June 2011
Volume 52, Issue 7
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Clinical Trials  |   June 2011
Transcorneal Electrical Stimulation for Patients with Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Exploratory Study
Author Affiliations & Notes
  • Andreas Schatz
    From the Centre for Ophthalmology and
  • Tobias Röck
    From the Centre for Ophthalmology and
  • Lubka Naycheva
    From the Centre for Ophthalmology and
  • Gabriel Willmann
    From the Centre for Ophthalmology and
  • Barbara Wilhelm
    the STZ eyetrial, University of Tübingen, Tübingen, Germany; and
  • Tobias Peters
    the STZ eyetrial, University of Tübingen, Tübingen, Germany; and
  • Karl Ulrich Bartz-Schmidt
    From the Centre for Ophthalmology and
  • Eberhart Zrenner
    From the Centre for Ophthalmology and
  • André Messias
    From the Centre for Ophthalmology and
    the Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, University of São Paulo, Ribeirão Preto, Brazil.
  • Florian Gekeler
    From the Centre for Ophthalmology and
  • Corresponding author: Florian Gekeler, Centre for Ophthalmology, Schleichstrasse 12-16, D-72076 Tübingen, Germany; gekeler@uni-tuebingen.de
  • Footnotes
    2  These authors contributed equally to the work presented here and should therefore be regarded as equivalent authors.
Investigative Ophthalmology & Visual Science June 2011, Vol.52, 4485-4496. doi:10.1167/iovs.10-6932
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      Andreas Schatz, Tobias Röck, Lubka Naycheva, Gabriel Willmann, Barbara Wilhelm, Tobias Peters, Karl Ulrich Bartz-Schmidt, Eberhart Zrenner, André Messias, Florian Gekeler; Transcorneal Electrical Stimulation for Patients with Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Exploratory Study. Invest. Ophthalmol. Vis. Sci. 2011;52(7):4485-4496. doi: 10.1167/iovs.10-6932.

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      © 2015 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose.: To assess the safety of transcorneal electrical stimulation (TES) and explore its efficacy in various subjective and objective parameters of visual function in patients with retinitis pigmentosa (RP).

Methods.: Twenty-four patients in this prospective, randomized, partially blinded, good-clinical-practice study underwent TES (5-ms biphasic pulses; 20 Hz; DTL electrodes) 30 minutes per week for 6 consecutive weeks. The patients were randomly assigned to one of three groups: sham, 66%, or 150% of individual electrical phosphene threshold (EPT). Visual acuity (VA), visual field (VF; kinetic, static), electroretinography (Ganzfeld, multifocal), dark-adaptation (DA), color discrimination, and EPTs were assessed at all visits or four times, according to the study plan.

Results.: TES using DTL electrodes was tolerated well; all patients finished the study. Two adverse (foreign body sensation), but no serious adverse events were encountered. There was a tendency for most functional parameters to improve (8/18) or to remain constant (8/18) in the 150% group. VF area and scotopic b-wave amplitude reached statistical significance (P < 0.027 and P < 0.001, respectively). Only desaturated color discrimination and VF mean sensitivity decreased. There was no obvious trend in the 66% group.

Conclusions.: TES was found to be safe in RP patients. Positive trends were discovered, but due to the small sample size of this exploratory study, statistical significance was reached only for VF area and scotopic b-wave amplitude. Further studies with larger sample sizes and longer duration are needed to confirm the findings and to define optimal stimulation parameters. (ClinicalTrials.gov number, NCT00804102.)

