LEBER’S HEREDITARY OPTIC NEUROPATHY

Signs and Symptoms

Most patients affected with Leber’s hereditary optic neuropathy (LHON) are males in early adulthood with vision loss occurring typically between the ages of 15 and 35.1-7 Ninety-five percent of patients will be affected by vision loss before age 50.3 Rarely, LHON may manifest after age 50.8 LHON affects approximately one in 14,000 males, and there is approximately a four-fold greater incidence in males than females.1-6 There is no racial predilection.1,3

Patients with LHON will experience a painless, acute or subacute loss of vision in one eye, typically deteriorating below the 20/400 level. Within two to four months, the fellow eye will progress to a similar level. The fellow eye’s vision loss often begins within several weeks of the first eye and typically reaches its nadir within six months of the start of visual deterioration in the primary eye. In some cases, vision loss occurs bilaterally at the initial presentation. A small percentage of patients may show spontaneous visual recovery, but most patients will not improve, becoming either visually disabled or legally blind. The loss of visual acuity is accompanied by a dense central or cecocentral scotoma, as well as impaired color vision. Despite an initial asymmetry, a relative afferent pupillary defect is typically not present.1-6

Funduscopic evaluation during the acute phase will demonstrate mild edema and hyperemia of the optic disc, teliangiectatic disc capillaries and parapapillary retinal nerve fiber layer (RNFL) swelling. Over time, optic disc pallor will develop initially on the temporal disc, with subsequent progression to diffuse optic atrophy.1-6

OCT can show a variable appearance depending upon the stage of the disease. In the disease with a duration of less than six months, there appears to be a thicker parapapillary RNFL in the superior, nasal and inferior quadrants and a higher 360° average RNFL thickness, but a thinner temporal quadrant compared to controls.9 In later stages, once diffuse optic atrophy occurs, there appears to be a thinner RNFL in all quadrants measured.10,11 Macular thickness is decreased early in the disease, indicating a specific preference for the small fibers of the papillomacular bundle.12

Pathophysiology

LHON is a maternally transmitted mitochondrial disease. There are three primary mtDNA mutations that account for approximately 95% of all LHON cases: 11778G>A (ND4 subunit), 14484T>C (ND6 subunit) and 3460G>A (ND1 subunit).2,3,13,14 Additionally, research has identified RPE65, 3635G>A and G11778A mtDNA mutations.15-17 LHON results from a decrease in mitochondrial respiratory chain complex activity, which is associated with a decrease in adenosine triphosphate (ATP) production. These mitochondrial mutations likely lead to a combination of reduced synthesis, increased oxidative stress and induction of cellular apoptosis.2 Reduced efficiency of ATP synthesis and increased oxidative stress are believed to sensitize the retinal ganglion cells to apoptosis, resulting in significant cell loss.1-4

There is a dramatic loss of retinal ganglion cells and their axons in LHON. Small caliber fibers of the papillomacular bundle are most damaged, and the larger peripheral cells are mostly spared. High energy demands of unmyelinated RNFL fibers may explain the reason that LHON targets the optic nerve.2

There are several environmental risk factors for the expression of LHON, including smoking, alcohol consumption and the use of certain antibiotics such as macrolides, aminoglycosides, ethambutol, isoniazid, linezolid, chloramphenicol and fluoroquinolones, as well as oral antiviral medications.18 Research suggests LHON also can be exacerbated by second-hand smoke within the environment.2

Management

LHON can be diagnosed by its characteristic clinical appearance, with OCT and mtDNA mutation testing providing adjunctive evidence.2 While patients carrying the ND6 subunit may spontaneously improve, most patients with LHON will be permanently visually disabled. Once optic atrophy has ensued, it is highly unlikely that there will be any therapeutic recovery. OCT suggests that a dynamic evolution of the acute stage of LHON continues for three months, which may represent a therapeutic window of opportunity.19

Because visual dysfunction in LHON is due to oxidative stress and apoptotic initiation, strategies ranging from neuroprotectants, antioxidants, anti-apoptotic- and anti-inflammatory compounds have been tested with mixed results.20 Most promising is idebenone, a quinine analog of coenzyme Q10 that was originally developed for the treatment of Alzheimer’s disease.18,20-23 Idebenone appears to have better ability to cross the blood-brain barrier and has higher delivery to mitochondria than coenzyme Q10.

The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) —a prospective, randomized, placebo-controlled study of 900mg/day of idebenone—showed prevention of further visual loss in patients with discordant visual acuities.21 Additionally, this dosing was seen to be safe and well tolerated throughout the study. Patients receiving idebenone significantly improved compared to placebo groups, and the therapeutic effect persisted beyond the study completion.21 Other studies have tested a combination administration of idebenone, vitamin B2 and vitamin C and suggest this approach may better assist recovery of vision in patients with LHON.22

Color defects are an early symptom in LHON, and idebenone treatment can protect the patient from loss of color vision, particularly those who are at imminent risk of acuity loss.23 Idebenone appears to have a particularly protective and restorative activity when administered to patients shortly after the LHON visual dysfunction begins.20 Since idebenone is safe and well tolerated, its use in early stage disease is recommended.7 Gene therapy, while promising, has not advanced as a practical solution. Adeno-associated virus-mediated gene therapy of a synthetic wild-type ND4 subunit gene is an area being explored.17

Patients diagnosed with LHON should be instructed to avoid environmental smoke, tobacco smoking and alcohol consumption. Patients should be advised to maintain a healthy diet rich in B vitamins, antioxidants and proteins. They should be counseled to avoid any stem cell treatments for optic nerve regeneration, as these therapies are unproven.2

Clinical Pearls

Patients, especially younger males, who present with evidence of unilateral optic nerve dysfunction without a relative afferent pupillary defect should be considered to have LHON. Subsequent bilateral involvement increases suspicion, and genetic testing confirms the disease.

The most common condition mimicking LHON is dominant optic atrophy (DOA), which is another mitochondrial dysfunction. In contrast to the acute vision loss in young adults seen in LHON, DOA presents with slowly progressive vision loss beginning in childhood and progressing over years to optic atrophy. DOA is frequently associated with a genetic mutation related to the production of the OPA1 protein.

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15. Kodroń A, Krawczyński MR, Tońska K, Bartnik E. m.3635G>A mutation as a cause of Leber hereditary optic neuropathy. J Clin Pathol. 2014;67(7):639-41.

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17. Lam BL, Feuer WJ, Schiffman JC, et al. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol. 2014;132(4):428-36.

18. La Morgia C, Carbonelli M, Barboni P, et al. Medical management of hereditary optic neuropathies. Front Neurol. 2014;5(141):1-7.

19. Barboni P, Carbonelli M, Savini G, et al. Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology. 2010;117(3):623-7.

20. Gueven N, Faldu D. Therapeutic strategies for Leber’s hereditary optic neuropathy: A current update. Intractable Rare Dis Res. 2013;2(4):130-5.

21. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134(Pt 9):2677-86.

22. Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000;20(3):166-70.

23. Rudolph G, Dimitriadis K, Büchner B, et al. Effects of idebenone on color vision in patients with leber hereditary optic neuropathy. J Neuroophthalmol. 2013;33(1):30-6.