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Changes in visual acuity from before to after skin electrical stimulation. LogMAR BCVA, logarithm of minimal angle resolution-converted best-corrected decimal visual acuity. Courses of individual cases.
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Leber hereditary optic neuropathy (LHON) is an intractable disease associated with mitochondrial DNA (mtDNA) mutations. In this preliminary, single-arm, prospective, open-label exploratory trial, we investigated the effectiveness and safety of skin electrical stimulation (SES) for cases of LHON harboring the mtDNA 11,778 mutation. Of the 11 enrolle...
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Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of...
Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder with the majority of patients harboring one of three primary mtDNA point mutations, namely, m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6). LHON is characterized by bilateral subacute loss of vision due to the preferential loss of r...
REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2- ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A ( MT-ND4 ) mutation and with duration of vision loss be...
Optic nerve disorders encompass a wide spectrum of conditions characterized by the loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. The etiology of these disorders can vary significantly, but emerging research highlights the crucial role of oxidative stress, an imbalance in the redox status characterized by an e...
Leber Hereditary Optic Neuropathy (LHON) affects a minority of carriers of causative mitochondrial DNA mutations. We investigated a cohort of patients with LHON, including m.11778G>A, m.3460G>A, m.14484T>C and DNAJC30 c.152A>G variants, and their asymptomatic maternal carrier relatives for additional potential associations with vision loss. We asse...
Citations
... Electrical stimulation therapy is thought to be effective when a patient's RGC are alive but nonfunctional or when progenitor-cell plasticity is retained (Kurimoto et al. 2020). Phosphenes are visual perceptions Fig. 4 The mean and changes in logMAR visual acuity during the study period. ...
Background
No effective treatment for NAION with strong evidence has been established till date. The aim of this investigator-led, prospective, non-randomized, open-label, uncontrolled multi-center exploratory clinical trial is to evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with NAION.
Methods
Five patients with monocular NAION underwent TdES (10-ms biphasic pulses, 1.0 mA, 20 Hz, 30 min) of the affected eye six times at 2-week intervals. The primary endpoint was the logarithm of the mini-mum angle of resolution (logMAR) visual acuity at 12 weeks compared with 0 weeks. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, and mean deviation (MD) of the Humphrey field analyzer (HFA) 10–2 and HFA Esterman test scores. Additionally, the safety of TdES was evaluated.
Results
LogMAR visual acuity improved by ≥ 0.1 in two eyes, and ETDRS visual acu-ity improved by ≥ 5 characters in one eye. The mean change in logMAR visual acuity from week 0 showed an increasing trend. The mean MD of HFA 10–2 showed no obvious change, while HFA Esterman score improved in four eyes. All patients completed the study according to the protocol, and no treatment-related adverse events were observed.
Conclusions
TdES treatment may have improved visual acuity and visual field in some patients. Further sham-controlled study in larger cohort is needed on its effectiveness.
Trial registration
UMIN, UMIN000036220. Registered 15 March, 2019, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041261 .
... They reported that the electrical phosphene thresholds at all frequencies were lowest in healthy subjects and highest in those with retinal artery occlusion. Electrical stimulation therapy is assumed to be effective when the patient's retinal ganglion cell is alive but dysfunctional or when progenitor cell plasticity remains [23]. Therefore, CRAO, which has a high phosphene threshold and causes severe and widespread death of RGC, may be a disease in which the effect of electrical stimulation is less likely to be obtained than in other diseases. ...
Purpose:
To evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with central retinal artery occlusion (CRAO).
Methods:
Five eyes of five patients with CRAO underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) six times at 2-week intervals. Only the affected eye was stimulated with 1.0-mA pulses in all patients. The primary endpoint was the best-corrected logMAR visual acuity. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, mean deviation of the Humphrey field analyzer (HFA) 10-2, and HFA Esterman test score. We also evaluated its safety.
