Behandling av retinitis pigmentosa med transkorneal elektrostimulering
- Felles uttalelse fra Nasjonalt fagmiljø på arvelige netthinnesykdommer
Medlemmer
Cecilie Bredrup, Overlege, Førsteamanuensis, Øyeavdelingen, Haukeland Universitetssykehus
Dordi Austeng, Overlege, Professor, St. Olav Universitetssykehus
Erlend Schanke Almaas, Overlege, St. Olav Universitetssykehus
Geir Bertelsen, Overlege, Førsteamanuensis, Øyeavdelingen, Universitetssykehuset Nord-Norge
Josephine Prener Holtan, Overlege, PhD, Øyeavdelingen, Oslo Universitetssykehus
Ragnheidur Bragadottir, Overlege, Professor, Øyeavdelingen, Oslo Universitetssykehus
Ragnhild Wivestad Jansson, Overlege, PhD, Øyeavdelingen, Haukeland Universitetssykehus
Innledning
Optimal øyehelseklinikk tilbyr behandling med Okustim til pasienter med Retinitis pigmentosa. Et samlet fagmiljø i Norge mener at denne behandlingen ikke har en dokumentert effekt. Det er ønskelig at eventuell behandling med Okustim gjøres som ledd i en klinisk studie. Pasienter med Retinitis pigmentosa er i en svært vanskelig situasjon og det er uheldig at det reklameres for at pasienter skal betale for ikke dokumentert behandling for denne sykdommen.
Bakgrunn for uttalelse: Retinitis pigmentosa er en arvelig netthinnesykdom. De fleste former for retinitis pigmentosa finnes det ingen behandling for. Transkorneal elektrisk stimulering er en eksperimentell metode utviklet i forbindelse med studier på netthinne- implantater. Teorien bak metoden er at man kan øke dannelsen av netthinnebeskyttende faktorer (nevrotrofiske faktorer) ved å tilføre øyet strøm gjennom tynne elektroder som legges på hornhinnen. Den største studien på effekten av transkorneal elektrisk stimulering hos pasienter med retinitis pigmentosa inkluderte 105 pasienter (inkl. 10 norske pasienter). Denne studien viste ikke effekt av behandlingen (1). I februar 2023 ble en ny artikkel vedrørende behandling med transkorneal elektrisk stimulering publisert (2). Artikkelen baserer seg på en reanalyse av data fra pasienter som tidligere har vært med i en studie, hvor effekten av transkorneal elektrisk stimulering ble undersøkt (3,4). Fagmiljøet har gjort en samlet vurdering basert på artikkelen publisert i 2023 (2). I tillegg har en uavhengig statistikker vurdert utregninger gjort i artikkelen.
Vurdering: Det er betydelige svakheter ved studien. Hovedinnvending er tolkningen av resultatene fra den statistiske analysen. Den aktuelle studien har et randomisert design, der man sammenligner en terapi med placebo. Dermed blir det viktigste funnet hva man finner når man sammenligner hoved-effektvariabelen (prosentvis reduksjon av synsfeltet) i terapigruppen og placebogruppen. Her er rapportert p-verdi lik 0.103, altså er forskjellen ikke statistisk signifikant. Sammenligning av treated eye og non-treated eye er mye mer usikker, blant annet fordi disse to øynene gjennomsnittlig var «klinisk forskjellige» ved behandlingsstart samt stor sannsynlighet for placebo effekt. I den statistiske analysen brukes ikke-parametriske metoder (Wilcoxon test, Mann Whitney U-test, etc.), som matematisk-statistisk forskning har vist at har vesentlige svakheter sammenlignet med parametriske tester (t-test etc.) Det var videre få pasienter inkludert i studien, ingen klassifikasjon av pasientene som deltok, hverken i forhold til type retinitis pigmentosa eller sykdomsstadium, og veldig kort oppfølgingstid.
Konklusjon: Hovedkonklusjonen fra studien er at det ikke er signifikant forskjell mellom behandlede pasienter og placebogruppen. Studien kan kanskje støtte en hypotese om at effekten av behandling er doseavhengig, men den beviser ikke at behandlingen har effekt. Til dette kreves studier som er designet for å måle effekten av behandling, hvor pasientene følges over lengre tid og hvor en kjenner til forventet forløp av sykdommen.
- Jolly JK, Wagner SK, Martus P, MacLaren RE, Wilhelm B, Webster AR, Downes SM, Charbel Issa P, Kellner U, Jägle H, Rüther K, Bertelsen M, Bragadóttir R, Prener Holtan J, van den Born LI, Sodi A, Virgili G, Gosheva M, Pach J, Zündorf I, Zrenner E, Gekeler F. Transcorneal Electrical Stimulation for the Treatment of Retinitis Pigmentosa: A Multicenter Safety Study of the OkuStim® System (TESOLA-Study). Ophthalmic Res. 2020;63(3):234-243. doi: 10.1159/000505001. Epub 2019 Nov 26. PMID: 31775146.
