9.6% (p = 0.005). In the treated group, for the stimulated eyes the ADR was 3.4% (p = 0.276), and for the non‐stimulated eyes it was 7.0% (p = 0.035). The difference between the ADR in the stimulated and non‐stimulated eyes was evident when only eyes stimulated with >0.8 mA (n = 9) were included. The progression in the stimulated eyes had almost stopped, the ADR was 2.7% (p = 0.397) compared to 9.2% (p = 0.022) in the non‐stimulated eyes. The analysis is limited by data variability, sample size and observation period.ConclusionThe analysis showed that the ADR can be markedly slowed by TcES in a dose‐dependent manner. Thus, regular use of TcES is an effective therapeutic method for slowing or arresting disease progression in RP.

Outcomes of transcorneal electrical stimulation therapy in the early stages of retinitis pigmentosa.

To investigate the effect of transcorneal electrical stimulation (TES) therapy in patients with retinitis pigmentosa (RP). We performed TES therapy in 21 patients with RP in 12 sessions with 1-week intervals. The following parameters obtained before and after the TES therapy were compared statistically; the best corrected visual acuity (BCVA, logMAR), Ishihara color vision level, multifocal electroretinography (mf-ERG) response, automated visual field (VF) outcome, and the 25-item low vision quality-of-life (LVQOL) questionnaire points. The mean age of patients (6 females; 15 males) was 31.67 ± 9.80 years (20-50 years). While increases in BCVA level, color vision level, mf-ERG response in p1 amplitude of ring 1, and LVQOL questionnaire points were statistically significant, changes in VF test and other mf-ERG responses were not. Twenty of the patients (95.24%) stated that they were satisfied with the TES therapy. No considerable side effect was observed in any patient due to the therapy. The TES therapy may be an effective and safe treatment modality in slowing the RP progression, especially in the early stages of the disease. Longer-term follow-ups in larger patient populations are warranted.

ECoG Power Alterations Across Stages of Prolonged Transcorneal Electrical Stimulation in the Blind Mice.

Transcorneal electrical stimulation (TES) is a noninvasive approach for activating the retina and its downstream components through the application of electric current on the cornea. Although previous studies have demonstrated the clinical relevance of TES for modulating neurons with improvements in visual evoked potentials (VEPs) and electroretinograms (ERGs), there are still huge gaps in knowledge of its effect on the brain structures. To determine the short-term impact as well as the aftereffects of TES on neural oscillatory power in retinal degeneration mice, we performed electrocorticography (ECoG) recording in the prefrontal and primary visual cortices at different stages of prolonged TES [transient stage, following prolonged stimulation (post-stimulation stage 1) and long after the end of the retinal stimulation (post-stimulation stage 2)]) under varying stimulation current amplitudes (400 µA, 500 µA and 600 µA). The results revealed asymmetric differences between short-term and long-term pTES under different stimulation current amplitudes. Specifically, in post-stimulation stage 1 we observed significant increase in ECoG power of theta, alpha and beta oscillations respectively compared with baseline pre-stimulation results. These effects were dependent on the stimulation current amplitude and stimulation stage. Transient TES was not sufficient to cause significant changes in the ECoG power of all accessed oscillations except in medium, high and ultra-gamma oscillations which significantly decreased in 400 µA and 500 µA stimulation groups respectively compared with pre-stimulation results. Regarding long-term stimulation, the increase in ECoG power of theta, alpha and beta oscillations observed in post-stimulation stage 1 was significantly maintained in post-stimulation stage 2.Clinical Relevance- These results could be of core importance for human TES protocols suggesting that following pTES and long after the end of the stimulation, TES current amplitudes could have relatively different impacts on the power/activity of cortical oscillations. For example, by increasing the activity of oscillations that have been reported to inhibit irrelevant neural processes and enable the brain to focus on more relevant neural processes thus, inducing better coordination in the cortex.

On the Design of an Efficient Inductive Wireless Power Transfer for Passive Neurostimulation Systems.

