Conversion to Leber Hereditary Optic Neuropathy After Hyperbaric Oxygen Therapy

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Conversion to Leber Hereditary Optic Neuropathy After Hyperbaric Oxygen Therapy Kirill Zaslavsky, MD, PhD, Laura Donaldson, MD, PhD, Edward Margolin, MD L eber’s hereditary optic neuropathy (LHON) occurs when carriers of specific mitochondrial genomic mutations convert to a symptomatic state with vision loss. We describe a case of a 35-year-old man with homoplasmy of m.11778G.A (MTND4) mutation who experienced severe bilateral vision loss within 1 month of receiving 50 courses of hyperbaric oxygen therapy. Retinal ganglion cell loss measured by thinning of the macular ganglion cell complex (GCC) was unusually rapid. This is the first report of iatrogenic hyperoxia as a trigger for LHON conversion, and we hypothesize that supraphysiologic oxygen is harmful in carriers with states of impaired mitochondrial oxygen utilization. CASE REPORT A 35-year-old man noticed severe bilateral painless vision loss occurring over the course of 2 days. His medical history was significant for concussion 2 years ago and refractive surgery in both eyes. The patient stated he does not smoke and has 1 drink of alcohol per week. He revealed he underwent approximately 50 rounds of hyperbaric oxygen therapy over the course of 2 months for post-concussion symptoms 1 month before onset of vision loss. There was no family history of vision loss. On examination, visual acuity was 20/200 in the right eye (RE) and 20/400 in the left eye (LE). Automated visual field testing (Humphrey Visual Field [HVF], 24-2 SITA Fast algorithm) demonstrated the presence of cecocentral scotomas in each eye (Fig. 1A). Peripapillary ocular coherence tomography showed thickening of the retinal nerve fiber layer (RNFL) in both eyes (Fig. 1B). Analysis of the GCC (sum of ganglion cell layer and inner plexiform layer thickness) demonstrated predominantly nasal and inferior thinning bilaterally (Fig. 1C). Ophthalmoscopy revealed mild optic nerve head edema, hyperemia, and peripapillary telangiectasia. MRI of the brain and Department of Ophthalmology and Vision Sciences (KZ, LD, EM), University of Toronto, Toronto, Canada; and Division of Neurology (EM), Department of Medicine, University of Toronto, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, Department of Ophthalmology and Visual Sciences, University of Toronto, 801 Eglinton Avenue West, Suite 301, Toronto ON M5N 1E3; E-mail: [e-mail]. e70 orbits with gadolinium was unremarkable. Lumbar puncture demonstrated normal composition. One month later, vision was 20/400 in each eye, there was no RAPD, and HVF demonstrated unchanged cecocentral scotomas in each eye (Fig. 2A). The mild thickening of peripapillary RNFL was stable (Fig. 2B). However, he now displayed diffuse thinning of the GCC, with both eyes losing on average 14 mm in 1 month (Fig. 2C). Both optic nerves were hyperemic with a wedge of temporal pallor (Fig. 2D). The rest of his neurological examination was normal. Genetic testing revealed m.11778G.A MTND4 mutation at homoplasmy. Treatment with oral idebenone 900 mg daily commenced, but 6 months later, visual acuity and HVF continued to deteriorate, with the patient achieving only counting fingers vision bilaterally, and RNFL thinning becoming apparent on peripapillary OCT (Fig. 2E). DISCUSSION LHON is caused by mutations affecting the mitochondrial electron transport chain (ETC). Increased accumulation of reactive oxygen species (ROS) preferentially damages the highly metabolically active retinal ganglion cells of papillomacular bundle leading to the loss of central acuity and cecocentral scotomas. Penetrance is variable with 50% in men and 10% in women. Smoking, heavy alcohol use, and exposure to toxins are associated with conversion to the affected state (1). This is the first reported case of LHON conversion after hyperbaric oxygen therapy. Supraphysiologic oxygen is widely believed to be toxic in the context of a dysfunctional mitochondrial