- Stett A, Schatz A, Gekeler F, Franklin J. Transcorneal Electrical Stimulation Dose-Dependently Slows the Visual Field Loss in Retinitis Pigmentosa. Transl Vis Sci Technol. 2023 Feb 1;12(2):29. doi: 10.1167/tvst.12.2.29. PMID: 36809335; PMCID: PMC9946045.
- Schatz A, Pach J, Gosheva M, Naycheva L, Willmann G, Wilhelm B, Peters T, Bartz-Schmidt KU, Zrenner E, Messias A, Gekeler F. Transcorneal Electrical Stimulation for Patients With Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Follow-up Study Over 1 Year. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):257-269. doi: 10.1167/iovs.16-19906. PMID: 28114587.
- Schatz A, Röck T, Naycheva L, Willmann G, Wilhelm B, Peters T, Bartz-Schmidt KU, Zrenner E, Messias A, Gekeler F. Transcorneal electrical stimulation for patients with retinitis pigmentosa: a prospective, randomized, sham-controlled exploratory study. Invest Ophthalmol Vis Sci. 2011 Jun 23;52(7):4485-96. doi: 10.1167/iovs.10-6932. PMID: 21467183.
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Tilsvar fra OkuVision angående faggruppens uttalelse om elektrostimulering:
Treatment of retinitis pigmentosa with transcorneal electrical stimulation
A commentary on the joint statement of the National Expert Group on Hereditary Retinal Diseases of Norway
Alfred Stett (1) , Andreas Schatz (2) , Florian Gekeler (2, 3) Jeremy Franklin (4)
1 Okuvision GmbH, Reutlingen, Germany
2 Centre for Ophthalmology, University Eye Hospital, Eberhard-Karls University Tübingen, Germany
3 Department of Ophthalmology, Klinikum Stuttgart, Germany
4 Institute of Medical Statistics and Computational Biology; University of Cologne, Köln, Germany
Commercial relationship disclosures
A. Stett, Okuvision GmbH (CEO, Employment); A. Schatz, None; F. Gekeler, None; J. Franklin, Okuvision GmbH (Financial Support)
Version: 2024-08-05
Background
The National Expert Group on Inherited Retinal Diseases of Norway believes that Transcorneal Electrical Stimulation (TES) therapy with OkuStim does not have a documented effect and considers it unfortunate that patients are being asked to pay for undocumented treatment. They base their finding on their assessment of the 2023 publication by Stett et al [1]. In their opinion, the main conclusion of this publication is that there is no significant difference between treated patients and the placebo group.
Contrary to the opinion of the expert group, we – the authors of the publication in question – have indeed described a significant dose-dependent difference between the treated patients and the placebo group in the publication. As the expert group’s conclusion is not congruent with our interpretation of the results and our conclusion, we would like to comment on the expert group’s statement below.
TES treatment vs. Placebo treatment
Our results are based on a re-analysis of data from the EST2 study, the results of which were published in 2017 [2]. In the EST2 study, individual current intensities were determined based on the threshold current for triggering phosphenes, patients were randomized to either 0% (placebo, n=20), 150% (n=15) or 200% (n=17) of the phosphene threshold and the visual field areas (VFA) were evaluated after one year of stimulation. A final visit took place 6 months after the end of treatment. All patients had advanced rod-cone dystrophy, mean age was 46 ± 15 years. At baseline, the VFAs of the treated eyes spanned a range from 338 to 15,632 deg 2 (median: 8,141 deg 2 , kinetic perimetry, target V4e).
In the new analysis, we hypothesized that the effect of TES does not depend on the strongly scattering phosphene thresholds (see our publication Fig. 1A), but on the administered current intensity. The analysis confirmed this hypothesis. A significant correlation (p = 0.047) was found between the reduction of the visual field area and the current intensity – the stronger the stimulation, the smaller the loss after one year of treatment (Fig. 5D). In the most stimulated subgroup of patients treated with currents of 0.8 mA to 1.0 mA, the visual field loss in the treated eye was significantly smaller compared to the placebo treatment group (p = 0.037; text page 11, left column, compare Figs. 5A,C). Furthermore, in 66% (6 of 9) of the stimulated eyes in this group, the visual field was larger after one year of treatment than at the beginning, compared to 11% (1 of 9) of the untreated partner eyes and 25% (5 of 20) of placebo-treated eyes (see text on page 14, right column). If the dependence on the current intensity is disregarded and the group of all TES-treated patients is compared with the placebo group, there was no significant difference between the two groups (p =0.103, see Fig. 5A,B).
As the reductions of the visual field determined are not normally distributed in all analyzed subgroups (Shapiro-Wilk test), the requirements for using t-tests were not met. In our analysis, we chose non-parametric tests (Wilcoxon signed rank test and Mann Whitney U-test) because they do not require specific assumptions about the distributions. If we disregard the non-normality of some distributions and still apply the t-test, the current-independent difference between the TES-treated eyes and the placebo-treated eyes is significant (p = 0.037), as is the difference in the eyes of the subgroup of patients treated with currents of 0.8 mA to 1.0 mA compared to the placebo treatment (p = 0.040).