In this paper, a minimally invasive wireless powered electronic lens (e-lens) with passive electrodes is presented for an ocular electrical stimulation. Previous research has focused on the differentiation property of the induction phenomenon and half wave rectifiers. However, these approaches are generally application specific, non efficient, suitable for low current, and deliver monophasic current stimulation. Existing rectifier-based techniques can lead to safety concerns as the offset voltage could change unpredictably. A new wireless power transfer circuit is presented for the design of an efficient system to wirelessly deliver charge-balanced biphasic waveforms through passive electrodes for transcorneal electrical stimulation. The absence of active components allows the development of a flexible e-lens system for therapeutic electrical stimulation of the eye.

Metabolic Long-Term Monitoring of Transcorneal Electrical Stimulation in Retinitis Pigmentosa

Introduction: Transcorneal electrical stimulation (TES) is a new therapeutical approach for retinitis pigmentosa (RP). With progression of RP, degeneration of photoreceptors results in lower oxygen consumption of the retina. Retinal oximetry (RO) is a noninvasive method to analyze oxygen saturation in retinal vessels and has shown promising short-term results as a therapy monitoring tool for TES. The aim of our study was to measure the long-term effects of TES on RO parameters over a period of 3 years (3Y). Methods: A total of 18 eyes of 9 subjects (5♀ 4♂) suffering from RP were examined at baseline (BL), 6 months, and 3Y of TES (OkuStim®) treatment. TES was performed for 30 min once a week at 200% of the individual phosphene threshold simultaneously on both eyes. The oxygen saturation was examined at BL and following TES therapy with the oxygen saturation tool of the Retinal Vessel Analyser (IMEDOS Systems UG, Jena, Germany). The global oxygen saturation parameters (in %), within 1.0–1.5 optic-disc diameters from the disc margin, in retinal arterioles (A-SO₂) and venules (V SO₂) were measured and their difference (A-V SO₂) was calculated. In addition, we recorded the diameters in the main arterioles (D-A) and venules (D-V). ANOVA-based linear mixed-effects models were employed for statistical analysis using SPSS®. Results: After 3Y of TES treatment both the mean A-SO₂ (from 96.35 ± 12.76% to 100.89 ± 5.87%, p = 0.22) and V SO₂ (from 62.20 ± 11.55% to 64.55 ± 8.24%, p = 0.77) increased slightly. The A-V SO₂, which corresponds to the oxygen consumption of the retina, presented also with a slight increment from 34.15 ± 9.68% at BL to 36.23 ± 7.71% without reaching statistical significance (p = 0.27). TES also did not appear to alter the vascular diameter parameters, D-A and D-V (p > 0.05). Conclusion: Our long-term observations indicate that TES therapy in RP might lead to a slight increment in oxygen consumption of the retina. However, a larger cohort and longer duration may be needed to adequately power a follow-up study and to confirm this trend reflecting a possible benefit of TES for RP.

Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression.

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

Transcorneal Electrical Stimulation and Platelet Rich Plasma Therapies in Retinitis Pigmentosa Disease

There is no cure for Retinitis Pigmentosa disease today. Recently, transcorneal electrical stimulation and platelet-rich plasma therapies have begun to take place in clinical practice during the treatment process. The main goals of these promising therapies are to slow the progression of the disease, to protect and increase visual functions. The presented review includes current information about these therapies.

Computational Modeling of Spatially Selective Retinal Stimulation With Temporally Interfering Electric Fields.

Retinal electrical stimulation is a widely utilized method to restore visual function for patients with retinal degenerative diseases. Transcorneal electrical stimulation (TES) represents an effective way to improve the visual function due to its potential neuroprotective effect. However, TES with single electrode fails to spatially and selectively stimulate retinal neurons. Herein, a computational modeling method was proposed to explore the feasibility of spatially selective retinal stimulation via temporally interfering electric fields. An eyeball model with multiple electrodes was constructed to simulate the interferential electric fields with various electrode montages and current ratios. The results demonstrated that the temporal interference (TI) stimulation would gradually generate an increasingly localized high-intensity region on retina as the return electrodes moved towards the posterior of the eyeball and got closer. Additionally, the position of the convergent region could be modulated by regulating the current ratio of different electrode channels. The TI strategy with multisite and steerable stimulation can stimulate local retinal region with certain convergence and a relatively large stimulation range, which would be a feasible approach for the spatially selective retinal neuromodulation.

