Leber hereditary optic neuropathy (LHON) is untreatable. Or so we have been told for many decades. We present a case that challenges this notion and supports the possibility that idebenone may indeed be therapeutic in patients with LHON 11778/ND4, as suggested by the recent prospective study by Klopstock et al (1) and the accompanying retrospective study by Carelli et al (2) recently published in the journal Brain. There have been reports of spontaneous improvement of visual acuity in some patients with LHON, particularly in those with the 14484/ND6 mutation; however, 11778/ND4 cases rarely recover and even so, such recovery is very incomplete and generally occurs 1–6 years following the onset of disease (3). We present a patient with LHON 11778/ND4 treated with long-term (9 months) high-dose idebenone, in whom improvement of several visual parameters was documented.
Over a 2-week period, a 31-year-old woman noted bilaterally decreased vision first in the left eye and then in the right. She had an aunt diagnosed with LHON, and the patient was soon diagnosed as well with the 11778/ND4 (homoplasmic) mitochondrial mutation. She was started on 900 mg of oral idebenone daily as well as a 3-day course of coenzyme Q10 (200 mg by mouth daily) and intravenous methylprednisolone (250 mg every 6 hours) within 2 weeks of her blood draw and 2 months after her initial symptoms of visual loss.
At that time, visual acuity was 20/200 in both eyes without a relative afferent pupillary defect. The patient was able to slowly see 7 or 8 Ishihara color plates. Automated visual fields are shown in Figure 1A. Fundus examination demonstrated optic nerve hyperemia and mild telangiectatic vascular changes with nerve fiber layer swelling in both eyes.
Two months later, her vision was 20/70 in right eye and 20/200 in left eye, with improvement in visual fields (Fig. 1B). The patient showed continued improvement, and 9 months after initiation of treatment, vision was 20/25 in each eye with intact color vision and marked improvements in her visual fields (Fig. 1C).
Initially, OCT of the retinal nerve fiber layer (RNFL) demonstrated diffuse RNFL thickening in all quadrants (Fig. 2A). Over a 7-month period of follow-up, RNFL thickness returned to normal (Fig. 2B, C).
This case report illustrates dramatic recovery of visual acuity, prevention of diffuse RNFL thinning (4), and near-complete resolution of central/paracentral scotomas in a patient with LHON 11778/ND4 treated early with high-dose idebenone. Although it is impossible to tell how the limited treatment with solumedrol and coenzyme Q10 affected the patient, we do not believe they had a significant impact on the patient's long-term visual recovery.
LHON is caused by a mitochondrial DNA mutation affecting respiratory complex I of the electron transport chain (3,5) most frequently at positions 11778/ND4, 14484/ND6, and 3460/ND1 (3,6,7). These mutations interfere with the interaction of complex I with coenzyme Q10, resulting in decreased ATP generation through oxidative phosphorylation and increased reactive oxygen species (ROS) (3,6,7).
Idebenone is a synthetic short chain benzoquinone and a coenzyme Q10 derivative that is able to cross both mitochondrial membranes and the blood–brain barrier (8). It is thought to work by shuttling electrons onto complex III, thereby bypassing the defective complex I of the electron transport chain. This may lead to greater ATP production and a reduction of oxidative stress that is detrimental to retinal ganglion cells and their fibers, particularly the small axons in the papillomacular bundle (3,6,9).
Perhaps most critically, the ROS generated by the LHON mutations accumulate and may lead to mitochondrial membrane depolarization with the consequential opening of the mitochondrial permeability transition pores, leading to retinal ganglion cell apoptosis (10). Quinones, such as idebenone, may inhibit this process (11).
Klopstock et al (1) published their results of a prospective, randomized placebo-controlled trial on 85 LHON patients, 55 treated with 900 mg/day (300 mg three times daily) of idebenone and 30 with placebo. All 3 major mutation types (11778, 3460, and 14484) were included. The primary endpoint was best recovery of visual acuity with treatment, and they came just short of showing statistical significance for this. However, post hoc subgroup analysis demonstrated statistically significant differences in secondary endpoints, including change in best visual acuity, change in visual acuity of the best eye, and changes in visual acuity of both eyes in patients with discordant visual acuities. Idebenone was, for 6 months, safe and well tolerated. The prospective, randomized, and placebo controlled design of the study was its strong suit. There were limitations as well. Subgroup analysis needs to be interpreted carefully, as each post hoc analysis offers another opportunity for the vicissitudes of chance. That there was not a greater effect seen in the primary endpoint probably reflected the short duration of the study (6 months) and the fact that many patients were entered in the study as much as 5 years after their loss of vision (and therefore with long-standing optic atrophy and less likelihood of recovery).
In the same issue of Brain is an accompanying retrospective review of LHON treated with idebenone. Carelli et al (2) looked at 103 patients with LHON (same 3 mutations), of which 44 were treated. They only included patients who began treatment within 1 year after visual loss and they followed up their patients for much longer (4–5 years). Their study showed that patients who were treated earliest had the best chance of recovery and that this recovery often continued for a year or 2 after treatment. However, this was a retrospective study with all the concomitant limitations of such, including variable treatment protocols (from 270 to 675 mg per day), different outcome measures, and the obvious issues of possible patient selection bias. Interestingly, they only found statistical significance with 11778 patients, probably because the 14484 patients had a high rate of spontaneous recovery and there were too few patients with 3460 for meaningful statistical analysis.
Taken together, these 2 studies complement each other and show similar results. Therefore, this line of treatment may hold potential for LHON and other mitochondrial disorders (12–15). Idebenone is a second-generation quinine (coenzyme Q10 is the first generation). A third-generation quinine molecule, EPI-743, may prove even more effective (16). Nevertheless, there are severe problems in extrapolating from a case report, a retrospective study, and from a randomized-controlled trial that did not reach its primary outcome measure. And will there be long-term risks associated with higher doses of idebenone taken over a lifetime?
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