Electrical stimulation has a long history in ophthalmology and was thought to be beneficial as early as 1873 by Dor 1 for the treatment of “amblyopia and amauroses” and for “retino-choroiditis with pigment infiltration,” “glaucoma, and white optic atrophy.” Recently, interest has been renewed by reports of efficacy in a small number of patients with nonarteritic ischemia, traumatic optic neuropathy, 2 and longstanding retinal artery occlusion. 3 In addition, interest has been raised by reports that the presence of a subretinal implant can promote visual functions in areas distant from the implant (Chow AY, et al. IOVS 2005;46:ARVO E-Abstract 1140), which has been attributed to the release of neurotrophic and other factors. 4,5  
Results in several animal experiments have supported the beneficial effects of electrical stimulation on the retinas of Royal College of Surgeons (RCS) rats in vivo 6 8 and in vitro, 9 on the survival of ganglion cells after optic nerve injury, 10 12 and on the survival of various retinal cell populations after light-induced retinal damage (Zhang H, et al. IOVS 2009;50:ARVO E-Abstract 3615). 13 Effects have been ascribed to the stimulation of the endogenous insulin-like growth factor (IGF)-1 system (Tagami Y, et al. IOVS 2008;49:ARVO E-Abstract 2059) 10,12 and enhanced release of Fgf2, 6 B-cell lymphoma 2 (Bcl-2) protein, ciliary neurotrophic factor (CNTF), and brain derived neurotrophic factor (BDNF). 13  
In most of those studies electrical currents were applied in transcorneal fashion with contact lens–type electrodes, 2,3 for which the term transcorneal electrical stimulation (TES) was coined. 
Although several reports of positive effects of TES in RCS rats as a widely used animal model of retinitis pigmentosa (RP) are available, 6 9 so far, no controlled scientific human studies have been reported for this condition. 
This prompted us to investigate the effects of TES in a pilot study in RP patients. We report on results of our partially blinded, sham-controlled pilot study, which was conducted according to good clinical practice (GCP). Our outcome measures were the safety of TES applied with DTL-electrodes and its efficacy in a variety of subjective and objective parameters of visual function. 
Material and Methods
Patient Selection
Twenty-four eyes of 24 patients were included; all had advanced RP (rod–cone dystrophy). Diagnosis was established by detailed history, funduscopy, electroretinography (ERG), and visual field (VF) examination. Inclusion criteria were age >18 years, visual acuity (VA) 0.02 to 0.9 (Snellen), and recordable ERG and VF results. Exclusion criteria were other ocular diseases (advanced diabetic retinopathy, retinal or choroidal neovascularization, exudative age-related macular degeneration), silicon oil tamponade, and severe general disease. 
Patients were recruited from the hospital's special retinal degeneration clinic. After inclusion they were randomized to one of the three treatment arms: sham stimulation or stimulation with 66% or with 150% of their individual electrical phosphene threshold (EPT) at 20 Hz. Mean age was 55.63 ± 14.79 (± SD), 51.63 ± 8.02, and 56.38 ± 13.39 years in the sham, 66%, and 150% groups, respectively (resp.). There was no statistically significant difference between groups (P = 0.72; ANOVA). 
Study Design
Patients and technicians who performed ERG, multifocal (mf)ERG, VF, dark adaptation (DA), and color discrimination tests were blinded to their treatment group for the entire study period. The examining doctor who performed VA, EPT, intraocular pressure (IOP), and slit-lamp examination was not blinded, because he or she was responsible for setting the stimulation parameters. The study was approved by the local ethics committee and local agencies. All patients gave written informed consent after explanation of the nature and possible consequences of the study; all procedures complied with the Declaration of Helsinki. 
The study was performed according to the standards of GCP, the European Union (EU) directive for medical devices, and the German Medical Product Law (MPG). The trial was supervised by STZ eyetrial, the clinical trial center at the Centre for Ophthalmology, University of Tübingen, which is a certified member of the European Vision Institute, Clinical Research Network (www.EVICR.net, European Vision Institute Research Network, Coimbra, Portugal). STZ eyetrial provided study documents, performed regular monitoring visits, and controlled all study documentation including, adverse events (AEs). All documents, especially inclusion criteria and study logs, were reviewed; all eCRF (electronic case report form) data were monitored, and source data verification was conducted according to the International Conference on Harmonisation (ICH; Geneva, Switzerland; www.ich.org), GCP guidelines. 
Patients were seen at nine visits: one baseline visit (visit 1), followed by six consecutive weekly visits (visits 2–7) with TES (dates varied a maximum of ±2 days) and two follow-up visits (visits 8 and 9): one 2 weeks and one 11 weeks after the last stimulation visit (the last dates varied a maximum of ±10 days). Visits 2, 3, 4, 6, and 7 were short visits that included VA, slit lamp biomicroscopy, and TES. Visits 1, 5, 8, and 9 were long visits and also included VF, color test, DA, ERG, mfERG, and optical coherence tomography (OCT). To adjust for learning effects in VF examinations, we performed the test at visits 1 and 2. 
Electrical Stimulation and Determination of Electrical Phosphene Thresholds
For electrical stimulation, a sterile single-use DTL electrode (Diagnosys UK, Ltd., Cambridge, UK) was used as the active electrode, as described in the original publication. 14 On the patient's request, a local anesthetic was applied to the lower fornix (e.g., oxybuprocaine hydrochloride). A gold-cup electrode (LKC Technologies, Inc., Gaithersburg, MD), as the counter electrode, was attached to the ipsilateral temple after thorough cleaning of the skin and application of contact paste. For stimulation a commercially available neurostimulator was adapted by the manufacturer to deliver current pulses within the range of the study (Twister; Dr. Langer Medical, Waldkirch, Germany). Rectangular biphasic current pulses (5-ms positive, directly followed by 5-ms negative) were applied for 30 minutes at a frequency of 20 Hz. Room light was turned on during the entire session. For sham stimulation, all electrodes and cables were attached and EPTs were determined, but stimulation was not turned on. 
To assess EPTs an alternative forced-choice method was used as described elsewhere. 15 The threshold was determined three times, and the average was formed at each study visit for calculation of individual stimulation strength according to treatment arm. 
Examination Techniques
Electroretinography.
Ganzfeld ERGs were registered according to the ISCEV standard (International Society for Clinical Electrophysiology of Vision) 16 using a desktop Ganzfeld (ColorDome) controlled by an ERG console (Espion E2; Diagnosys LLC, Cambridge, UK). After 30 minutes of DA and application of two drops of tropicamide 0.5% (Mydriatikum; Stulln, Stulln, Germany) custom-constructed DTL electrodes 14,15 and gold-cup electrodes (VIASYS Health care, Warwick, UK) were positioned on the forehead and the temples. The ERG protocol consisted of four steps, with intensities from 0.1 to 3 phot cd · s/m2 and 4-ms duration (white flash, 6500 K). Two single-flash responses were used as the rod protocol, and a single-flash response (3 phot cd · s/m2 with a background illumination of 30 phot cd/m2, i.e., the standard flash [SF]) and a 30-Hz flicker were chosen as the cone protocol. Impedance level was <10 kΩ. A band-pass filter was applied from 0.3 to 300 Hz using the machine's built-in software algorithm. ERG potentials <5 μV were excluded from the analysis. 
