Analyzing change in color vision for patients with discordant VA (defined as a difference of logMAR ≥0.2 corresponding to 2 lines on the ETDRS chart between eyes at baseline) revealed a larger difference in the change of both protan and tritan color contrast between placebo- and idebenone-treated patients at weeks 12 and 24, predominantly carried by a more profound worsening in the placebo group (Tables 2 and 3). For patients with discordant VA, there was good correlation between change in VA previously reported (19) and change in color contrast sensitivity from baseline to week 24 (correlation between change in VA and protan: R2 = 0.532, P < 0.001; correlation between change in VA and tritan: R2 = 0.358, P < 0.001).
Subgroup analysis showed that idebenone was particularly effective in improving tritan color vision in patients younger than 30 years. There was also better efficacy in patients with less than 1 year since diagnosis in the tritan domain, although this did not reach statistical significance, possibly because of the small number of patients in this subgroup. This trend in efficacy was not apparent for the protan color domain.
The changes in color vision between the idebenone- and placebo-treated patients also were evident by responder analyses. For both color domains, there was a higher proportion of patients with at least one eye improving in color contrast sensitivity for the idebenone group compared with the placebo group (eyes improving in color contrast sensitivity for protan: idebenone, 15 of 56 [27%] and placebo, 2 of 22 [9%], P = 0.127; for tritan: idebenone, 18 of 56 [32%] and placebo, 2 of 22 [9%], P = 0.043). Confining the analysis to patients with discordant VA showed that only idebenone-treated patients reported improved color vision (eyes improving in color contrast sensitivity for protan: idebenone, 8 of 24 [33%] and placebo, 0 of 8 [0%], P = 0.081; for tritan: idebenone, 10 of 24 [42%] and placebo, 0 of 8 [0%], P = 0.035). A similar pattern of greater benefit of idebenone over placebo also was seen for responder analyses requiring a minimum improvement of 5% or 10% in color contrast sensitivity for both protan and tritan domains (data not shown).
Impaired color vision is an early sign of visual impairment in LHON patients, often preceding loss of VA and also detectable in asymptomatic carriers of the disease (7,22). We analyzed data from acutely affected LHON patients enrolled in a prospective, randomized, and controlled intervention study to further characterize the relation of impaired red–green (protan) and blue–yellow (tritan) color vision with the patients' disease history. The majority of patients who reported symptom onset not longer than 5 years before the study had already developed considerable color confusion in both color domains. Specifically, substantial color confusion (>90%) was already seen in young patients (≤20 years of age) and in patients with short disease history (≤1 year). Taken together, these findings confirm previous observations that loss of color vision is an early pathological sign in LHON.
We recently reported the efficacy of idebenone in protecting and facilitating the recovery of VA in LHON patients participating in the placebo-controlled RHODOS study (19). In an independent retrospective study, Carelli et al (20) also reported efficacy of idebenone, particularly in recovery of vision.
The main objective of this study was to further characterize the therapeutic potential of idebenone to protect patients from developing dyschromatopsia. Idebenone is capable of shuttling electrons from the cytosol onto the complex III of the mitochondrial electron transport chain, thereby bypassing complex I, which is deficient in LHON patients (23). This is of great importance in LHON because of the high energy requirements of retinal ganglion cells and their axons, particularly for their unmyelinated sections (4,5).
The current study investigated the change in color vision in a subgroup of LHON patients enrolled in the RHODOS study. Compared with patients receiving placebo, those treated with idebenone experienced less impairment of protan color vision and a statistically significant improvement in tritan color vision. Of interest is our finding that idebenone was particularly effective in improving/preserving color vision in the subgroup of patients younger than 30 years and in recently diagnosed patients (<1 year since diagnosis). This finding likely reflects the known better potential for recovery in younger-onset LHON patients and the benefit of earlier treatment of the disease. The RHODOS study allowed enrollment of patients diagnosed as long as 5 years earlier, resulting in a mean time since disease onset of approximately 2 years. From the natural history of the disease, it can be expected that the majority of patients will already have optic atrophy and loss of retinal ganglion cells, resulting in a smaller likelihood of benefit, which may have diluted the overall therapeutic effect. Detecting efficacy of idebenone even in this heterogeneous LHON population is therefore remarkable.
Idebenone also appeared very effective in protection from loss of VA in patients with discordant interocular vision, defining patients at highest risk of further vision loss (19). This effect of idebenone in patients with discordant VA was also seen for both protan and tritan color vision.
