SCIENTIFIC COMMENTARIES Treatment of Leber hereditary optic neuropathy

A 20-year-old otherwise healthy male, with a known family history of Leber hereditary optic neuropathy (LHON) presents with acute visual loss in one eye. He is accompanied at his appointment by his elder brother who lost vision in both eyes 3 years earlier and by his sister who is asymptomatic. They all ask you what can possibly be done. The past two decades have witnessed remarkable advances in our understanding of the clinical presentation, genetics and even the pathophysiology of LHON, a maternally inherited cause of usually blinding bilateral visual loss caused by point mutations in the mitochondrial DNA (Newman, 2005; Yu-Wai-Man et al., 2009, 2011; Fraser et al., 2010). However, investigations into potential therapies for LHON and other mitochondrial disorders are still in their nascency. In this issue of Brain, Klopstock et al. (2011) report on the first randomized placebo-controlled treatment trial of any agent in patients with LHON. This trial also represents one of the first adequately powered randomized controlled treatment trials for any mitochondrial DNA disease. In most patients with LHON, visual loss is devastating and permanent, with acuities typically worse than 20/200 in both eyes (Newman, 2005; Yu-Wai-Man et al., 2009, 2011; Fraser et al., 2010). Approximately 50% of patients with visual loss from LHON will experience sequential eye symptoms, with intervals between affected eyes ranging from days to months, but typically at an interval of 2–4 months (Newman et al., 1991; Riordan-Eva et al., 1995). At least 97% of patients with visual loss in one eye will have the second eye involved within 1 year (Newman et al., 2005). In some patients, visual recovery may occur after acute visual loss, sometimes manifested as a ‘fenestration’ within a visual field defect (the so-called donut or bagel scotoma) or with more diffuse return of central visual acuity and colour vision, usually bilaterally (Stone et al., 1992; Riordan-Eva et al., 1995; Newman, 2005). Visual recovery, when it occurs, generally happens slowly between 6 and 12 months after the onset of visual loss; however, sudden dramatic improvement in vision may occur many years after symptom onset (Stone et al., 1992; Newman, 2005). The most important prognostic factor for visual recovery in patients with LHON is a favourable mutation status. Indeed, among the three primary LHON mutations, clinical phenotype is virtually indistinguishable, with the only consistent mutationdependent clinical feature being the prognosis for spontaneous recovery of visual acuity. The ‘14484’ mutation has a 37–71% chance of some degree of visual improvement, whereas the ‘11778’ mutation has only a 4% chance (Stone et al., 1992; Oostra et al., 1994; Riordan-Eva et al., 1995; Newman, 2005). The ‘3460’ mutation appears to have the same chance of recovery as the ‘11778’ mutation, but numbers are too small for meaningful comparison. An additional positive prognostic feature is an age of onset 520 years, and especially 510 years (Newman, 2005; Barboni et al., 2006). It has also been suggested that thicker retinal nerve fibre layer and larger optic disc vertical diameter on optical coherence tomography may be associated with a better visual prognosis (Barboni et al., 2005, 2006; Ramos et al., 2009). The pathogenesis of LHON likely involves a combination of decreased complex-I driven ATP production, increased free radical production and ultimately retinal ganglion cell apoptosis (Fraser et al., 2010; Yu-Wai-Man et al., 2011). Proposed treatments for LHON include low vision aids, avoidance of potential precipitants of visual loss, general therapies for mitochondrial disorders, anti-apoptotic agents and a variety of gene therapies (Fraser et al., 2010; Yu-Wai-Man et al., 2011). Symptomatic treatments should be considered in all patients with vision-impairing optic neuropathies to improve quality of life, in particular to aid with reading, communication, gainful employment, navigation and self-operation of a motor vehicle. Low vision aids may benefit patients with severe vision loss from optic neuropathies. In particular, patients with LHON are often young adults with preserved peripheral vision, who make excellent candidates for low vision rehabilitation. Although avoiding agents that may act as mitochondrial ‘stressors’ is a non-specific recommendation for all patients with disorders having a presumed mitochondrial pathophysiology, there is no study that has shown proven benefit (Chinnery et al., 2006). One recent epidemiological study suggested that vision loss does indeed occur more often in individuals at risk for LHON who smoke, and possibly those with heavy alcohol intake (Kirkman et al., 2009). It is, therefore, prudent to caution patients to avoid tobacco use, excessive alcohol intake, cyanide-containing products, medications that may have mitochondrial toxicity and environmental toxins, especially during the acute phase of visual loss (Newman, 2009). Directed therapies for mitochondrial disorders are very limited. A 2006 Cochrane review of 678 abstracts and articles found no evidence supporting any intervention in the management of mitochondrial disease (Chinnery et al., 2006). General therapies Brain 2011: 134; 2447–2455 | 2447