mfERGs were recorded with a VEP imaging system (VERIS; Electro-Diagnostic Imaging Inc., Redwood City, CA, with Veris Science, ver. 4.9.1 software) with a 21-in. screen (resolution, 1024 × 768, model UHR21L; Nortech Imaging Technologies, Plymouth, MA) positioned 32 cm in front of the subject. The visual field stimulated subtended an area of 60° × 55°; 61 hexagons were presented with alternating black (5 cd/m2) and white (100 cd/m2) fields. The built-in software algorithm allowed recordings between 10 and 100 Hz (band-pass filter), amplified by a factor of 200,000. The mfERGs were analyzed in rings, according to the ISCEV. 17  
Visual Field.
A retinal perimeter (Octopus 900; Haag-Streit Inc., Köniz, Switzerland) was used to conduct VF examinations; background luminance was 10 cd/m2. For semiautomatic kinetic perimetry up to 90° eccentricity, white stimuli (Goldmann III4e with a constant angular velocity of 3 deg/s) were used. Stimuli were presented every 15°. Isopter and scotoma areas (in square degrees) were quantified with the built-in software algorithm. As a quality criterion for the kinetic perimetry, the blind spot was detected with at least five stimuli of Goldmann size I4e at 2 deg/s. White-on-white static perimetry was conducted with the fast threshold strategy GATE (German Adaptive Thresholding Estimation) 18 up to 85° eccentricity. A test grid consisting of 86 stimulus locations, which were condensed toward the center, was applied (stimulus size: Goldmann III, presentation duration: 200 ms, response time: 1200 ms). 
Optical Coherence Tomography.
An optical coherence tomograph (Stratus OCT Model 3000; Carl Zeiss Meditec GmbH, Oberkochen, Germany) scanned in radial lines mode; foveal thickness was retrieved after manual verification of the detection borders of the software algorithm. 
Ophthalmic Examination.
Snellen VA was assessed with a projector at a viewing distance of 6 m (SCP-660; Nidek Inc., Fremont, CA). 
Intraocular pressure was tested with Goldmann applanation tonometry (Haag Streit, Köniz, Switzerland). 
Measurement of Rod and Cone Threshold Sensitivity.
An adaptometer was used to determine final thresholds for cones (red test light, 625 nm) and rods (green test light, 530 nm) after 20 minutes of DA with maximally dilated pupils (DARKadaptometer; Roland Consult Stasche&Finger, GmbH, Brandenburg, Germany). 
Color Discrimination.
Color discrimination was tested monocularly with Farnsworth D-15 19 (saturated) and Lanthony desaturated D-15 20 presented in a lightbooth (Judge II; Gretag MACBETH, Neu-Isenburg, Germany) at 6500 K. The saturated test was scored according to the color confusion index (CCI) 21 and the desaturated test with the total error score. 22 Scoring was performed with web-based software (http://www.torok.info/colorvision/d15.htm, developed by Béla Török, Department of Ophthalmology, Kantonsspital St. Gallen, St. Gallen, Switzerland). 
Blood Tests and General Examination.
Examinations at visits 1 and 9 included general appearance; neck, extremities, and joints; skin and lymph nodes; auscultation of lungs and heart; and venous blood samples for complete blood count, electrolytes, and basic renal and hepatic values. Pulse rate, blood pressure, and body temperature were taken at all visits. 
Statistical Analysis
Ten percent of all data extracted from the eCRFs were randomly chosen to be double-checked manually using the monitoring process before statistical analysis was performed (JMP, ver. 8.0.1.0; SAS Institute, Inc., Cary, NC). Descriptive statistics were used to summarize data as the means and 95% confidence intervals (CIs). To analyze the influence of treatment, intraindividual differences were calculated for each subject between baseline and follow-up visits. Comparison between treatment groups was performed using the method of restricted maximum likelihood (REML) to estimate the development of parameters under treatment during visits for each group. In contrast to maximum-likelihood estimation, REML can produce unbiased estimates of variance parameters. 23 To compare groups, we applied the Tukey-Kramer post hoc test, with a global level of significance set at P < 0.05. Because of the exploratory character of the study, no single endpoints were declared, and no adjustment for multiple testing was performed. 
Results
All 24 patients completed the entire follow-up period. Electrical stimulation via DTL electrodes was tolerated well, as reported before, 15 even when electrodes where used not just for threshold determinations with short current pulses but continuously for 30 minutes with suprathreshold currents. 
Baseline values of the groups did not differ significantly, with the exception of cone threshold sensitivity (P = 0.031). Stimulation current was 0.23 ± 0.13 and 0.36 ± 0.18 mA in the 66% and 150% group, resp. (overall mean ± SD). 
One patient reported a mild foreign body sensation and showed minor irritation of the conjunctiva after IOP measurement, which we attributed to the anesthetic drops. Another patient experienced a foreign body sensation once after stimulation, which resolved after prescription of artificial tears twice hourly for 1 day. No other AEs or serious adverse events (SAEs) were encountered. 
General examination and blood test results were all within normal ranges at all visits. 
During study visits, the dark-adapted a-wave amplitude, elicited by an ISCEV SF, changed by 6.72, −0.07, and 0.64 μV in the 150%, 66%, and sham groups, resp. (mean REML; P = 0.49; Table 1, Fig. 1). The b-wave amplitude changed by 8.79, −8.82, and −8.43 μV in the 150%, 66%, and sham groups, resp.; the 150% group differed significantly (P = 0.027; Table 1, Fig. 1). No obvious change occurred for the implicit times (P = 0.90 and 0.96 for a- and b-wave, resp.; Table 1, Fig. 1). In the photopic ERG the a-wave amplitude changed 1.11, −10.35, and 2.77 μV in the 150%, 66%, and sham groups resp.; this inconsistent behavior did not reach statistical significance (P = 0.062; Table 1, Fig. 2). The b-wave amplitude changed by 6.66, −0.31, and −0.21 μV in the 150%, 66%, and sham groups, resp. (P = 0.082; Table 1, Fig. 2). No obvious change occurred for implicit times (P = 0.80 and 0.25 for a- and b-wave, resp.; Table 1; Fig. 2). Snellen VA (in logMAR) changed 0.017, 0.039, and 0.067 in the 150%, 66%, and sham groups, resp.; the changed was not statistically significant (P = 0.22; Table 1, Fig. 3). Visual field area changed by 17%, −9%, and −6% in the 150%, 66%, and sham groups, resp. (P < 0.001; Table 1, Fig. 4). Mean sensitivity in the VF changed by −0.18, −0.09, and 0.66 dB in the 150%, 66%, and sham groups, resp. (P = 0.12; Table 1, Fig. 4). The final threshold of rod sensitivity decreased by 0.39, 0.081, and 0.043 cd/m2 in the 150%, 66%, and the sham groups, resp. (P = 0.53; Table 1, Fig. 5). The final threshold of cone sensitivity decreased by 0.19, −0.019, and −0.084 cd/m2 in the 150%, 66%, and the sham groups, resp. (P = 0.46; Table 1; Fig. 5). The sensitivity of electrically evoked phosphenes at 20 Hz increased by 43%, 25%, and 27% in the 150%, 66%, and sham groups, resp. (P = 0.73; Table 1, Fig. 6). The CCI of the Farnsworth D-15 saturated changed by 0.058, −0.04, and −0.24 in the 150%, 66%, and sham groups, resp.; values changed significantly (P = 0.034; Table 1). The TES of the Lanthony desaturated D-15 changed by 27.99, 2.98, and 14 in the 150%, 66%, and sham groups, resp.; values did not change significantly (P = 0.72; Table 1). 
Table 1.
 
