Optic Neuropathy, Causes, Symptoms, Diagnosis, Treatment

• Brimonidine is a topical α-2 agonist that is commonly used to lower intraocular pressure in the management of glaucoma.^[rx] Some studies have suggested that brimonidine can exert a synergistic RGC neuroprotective effect by upregulating a number of antiapoptotic factors and by blocking glutamate excitotoxicity induced by mitochondrial oxidative stress.^[rx] Topical brimonidine has therefore been tested as a prophylactic agent for second-eye involvement in an open-labelled study of nine patients with unilateral acute visual loss secondary to LHON.^[rx] Brimonidine failed to prevent fellow eye involvement, and there was no evidence of any visual benefit following the onset of visual loss. Although this study was negative, raised intraocular pressure has been linked with an increased risk of visual loss in LHON and an agent with putative neuroprotective properties such as brimonidine could represent an ideal choice of treatment for unaffected LHON carriers diagnosed with glaucoma or ocular hypertension.

Steroids and immunosuppressants

• Patients with LHON are not infrequently treated with high-dose steroids before a molecular diagnosis has been secured to exclude the possibility of an inflammatory optic neuropathy. Steroids do not prevent the involvement of the fellow unaffected eye in LHON, and there has been no reported benefit on disease progression and the final visual outcome.^[rx] In an in vitro experimental paradigm involving the supplementation of the culture media with hydrogen peroxide, LHON cybrids harbouring the m.11778G>A mutation showed an increased sensitivity to oxidative stress.^[rx] This increased susceptibility to undergo apoptosis was postulated to be secondary to a toxic rise in intracellular calcium and the activation of the mitochondrial transition pore (MTP). Pre-treatment with cyclosporin A blunted the deleterious consequences of hydrogen peroxide by blocking the MTP pore, indicating a possible therapeutic pathway for LHON. The antiapoptotic effect of cyclosporine A has also been demonstrated in LHON cybrids harbouring the m.14484T>C and m.14279G>A mutations.⁷⁵ On the basis of these in vitro data, a French study is currently underway recruiting patients with unilateral visual loss from LHON for treatment with cyclosporin A in an attempt to prevent the involvement of the fellow eye (Dr Dominique Bonneau, University of Angers, France, personal communication).

Hyperbaric oxygen therapy

• There is highly anecdotal ‘internet’ evidence of patients with LHON benefiting from hyperbaric oxygen therapy (HBOT) (http://hyperbariclink.blogspot.co.uk/2012/06/in-news-hyperbaric-oxygen-therapy-for.html, accessed on 8 December 2013). The purported rationale for this treatment is to provide increased levels of oxygen to RGCs during the acute phase of LHON with the aim of improving mitochondrial biogenesis.
• HBOT is a controversial treatment modality that has been applied with limited success to other optic nerve disorders such as radiation-induced optic neuropathy and anterior ischaemic optic neuropathy.^[rx] Given the rather slim evidence base, the theoretical toxic effects of supraphysiological levels of oxygen in LHON should be considered in the context of a dysfunctional mitochondrial respiratory chain that is already producing increased ROS levels.

Near-infrared light therapy

• Near-infrared light (NIR) therapy has been shown to improve mitochondrial function and cellular survival in various models of wound healing, neurodegeneration and methanol-induced retinal toxicity.^[rx]Although these findings are not universally accepted and the mechanisms are not fully understood, NIR photobiomodulation is thought to increase ATP synthesis by stimulating the activity of cytochrome c oxidase (complex IV).^[rx]
• The application of NIR therapy to RGCs via a light-emitting diode has therefore been proposed as a possible rescue strategy for LHON. A study was initiated to investigate the visual benefit of NIR therapy in affected LHON carriers, but it has been terminated because of the inability to record reliable pERG measurements, which was the planned primary outcome measure, due to poor subject fixation (http://clinicaltrials.gov/ct2/show/NCT01389817?term=LHON+whelan&rank=1, accessed on 8 December 2013).

• Compared with LHON, the rate of RGC loss in DOA is relatively slow and the detection of a clinically meaningful benefit over the course of a 1- or 2-year treatment trial is a major methodological consideration. Long-term natural history studies are therefore urgently needed to more precisely define the visual parameters that are most sensitive at detecting a significant change in optic nerve structure and function for insidiously progressive optic nerve disorders like DOA . Idebenone has recently been evaluated in a limited case series involving seven patients with DOA and confirmed pathogenic OPA1 mutations.^[rx]
• A variable daily dose of idebenone was used (270–675 mg), and all the patients were treated and reviewed for at least 1 year. No adverse drug reactions were reported and some improvement in visual function was reported for five of the seven idebenone-treated patients. The results of this pilot study remain preliminary and a randomised, placebo-controlled trial with an adequate duration of follow-up will be needed to prospectively evaluate the possible benefit of using idebenone in DOA.
• Looking into the future, an open-labelled study of EPI-743 for patients with DOA is currently under preparation (Dr Valerio Carelli, University of Bologna, Italy, personal communication), and the potential benefit of near-infrared light in rescuing RGC loss is also being tested in a mouse model of DOA harbouring a splice site mutation (c.1065+5g>a) within intron 10 of the Opa1 gene (Professor Marcela Votruba, Cardiff University, UK).^[rx]

