Characteristics of Japanese patients with Leber’s hereditary optic neuropathy and idebenone trial: a prospective, interventional, non-comparative study

Abstract

With interest we read the article by Ishikawa et al. about an uncontrolled, prospective, intervention study of 51 patients with Leber’s hereditary optic neuropathy (LHON) due to the ND4 variant m.11778G>A treated with idebenone (900 mg/ day) over 24 weeks [1]. Improvement of > 0.2 logMAR was achieved in 25.5% after 24 weeks and in 33.3% after 48 weeks of follow-up [1]. We have the following comments and concerns. The main shortcoming of the study is its design [1]. The study is uncontrolled, why it remains unclear if the figures provided as success rates are truly reliable. Baseline values of best corrected visual acuity (BCVA), visual fields, clinical fusion frequency (CFF), and retinal ganglion cell layer complex thickness (RGCLcT) were compared with those at 24 and 48 weeks after starting treatment respectively. These parameters were neither compared with a group of healthy or disease controls. If the therapeutic effect of idebenone depends on the severity at onset, misleading results may ensue. Another shortcoming is that heteroplasmy rates of the variant were not provided. Knowing heteroplasmy rates is crucial as they may determine the phenotype, and the course and outcome. Though heteroplasmy rates are usually high in LHON patients or even homoplasmic (100%), exact figures are essential. A further shortcoming is that it is not described how adherence to taking the study medication was controlled. Another shortcoming refers to the reporting of side effects. Though idebenone is usually well tolerated, side effects, such as nausea, vomiting, stomach pain, loose stools, tachycardia, or an increased risk of infection have been reported [2]. However, the article does not mention anything about side effects except that all patients tolerated the study drug. Thus, we should be informed how many patients experienced any of the previously described or new adverse reactions. Spontaneous remission varies between the different LHON mutations. Spontaneous remission of the m.11778G>A variant is rare but has been occasionally reported [2]. Thus, we should know in how many of the included patients was the presumed treatment effect rather attributable to spontaneous remission than to idebenone. In patients to whom idebenone is given after onset of the disease the therapeutic effect may be limited or even absent. We should know if the therapeutic effect correlated negatively with the latency between onset and beginning of the treatment. The authors assume that reduced ATP production leads to oxidative stress and consecutively to necrosis of retinal ganglion cells (RGCs) and thus optic atrophy [1]. However, spontaneous recovery has been reported in 6–8% of the LHON cases. How do the authors explain recovery if RGCs no longer exist? How do the authors explain that RGCLcT remains unchanged under idebenone whereas BCVA improves? Is there a need to replace the pathophysiological concept of cell death to functional impairment with only cell atrophy? It is not conceivable why patients with elevated transaminases, epilepsy, delirium, or hallucinations, patients with agranulocytosis, and patients with chronic renal failure were excluded. In all studies on idebenone carried out in LHON so far hardly any side effects were reported. Thus, it is quite unlikely that idebenone would have enhanced the abnormalities used as exclusion criteria. Overall, the interesting study by Ishikawa et al. has a number of shortcomings, which should be met before drawing conclusion as have been provided. Testing the therapeutic * The Editors, Japanese Journal of Ophthalmology [email protected]