Raw Data of the Tested Parameters in the Three Stimulation Groups
Table 1.
 
Raw Data of the Tested Parameters in the Three Stimulation Groups
Test Subtest (Unit Raw Data; Unit REML) Group Raw Data REML
95% CI
Visit 1 or Mean of Visits 1 + 2 Visit 5 Visit 8 Visit 9 P Means Lower Upper
Scotopic ERG SF a-wave ampl. (μV; μV) Sham 20.6 ± 13.9 16.6 ± 11.6 21.7 ± 12 21.9 ± 7.8 0.64 −9.64 10.92
66% 18.8 ± 7.4 15.8 ± 2.8 18.7 ± 4.6 16.8 ± 6.5 −0.07 −10.35 10.21
150% 36 ± 37.1 40.2 ± 35.8 44.7 ± 33.2 43.2 ± 40.7 0.49 6.72 −2.38 15.81
SF a-wave impl. (ms; ms) Sham 24.3 ± 8.8 21 ± 6.8 19.8 ± 4.2 26.4 ± 11.7 1.29 −4.55 7.13
66% 19.5 ± 4 19.3 ± 4.9 23.4 ± 7.7 23.5 ± 7.6 2.83 −3.01 8.66
150% 20.6 ± 3.4 22.4 ± 4.9 23 ± 7.3 21.6 ± 2.2 0.9 1.73 −3.46 6.93
SF b-wave ampl. (μV; μV) Sham 34.9 ± 12.6 30.8 ± 5 24.4 ± 8.2 24.7 ± 10.8 −8.43 −19 2.14
66% 35.2 ± 20.3 37.9 ± 9.6 22.9 ± 15.5 19.6 ± 14 −8.82 −19.39 1.75
150% 67 ± 72.3 73.7 ± 79.2 66.7 ± 65.7 86.8 ± 84 0.027 8.79 −0.54 18.13
SF b-wave impl. (ms; ms) Sham 59.5 ± 15.5 58.2 ± 11.6 56.4 ± 11.6 58.4 ± 8.2 −1.62 −7.72 4.47
66% 59.5 ± 3.8 58.7 ± 4 60.2 ± 4.8 59.5 ± 14.7 −0.95 −7.405 5.14
150% 56.8 ± 3.1 55.8 ± 1.8 56.6 ± 3.7 56.2 ± 5.8 0.96 −0.6 −5.96 4.76
Photopic ERG SF a-wave ampl. (μV; μV) Sham 4.4 ± 1.9 6.8 ± 5.6 7.9 ± 3.4 6.2 ± 3.3 2.77 −4.83 10.37
66% 15.9 ± 13.8 4 ± 2.4 5 ± 3.8 10 ± 8.2 −10.35 −18.83 −1.87
150% 9.6 ± 3 10 ± 7.3 9.9 ± 4.5 10.8 ± 5.3 0.062 1.11 −7.4 9.62
SF a-wave impl. (ms; ms) Sham 22 ± 7 17.8 ± 2.2 16 ± 4.6 20.7 ± 6.5 −2.25 −6.49 1.99
66% 18.2 ± 2.5 15.8 ± 1 16.6 ± 7.2 20.2 ± 6.9 −0.79 −5.5 3.92
150% 17.8 ± 1.5 19.8 ± 4.7 15.3 ± 2.5 15.7 ± 2.3 0.8 −0.51 −5.27 4.24
SF b-wave ampl. (μV; μV) Sham 17 ± 7 20.6 ± 11.6 25.5 ± 11.6 19.4 ± 16.3 −0.21 −4.68 4.26
66% 21.7 ± 14.4 20.2 ± 13.2 22.6 ± 13.6 17.3 ± 12.6 −0.31 −5.19 4.57
150% 29 ± 13.2 27.6 ± 15.3 39.4 ± 14.7 33 ± 20.3 0.082 6.66 1.62 11.69
SF b-wave impl. (ms; ms) Sham 38 ± 3.9 38.3 ± 4.5 37.4 ± 4.1 40 ± 5.1 1.13 −0.53 2.79
66% 37.5 ± 5.3 36 ± 3.9 36.8 ± 5.3 37.7 ± 4.1 −0.83 −2.67 1
150% 36 ± 4.2 36.2 ± 4.2 36.3 ± 5 36.2 ± 3.3 0.25 −0.077 −1.94 1.78
Visual acuity Snellen (logMAR, logMAR) Sham 0.18 ± 0.15 0.18 ± 0.15 0.16 ± 0.17 0.15 ± 0.18 0.017 −0.025 0.058
66% 0.23 ± 0.21 0.18 ± 0.22 0.18 ± 0.22 0.19 ± 0.23 0.039 0.0023 0.08
150% 0.33 ± 0.3 0.25 ± 0.24 0.26 ± 0.34 0.25 ± 0.33 0.22 0.067 0.026 0.11
Visual field area (deg2; %) Sham 5265.94 ± 4065.7 5311.15 ± 4109.04 5233.7 ± 4049.02 4812.33 ± 3739.48 0.94 0.81 1.07
66% 3174.27 ± 3156.25 3006.85 ± 3020.95 2967.24 ± 2980.18 3042.3 ± 3165.97 0.91 0.78 1.05
150% 4681.1 ± 4741.55 4823.81 ± 4836.87 5112.81 ± 4818.73 5176.65 ± 4752.32 <0.001 1.17 1.04 1.3
mean sensitivity (dB; dB) Sham 4.99 ± 3.95 5.3 ± 3.85 5.86 ± 3.94 5.78 ± 4.23 0.66 0.026 1.29
66% 4.5 ± 3.62 4.14 ± 3.2 4.84 ± 3.91 4.25 ± 3.6 −0.09 −0.72 0.54
150% 6.2 ± 4.14 6.05 ± 3.96 5.94 ± 4.33 6.06 ± 4.09 0.12 −0.18 −0.82 0.45
Absolute threshold/sensitivity; phosphenes evoked at 20 Hz (μmA; %) Sham 0.39 ± 0.25 0.31 ± 0.25 0.32 ± 0.17 0.36 ± 0.2 1.27 0.9 1.65
66% 0.38 ± 0.2 0.32 ± 0.17 0.32 ± 0.12 0.28 ± 0.08 1.25 0.87 1.62
150% 0.33 ± 0.18 0.24 ± 0.13 0.23 ± 0.13 0.28 ± 0.23 0.73 1.43 1.06 1.81
mf ERG (mean of rings 1–5) Amplitude (μV; μV) Sham 8.94 ± 8.07 9.12 ± 8.59 9.87 ± 9.7 10.62 ± 11.33 −0.39 −3.1 2.32
66% 12.1 ± 10.97 10.87 ± 10.31 11.78 ± 10.57 12.21 ± 10.55 −1.49 −3.92 0.95
150% 10.37 ± 12.02 10.54 ± 10.81 8.9 ± 10.72 8.74 ± 10.71 0.76 −1.54 −4.12 1.05
Implicit time (ms; ms) Sham 34.48 ± 5.66 34.28 ± 4.68 32.77 ± 4.19 33.67 ± 4.85 0.22 −1.73 2.17
66% 32.73 ± 4.79 32.35 ± 3.78 32.27 ± 4.82 31.37 ± 2.97 −1.12 −2.87 0.63
150% 33.99 ± 5.16 33.75 ± 2.88 33.32 ± 3.19 34.05 ± 4.82 0.48 0.12 −1.74 1.98
Final threshold rod and cone sensitivity Rod (cd/m2; cd/m2) Sham −1.36 ± 1.4 −1.76 ± 1.37 −1.88 ± 1.26 −1.8 ± 0.8 0.043 −0.56 0.65
66% −2.03 ± 1.67 −1.88 ± 1.12 −2 ± 1.74 −2.17 ± 1.46 0.081 −0.4 0.56
150% −0.95 ± 0.94 −1.35 ± 1.49 −1.64 ± 1.38 −1.24 ± 0.88 0.53 0.39 −0.05 0.83
Cone (cd/m2; cd/m2) Sham −0.75 ± 1.1 −0.64 ± 1.26 −0.9 ± 1.2 −1 ± 0.94 −0.084 −0.48 0.31
66% −1.52 ± 1.17 −0.99 ± 1.08 −1.32 ± 1.35 −1.7 ± 0.95 −0.019 −0.33 0.3
150% 0.06 ± 0.89 0.04 ± 0.96 −0.23 ± 0.84 −0.24 ± 0.9 0.46 0.19 −0.1 0.48
Color discrimination Farnsworth D-15 saturated (CCI) (-;-) Sham 1.64 ± 0.72 1.55 ± 0.67 1.78 ± 0.71 1.43 ± 0.54 0.058 −0.1 0.21
66% 1.74 ± 1.08 1.58 ± 0.92 1.65 ± 1.19 1.7 ± 0.99 −0.04 −0.2 0.12
150% 1.77 ± 0.68 2 ± 0.9 1.92 ± 0.9 1.8 ± 0.83 0.034 −0.24 −0.4 −0.08
Lanthony D-15 desaturated (total error score) (-;-) Sham 172.5 ± 183.9 124.2 ± 134.3 153.5 ± 128.8 154.5 ± 156.06 27.99 −14.13 70.1
66% 130.57 ± 146.5 138 ± 164.18 179.43 ± 277.28 131.43 ± 172.85 2.98 −43.07 49.04
150% 225.7 ± 229.3 207.43 ± 195.39 214 ± 235.97 210.86 ± 242.55 0.72 14 −30.96 58.97
OCT Foveal thickness, radial lines (μm; μm) Sham 189.4 ± 55.9 190.7 ± 55.7 189.4 ± 52.2 177.8 ± 66.7 3.42 −10.4 17.2
66% 211.7 ± 55.7 213 ± 51.4 206.2 ± 58.3 198.8 ± 56.2 5.69 −8.13 19.5
150% 187.6 ± 45.9 193.4 ± 56.1 181 ± 56.1 173.4 ± 75.7 0.97 5.02 −8.8 18.84
Figure 1.
 
Development of scotopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). Left: data from the different treatment arms of the study at all visits that included ERG registrations (visits 1, 5, 8, and 9) as differences in comparison to the baseline value (visit − baseline; 0, sham stimulation; 0.66, 66%; and 1.5, 150% stimulation strength of individual phosphene threshold at 20 Hz). Dots: single values of one individual; bars: the lower and higher 95% CIs of the group; for better visibility groups have been jittered (left, sham; middle, 66%; right, 150%). Right: the estimated mean change in each group over all visits, as calculated by an REML model (bars, 95% CI). The P values calculated by this method describe the probability that the strength of TES influenced development of the respective parameter. Raw data are given in Table 1.
Figure 1.
 
Development of scotopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). Left: data from the different treatment arms of the study at all visits that included ERG registrations (visits 1, 5, 8, and 9) as differences in comparison to the baseline value (visit − baseline; 0, sham stimulation; 0.66, 66%; and 1.5, 150% stimulation strength of individual phosphene threshold at 20 Hz). Dots: single values of one individual; bars: the lower and higher 95% CIs of the group; for better visibility groups have been jittered (left, sham; middle, 66%; right, 150%). Right: the estimated mean change in each group over all visits, as calculated by an REML model (bars, 95% CI). The P values calculated by this method describe the probability that the strength of TES influenced development of the respective parameter. Raw data are given in Table 1.
Figure 2.
 