TESOLA Study
The TESOLA study [3] mentioned by the expert group must be seen against the background of the dependence of the effects of TES on current intensity. In the TESOLA study, the stimulation current was 150% of the phosphene threshold, with a distribution that was probably similar to the distribution in the EST2 study (Fig. 1B). The TESOLA study was a safety study (see clinical trial ID NCT01835002). The purpose was to expand the safety assessment of repeated applications of an electrical current from a DTL-like electrode in patients with RP. The primary outcome measure was safety, indicated by the frequency and severity of adverse events. The primary endpoint was reached. No serious adverse events (SAEs) related to the device and therapy occurred throughout the study. A common adverse event was transient dry eyes, which was easily treatable with eye drops. The visual fields and visual acuity of the stimulated and non-stimulated eyes remained objectively stable during the entire observation period, and no effect of the treatment in terms of an improvement in visual function could be demonstrated.
However, the study was not designed to provide information on efficacy. The duration of treatment was only 6 months, which is too short in view of the great variability of the slow natural course of the disease. In addition to the scattering of the individual results due to the dependence on the current intensity, the methods for recording the visual field were not uniform in the different study centers, which further increased the variability of the data.
Placebo effect
The expert group notes that the comparison between treated and untreated eyes is uncertain and the probability of a placebo effect is high, as the two eyes differed clinically at the beginning of the study. In our publication, we discussed the choice of the study eye (see discussion, page 15, right column) and showed that the visual fields of the two eyes were not statistically different at baseline (see Supplementary Material). A potential placebo effect should have become apparent in the group with placebo treatment. However, there was no significant difference between the two eyes in this group (see Fig. 5A). Furthermore, the main statements of the paper do not concern the comparison between treated and untreated eyes, but the dependence of the effect in the treated eye on the stimulus intensity and the comparison with the placebo treatment.
Conclusion
The main conclusion of the re-analysis of the data from the EST2 study is that there was a current strength-dependent, significant difference between the visual field loss of the treated patients and the placebo group over the treatment period of one year. Other effects of TES are documented in an increasing number of publications of clinical study results. In vitro and in vivo evidence on TES and other ocular stimulation approaches in eye diseases are the subject of recent reviews [4,5]. This is not proof of the slowing effect of TES on visual field loss over several years. The long-term effect of TES treatment is being investigated in an ongoing multicenter study in Germany, which is fully funded by the statutory health insurance funds [6]. For this study, 140 RP patients were recruited, each of whom will be treated with TES for 3 years. The study will be completed and analyzed in 2026.
Stabilization and slowing of the disease is of great importance for RP patients as long as there are no curative therapies. TES with Okustim was developed as a neuroprotective therapy to slow the progression of the disease. Regular use of TES is not a guarantee against progressive vision loss in individual cases. It is a way of preserving retinal function for longer and postponing severe visual impairment until later in life. To ensure that this option does not remain a self-pay service, we are campaigning for the costs of the therapy to be covered by the healthcare systems. Until then, it is up to patients to decide whether they want to pay for the therapy themselves. Like the expert group, we regret this.
References
- Stett A, Schatz A, Gekeler F, Franklin J. Transcorneal Electrical Stimulation Dose-Dependently Slows the Visual Field Loss in Retinitis Pigmentosa. Transl Vis Sci Technol. 2023 Feb 1;12(2):29. doi: 10.1167/tvst.12.2.29. PMID: 36809335; PMCID: PMC9946045.
- Schatz A, Pach J, Gosheva M, Naycheva L, Willmann G, Wilhelm B, Peters T, Bartz-Schmidt KU, Zrenner E, Messias A, Gekeler F. Transcorneal Electrical Stimulation for Patients With Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Follow-up Study Over 1 Year. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):257-269. doi: 10.1167/iovs.16-19906. PMID: 28114587.
- Jolly JK, Wagner SK, Martus P, MacLaren RE, Wilhelm B, Webster AR, Downes SM, Charbel Issa P, Kellner U, Jägle H, Rüther K, Bertelsen M, Bragadóttir R, Prener Holtan J, van den Born LI, Sodi A, Virgili G, Gosheva M, Pach J, Zündorf I, Zrenner E, Gekeler F. Transcorneal Electrical Stimulation for the Treatment of Retinitis Pigmentosa: A Multicenter Safety Study of the OkuStim® System (TESOLA-Study). Ophthalmic Res. 2020;63(3):234-243. doi: 10.1159/000505001. Epub
2019 Nov 26. PMID: 31775146. - Li J, Zhou W, Liang L, Li Y, Xu K, Li X, Huang Z, Jin Y. Noninvasive electrical stimulation as a neuroprotective strategy in retinal diseases: a systematic review of preclinical studies. J Transl Med 2024;22(1):28. DOI: 10.1186/s12967-023-04766-4.
- Liu, J., Tong, K., Lin, Y., Lee, V. W. H., So, K. F., Shih, K. C., Lai, J. S. M., & Chiu, K. Effectiveness of Microcurrent Stimulation in Preserving Retinal Function of Blind Leading Retinal Degeneration
and Optic Neuropathy: A Systematic Review. Neuromodulation 2021;24(6):992-1002. doi:
10.1111/ner.13414.