15-year-old male presented to the CHLA ED with decreased vision in both eyes
Patient saw an eye doctor one month prior and was told that his nerve was swollen in the left eye. After leaving, he noticed the vision in the right eye getting worse
Exam Findings
BCVA of 10 feet 125 in the right eye and eight feet 250 in the left eye
Pupils round and reactive with a relative afferent pupillary defect in the left eye
Inability to see the color plates for testing
Normal anterior segment slit lamp exam
Figure 1: Dilated fundus exam showing optic nerve hyperemia and blurring of the disc margin with sparing the temporal rim in the right eye (left). Temporal pallor and gliosis of the optic nerve. Papillo-macular nerve fiber layer loss in the left eye (right).
Differential Diagnosis
Compressive optic neuropathy
Foster Kennedy syndrome causing left optic nerve atrophy and optic nerve swelling of the right eye due to elevated intracranial pressure from a mass
Ischemic optic neuropathy
Sequential NAION
Inflammatory/infectious optic neuropathy
Additional Investigations
Figure 2: Distal end of the optic nerves just proximal to the optic discs are slightly hypoplastic with subtle T2 hyperintensity, left worse than right shown above.
Unremarkable MRI of the brain with and without contrast. Also MRI spine was unremarkable
Unremarkable MR venogram with no MR evidence of venous thrombosis
LP with normal opening pressure and CSF studies
Other labs unremarkable
Differential diagnosis now included
NMO spectrum disease
Lebers Hereditary Optic Neuropathy (LHON)
Inflammatory Process
Mitochondrial genetic testing was Positive for 11778 mitochondrial mutation
Diagnosis
Lebers Hereditary Optic Neuropathy (LHON)
Pathophysiology
LHON was the first mitochondrial disease to be recognized and the first disorder recognized to be maternally inherited and the first to be attributed to a point mutation in mitochondrial DNA (mtDNA).
Unlike nuclear DNA, mtDNA replicates continuously and independently of the cell cycle in both dividing and non-dividing cells. Heteroplasmy and replicative segregation contribute to the heterogeneity of mitochondrial disease phenotypes.
Mitochondrial DNA mutation, most frequently 11778 position. Less commonly at 3460 or 14484 locations (90% of all cases)
Spontaneous visual recovery is more common in patients with the 14484 mutation, with a partial recovery rate of 37%-58%, while the 11778 mutation has the lowest partial recovery rate of 4%.
Clinical triad of LOHN includes:
Hypermia and elevation of the ONH, with thickening of the peripapillary retina (does not leak on FA – pseudoedema)
Peripapillary telangiectasia
Tortuosity of the medium sized retinal arterioles
Treatment
There are no current treatment paradigms for LHON
Patient was seen back in neuro-ophthalmology two months after discharge and provided with information regarding clinical trials in progress
Prognosis and Future Directions
Although no current accepted clinical treatments exist for LHON, there are active clinical trials recruiting patients. The trials center on two main avenues to treat LHON, pharmacologic and genetic approaches
Use of short-chain ubiquinone analogs such as Idebenone that easily enter the brain and reach mitochondria, unlike coenzyme Q10. Idebenone has been shown to bypass complex I and maintain ATP production, and it inhibits lipid peroxidation to protect mitochondria from oxidative damage.
Figure 3: Gene therapy with an AAV vector carrying the wild-type ND4 gene as well as use of the SOD2 gene, which detoxifies free radicals in mitochondria.
With the advent of AAV2-hRPE65v2 in Lebers congenital amarousis as the first gene therapy, there is promise of genomic approaches to treat neurodegenerative conditions such as LHON
References
Dunbar et al. Gene Therapy Comes of Age, Science, 2018, 359: eaan4672.
Karanjia et al. Treatment of Leber’s Hereditary Optic Neuropathy, Current Pharm Design, 2017, 23: 624-628.
Meyerson et al., Leber Hereditary Optic Neuropathy: Current Perspectives, Clin Ophthalmol, 2015, 9: 1165-1176.
Russell et al., Efficacy and Safety of Voretigene Neparvovec (AAV2-hRPE65v2) in Patients with RPE65-Mediated Inherited Retinal Dystrophy: A Randomized, Controlled, Open-Label, Phase 3 Trial, Lancet, 2017, 390: 849-860.
Contact
Mark Borchert, MD, Associate Professor of Clinical Ophthalmology, mborchert@chla.usc.edu