Development of photopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). The format is analogous to that of Figure 1.
Figure 2.
 
Development of photopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). The format is analogous to that of Figure 1.
Figure 3.
 
Development of Snellen VA in the different treatment arms. The format is analogous to that of Figure 1. Snellen VA was tested with a standard projector at 6 m.
Figure 3.
 
Development of Snellen VA in the different treatment arms. The format is analogous to that of Figure 1. Snellen VA was tested with a standard projector at 6 m.
Figure 4.
 
Development of VF area and mean sensitivity in the different treatment arms. The format is analogous to that of Figure 1. VF area was tested by semiautomatic kinetic perimetry up to 90° eccentricity (Goldmann III4e). Mean sensitivity was calculated from static perimetry with the fast threshold strategy GATE, with up to 85° eccentricity and 86 stimulus locations (stimulus size: Goldmann III).
Figure 4.
 
Development of VF area and mean sensitivity in the different treatment arms. The format is analogous to that of Figure 1. VF area was tested by semiautomatic kinetic perimetry up to 90° eccentricity (Goldmann III4e). Mean sensitivity was calculated from static perimetry with the fast threshold strategy GATE, with up to 85° eccentricity and 86 stimulus locations (stimulus size: Goldmann III).
Figure 5.
 
Development of cone and rod sensitivity in the different treatment arms. The format is analogous to that of Figure 1. Sensitivity for cones was assessed with a red test light for cones and a green test light for rods.
Figure 5.
 
Development of cone and rod sensitivity in the different treatment arms. The format is analogous to that of Figure 1. Sensitivity for cones was assessed with a red test light for cones and a green test light for rods.
Figure 6.
 
Development of electrical phosphene thresholds in the different treatment arms. The format is analogous to that of Figure 1. The threshold was assessed using DTL electrodes at a stimulation frequency of 20 Hz.
Figure 6.
 
Development of electrical phosphene thresholds in the different treatment arms. The format is analogous to that of Figure 1. The threshold was assessed using DTL electrodes at a stimulation frequency of 20 Hz.
Improvement in VF area from the first to last visits is shown in Figure 7, with corresponding fundus photographs from four selected patients of the 150% stimulation group. 
Figure 7.
 
Fundus photographs and development of static and kinetic VF results in four selected patients of the group treated with 150% of individual phosphene threshold at 20 Hz. Although static VF results did not show a clear behavior in all four patients, enlargement of the kinetic VF area was observed.
Figure 7.
 
