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Show Letters to the Editor Assessing the Treatment Effect of Idebenone in Leber Hereditary Optic Neuropathy Requires Appropriate Study Designs W ith interest we read the article by Catarino et al (1) about a retrospective, multicenter, open-label, noncontrolled study on the effect of idebenone in 87 patients with genetically confirmed Leber hereditary optic neuropathy (LHON) with onset on the most recent eye .1 year before enrolment. Each included patient carried one of the 3 major LHON mutations (1). It was found that idebenone (900 mg/d) has a beneficial effect regarding recovering lost vision and maintaining good residual vision in a real-world setting (1). It was concluded that idebenone should be initiated early and be maintained .24 m to maximize efficacy (1). We have the following comments and concerns. The main shortcoming of the study is the design. To assess the effect of a drug, a multicenter, double-blind, placebo-controlled trial would be more suitable than a multicenter, open-label, uncontrolled trial. Furthermore, not all 87 patients seem to have received the same dosage of idebenone and the duration of treatment was variable as well given the introductory sentence of the “method” section saying “The idebenone dosage and duration of therapy were entirely at the discretion of the treating physician” (1). The range of treatment duration was wide (2.4–70.4 m) (1). The number of follow-up investigations was not standardized and ranged from 1 to several visits (1). Spontaneous recovery occurs with all 3 major LHON mutations, but more frequently with the m.3460 G.A and the m.14484T.C variant than with the m.11778 G.A variant (2). Although the authors argument that the clinically relevant recovery rates (CRR) calculated in the presented study exceeded reported rates of spontaneous recovery (m.11778 G.A: ,4%, across all mutations in the RHODOS study: 10.3% over 6 m), it remains unclear how many of the included patients experienced spontaneous recovery and how many truly profited from idebenone. Because the authors concluded that “a treatment duration of at least 18–24 months is needed to maximize the probability of CRR,” it is not comprehensible why patients with a treatment duration ,18 months were included in the study. It is warranted to repeat the study with only patients being on idebenone for .18 months. Missing is the information how many patients took dosages , or .900 mg/d, about the adherence to the treat- Letters to the Editor: J Neuro-Ophthalmol 2023; 43: e93-96 ment, how the placebo effect was eliminated, and how adherence was monitored. Missing is also the information about the current medication each patient was taking in addition to idebenone. LHON may not only be a disorder restricted to the retinal ganglion cells, but may also affect organs or systems other than the eyes (LHON plus) (3). We should know how many of the 87 patients had LHON plus manifesting in the brain, the spinal cord, the peripheral nerves, or the heart and how multisystem disease was treated. There are indications that LHON can be associated with rapidly progressive optic atrophy (4). Optic atrophy may be a limitation of the idebenone treatment effect and may determine the outcome of LHON patients. Thus, we should know how many of the 87 included patients had already developed optic atrophy before or after onset of idebenone treatment. Overall, the interesting study by Catarino et al has a number of shortcomings, which should be addressed before drawing final conclusions. The study design applied is not appropriate to determine the treatment effect of idebenone, why the conclusions are questionable. Author contribution: J. Finsterer: design, literature search, discussion, first draft, critical comments; all authors have read the journal's position on issues involved in ethical publication. Josef Finsterer, MD, PhD Klinik Landstrasse, Messerli Institute, Vienna, Austria. The author reports no conflicts of interest. REFERENCES 1. Catarino CB, von Livonius B, Priglinger C, Banik R, Matloob S, Tamhankar MA, Castillo L, Friedburg C, Halfpenny CA, Lincoln JA, Traber GL, Acaroglu G, Black GCM, Doncel C, Fraser CL, Jakubaszko J, Landau K, Langenegger SJ, Muñoz-Negrete FJ, Newman NJ, Poulton J, Scoppettuolo E, Subramanian P, Toosy AT, Vidal M, Vincent AL, Votruba M, Zarowski M, Zermansky A, Lob F, Rudolph G, Mikazans O, Silva M, Llòria X, Metz G, Klopstock T. Real-world clinical experience with idebenone in the treatment of leber hereditary optic neuropathy. J Neuroophthalmol. 2020;40:558–565. 2. Majander A, Bowman R, Poulton J, Antcliff RJ, Reddy MA, Michaelides M, Webster AR, Chinnery PF, Votruba M, Moore AT, Yu-Wai-Man P. Childhood-onset Leber hereditary optic neuropathy. Br J Ophthalmol. 2017;101: 1505–1509. 3. Finsterer J, Zarrouk-Mahjoub S. Leber's hereditary optic neuropathy is multiorgan not mono-organ. Clin Ophthalmol. 2016;10:2187–2190. 4. Wang L, Klingeborn M, Travis AM, Hao Y, Arshavsky VY, Gospe SM III. Progressive optic atrophy in a retinal ganglion cellspecific mouse model of complex I deficiency. Sci Rep. 2020;10:16326. e95 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