The anatomical substrate underlying the preservation of color vision (and VA) in idebenone-treated patients might be stabilization of RNFL thickness. In untreated LHON patients, initial swelling of the RNFL is followed by atrophic thinning, particularly affecting the papillomacular bundle (24,25). This dynamic change in RNFL thickness in LHON patients possibly reflects the progressive metabolic crisis occurring in small-diameter retinal ganglion cells. Idebenone preserved the RNFL thickness in patients with a short disease history (i.e. <6 months from symptom onset) (19), which is reflected in better preserved VA and color vision. Patients receiving placebo experienced atrophy of the RNFL in the inferior and superior quadrants associated with vision loss and dyschromatopsia. These findings suggest that for maximal benefit, patients with LHON should be treated with idebenone early in their clinical course.
The authors thank Nick Coppard and Günther Metz (both Santhera Pharmaceuticals) for help in the interpretation of the data, and Professor Geoffrey Arden for very valuable discussions on methods and results of this study. The authors are indebted to the patients who volunteered for this study and they also thank all doctors who have transferred patients into this trial.
1. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114.
2. Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. 2010;55:299–334.
3. Sadun AA, La Morgia C, Carelli V. Leber's hereditary optic neuropathy. Curr Treat Options Neurol. 2011;13:109–117.
4. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004;23:53–89.
5. Sadun AA, Win PH, Ross-Cisneros FN, Walker SO, Carelli V. Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc. 2000;98:223–232.
6. Grigsby SS, Vingrys AJ, Benes SC, King-Smith PE. Correlation of chromatic, spatial, and temporal sensitivity in optic nerve disease. Invest Ophthalmol Vis Sci. 1991;32:3252–3262.
7. Ventura DF, Gualtieri M, Oliveira AGF, Costa MF, Quiros P, Sadun F, de Negri AM, Salomao SR, Berezovsky A, Sherman J, Sadun AA, Valerio Carelli V. Male prevalence of acquired color vision defects in asymptomatic carriers of Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2007;48:2362–2370.
8. Harding AE, Sweeney MG, Govan GG, Riordan-Eva P. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet. 1995;57:77–86.
9. Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995;118:319–337.
10. Zanna C, Ghelli A, Porcelli AM, Martinuzzi A, Carelli V, Rugolo M. Caspase-independent death of Leber's hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and endonuclease G. Apoptosis. 2005;10:997–1007.
11. Baracca A, Solaini G, Sgarbi G, Lenaz G, Baruzzi A, Schapira AHV, Martinuzzi A, Carelli V. Severe impairment of complex I-driven adenosine triphosphate synthesis in Leber hereditary optic neuropathy cybrids. Arch Neurol. 2005;62:730–736.
12. Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF. Inherited mitochondrial optic neuropathies. J Med Genet. 2009;46:145–158.
13. Spruijt L, Kolbach DN, de Coo RF, Plomp A, Bauer NJ, Smeets HJ, De Die-Smulders C. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol. 2006;141:676–682.
14. Mashima Y, Hiida Y, Oguchi Y. Remission of Leber's hereditary optic neuropathy with idebenone. Lancet. 1992;340:368–369.
15. Carelli V, Barboni P, Zacchini A, Mancini R, Monari L, Cevoli S, Liguori R, Sensi M, Lugaresi E, Montagna P. Leber's hereditary optic neuropathy (LHON) with 14484/ND6 mutation in a North African patient. J Neurol Sci. 1998;160:183–188.
16. Carelli V, Valentino ML, Liguori R, Meletti S, Vetrugno R, Provini F, Mancardi GL, Bandini F, Baruzzi A, Montagna P. Leber's hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases. J Neurol Neurosurg Psychiatry. 2001;71:813–816.
17. Cortelli P, Montagna P, Pierangeli G, Lodi R, Barboni P, Liguori R, Carelli V, Iotti S, Zaniol P, Lugaresi E, Barbiroli B. Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study. J Neurol Sci. 1997;148:25–31.
18. Mashima Y, Kigasawa K, Wakakura M, Yoshihisa O. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000;20:166–170.
19. 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 PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011;134:2677–2686.
20. Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni P. Idebenone treatment in Leber's hereditary optic neuropathy. Brain. 2011;134:e188.
21. Arden GB, Wolf JE. Colour vision testing as an aid to diagnosis and management of age related maculopathy. Br J Ophthalmol. 2004;88:1180–1185.
22. Quiros PA, Torres RJ, Salomao S, Berezovsky A, Carelli V, Sherman J, Sadun F, De Negri A, Belfort R, Sadun AA. Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study. Br J Ophthalmol. 2006;90:150–153.
23. Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier-Fruh I, Anklin C, Dallmann R, Gueven N. NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS One. 2011;6:e17963.
24. Barboni P, Savini G, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, di Vivo A, Carelli V. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's hereditary optic neuropathy. Ophthalmology. 2005;112:120–126.
25. Barboni P, Carbonelli M, Savini G, do Ramos C, Carta A, Berezovsky A, Salomao SR, Carelli V, Sadun AA. Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology. 2010;117:623–627.