Optical coherence tomography angiography findings in transcorneal electrical stimulation in retinitis pigmentosa

PurposeTranscorneal electrical stimulation (TES) is a novel treatment approach for patients with retinitis pigmentosa (RP). The aim of our study was to observe changes in optical coherence tomography angiography (OCTA) that would be attributed to TES treatment.MethodsA total of 43 eyes of 22 subjects (11♀ 11♂) suffering from RP were examined at baseline (BL), after first stimulation (TS), 1 week after first stimulation (1W) and six months (6M) after treatment initiation. TES was performed simultaneously on both eyes for 30 minutes weekly. 9 × 15 mm OCTA scans were recorded with a PLEX Elite 9000 swept‐source OCTA device (Carl Zeiss Meditec AG, Jena). Vascular density metrics as perfusion density (PD) and vessel density (VD) were calculated automatically for the macular area by using standardized ETDRS grids. In addition, the capillary perfusion density (CPD) and the capillary flux index (CFI) of the peripapillary nerve fibre layer microvasculature in all four quadrants of an annulus centred at the optic disc were measured. All parameters were determined over all retinal layers and separately for the superficial (SCP) and deep capillary plexus (DCP). ANOVA‐based linear mixed‐effects models were calculated with SPSS®.ResultsThroughout the course of TES treatment, the macular VD and PD of all retinal layers in all subsections showed a slight decrement without reaching statistical significance (p > 0.05), also when analysed separately in the SCP (p > 0.06) and DCP (p > 0.11). In analogy, the average CPD and CFI also presented with a slight decrement (p > 0.19). When analysed in subsections, the temporal macular subsections showed significantly lower VD and PD values when compared to the other subsections of the ETDRS grid.ConclusionsOur preliminary data with SS‐OCTA indicate that vascular density metrics in the macular region and the peripapillary microvasculature remain unaffected despite ongoing TES treatment.

Optical coherence tomography angiography findings in patients undergoing transcorneal electrical stimulation for treating retinitis pigmentosa

PurposeTranscorneal electrical stimulation (TES) is a novel treatment approach for patients with retinitis pigmentosa (RP). The aim of our study was to observe changes in optical coherence tomography angiography (OCTA) that would be attributed to TES treatment.MethodsA total of 73 eyes were included: 43 eyes of 22 subjects (11 ♀, 11 ♂) suffering from RP were examined at baseline (BL), after first stimulation (TS), 1 week (1W), and 6 months (6M) after treatment initiation and were compared with 30 control eyes of 15 subjects (8 ♀, 7 ♂). TES was performed simultaneously on both eyes for 30 min weekly. OCTA scans of 9 × 15 mm were recorded with a PLEX Elite 9000 swept-source OCTA device (Carl Zeiss Meditec AG, Jena). Vascular density metrics such as perfusion density (PD) and vessel density (VD) were calculated automatically for the macular area by using standardised extended early treatment diabetic retinopathy study (ETDRS) grids centred around the fovea. In addition, the capillary perfusion density (CPD) and the capillary flux index (CFI) of the peripapillary nerve fibre layer microvasculature in all four quadrants of an annulus centred at the optic disc were measured. All parameters were determined over all retinal layers and separately for the superficial (SCP) and deep capillary plexus (DCP). ANOVA-based linear mixed-effects models were calculated with SPSS®.ResultsThroughout the course of TES treatment, the macular VD and PD of all retinal layers in all subsections showed a slight decrement without reaching statistical significance, also when analysed separately in the SCP and DCP (p > 0.08). In analogy, the average CPD and CFI also presented with a slight decrement (p > 0.20). However, when compared with controls, most OCTA parameters showed a significant decrement (p < 0.05). When analysed systematically in all subsections of the extended ETDRS grid, the temporal macular subsections within the outer ring (radius 1.5–3 mm) and also of the peripheral C1, C2, and C3 rings (radius 3–7.5 mm) showed lower VD and PD values when compared with the other subsections (p < 0.05).ConclusionVascular density metrics in the macular region and the peripapillary microvasculature appear to remain unaffected by continuous TES treatment within a period of 6 months.