Results:
The logMAR visual acuity at 12 weeks was improved by 0.1 or more in two patients and was maintained in two patients compared to the baseline. No obvious changes in the mean logMAR visual acuity, ETDRS visual acuity, mean deviation, and HFA Esterman score were observed at 12 weeks compared to the baseline. All five enrolled patients completed the study according to the protocol. No treatment-related adverse events were observed during this study.
Conclusion:
In this study, logMAR visual acuity was slightly improved in two patients, confirming the safety of TdES. Since CRAO has no established treatment method, further research into the effects of TdES treatment in CRAO patients may be beneficial.
... Recent small preliminary studies have looked at safety and efficacy of skin electrical stimulation in patients with chronic phase LHON with some promising results. Current studies have a lack of randomization and/or control arm, therefore further research is needed [65,66]. ...
Leber’s Hereditary Optic Neuropathy (LHON) is the most common primary mitochondrial DNA disorder. It is characterized by bilateral severe central subacute vision loss due to specific loss of Retinal Ganglion Cells and their axons. Historically, treatment options have been quite limited, but ongoing clinical trials show promise, with significant advances being made in the testing of free radical scavengers and gene therapy. In this review, we summarize management strategies and rational of treatment based on current insights from molecular research. This includes preventative recommendations for unaffected genetic carriers, current medical and supportive treatments for those affected, and emerging evidence for future potential therapeutics.
... Photoreceptor dystrophies and degenerative diseases of the retina are major causes of blindness worldwide, ranging till 5-14% in age-related macular degeneration [1]. In recent studies, electric fields (EF, e.g., via transcorneal electric stimulation -TCES) have been successfully applied to treat such retinal diseases [2][3][4][5][6] as well of degenerative diseases of the optic nerve [7,8]. ...
Introduction:
Studies show that electric fields are used as therapy during nerve and tissue injuries along with trans-retinal stimulation. However, cellular and molecular changes induced by such treatments remain largely unknown especially in retinal photoreceptor cells. In vitro studies show that direct current electric fields (dcEF) were known to influence cell division, polarity, shape, and motility. Here we could characterize for the first time the reactions of 661W, a retinal cone photoreceptor especially regarding organelle polarization, membrane polarization of mitochondria, O2 consumption, ATP/ADP ratio and gene expression.
Methods:
The 661W cells were stimulated with a constant dcEF of field strength 5 V/cm during 30 min or 5 h depending on the parameters studied.
Results:
In response to dcEF, the cells aligned perpendicular to the field by forming a leading edge with extended membrane protrusions towards the cathode. Using immunofluorescence and live cell imaging, we show that the cell membrane depolarized at the cathodal side. The microtubules spread into the direction of migration. Also, the microtubule organization center re-oriented into this direction. Concomitantly with the microtubules, actin filaments reorganized in an asymmetrical fashion mainly at the cathodal side. The Golgi apparatus, which is involved in many steps of actin synthesis, moved to the cathodal side. In the last 2 h of the 5 h experiment, microtubules positioned themselves at the rear (anodal side), like the nucleus. The averaged displacement of the whole cells under dcEF was 155% of control for 3 V/cm and 235% for 5 V/cm. The average speed increased by 142% and 243% respectively. Inside the cells mitochondria moved to the cathodal side, where the energy consuming producing processes take place. In this line, we measured an increase in ATP production and O2 consumption. Mitochondrial calcium was found more on the anodal side, at the site of the nucleus with its calcium delivering endoplasmic reticulum. In addition, oxymetry studies reveal an increased ATP synthesis by 115.2% and oxygen consumption by 113.3% 3 h after dcEF stimulation. An analysis of differentially expressed genes by RNA sequencing revealed an upregulation of genes involved in cellular movement, cell to cell and intracellular signaling, molecular transport, assembly and organization.
Conclusions:
The mechanisms found can enhance our understanding regarding the beneficial effects of EF treatment in retinal diseases.
... Previous studies have reported on improved visual function of eyes with traumatic and ischaemic optic neuropathy, 19 retinal artery occlusion, 20 21 dry age-related macular dystrophy, 22 23 glaucoma, 24 Leber hereditary optic neuropathy 25 and RP following TdES with corneal electrodes. ...
