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Transcorneal electrical stimulation for the treatment of retinitis pigmentosa: results from the TESOLAUK trial.

ABSTRACT: Objective:To explore the impact of weekly transcorneal electrical stimulation (TES) over a 6-month period as a treatment for retinitis pigmentosa (RP). Methods and analysis:A prospective open-label observational trial was carried out assessing weekly TES in participants with RP for a period of 6?months followed by observation for a further 6?months. Clinical examination and investigations were carried out at 3?monthly intervals for a total of 12 months. The primary outcome measure explored safety through a descriptive analysis of adverse effects with secondary outcome measures evaluating structural and functional efficacy. Results:Seven male and seven female participants with RP aged 18-80 years were recruited. TES was well tolerated with no serious adverse events reported. Two participants reported transient foreign body sensation and one participant had discomfort underneath the skin electrode. Following 6?months of TES, best-corrected visual acuity increased by 1.1±1.4 letters in the control arm and 0.93±1.4 letters in the treated arm. Central microperimetry threshold sensitivity rose by 0.02±0.5 decibels (dB) and 0.37±0.4?dB and Goldmann visual field volume by 0.16±0.09 steradians (sr) vs 0.22±0.12?sr for the control and treated eye, respectively. There was no statistical significance seen between eyes following the treatment or observation period. Conclusion:This small open-label clinical trial showed that TES was safe and well tolerated in patients with RP. Visual function measurements at 6 months demonstrated no significant difference between the control and treated eyes. The results justify a larger clinical trial over a longer period of time in order to identify any treatment effect.

SUBMITTER: Wagner SK

PROVIDER: S-EPMC5751865 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Transcorneal electrical stimulation for the treatment of retinitis pigmentosa: results from the TESOLAUK trial.

Wagner Siegfried K SK Jolly Jasleen K JK Pefkianaki Maria M Gekeler Florian F Webster Andrew R AR Downes Susan M SM Maclaren Robert E RE

BMJ open ophthalmology 20171214 1

<h4>Objective</h4>To explore the impact of weekly transcorneal electrical stimulation (TES) over a 6-month period as a treatment for retinitis pigmentosa (RP).<h4>Methods and analysis</h4>A prospective open-label observational trial was carried out assessing weekly TES in participants with RP for a period of 6 months followed by observation for a further 6 months. Clinical examination and investigations were carried out at 3 monthly intervals for a total of 12 months. The primary outcome measure ...[more]

PMID: 29354722

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Project description: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.

Project description:PURPOSE:A small-scale randomized controlled trial conducted by our group found that four of seven retinitis pigmentosa (RP) subjects who received six weekly Transcorneal Electrical Stimulation (TES) sessions developed significant improvements in visual acuity (VA), quick contrast sensitivity function (qCSF), and/or Goldmann visual fields (GVF). We longitudinally monitored three of these participants for declining visual function due to natural RP progression to determine the duration of their responses and administered retreatments. METHODS:Over a period of 29-35 months, repeated ETDRS VA, qCSF and/or GVF tests and three to six TES treatment courses consisting of six weekly sessions were administered in each eye of three RP participants every four to 16 months in an unmasked, prospective case series study. RESULTS:For two participants, there were significant VA improvements of 44-52 letters (0.88-1.04 logMAR) and 15-23 letters (0.3-0.46 logMAR) in the worse eye at baseline after each of three or four treatment courses of TES compared to initial baseline. They had no significant decreases from baseline for VA or qCSF over 29 to 35 months, The third participant had a significant mean improvement in VA in the eye with better baseline vision (p = 0.004) and binocularly (p < 0.001) following six treatment courses over the 29-month period. For the first two participants, mean annual rates of GVF change for each eye ranged from -5% to 0% with the V4e stimulus, and -26% to +33% the III4e stimulus. The third participant's mean annual GVF changes were +14 to +35%, with a statistically significant improvement across 29 months for both the V4e and III4e stimuli in the right eye (p = 0.045; p = 0.015) and the V4e stimulus in the left eye (p = 0.047). CONCLUSION:Following encouraging visual improvements after TES that lasted for several months, it appears it may be possible to restore and prevent slowly diminishing vision over time with retreatments, which requires confirmation in a large-scale randomized controlled trial.