Fundus photographs and development of static and kinetic VF results in four selected patients of the group treated with 150% of individual phosphene threshold at 20 Hz. Although static VF results did not show a clear behavior in all four patients, enlargement of the kinetic VF area was observed.
Raw data of the long visits and results of the REML calculations are given in Table 1
To assess a possible association between changes in different parameters, Figure 8 shows the scotopic and photopic b-wave amplitudes of the ERG versus Snellen VA, and in Figure 9, ERG parameters versus VF area. In both figures, the 95% confidence ellipses of the sham and the 66% groups are approximately centered, with nearly equal areas in each quadrant indicating a tendency for patients in this group to neither improve nor deteriorate in either parameter. Especially for the scotopic b-wave amplitudes, a tendency for the lower right quadrant is obvious, which indicates that most of these patients gained in VA but lost in ERG values. The ellipses of the 150% group have their center in the upper right quadrant with most points positioned there, which indicates an improvement in both parameters in this group for most of the patients. 
Figure 8.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). Dots: data from the individual patients, given as differences between each visit and baseline for all visits; VA data were calculated after transformation into logMAR. Shaded areas: 95% confidence ellipses; the position of the center of the ellipse is an indicator of the change in most of the respective group (e.g., a position in the top right quadrant shows that most patients experienced an improvement in both parameters and a position in the bottom left quadrant that they experienced a deterioration in both parameters), whereas a position in one of the other quadrants indicates improvement in one and deterioration in the other parameter.
Figure 8.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). Dots: data from the individual patients, given as differences between each visit and baseline for all visits; VA data were calculated after transformation into logMAR. Shaded areas: 95% confidence ellipses; the position of the center of the ellipse is an indicator of the change in most of the respective group (e.g., a position in the top right quadrant shows that most patients experienced an improvement in both parameters and a position in the bottom left quadrant that they experienced a deterioration in both parameters), whereas a position in one of the other quadrants indicates improvement in one and deterioration in the other parameter.
Figure 9.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (standard flash; both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). The format is analogous to that of Figure 8.
Figure 9.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (standard flash; both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). The format is analogous to that of Figure 8.
Discussion
Retinitis pigmentosa is a progressive disease that eventually leads to blindness due to degenerative processes in the retina or its adjacent tissue. 24 Although many promising treatments, each with a set of potential disadvantages, are being investigated, none of them has yet found clinical acceptance. 24 Among them are vitamin A supplement, 25 CNTF delivered by encapsulated cell intraocular implants, 26 and gene therapy in animals 27 and in humans with a subform of RP (Leber's congenital amaurosis). 28 In late stages of the disease, when patients are approaching blindness, sub- and epiretinal electronic implants have shown considerable potential (Humayun MS, et al. IOVS 2009;50:ARVO E-Abstract 4744). 29  
TES has several potential advantages over other treatments, such as being minimally invasive and applicable in a routine manner, even at home, and has shown potential in several ocular diseases in humans and in animal models (see the introduction). It has been tested in age-related macular degeneration (AMD) and since had been published in non–peer-reviewed journals, causing the American Academy of Ophthalmology to issue a statement that (although risks seemed low) insufficient scientific evidence is available to support its use in AMD (http://one.aao.org/asset.axd?id=f77155a3-802a-4f6c-9891-9e65e38d84af/; American Academy of Ophthalmology, San Francisco, CA). 
For TES in RP patients, there is, to the best of our knowledge, only one preliminary report of a small prospective study in 12 RP patients, which postulates positive effects only in VA, but no change in ERG and VF (Lopez-Miranda et al. IOVS 2010;51:ARVO E-Abstract1356). Unfortunately, the study lacked several parameters of GCP such as sham control and blinding or randomization procedures, which limits its validity. 
Our study was prospective, randomized, and sham-controlled. It was partially blinded (i.e., examiners for VF, ERG, mfERG, DA, and color discrimination were blinded to the treatment group). Study doctors who performed VA and EPT measurements were not blinded, because they had to start electrical stimulation with the software. The patients were blinded to treatment for the duration of the study. 
Within the paradigm of our study—weekly stimulation of 30 minutes for 6 consecutive weeks (application of TES using DTL electrodes)—we found TES to be safe. Only two minor AEs, but no SAEs, were encountered during the follow-up of 4 months, with an accumulated stimulation time of 48 hours. This finding in RP patients, however, should be transferred to other ocular diseases cautiously, especially to those in which growth factors play an important role, such as diabetic retinopathy or AMD. In addition, we found that DTL electrodes were tolerated very well and seemed as apt for continuous stimulation in TES as they were for phosphene threshold assessment. 15 DTL electrodes bear important potential advantages over many other electrodes, among them their high tolerability and cheap production costs. 
We found a tendency toward improvement in the eight examinations after TES: scotopic a- and b-wave amplitudes of the ERG, the photopic b-wave amplitude, Snellen VA, VF area, sensitivity for electrical phosphenes, and cone and rod threshold sensitivity. Some of these changes were small or did not reach statistical significance. 
Statistically significant improvement under treatment was discovered in the 150% group for one psychophysical test (i.e., VF area, which increased by 17% in the 150% group, whereas it decreased by 9% and 6% in the 66% and sham groups, resp.; P < 0.001; Table 1, Figs. 4, 7). VF was tested in a double-blind manner; neither technicians nor patients were aware of treatment group. Statistically significant improvement was also found in one objective test: The scotopic b-wave amplitude to an SF increased by 8.79 μV in the 150% group, whereas it decreased by 8.82 and 8.43 μV in the 66% and sham groups, resp. (P = 0.027; Table 1; Fig. 1). Figure 7 shows improvements in VF area in four patients of the 150% group: In three, the central remaining island of VF increased, in one a peripheral island increased considerably, and in three the remaining islands connected to form a larger area. 
Although the pattern for amelioration was consistent over many parameters, we also found several parameters that showed worsening. The decline in one of them, the desaturated color discrimination test, was statistically significant (Table 1). For this worsening we do not have a clear explanation. We do not, however, believe that it reflects a true deterioration of macular function, as many other parameters showed a tendency to improve. The worsening of mean sensitivity in the visual fields in the two treatment groups was slight and nonsignificant. 
Although the safety of TES may be more easily proven and more readily acceptable, it is much more challenging to prove the efficacy of treatment in a disease such as RP. The natural course of disease progression in these patients can be highly variable, with years of stagnation at any level followed by sudden worsening, sometimes occurring rapidly, within weeks. 24 This fact and the decades-long, mostly genetically determined degeneration processes make it inherently difficult to prove the efficacy of any treatment. Even well-conducted studies with several hundreds of patients with treatment and examination over several years receive considerable criticism. 30  
Originally, our exploratory study with a limited number of patients and limited treatment and study period was therefore not powered to form a definitive judgment as to clinical efficacy. We found it all the more remarkable that there was a visible pattern of improvement of in visual function parameters, with two of them reaching statistical significance (VF area and b-wave amplitude to scotopic SF). We are certainly aware of the fact that our study at this point cannot provide unambiguous evidence of efficacy to support use of TES in all RP patients. 
Acknowledging the fact that our trial was small and that most results are not statistically significant, we would still propose for further studies that 150% of the individual EPT rather than 66% be considered, as statistical significance was only reached for the 150% group (VF area and scotopic b-wave amplitude). 
We believe that sham-stimulated control eyes constitute the most solid and acceptable control in the situation of our study. Using the contralateral eye as a control could be incorrect since stimulation of this eye cannot not be excluded, as some small amount of current might still pass from the stimulated eye. 
Most researchers, including us, have used 20 Hz as the stimulation frequency for ocular tissue (Zhang H, et al. IOVS 2009;50:ARVO E-Abstract 3615; Naycheva L, et al. IOVS 2009;50:ARVO E-Abstract 5412; Willmann G, et al. IOVS 2010;51:ARVO E-Abstract 3713). 2,3,7,8,10 12 The decision has been based on the fact that 20 Hz shows the lowest stimulation thresholds necessary to create visual percepts. However, it is unclear whether the fact that the psychophysical threshold is lowest at 20 Hz necessarily implies that all other potential mechanisms of action of TES are best supported by a frequency of 20 Hz. However, recently Morimoto et al. 31 supported the use of this frequency in their systematic study of optimal TES parameters in axotomized RCS rats. They also found the optimal current range to be 100 to 200 μA and stimulation time to be at least 30 minutes, which is in good accordance with most of the previously mentioned human studies and our trial. 
Potential criticism of our design may be that patients felt the electrical stimulation through the DTL electrodes. Although it is true that most patients did feel phosphene testing and some of them also definitively felt the first seconds at the beginning of the 30-minute stimulation period, it was remarkable that most of the patients repeatedly asked the study doctor which treatment group they were assigned to. A solution for this potential problem in future studies could be to start in all groups with 1 or 2 seconds of slowly fading suprathreshold stimulation which would mask the true stimulation for the rest of the 30 minutes. 
The decision to use individual phosphene thresholds in our study instead of fixed, predefined amplitudes in each group was based on several thoughts. First, we believed that the stimulation strength that is necessary to produce an effect is dependent on the stage of the disease (i.e., a more severely degenerated retina should require higher current amplitudes). Since EPT is a measure of disease stage, 15 it can be taken as an indicator for stimulation strength. Second, we see a potential beneficial effect of stimulating suprathreshold, since this method ensures activation of the remaining retinal cells, especially the ganglion cells, and also the whole visual system, an effect that would go beyond stimulation of, for example, Müller cells to enhance production of neurotrophic factors. 10  
TES could have several potential advantages over other treatments. First, it is minimally invasive and bears almost no danger of adverse or even serious adverse reactions, such as endophthalmitis after intraocular injections or very severe AEs (e.g., as occurs with gene therapy). Second, EST is cheap, costs of electrodes are low, and a stimulator can be built using standard electronic components. Furthermore, parameters of TES can be easily adjusted, and there are possibilities of evaluating stimulation parameters after treatment periods through storage of impedance and other parameters in the stimulator unit. TES can also stimulate all ocular structures, including the retina, choroid, ciliary body, ganglion cells, and optic nerve. On the hypothesis that TES exerts its effect, even if only partially, through activation of any these structures and their respective neurotrophic factors and pathways, it could be beneficial to simultaneously affect the expression of a variety of these factors. 
In conclusion, our data convincingly show that TES using DTL electrodes is safe in RP patients. Effects in our study were positive but small; several parameters of visual function improved significantly during treatment in the 150% stimulation group, such as the area of the kinetic VF and the scotopic b-wave amplitude of the ERG. Considering the short duration of the study, we find our data promising and see ourselves in a position of being able to recommend and correctly design adequately powered, larger studies. These studies will include many more patients and should be conducted over a much longer period, to balance out random changes or differences in disease progression. 
Footnotes
 Supported by Okuvision GmbH, Reutlingen, Germany.
Footnotes
 Disclosure: A. Schatz, Okuvision GmbH (F); T. Röck, Okuvision GmbH (F); L. Naycheva, Okuvision GmbH (F); G. Willmann, Okuvision GmbH (F); B. Wilhelm, Okuvision GmbH (F); T. Peters, Okuvision GmbH (F); K.U. Bartz-Schmidt, Okuvision GmbH (F); E. Zrenner, Okuvision GmbH (F); A. Messias, Okuvision GmbH (F); F. Gekeler, Okuvision GmbH (F)
The authors thank Klaus Dietz, head emeritus of the Institute of Biometry in Medicine (University of Tübingen, Germany), for indispensable initial support in evaluating the data and using the statistical models for this study; technicians Ulricke Kessler, Katharina Endress, and Susanne Kramer for performing excellent examinations; and Laura Stecher for help in data entry. 
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Figure 1.
 
Development of scotopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). Left: data from the different treatment arms of the study at all visits that included ERG registrations (visits 1, 5, 8, and 9) as differences in comparison to the baseline value (visit − baseline; 0, sham stimulation; 0.66, 66%; and 1.5, 150% stimulation strength of individual phosphene threshold at 20 Hz). Dots: single values of one individual; bars: the lower and higher 95% CIs of the group; for better visibility groups have been jittered (left, sham; middle, 66%; right, 150%). Right: the estimated mean change in each group over all visits, as calculated by an REML model (bars, 95% CI). The P values calculated by this method describe the probability that the strength of TES influenced development of the respective parameter. Raw data are given in Table 1.
Figure 1.
 