Drug screening and development

• With idebenone and EPI-743, we are witnessing the first tentative steps in our effort to try and modulate disease progression for mitochondrial optic neuropathies. Several research groups worldwide are actively pursuing the identification of novel neuroprotective agents for other, more prevalent, optic nerve disorders such as glaucoma and anterior ischaemic optic neuropathy, the results of which are likely to be highly relevant for LHON and DOA.^{[rx, rx]}
• The technological revolution of the past decade has also launched a new era of personalised medicine with powerful complementary approaches that combine the in vitro screening of small molecule libraries with further in vivo validation using existing animal models. Greater collaboration with the pharmaceutical industry will be an important element of this major translational push for rare genetic disorders.
• More than ever, clinical academics will have an important role to play in taking the lead and setting the broad directions for the clinical evaluation and validation of new drugs for inherited optic neuropathies. Some obvious candidates are compounds that are thought to activate mitochondrial biogenesis, for example oestrogen-like molecules and acetyl-L-carnitine (ALCAR), which is derived from the acetylation of L-carnitine within mitochondria. ALCAR has the advantageous property of crossing the blood–brain barrier, and this molecule promotes OXPHOS by upregulating the transcript levels of ‘master’ genes involved in mitochondrial biogenesis, namely PGC-1α, PGC-1β, and TFAM.^[rx,rx] A study is currently nearing completion looking at the effect of ALCAR on neuronal conduction along the visual pathways in patients with chronic LHON and disease duration of more than 2 years (http://apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2009-016982-26-IT, accessed on 8 December 2013).

Gene therapy

• Gene replacement therapy for LHON is an attractive strategy, given the easy anatomical accessibility of the RGC layer for direct manipulation. However, the double-membrane nature of mitochondria presents a formidable series of technical challenges that need to be overcome. First and foremost, a highly efficient vector is needed to penetrate the relatively impermeable inner mitochondrial membrane and to allow a sufficient number of mitochondria to be transfected in order to achieve the desired gene replacement effect. A possible solution is to bypass the mitochondrial genome altogether by using an elegant alternative approach that relies on the nuclear allotopic expression of the gene of interest.^[rx]
• The relevant mtDNA gene can be efficiently transfected into the nuclear compartment with an adeno-associated virus (AAV) vector after it has been reconfigured to fit the slightly different coding system operating within the nuclear genome. This hybrid nuclear-encoded protein has also been engineered with a specific targeting sequence to facilitate its efficient import into mitochondria, thereby compensating for the missing or dysfunctional mitochondrial protein. The potential of this gene therapy approach in rescuing the disease phenotype was first demonstrated in m.11778G>A LHON cybrids.^[rx]
• The ability to rescue RGCs and improve visual function was subsequently confirmed in vivoby two independent research groups working on LHON rodent models expressing mutated ND4 (m.11778G>A) complex I subunits.^{[rx, rx]} These groundbreaking experiments are paving the way for more advanced studies involving primates and ultimately patients with LHON (http://www.gensight-biologics.com/, accessed on 8 December 2013). However, a note of caution is required here given the ongoing debate as to whether the imported wild-type ND4 subunit actually integrates into the native complex I to produce a stable functional unit within the inner mitochondrial membrane.[^rx]

Stem cells

• The therapeutic potential of stem cells is being investigated for a wide range of genetic eye disorders, and patients with mitochondrial optic neuropathies will frequently enquire with their clinicians whether they are likely to benefit from this form of treatment.^[rx] Various poorly monitored ‘stem cell institutes’ worldwide are promoting the use of non-validated experimental protocols, and patients with LHON and DOA need to be carefully advised before embarking on multiple expensive courses of treatment with the possible associated biological risks. In sharp contrast to this unregulated parallel market, there are a number of well-established research programmes that are rigorously assessing the possible application of stem cell technology for optic nerve disorders.^{[rx], [rx]} Two main paradigms are being explored, namely the generation and transplantation of RGCs, or the use of specific stem cell populations to generate trophic factors that promote RGC survival.^{[rx], [rx]} The technique for generating and purifying mature RGCs from embryonic stem cells or induced pluripotent stem cells is still in its infancy. Another major complicating factor is how to integrate these differentiated RGCs into the retina and then force them to make the right topographical connection. At least in the short term, it is more likely that human-derived RGCs will provide the ideal tool for drug screening and understanding the basic mechanisms regulating RGC physiology in both health and disease states.^{[rx, rx]}