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Show Is Leber Hereditary Optic Neuropathy Treatable? Encouraging Results With Idebenone in Both Prospective and Retrospective Trials and An Illustrative Case Esfandiar J. Sabet-Peyman, MD, Khizer R. Khaderi, MD, Alfredo A. Sadun, MD, PhD Abstract: A 31-year-old woman developed subacute bilateral visual loss over a 2-week period. Two months later, the diagnosis of Leber hereditary optic neuropathy (LHON) 11778/ND4 was established and the patient was treated with 900 mg of idebenone daily. Over the ensuing 9 months, visual acuity improved from 20/200 to 20/25 in each eye with near-total resolution in visual field abnormalities. Our case report is in agreement with 2 large published series of patients with LHON treated with idebenone, raising hope for treatment of this visually devastating mitochondrial disorder. Journal of Neuro-Ophthalmology 2012;32:54-57 doi: 10.1097/WNO.0b013e318241da45 © 2012 by North American Neuro-Ophthalmology Society Leber hereditary optic neuropathy (LHON) is untreat-able. 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 re-cent prospective study by Klopstock et al (1) and the ac-companying 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. CASE REPORT 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 methylpredniso-lone (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). DISCUSSION 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 Department of Ophthalmology (EJS-P, KRK, AAS), Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. Dr Sadun has used, and published on the use of, both idebenone and EPI-743. He is currently the Principal Investigator of a Food and Drug Administration-approved clinical trial of EPI-743 in Leber hereditary optic neuropathy. Dr Sadun has not received any compensation, honoraria, or consulting fees in this regard and has no proprietary interests. Dr Sabet-Peyman and Khaderi report no conflicts of interest. Address correspondence to Alfredo A. Sadun, MD, Department of Ophthalmology, Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033; E-mail: asadun@usc.edu 54 Sabet-Peyman et al: J Neuro-Ophthalmol 2012; 32: 54-57 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 FIG. 1. Sequential pattern deviation plots of automated visual fields. Right eye is represented in right column and left eye in left column. A. At baseline, visual fields show a small central scotoma in the right eye (9/14 fixation losses, 33% false positives, 20% false negatives) and an inferiorly displaced (by eccentric fixation) larger paracentral scotoma in the left eye (12/13 fixation losses, 46% false positives, 20% false negatives). B. Two months after starting treatment, there is improvement in the central scotoma on the right (3/13 fixation losses, 25% false positives, 12% false negatives) and the paracentral scotoma on the left (4/13 fixation losses, 21% false positives, 1% false negatives). C. Five months after starting treatment, there is near total resolution of central scotoma in the right eye (6/11 fixation losses, 16% false positives, 0% false negatives) and mild im-provement of paracentral scotoma in the left eye (6/11 fixation losses, 12% false positives, 1% false negatives). Sabet-Peyman et al: J Neuro-Ophthalmol 2012; 32: 54-57 55 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Q10, resulting in decreased ATP generation through oxida-tive 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 elec-tron transport chain. This may lead to greater ATP pro-duction and a reduction of oxidative stress that is detrimental to retinal ganglion cells and their fibers, partic-ularly 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 mitochon-drial 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 prospec-tive, 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 statis-tical significance for this. However, post hoc subgroup anal-ysis 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 acu-ities. 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 retrospec-tive 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. Interest-ingly, 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 random-ized- 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? REFERENCES 1. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths P, Meier T, Chinnery P. A randomized placebo-controlled FIG. 2. Sequential optical coherence topography. A. Base-line measurements show diffuse swelling of the RNFL, especially superiorly (157 mm in the right eye and 163 mm in the left eye) and inferiorly (153 mm in the right eye and 173 mm in the left eye). B. Two months after starting the treat-ment, there is a decreased thickness of the superotemporal and inferotemporal nerve fiber layer. C. Five months after starting the treatment, there is normalization of the RNFL, except for small areas of thinning superotemporally and inferotemporally. OD, right eye; OS, left eye. 56 Sabet-Peyman et al: J Neuro-Ophthalmol 2012; 32: 54-57 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011;134:2677-2686. 2. 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