Development of scotopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). Left: data from the different treatment arms of the study at all visits that included ERG registrations (visits 1, 5, 8, and 9) as differences in comparison to the baseline value (visit − baseline; 0, sham stimulation; 0.66, 66%; and 1.5, 150% stimulation strength of individual phosphene threshold at 20 Hz). Dots: single values of one individual; bars: the lower and higher 95% CIs of the group; for better visibility groups have been jittered (left, sham; middle, 66%; right, 150%). Right: the estimated mean change in each group over all visits, as calculated by an REML model (bars, 95% CI). The P values calculated by this method describe the probability that the strength of TES influenced development of the respective parameter. Raw data are given in Table 1.
Figure 2.
 
Development of photopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). The format is analogous to that of Figure 1.
Figure 2.
 
Development of photopic a- and b-wave amplitudes and implicit times in the different treatment arms (Ganzfeld ERG, standard flash: 3 cd · s/m2). The format is analogous to that of Figure 1.
Figure 3.
 
Development of Snellen VA in the different treatment arms. The format is analogous to that of Figure 1. Snellen VA was tested with a standard projector at 6 m.
Figure 3.
 
Development of Snellen VA in the different treatment arms. The format is analogous to that of Figure 1. Snellen VA was tested with a standard projector at 6 m.
Figure 4.
 
Development of VF area and mean sensitivity in the different treatment arms. The format is analogous to that of Figure 1. VF area was tested by semiautomatic kinetic perimetry up to 90° eccentricity (Goldmann III4e). Mean sensitivity was calculated from static perimetry with the fast threshold strategy GATE, with up to 85° eccentricity and 86 stimulus locations (stimulus size: Goldmann III).
Figure 4.
 
Development of VF area and mean sensitivity in the different treatment arms. The format is analogous to that of Figure 1. VF area was tested by semiautomatic kinetic perimetry up to 90° eccentricity (Goldmann III4e). Mean sensitivity was calculated from static perimetry with the fast threshold strategy GATE, with up to 85° eccentricity and 86 stimulus locations (stimulus size: Goldmann III).
Figure 5.
 
Development of cone and rod sensitivity in the different treatment arms. The format is analogous to that of Figure 1. Sensitivity for cones was assessed with a red test light for cones and a green test light for rods.
Figure 5.
 
Development of cone and rod sensitivity in the different treatment arms. The format is analogous to that of Figure 1. Sensitivity for cones was assessed with a red test light for cones and a green test light for rods.
Figure 6.
 
Development of electrical phosphene thresholds in the different treatment arms. The format is analogous to that of Figure 1. The threshold was assessed using DTL electrodes at a stimulation frequency of 20 Hz.
Figure 6.
 
Development of electrical phosphene thresholds in the different treatment arms. The format is analogous to that of Figure 1. The threshold was assessed using DTL electrodes at a stimulation frequency of 20 Hz.
Figure 7.
 
Fundus photographs and development of static and kinetic VF results in four selected patients of the group treated with 150% of individual phosphene threshold at 20 Hz. Although static VF results did not show a clear behavior in all four patients, enlargement of the kinetic VF area was observed.
Figure 7.
 
Fundus photographs and development of static and kinetic VF results in four selected patients of the group treated with 150% of individual phosphene threshold at 20 Hz. Although static VF results did not show a clear behavior in all four patients, enlargement of the kinetic VF area was observed.
Figure 8.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). Dots: data from the individual patients, given as differences between each visit and baseline for all visits; VA data were calculated after transformation into logMAR. Shaded areas: 95% confidence ellipses; the position of the center of the ellipse is an indicator of the change in most of the respective group (e.g., a position in the top right quadrant shows that most patients experienced an improvement in both parameters and a position in the bottom left quadrant that they experienced a deterioration in both parameters), whereas a position in one of the other quadrants indicates improvement in one and deterioration in the other parameter.
Figure 8.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). Dots: data from the individual patients, given as differences between each visit and baseline for all visits; VA data were calculated after transformation into logMAR. Shaded areas: 95% confidence ellipses; the position of the center of the ellipse is an indicator of the change in most of the respective group (e.g., a position in the top right quadrant shows that most patients experienced an improvement in both parameters and a position in the bottom left quadrant that they experienced a deterioration in both parameters), whereas a position in one of the other quadrants indicates improvement in one and deterioration in the other parameter.
Figure 9.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (standard flash; both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). The format is analogous to that of Figure 8.
Figure 9.
 
Association of individual changes in scotopic (top row) and photopic (bottom row) ERG b-wave amplitudes (standard flash; both to Ganzfeld standard flashes with 3 cd · s/m2) and visual acuity (VA; Snellen). The format is analogous to that of Figure 8.
Table 1.
 
Raw Data of the Tested Parameters in the Three Stimulation Groups
Table 1.
 