Excitation of the Pre-frontal and Primary Visual Cortex in Response to Transcorneal Electrical Stimulation in Retinal Degeneration Mice

Retinal degeneration (rd) is one of the leading causes of blindness in the modern world today. Various strategies including electrical stimulation are being researched for the restoration of partial or complete vision. Previous studies have demonstrated that the effectiveness of electrical stimulation in somatosensory, frontal and visual cortices is dependent on stimulation parameters including stimulation frequency and brain states. The aim of the study is to investigate the effect of applying a prolonged electrical stimulation on the eye of rd mice with various stimulation frequencies, in awake and anesthetized brain states. We recorded spontaneous electrocorticogram (ECoG) neural activity in prefrontal cortex and primary visual cortex in a mouse model of retinitis pigmentosa (RP) after prolonged (5-day) transcorneal electrical stimulation (pTES) at various frequencies (2, 10, and 20 Hz). We evaluated the absolute power and coherence of spontaneous ECoG neural activities in contralateral primary visual cortex (contra Vcx) and contralateral pre-frontal cortex (contra PFx). Under the awake state, the absolute power of theta, alpha and beta oscillations in contra Vcx, at 10 Hz stimulation, was higher than in the sham group. Under the anesthetized state, the absolute power of medium-, high-, and ultra-high gamma oscillations in the contra PFx, at 2 Hz stimulation, was higher than in the sham group. We also observed that the ultra-high gamma band coherence in contra Vcx-contra PFx was higher than in the sham group, with both 10 and 20 Hz stimulation frequencies. Our results showed that pTES modulates rd brain oscillations in a frequency and brain state-dependent manner. These findings suggest that non-invasive electrical stimulation of retina changes patterns of neural oscillations in the brain circuitry. This also provides a starting point for investigating the sustained effect of electrical stimulation of the retina to brain activities.

Transcorneal Electrical Stimulation Reduces Neurodegenerative Process in a Mouse Model of Glaucoma.

Glaucoma is a neurodegenerative disease in which the retinal ganglion cell axons of the optic nerve degenerate concomitant with synaptic changes in the retina, leading finally to death of the retinal ganglion cells (RGCs). Electrical stimulation has been used to improve neural regeneration in a variety of systems, including in diseases of the retina. Therefore, the focus of this study was to investigate whether transcorneal electrical stimulation (TES) in the DBA2/J mouse model of glaucoma could improve retinal or optic nerve pathology and serve as a minimally invasive treatment option. Mice (10months-old) received 21 sessions of TES over 8weeks, after which we evaluated RGC number, axon number, and anterograde axonal transport using histology and immunohistochemistry. To gain insight into the mechanism of proposed protection, we also evaluated inflammation by quantifying CD3+ T-cells and Iba1+ microglia; perturbations in metabolism were shown via the ratio pAMPK to AMPK, and changes in trophic support were tested using protein capillary electrophoresis. We found that TES resulted in RGC axon protection, a reduction in inflammatory cells and their activation, improved energy homeostasis, and a reduction of the cell death-associated p75NTR. Collectively, the data indicated that TES maintained axons, decreased inflammation, and increased trophic factor support, in the form of receptor presence and energy homeostasis, suggesting that electrical stimulation impacts several facets of the neurodegenerative process in glaucoma.

Non-invasive current stimulation in vision recovery: a review of the literature.

Background:Around 253 million people worldwide suffer from irreversible visual damage. Numerous studies have been carried out in order to unveil the effects of electrical stimulation (ES) as a useful tool for rehabilitation for different visual conditions and pathologies.Objective:This systematic review aimed to 1) examine the current evidence of ES efficacy for the treatment of visual pathologies and 2) define the corresponding degree of the recommendation of different ES techniques.Methods:A systematic review was conducted in MEDLINE and Cochrane Library database to collect documents published between 2000 and 2018. For each study, Level of Evidence of Effectiveness of ES as well as the Class of Quality for the treatment of different visual pathologies were determined.Results:Thirty-eight articles were included. Studies were grouped according to the pathology treated and the type of stimulation administered. The first group included studies treating pre-chiasmatic pathologies (age-related macular degeneration, macular dystrophy, retinal artery occlusion, retinitis pigmentosa, glaucoma, optic nerve damage, and optic neuropathy) using pre-chiasmatic stimulation; the second group included studies treating both pre-chiasmatic pathologies (amblyopia, myopia) and post-chiasmatic pathologies or brain conditions (hemianopsia, brain trauma) by means of post-chiasmatic stimulation. In the first group, repetitive transorbital alternating current stimulation (rtACS) reached level A recommendation, and transcorneal electrical stimulation (tcES) reached level B. In the second group, both high-frequency random noise stimulation (hf-RNS) and transcranial direct current stimulation (tDCS) reached level C recommendation.Conclusions:Study’s findings suggest conclusive evidence for rtACS treatment. For other protocols results are promising but not conclusive since the examined studies assessed different stimulation parameters and endpoints. A comparison of the effects of different combinations of these variables still lacks in the literature. Further studies are needed to optimize existing protocols and determine if different protocols are needed for different diseases.