Introduction
Previously, we conducted a clinical trial to evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes to improve the visual functions in patients with retinitis pigmentosa (RP). No adverse events were related to the treatment during follow-up examinations, and TdES significantly improved the mean visual acuity and visual field sensitivity.
Methods and analysis
We developed a study protocol for a prospective, multicentre, randomised, double-masked and sham-controlled clinical trial, planned to commence on June 2021. We intend to compare the maintenance or improvement in best-corrected visual acuity, and safety of TdES using skin electrodes between patients with RP and the sham group. The primary endpoint comprises the superiority of the logarithm of the minimum angle of resolution (logMAR) visual acuity change at week 24 from baseline in the treatment and sham groups. Secondary endpoints involve the comparison of the treatment and sham groups at week 24 for the logMAR visual acuity, early treatment diabetic retinopathy study visual acuity, the mean deviation value of Humphrey field analyser 10-2, monocular Humphrey Esterman visual field test score, ellipsoid zone length, central foveal thickness and 25-item National Eye Institute Visual Function Questionnaire score. We intend to enrol 50 patients from three Japanese institutions within 1 year and follow them up for 1 years.
Ethics and dissemination
The protocol was approved by the institutional review board at the Chiba University Hospital and two other institutions, and was registered with the Japan Registry of Clinical Trials on 17 May 2021. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and is in accordance with Good Clinical Practice standards. The findings will be published in a peer-reviewed journal.
Trial registration number
JRCT2032210094.
... [8][9][10][11][12] Recently, we have applied skin ES (SES), usually classified as transorbital ES, to 10 cases of LHON harbouring a G11778A mutation. 13 14 The short-term results from six consecutive SES sessions every 2 weeks indicated a significant best-corrected visual acuity (BCVA), and half of the subjects experienced a gradual improvement in visual field sensitivities until 2 months following the last SES session. In addition, there were no adverse effects associated with SES, such as skin issues resulting from the attached electrode gel pads. ...
... In patients with LHON with a BCVA <0.01, a therapeutic effect cannot be expected. 14 The exclusion criteria are as follows: (1) BCVA <0.01; (2) smoking history within half a year before the initiation of the study; (3) use of electronic devices, such as a pacemaker; (4) history of intraocular surgery within a year; (5) ongoing treatment for any ocular disease; (6) history of idebenone treatment within a year; (7) ongoing treatment with either ethambutol, chloramphenicol, linezolid, erythromycin, streptomycin, antiretroviral drugs, amiodarone, infliximab, clioquinol, dapsone, quinine, pheniprazine, suramin sodium or isoniazid; (8) history of epilepsy; (9) pregnancy; (10) severe dermatitis; (11) participation in other clinical studies and (12) inappropriate cases as judged by physicians who are responsible for the study. The rationale for each criterion is as follows: (1) as for patients with LHON with a BCVA <0.01, a therapeutic effect cannot be expected; (2) smoking is considered an environmental factor in the onset and progression of LHON; (3) and (8) the instruments could affect other electronic medical devices or induce epileptic stroke; (4) and (5) intraocular surgery or other eye diseases affect visual function; (6) and (7) idebenone or other medications affect the optic nerve, especially idebenone, which has been reported to improve visual field sensitivities of patients with LHON; (9) the effect of SES on a foetus is unknown; (10) gel pads for ES adversely affect the skin; and (11) and (12) these are established from an ethical point of view. ...
... The primary outcome is defined as the difference in logMAR BCVA between baseline and 1 week after the final session of SES. Based on our previous study, 14 the null hypothesis is the mean difference in logMAR BCVA at baseline and 1 week after the last session of SES (−0.10) as analysed using a one-sample t-test with a two-sided significance level of 5%. Rejection of the null hypothesis indicates that the tested frequent SES protocol was judged to be superior to that of the previous SES protocol. ...