Raw Data of the Tested Parameters in the Three Stimulation Groups
Test Subtest (Unit Raw Data; Unit REML) Group Raw Data REML
95% CI
Visit 1 or Mean of Visits 1 + 2 Visit 5 Visit 8 Visit 9 P Means Lower Upper
Scotopic ERG SF a-wave ampl. (μV; μV) Sham 20.6 ± 13.9 16.6 ± 11.6 21.7 ± 12 21.9 ± 7.8 0.64 −9.64 10.92
66% 18.8 ± 7.4 15.8 ± 2.8 18.7 ± 4.6 16.8 ± 6.5 −0.07 −10.35 10.21
150% 36 ± 37.1 40.2 ± 35.8 44.7 ± 33.2 43.2 ± 40.7 0.49 6.72 −2.38 15.81
SF a-wave impl. (ms; ms) Sham 24.3 ± 8.8 21 ± 6.8 19.8 ± 4.2 26.4 ± 11.7 1.29 −4.55 7.13
66% 19.5 ± 4 19.3 ± 4.9 23.4 ± 7.7 23.5 ± 7.6 2.83 −3.01 8.66
150% 20.6 ± 3.4 22.4 ± 4.9 23 ± 7.3 21.6 ± 2.2 0.9 1.73 −3.46 6.93
SF b-wave ampl. (μV; μV) Sham 34.9 ± 12.6 30.8 ± 5 24.4 ± 8.2 24.7 ± 10.8 −8.43 −19 2.14
66% 35.2 ± 20.3 37.9 ± 9.6 22.9 ± 15.5 19.6 ± 14 −8.82 −19.39 1.75
150% 67 ± 72.3 73.7 ± 79.2 66.7 ± 65.7 86.8 ± 84 0.027 8.79 −0.54 18.13
SF b-wave impl. (ms; ms) Sham 59.5 ± 15.5 58.2 ± 11.6 56.4 ± 11.6 58.4 ± 8.2 −1.62 −7.72 4.47
66% 59.5 ± 3.8 58.7 ± 4 60.2 ± 4.8 59.5 ± 14.7 −0.95 −7.405 5.14
150% 56.8 ± 3.1 55.8 ± 1.8 56.6 ± 3.7 56.2 ± 5.8 0.96 −0.6 −5.96 4.76
Photopic ERG SF a-wave ampl. (μV; μV) Sham 4.4 ± 1.9 6.8 ± 5.6 7.9 ± 3.4 6.2 ± 3.3 2.77 −4.83 10.37
66% 15.9 ± 13.8 4 ± 2.4 5 ± 3.8 10 ± 8.2 −10.35 −18.83 −1.87
150% 9.6 ± 3 10 ± 7.3 9.9 ± 4.5 10.8 ± 5.3 0.062 1.11 −7.4 9.62
SF a-wave impl. (ms; ms) Sham 22 ± 7 17.8 ± 2.2 16 ± 4.6 20.7 ± 6.5 −2.25 −6.49 1.99
66% 18.2 ± 2.5 15.8 ± 1 16.6 ± 7.2 20.2 ± 6.9 −0.79 −5.5 3.92
150% 17.8 ± 1.5 19.8 ± 4.7 15.3 ± 2.5 15.7 ± 2.3 0.8 −0.51 −5.27 4.24
SF b-wave ampl. (μV; μV) Sham 17 ± 7 20.6 ± 11.6 25.5 ± 11.6 19.4 ± 16.3 −0.21 −4.68 4.26
66% 21.7 ± 14.4 20.2 ± 13.2 22.6 ± 13.6 17.3 ± 12.6 −0.31 −5.19 4.57
150% 29 ± 13.2 27.6 ± 15.3 39.4 ± 14.7 33 ± 20.3 0.082 6.66 1.62 11.69
SF b-wave impl. (ms; ms) Sham 38 ± 3.9 38.3 ± 4.5 37.4 ± 4.1 40 ± 5.1 1.13 −0.53 2.79
66% 37.5 ± 5.3 36 ± 3.9 36.8 ± 5.3 37.7 ± 4.1 −0.83 −2.67 1
150% 36 ± 4.2 36.2 ± 4.2 36.3 ± 5 36.2 ± 3.3 0.25 −0.077 −1.94 1.78
Visual acuity Snellen (logMAR, logMAR) Sham 0.18 ± 0.15 0.18 ± 0.15 0.16 ± 0.17 0.15 ± 0.18 0.017 −0.025 0.058
66% 0.23 ± 0.21 0.18 ± 0.22 0.18 ± 0.22 0.19 ± 0.23 0.039 0.0023 0.08
150% 0.33 ± 0.3 0.25 ± 0.24 0.26 ± 0.34 0.25 ± 0.33 0.22 0.067 0.026 0.11
Visual field area (deg2; %) Sham 5265.94 ± 4065.7 5311.15 ± 4109.04 5233.7 ± 4049.02 4812.33 ± 3739.48 0.94 0.81 1.07
66% 3174.27 ± 3156.25 3006.85 ± 3020.95 2967.24 ± 2980.18 3042.3 ± 3165.97 0.91 0.78 1.05
150% 4681.1 ± 4741.55 4823.81 ± 4836.87 5112.81 ± 4818.73 5176.65 ± 4752.32 <0.001 1.17 1.04 1.3
mean sensitivity (dB; dB) Sham 4.99 ± 3.95 5.3 ± 3.85 5.86 ± 3.94 5.78 ± 4.23 0.66 0.026 1.29
66% 4.5 ± 3.62 4.14 ± 3.2 4.84 ± 3.91 4.25 ± 3.6 −0.09 −0.72 0.54
150% 6.2 ± 4.14 6.05 ± 3.96 5.94 ± 4.33 6.06 ± 4.09 0.12 −0.18 −0.82 0.45
Absolute threshold/sensitivity; phosphenes evoked at 20 Hz (μmA; %) Sham 0.39 ± 0.25 0.31 ± 0.25 0.32 ± 0.17 0.36 ± 0.2 1.27 0.9 1.65
66% 0.38 ± 0.2 0.32 ± 0.17 0.32 ± 0.12 0.28 ± 0.08 1.25 0.87 1.62
150% 0.33 ± 0.18 0.24 ± 0.13 0.23 ± 0.13 0.28 ± 0.23 0.73 1.43 1.06 1.81
mf ERG (mean of rings 1–5) Amplitude (μV; μV) Sham 8.94 ± 8.07 9.12 ± 8.59 9.87 ± 9.7 10.62 ± 11.33 −0.39 −3.1 2.32
66% 12.1 ± 10.97 10.87 ± 10.31 11.78 ± 10.57 12.21 ± 10.55 −1.49 −3.92 0.95
150% 10.37 ± 12.02 10.54 ± 10.81 8.9 ± 10.72 8.74 ± 10.71 0.76 −1.54 −4.12 1.05
Implicit time (ms; ms) Sham 34.48 ± 5.66 34.28 ± 4.68 32.77 ± 4.19 33.67 ± 4.85 0.22 −1.73 2.17
66% 32.73 ± 4.79 32.35 ± 3.78 32.27 ± 4.82 31.37 ± 2.97 −1.12 −2.87 0.63
150% 33.99 ± 5.16 33.75 ± 2.88 33.32 ± 3.19 34.05 ± 4.82 0.48 0.12 −1.74 1.98
Final threshold rod and cone sensitivity Rod (cd/m2; cd/m2) Sham −1.36 ± 1.4 −1.76 ± 1.37 −1.88 ± 1.26 −1.8 ± 0.8 0.043 −0.56 0.65
66% −2.03 ± 1.67 −1.88 ± 1.12 −2 ± 1.74 −2.17 ± 1.46 0.081 −0.4 0.56
150% −0.95 ± 0.94 −1.35 ± 1.49 −1.64 ± 1.38 −1.24 ± 0.88 0.53 0.39 −0.05 0.83
Cone (cd/m2; cd/m2) Sham −0.75 ± 1.1 −0.64 ± 1.26 −0.9 ± 1.2 −1 ± 0.94 −0.084 −0.48 0.31
66% −1.52 ± 1.17 −0.99 ± 1.08 −1.32 ± 1.35 −1.7 ± 0.95 −0.019 −0.33 0.3
150% 0.06 ± 0.89 0.04 ± 0.96 −0.23 ± 0.84 −0.24 ± 0.9 0.46 0.19 −0.1 0.48
Color discrimination Farnsworth D-15 saturated (CCI) (-;-) Sham 1.64 ± 0.72 1.55 ± 0.67 1.78 ± 0.71 1.43 ± 0.54 0.058 −0.1 0.21
66% 1.74 ± 1.08 1.58 ± 0.92 1.65 ± 1.19 1.7 ± 0.99 −0.04 −0.2 0.12
150% 1.77 ± 0.68 2 ± 0.9 1.92 ± 0.9 1.8 ± 0.83 0.034 −0.24 −0.4 −0.08
Lanthony D-15 desaturated (total error score) (-;-) Sham 172.5 ± 183.9 124.2 ± 134.3 153.5 ± 128.8 154.5 ± 156.06 27.99 −14.13 70.1
66% 130.57 ± 146.5 138 ± 164.18 179.43 ± 277.28 131.43 ± 172.85 2.98 −43.07 49.04
150% 225.7 ± 229.3 207.43 ± 195.39 214 ± 235.97 210.86 ± 242.55 0.72 14 −30.96 58.97
OCT Foveal thickness, radial lines (μm; μm) Sham 189.4 ± 55.9 190.7 ± 55.7 189.4 ± 52.2 177.8 ± 66.7 3.42 −10.4 17.2
66% 211.7 ± 55.7 213 ± 51.4 206.2 ± 58.3 198.8 ± 56.2 5.69 −8.13 19.5
150% 187.6 ± 45.9 193.4 ± 56.1 181 ± 56.1 173.4 ± 75.7 0.97 5.02 −8.8 18.84
Copyright © Association for Research in Vision and Ophthalmology
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