ETC and states of impaired oxygen utilization (2). The strongest evidence comes from studies on Leigh syndrome, a neurodevelopmental disease caused by NDUFS4 mutations leading to dysfunction in complex I of the ETC, similar to LHON. In Ndufs4 knockout mice, hyperoxia accelerates death, whereas hypoxia greatly improves survival (3). Although no direct evidence showing impaired oxygen utilization in patients with LHON exists, fibroblasts derived from patients with LHON with m. 11778G.A show increased accumulation of ROS and sensitivity to cigarette smoke concentrate relative to controls (4). Zaslavsky et al: J Neuro-Ophthalmol 2023; 43: e70-e73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Bilateral optic neuropathy at presentation. A. Automated visual field testing (24-2 SITA Fast) demonstrates bilateral cecocentral scotomas. (B) Peripapillary OCT shows mild bilateral RNFL thickening. (C) Ganglion cell analysis of the macular GCC shows predominantly nasal thinning progressing inferiorly and temporally more in the left eye than the right eye. (D) Color fundus photography shows bilateral mild optic disc edema, hyperemia, and circumpapillary telangiectasia. GCC, ganglion cell complex; RNFL, retinal nerve fiber layer. Hyperoxia may be a particularly potent trigger of LHON conversion. Blood free radical levels have been shown to increase immediately after one 20 minute session of hyperbaric therapy (5). Although severe bilateral vision loss can occur in 25%–50% of m.11778G.A carriers, rates of vision loss are variable (6). Our patient experienced rapid, bilateral, and severe visual deterioration closely after hyperbaric oxygen therapy. As the peripapillary RNFL is elevated before and during conversion (6), the loss of retinal ganglion cells in LHON is best captured by optical coherence tomography of the macular GCC. Rates of GCC thinning in the first months after conversion can be estimated at Zaslavsky et al: J Neuro-Ophthalmol 2023; 43: e70-e73 approximately 10%, or 6.5–8 mm, thinning per month (7). Our patient showed a doubling of this rate, losing approximately 20% or 14 mm per month bilaterally. We describe the first reported case of hyperbaric oxygen therapy triggering conversion of LHON. It is tragic that this patient underwent hyperbaric therapy for post-concussion syndrome, an indication for which it has no proven benefit (8). Carriers of LHON mutations should be counseled not to undergo hyperbaric therapy unless it is medically necessary, and patients considering this treatment should be questioned regarding a family history of vision loss in the maternal lineage. e71 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Progression of optic neuropathy at 1-month and 6-month follow-up. A. Automated visual field testing (24-2 SITA Fast) demonstrates bilateral cecocentral scotomas. (B) Peripapillary OCT shows mild bilateral RNFL thickening. (C) Ganglion cell analysis of the macular GCC shows diffuse thinning with significantly reduced average thickness (14 mm bilaterally) relative to the previous assessment. (D) Color fundus photography shows bilateral mild optic disc edema, hyperemia, and increasing temporal pallor compared with the previous assessment. (E) Total deviation on HVF and peripapillary OCT at the 6-month visit showing progression of visual field loss and RNFL thinning. GCC, ganglion cell complex; RNFL, retinal nerve fiber layer. e72 Zaslavsky et al: J Neuro-Ophthalmol 2023; 43: e70-e73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence STATEMENT OF AUTHORSHIP Conception and design: E. Margolin, L. Donaldson, K. Zaslavsky; Acquisition of data: E. Margolin, L. Donaldson, K. Zaslavsky; Analysis and interpretation of data: E. Margolin, L. Donaldson, K. Zaslavsky. Drafting the manuscript: E. Margolin, L. Donaldson, K. Zaslavsky; Revising it for intellectual content: E. Margolin, L. Donaldson, K. Zaslavsky. Final approval of the completed manuscript: E. Margolin, L. Donaldson, K. Zaslavsky. REFERENCES 1. 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