Introduction
Leber hereditary optic neuropathy (LHON) is an acute or subacute inherited optic neuropathy caused by mitochondrial mutations. More than 90% of patients with LHON have one of three point mutations (ie, G3460A, G11778A and T14484C). We previously reported that a 12-week session of skin electrical stimulation (SES) with a 2-week interval significantly improved visual acuity and field tests 1 week after the last stimulation and without adverse effects in 10 cases of LHON carrying the mt DNA G11778A mutation. In the present study, we will examine the magnitude and persistence of the efficacy and presence or absence of adverse events using SES with a more frequent stimulation protocol.
Methods and analysis
This study will be a single-arm, open-labelled, non-randomised clinical study that analyses 15 cases of LHON with G11778A mutation. All participants will take a portable SES device home and perform SES by themselves every other day for 12 weeks. The logarithm for the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) at 1 week after the last SES will be measured as the primary outcome. LogMAR BCVA will be measured at four and 8 weeks after the last SES treatment. The Humphrey visual field sensitivity test using size V stimulation and critical fusion frequency at 1, 4 and 8 weeks after the last SES session will be secondary outcome measurements. Slit-lamp examination, optical coherence tomography and specular microscopy will also be performed to verify the safety of SES.
Ethics and dissemination
The protocol was approved by the Institutional Review Board at Kobe University, Japan (Approval No.C190030). This study is in progress and deserves Pre-result. All documents communicating with the ethics committee will be reposited by the researcher. Modifications to the protocol will be reviewed by the ethics committee and implemented after approval. Data monitoring will be performed by a researcher who is not involved in the study every 6 months after approval. The research summary results will be registered in the Japan Registry of Clinical Trials (jRCTs) and made available to participants in accordance with the terms described in the documents. In addition, the results of this study will be presented at domestic and international meetings and published in peer-reviewed journals within a year after data is fixed.
Trial registration number
jRCTs052200033.
Hereditary optic neuropathies result from defects in the human genome, both nuclear and mitochondrial. The two main and most recognised phenotypes are dominant optic atrophy and Leber hereditary optic neuropathy. Advances in modern molecular diagnosis have expanded our knowledge of genotypes and phenotypes of inherited disorders that affect the optic nerve, either alone or in combination, with various forms of neurological and systemic degeneration. A unifying feature in the pathophysiology of these disorders appears to involve mitochondrial dysfunction, suggesting that the retinal ganglion cells and their axons are especially susceptible to perturbations in mitochondrial homoeostasis. As we better understand the pathogenesis behind these genetic diseases, aetiologically targeted therapies are emerging and entering into clinical trials, including treatments aimed at halting the cascade of neurodegeneration, replacing or editing the defective genes or their protein products, and potentially regenerating damaged optic nerves, as well as preventing generational disease transmission.
Purpose
The purpose of this study was to evaluate the 3‐year surgical outcome of the sulcus fixation of Baerveldt glaucoma implant (BGI), focusing on corneal damage.
Methods
This prospective observational study included 37 patients who underwent a median of two previous glaucoma surgeries and sulcus fixation of BGI for the first time. Each patient’s intraocular pressure (IOP), glaucoma drug score, corneal endothelial cell density (ECD), and logMAR‐converted best‐corrected visual acuity (VA) were measured preoperatively and postoperatively until 36 months after surgery. Complete success was defined as reduced IOP (5–21 mmHg and >20% rate), without corneal damage (postoperative development of decompensation, unmeasurable ECD, or reduction in ECD of >20%), without loss of light perception, and without additional surgery requirement. Qualified success was defined by excluding the corneal criteria from complete success.
Results
A total of 51% (19/37) patients experienced complete treatment success, whereas 86% (32/37) had qualified success. The median IOP (glaucoma drug score) decreased from 26 mmHg (5) to 15 mmHg (2) at three years postoperatively. The median postoperative ECD (reduction rate) decreased from 1838 cells/cm² preoperatively to 1587 cells/mm² (14%) at one year, 1358 cells/mm² (26%) at two years, and 1228 cells/mm² (33%) at three years postoperatively. One month after surgery, the VA was significantly reduced from preoperative values but did not decline after that.
Conclusion
Sulcus fixation of BGI was effective for IOP reduction. However, ECD decreased over time.