Effect of Transcorneal Electrical Stimulation on Patients with Retinitis Pigmentosa.

Purpose: In this study, the aim was to evaluate the safety of transcorneal electrical stimulation (TES) treatment in retinitis pigmentosa (RP) patients and to investigate the effect of TES to the visual acuity (VA), visual field (VF), and multifocal electroretinogram (mfERG) findings. Methods: Two hundred two eyes of 101 RP patients with different stages were studied. TES was applied for 30 min once a week for 8 consecutive weeks. Two hundred eyes of 100 RP patients were enrolled as control. After the 2-month TES therapy sessions, patients were followed for 4 months without treatment. Examinations were done at the baseline before TES treatment and 1 and 6 months after the treatment. Best-corrected VA (BCVA), color fundus photography, VF test, optical coherence tomography, and mfERG tests were done at each visit. Results: The mean BCVA and VF tests improved 1 month after the beginning of TES treatment and the improvements were statistically significant (P < 0.05). There was an improvement in p1 wave amplitude in rings 1, 2, and 3 at the first month. The latency of the p1 wave showed a statistically significant shortening in rings 1 and 2. These improvements partially disappeared at 6-month follow-up. There were no serious ocular side effects related to the therapy. Mild dry eye symptoms were observed, which were revealed by artificial tears. Conclusions: TES is a safe therapy without any serious advers effects. Although it can improve VA and VF of RP patients, the beneficial effects could be transient and repeated sessions can be necessary for maintaining the efficiency.

Retinal neurovascular responses to transcorneal electrical stimulation measured with optical coherence tomography.

Noninvasive transcorneal electrical stimulation (TES) has emerged as a potential strategy to facilitate visual restoration and promote retinal cell survival for certain retinal and optic nerve diseases owing to its neuroprotective effects. However, the neurovascular responses of retinal neurons evoked by TES have not been completely determined. To investigate this issue, we utilized a custom-designed spectral-domain optical coherence tomography (SD-OCT) to record the retinal neural and vascular responses under TES in vivo simultaneously. Significant increases of both positive and negative intrinsic optical signal (IOS) changes were recorded in all three segmented retinal layers, which mainly related to neural activities. However, the changes of TES-induced retinal vascular responses, including blood velocity, cross-sectional area of vessel, and blood flow, were not significant. It suggests that TES mainly elicited neural responses in retina, while no significant vascular responses were evoked. Our results provide experimental evidence to the mechanism of retinal neurovascular coupling under TES. Additionally, the present study also suggests that SD-OCT could be utilized as a promoting method to explore neurovascular responses under retinal stimulation in clinical treatment and technology. Impact statement Noninvasive transcorneal electrical stimulation (TES) has emerged as an effective treatment for certain retinal and optic nerve diseases owing to its neuroprotective effects. However, the retinal neurovascular responses evoked by TES have not been completely determined. To investigate this issue, we utilized a custom-designed spectral-domain optical coherence tomography (SD-OCT) to record the retinal neural and vascular responses evoked by TES in vivo simultaneously. The present study suggested that TES mainly elicited neural responses in retina, while no significant vascular responses were evoked. Our results provide experimental evidence to the mechanism of retinal neurovascular coupling evoked by TES. Additionally, the present study also suggests that SD-OCT could be utilized as a promoting method to explore neurovascular responses under retinal electrical stimulation.