Project description:Purpose: To investigate the effect of transcorneal electrical stimulation (TES) on the retina of wildtype Brown Norway (BN) rats by gene expression profiling. Methods: TES was applied to BN adult wildtype rat retina in vivo for 1h (1ms biphasic pulses at 20Hz; current: 200 M-BM-5A). RNA was isolated, processed and used for microarray-based expression profiling 4hrs after initial TES. An expression profile was generated for genes differentially expressed at 4hrs after TES vs. sham stimulated animals using a fold change cutoff of 1.2. We validated the profile by real-time quantitative reverse transcription-polymerase chain reaction (qPCR). In addition, the application of TES was verified at the structural and functional level. Results: Transcriptome changes associated with TES vs. sham stimulated BN wildtype retina were identified. 490 genes were differentially expressed in TES and included well-known genes as well as a large number of novel genes. Electrophysiological recordings showed physiological retinal function after TES and structural in vivo and ex vivo studies revealed intact retinal layers. Conclusion: Our results demonstrate that TES applied to the retina of wildtype BN rats induce a variety of transcriptome level changes and may help to understand the mechanisms underlying TES. In addition TES has no negative effect on structure and function of wildtype BN retina 24hrs after application. RNA isolation and Microarray studies 4 animals were euthanized 4h after TES or respective sham treatment. Extraction of total RNA was performed using the RNeasy Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. QIAshredder mini-spin columns (Qiagen) as well as needle and syringe homogenization were applied for tissue homogenization. To ensure proper integrity all RNA used in our experiments showed single peaks for the 18S and 28S bands as determined by the Agilent 2100 Bioanalyzer using the RNA 6000 Nano LabChip Kit (both Agilent Technologies Inc., CA, USA) following the manufacturer's instructions. The purity and concentration of total RNA was determined by absorbance measurements at 260 and 280nm using a Nanodrop ND-1000 spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA). All RNA that did not have a 260/280 ratio between 1.9 and 2.1 was discarded to ensure high quality of samples. Respective RNAs from stimulated and sham samples were used to generate double-stranded cDNA with the T7-oligo (dT) primer according to GeneChipM-BM-. (Affymetrix Inc., Santa Clara, CA, USA) two cycle target labeling protocol as described by the manufacturer. The processed cDNA was hybridized to Affymetrix GeneChipM-BM-. Rat Gene 1.0 ST arrays for 18M-bM-^@M-^S24h (Affymetrix Inc.). Four TES and four sham replicates were used for hybridization to Microarray GeneChipsM-BM-.. Each microarray was washed and stained with streptavidinM-bM-^@M-^Sphycoerythrin and scanned at a 6M-NM-<m resolution with Agilent Technologies model G2500A GeneArray scanner. A visual quality control measurement was performed to ensure proper hybridization after each chip was scanned. Additional quality control parameters such as scaling factors used to normalize the chips, average background, and noise were also evaluated. Microarray analysis For statistical analysis of microarray data all cell files were imported to GeneSpring GX software (Agilent Technologies Inc.) where GC-RMA algorithm was applied to yield log signal values on each probe set. All transcripts with a minimum change of 1.2 fold together with a p value less than 0.05 were selected using Significance Analysis of Microarray (SAM) (Tusher VG, 2001). The visualization of the relationships between the samples by principal component analysis (PCA) based on the GC-RMA signal and hierarchical clustering using the Pearson correlation was obtained using PARTEK Genomics Suite version 6.4. All differentially regulated genes were imported into Ingenuity Pathway Analysis (Ingenuity Systems, CA, USA) for generation of networks and canonical pathway analysis. The data set containing all significant gene identifiers along with corresponding expression and significance values was uploaded into the application. Each identifier was mapped to its corresponding object in Ingenuity's Knowledge Base. The set fold change cutoff identified all molecules whose expression was significantly differentially regulated. These network eligible molecules were overlaid onto a global molecular network developed from information contained in IngenuityM-bM-^@M-^Ys Knowledge Base. Networks were then algorithmically generated based on their connectivity. The functional analysis of a network identified the biological functions using a right-tailed FisherM-bM-^@M-^Ys exact test that were most significant to the molecules in the network. Canonical pathways analysis identified the pathways from the Ingenuity Pathways Analysis library of canonical pathways that were most significant to the data set. The significance of the association between the data set and the canonical pathway was measured in 2 ways: 1) A ratio of the number of molecules from the data set that map to the pathway divided by the total number of molecules that map to the canonical pathway is displayed. 2) FisherM-bM-^@M-^Ys exact test was used to calculate a p-value determining the probability that the association between the genes in the dataset and the canonical pathway is explained by chance alone.

Dataset Information

Transcorneal electrical stimulation for the treatment of retinitis pigmentosa: results from the TESOLAUK trial.

Publications

Transcorneal electrical stimulation for the treatment of retinitis pigmentosa: results from the TESOLAUK trial.

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