What is the Lebers Hereditary Optic Neuropathy LHON

What is the Leber’s Hereditary Optic Neuropathy (LHON)? • LHON is a rare ganglion cell degeneration; the papillomacular bundle is particularly affected. • The condition is caused by maternally inherited mitochondrial DNA point mutations, most frequently (50 – 90%) at nucleotide position 11778 (G to A) in the MT-ND 4 gene. • Prevalence: 3, 22 per 100. 000 (GB) • Typical patient: male 15 -35 years, (M/F~5/1) atypical cases: females 10 -60 years. The diagnosis of LHON should therefore be considered in any patient with bilateral optic neuropathy, irrespective of age.

What are the symptoms of Leber’s Hereditary Optic Neuropathy ? • Acute or subacute severe loss of central vision. • Painless • Unilateral (50%) – bilateral (50%) • In initially unilateral cases, the fellow eye becomes similarly affected within weeks or months. • Colour vision is likely to be subnormal. • Additional manifestations: neuromuscular dysfunction (dystonia, tremor, numbness, weakness and arrhythmias - LHON plus).

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ? Subtle and easily overlooked - some patients have entirely normal disk. Typical cases: • Disc hyperaemia with obscuration of the disc margins. • Dilated capillaries on the disc surface. (telangiectatic microangiopathy) • Telangiectatic microangiopathy may be present in asymptomatic female relatives. • Swelling of the peripapillary RNFL (pseudo-oedema). • Dilatation and tortuosity of posterior pole vasculature. • Subsequently, the vessels and pseudooedema regress, and severe optic atrophy supervenes, with RNFL dropout most pronounced in the papillomacular bundle.

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ? • Disc hyperaemia with obscuration of the disc margins.

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ? • Dilated capillaries on the disc surface. (telangiectatic microangiopathy) • Telangiectatic microangiopathy may be present in asymptomatic female relatives.

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ? • Swelling of the peripapillary RNFL (pseudo-oedema).

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ? Dilatation and tortuosity of posterior pole vasculature

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ?

What are the signs/findings of Leber’s Hereditary Optic Neuropathy ? ACUTE STAGE CHRONIC STAGE

Visual fields in LHON Visual field defects usually consist of central or centrocaecal scotomas, with preserved peripheral vision.

The Optical Coherence Tomographic Profile of Leber Hereditary Optic Neuropathy Thomas R. Hedges, a Marisa Gobuty, a Richard A. Manfready, a Natalie Erlich-Malona, a Caitlin Monaco, a and. Carlos E. Mendoza-Santiestebana, b, c Twenty-one patients were evaluated for LHON between 2010 and 2014. Of these, five men and two women met the inclusion criteria and were analysed with respect to visual acuity, visual field, RNFL, and GCC. Age at symptom onset ranged from 20 to 78 years (mean age: 34 years). RESULTS: • In 12 of 14 eyes in the early acute phase (within 12 weeks), OCT demonstrated GCC thinning (average GCC thickness from all 14 eyes was 68. 4 μm). RNFL swelling was observed in 12/14 eyes (average RNFL thickness from all 14 eyes was 124 μm). Peripapillary telagiectasias were present in 11 of 14 eyes. VA ranged from 20/25 to CF (count fingers) 1 ft. • In the late acute phase, 12 weeks after symptom onset, there was more severe central vision was loss. GCC thickness had decreased further in 11 of 14 eyes tested at this phase of the disease (average GCC thickness was 57. 4 μm), and RNFL swelling had decreased (average RNFL thickness 113. 5 μm). All eyes had lost vision to less than 20/200. • In the chronic phase (24 weeks or more after onset of symptoms), OCTs were available in 10 of 14 eyes. Severe GCC loss occurred in all 10 eyes in the late phase (average GCC thickness was 50. 8 μm). All eyes showed a decrease in average RNFL thickness (average RNFL thickness was 72. 7 μm). Visual acuities ranged from 4/200 to hand motions

The Optical Coherence Tomographic Profile of Leber Hereditary Optic Neuropathy Thomas R. Hedges, a Marisa Gobuty, a Richard A. Manfready, a Natalie Erlich-Malona, a Caitlin Monaco, a and. Carlos E. Mendoza-Santiestebana, b, c OCT findings throughout the early acute, late acute, and chronic phases in a patient (patient 4) with decreased vision bilaterally (20/30 and 20/50) 3 weeks after symptom onset. In the early acute phase, GCC defects are noted bilaterally with RNFL swelling. In the late acute phase, severe GCC thinning is present with persistent RNFL swelling. In the chronic phase, severe GCC thinning is present with RNFL thinning noted temporally.

The Optical Coherence Tomographic Profile of Leber Hereditary Optic Neuropathy Thomas R. Hedges, a Marisa Gobuty, a Richard A. Manfready, a Natalie Erlich-Malona, a Caitlin Monaco, a and. Carlos E. Mendoza-Santiestebana, b, c A 19 -year-old student was referred for 4 weeks of worsening vision in the right eye. In the affected right eye, OCT showed RNFL swelling with diffuse GCC loss (VA CF). In the unaffected left eye, RNFL thickening with sectoral GCC thickening and thinning was detected (VA 20/15). At the onset of vision loss in the early acute phase, GCC thinning with RNFL swelling was detected. In the chronic phase, thinning of both the RNFL and GCC was observed.

What is the prognosis and treatment of LHON? Prognosis is poor: • Most patients suffer permanent bilateral visual loss with a final VA of 6/60 or less. • The 11778 mutation carries the worst prognosis. • Some visual recovery may occur in a minority of cases even years later. Treatment: • None • Dietary deficiencies should be avoided, particularly of B 12. • Cyanocobalamin (but not the hydroxocobalamin) form of vitamin B 12 has been reported to worsen outcomes. • Smoking and excessive alcohol consumption should be discouraged, theoretically in order to minimize mitochondrial stress. • Gene therapy is under active investigation. KANSKI 8 TH ED. 2016

Idebenone in the treatment of LHON • Idebenone (Raxone(®)), a short-chain benzoquinone, is the only disease-specific drug approved to treat visual impairment in adolescents and adults with Leber's hereditary optic neuropathy (LHON) • Antioxidant properties and ability to act as a mitochondrial electron carrier. • Idebenone overcomes mitochondrial complex I respiratory chain deficiency in patients with LHON by transferring electrons directly to mitochondrial complex III (by-passing complex I) restoring cellular energy (ATP) production and re-activating inactive -but-viable retinal ganglion cells • ‘’. . oral idebenone 900 mg/day for 24 weeks has persistent beneficial effects in preventing further vision impairment…’’