Retinal vessel oximetry as a sensitive metabolic monitoring method for transcorneal electrical stimulation in retinitis pigmentosa

AbstractBackgroundTranscorneal electrical stimulation (TES; OkuStim®) is a novel therapy method for patients with retinitis pigmentosa (RP). With progression of RP, loss of photoreceptors leads to less oxygen consumption and lower demand in the inner retina. Retinal oximetry (RO) as a non‐invasive method to analyze oxygen saturation in retinal vessels promises to be a useful therapy monitoring tool. The aim of our study was to compare the RO parameters at baseline and following TES.MethodsA total of 43 eyes of 22 subjects (11♀ 11♂) suffering from RP were examined. Stimulation was performed for 30 minutes weekly at 200% of the individual phosphene threshold on both eyes. The oxygen saturation was examined at baseline (BL), 1 week and 6 months after TES stimulation with the oxygen saturation tool of the Retinal Vessel Analyser (IMEDOS Systems UG, Germany). The global oxygen saturations, within 1.0–1.5 optic disc diameters from the disc margin, in retinal arterioles (A‐SO2; %) and venules (V‐SO2; %) were estimated and their difference (A‐V SO2; %) was calculated. In addition, we evaluated the diameters in the corresponding arterioles (D‐A; μm) and venules (D‐V; μm). ANOVA‐based linear mixed‐effects models were calculated with SPSS®.ResultsSix months after TES the A‐SO2 showed a tendency to increase (from 96.48 ± 12.27% to 100.15 ± 5.56%, p = 0.09), while the V‐SO2 showed a slight decrease (from 61.61 ± 12.78% to 59.79 ± 11.15%, p = 0.48). The A‐V SO2, which represents the oxygen consumption of the retina, showed a significant increase from 34.87 ± 9.38% at BL to 41.36 ± 9.18% after 6 months (p = 0.02). TES had no influence on the D‐A and D‐V (p &gt; 0.6).ConclusionThese data indicate that TES therapy in RP leads to an increased oxygen consumption of the retina. Thus, RO proves to serve as a sensitive monitoring method for TES therapy in RP patients.

Transcorneal Electrical Stimulation for the Treatment of Retinitis Pigmentosa: A Multicenter Safety Study of the OkuStim® System (TESOLA-Study)

Background: Transcorneal electrical stimulation (TES) has been suggested as a possible treatment for retinitis pigmentosa (RP). Objective: To expand the safety assessment of repeated applications of an electrical current from a DTL-like electrode in patients with RP. Methods: This single-arm open label interventional safety trial included a total of 105 RP patients from 11 European centers, who received weekly TES for 6 months on 1 eye followed by observation for another 6 months without stimulation. The primary outcome measure was safety, indicated by the frequency and severity of adverse events. Secondary measures included intraocular pressure and central retinal thickness. Visual field and visual acuity were examined using the methods available at each site. Results: Dry eye sensation was the most common adverse event recorded (37.5%). Serious adverse events secondary to TES were not observed. Most adverse events were mild and all resolved without sequelae. The secondary outcome measures revealed no significant or clinically relevant changes. Conclusion: The present results confirm the excellent safety profile of TES. Transient dry eye symptoms were the most common adverse event.

Metabolic monitoring of transcorneal electrical stimulation in retinitis pigmentosa.

Transcorneal electrical stimulation (TES) is a novel treatment approach for patients with retinitis pigmentosa (RP). With progression of RP, loss of photoreceptors leads to less oxygen consumption and lower demand in the retina. Retinal oximetry (RO), as a non-invasive method to analyse oxygen saturation in retinal vessels, promises to be a useful therapy monitoring tool. The aim of our study was to observe changes in RO that would be attributed to therapeutic intervention. A total of 43 eyes of 22 subjects (11♀ 11♂) suffering from RP were examined at baseline, after the first stimulation, 1 week and 6 months after TES (OkuStim®). Stimulation was performed for 30 min weekly at 200% of the individual phosphene threshold, simultaneously on both eyes. The oxygen saturation was examined at baseline and following TES stimulation with the oxygen saturation tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The global oxygen saturation parameters (in %), within 1.0-1.5 optic disc diameters from the disc margin, in retinal arterioles (A-SO2) and venules (V-SO2) were estimated and their difference (A-V SO2) was calculated. In addition, we evaluated the diameters (in μm) in the corresponding arterioles (D-A) and venules (D-V). ANOVA-based linear mixed-effects models were calculated with SPSS®. Six months after TES treatment, the mean A-SO2 increased (from 96.48 ± 12.27 to 100.15 ± 5.56%, p = 0.09), while the V-SO2 decreased (from 61.61 ± 12.78 to 59.79 ± 11.15%, p = 0.48). The A-V SO2, which represents the oxygen consumption of the retina, showed a statistically significant increase from 34.87 ± 9.38% at baseline to 41.36 ± 9.18% after 6 months (p = 0.02). TES had no influence on the D-A and D-V (p > 0.6). These data indicate that TES therapy in RP leads to an increased oxygen consumption of the retina. RO may thus serve as a sensitive monitoring method for TES therapy in RP.

Electrically Evoked Potentials Are Reduced Compared to Axon Numbers in Rhodopsin P347L Transgenic Rabbits With Severe Photoreceptor Degeneration.

To determine the relationship between the amplitudes of the electrically evoked potentials (EEPs) and the number of optic nerve axons at a late stage of retinal degeneration in rhodopsin P347L transgenic (Tg) rabbits, a model of retinitis pigmentosa. Six eyes of six wild-type (WT) (43.8 ± 7.5 months of age) and six eyes of six Tg (40.3 ± 2.6 months of age) rabbits were studied. The EEPs were elicited by 1 to 5 mA of transcorneal electrical stimulation. The first positive wave, the P1 component, was analyzed. After euthanasia, the number of axons in the optic nerve was counted. The threshold current to elicit a P1 was significantly higher in Tg rabbits than WT rabbits. The amplitude of P1 elicited by 5 mA in Tg rabbits was about 24% of that in WT rabbits (P < 0.01). The number of axons in the optic nerve of Tg rabbits was reduced to about 59% of that of WT rabbits (P < 0.01). The correlation between the axon number and the amplitude of the P1 in Tg and WT rabbits was not significant. The mean ratio of the P1 amplitude/axon in Tg rabbits was decreased to 53% of that in WT rabbits (P < 0.05). The degree of reduction in the EEP in Tg rabbits is more severe than the reduction in the number of optic nerve axons. The use of transcorneal electrical stimulation to determine the suitable candidates for prosthesis at the end-stage of retinitis pigmentosa may underestimate the condition of the optic nerves.

A study protocol for evaluating the efficacy and safety of skin electrical stimulation for Leber hereditary optic neuropathy: a single-arm, open-label, non-randomized prospective exploratory study.

Background: Leber hereditary optic neuropathy (LHON) is a maternally inherited disease caused by three missense mutations of mitochondrial (mt) DNA, ie, m 3460 G>A, m 11778 G>A, or m 14484 T>C in the greater portion of LHON. m 11778 G>A mutation is especially observed in >90% of the cases in Japanese families. Although spontaneous remission of visual function infrequently occurs, effective treatment for LHON remains unestablished. Transcorneal electrical stimulation has been shown to be efficacious in individuals with optic neuropathy. However, due to potential risk of corneal damage, repeated treatments are not permissible. In this exploratory study, we will be conducting skin electrical stimulation (SES) as an intervention for patients with LHON having 11778 missense mutation and investigate effectiveness and safety of SES.Methods: This is a single-arm, prospective, open-label exploratory trial focused on patients with LHON having 11778 missense mutation. Eleven patients will be enrolled and receive six consecutive SES once every 2 weeks up to 10 weeks. The safety of the SES will be monitored with specular microscopy, slit-lamp biomicroscopy, fundus examinations, and the observation of facial skin. The primary outcome measure will be the averaged l ogarithm of minimum angle resolution (logMAR) converted visual acuity 1 week after the last SES. Secondary outcome measures include changes, in logMAR at 4 and 8 weeks after the last SES, such as visual field indices measured using Humphrey visual field and microperimetry-3, the thickness of peripapillary retinal fiber and macular ganglion cell complex, multifocal visual evoked potentials, critical flicker frequency, and color vision.Discussion: The results of this proposed proof-of-concept feasibility trial will help plan and execute a larger definitive trial to test SES as an effective strategy for LHON and related optic neuropathies and help establish a beneficial treatment for LHON.