Severe Leber Hereditary Optic Neuropathy Plus Disease in a Middle-Aged Man.

A 50-year-old African American man with hypertension, atrial fibrillation, and congestive heart failure presented with progressive vision loss in both eyes over 3 months. He described blurriness and dimming of vision and changes in color perception. The patient also endorsed ascending numbness and paresthesias from his feet to hips bilaterally, with an onset 6 months before vision loss. Previous treatment with intravenous corticosteroids had failed to improve his symptoms. On examination, his best-corrected visual acuity was 20/100 in the right eye and 20/200 in the left eye, and he could read only the control Ishihara color plate with either eye. Pupils were briskly reactive bilaterally with no relative afferent pupillary defect. Visual fields were full to confrontation bilaterally. The neurological examination was notable for diminished light touch and vibratory sensation to the midcalf bilaterally but intact temperature sensation and no sensory level. Reflexes were normal throughout. Slit-lamp examination of the anterior segment was unremarkable, whereas dilated fundus examination was notable only for equivocal temporal pallor of both optic discs (Fig. 1A). Optical coherence tomography showed normal average retinal nerve fiber layer (RNFL) thickness, with borderline temporal thinning potentially suggestive of injury to the papillomacular bundle (Fig. 1B); this was confirmed on ganglion cell layer analysis, which revealed marked thinning within the macula bilaterally (Fig. 1C). The patient underwent contrast-enhanced MRI of the brain, orbits, and spine, which revealed no pathology along the afferent visual pathways but demonstrated a mildly enhancing, longitudinally extensive T2 hyperintense spinal lesion from C1 to T9, centered on the dorsal columns (Fig. 1D). He was admitted by the neurology service for treatment of presumed neuromyelitis optica (NMO). After 5 sessions of plasmapheresis, he endorsed mild improvement in his lower extremity symptoms; treatment was continued with intravenous immunoglobulin over 5 additional days without any further symptomatic improvement. Testing for serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies returned negative by the end of the hospitalization. Additional inpatient diagnostic workup included unremarkable serum vitamin B12, folic acid, thiamine, and paraneoplastic panel. Serum copper concentration was markedly low (39 mg/dL; reference range 72–166 mg/dL) and was initially believed to explain the combination of bilateral optic neuropathy and dorsal column pathology. However, this proved to be artifactual, resulting from the sample being obtained immediately after a plasmapheresis session; the serum copper concentration was normal (95 mg/dL) when repeated without any copper supplementation. Urine heavy metal screen was remarkable for elevated arsenic (35 mg/24 h), but on fractionation, this was found to represent an organic form of arsenic consistent with the patient’s reported frequent consumption of seafood. Organic “fish arsenic”—predominantly arsenobetaine—does not accumulate in the body long term and, unlike inorganic arsenic, is typically considered innocuous (1). Finally, syphilis testing revealed discordant results, with positive treponema pallidum antibodies and negative RPR. Cerebrospinal fluid analysis revealed a mildly elevated protein concentration (62 mg/dL) but normal white blood cell count (3 mm23), glucose (56 mg/dL), and immunoglobulin G index (0.48), no oligoclonal bands, and negative venereal disease research laboratory. Based on this analysis, neurosyphilis was believed unlikely, but he was treated with intravenous penicillin followed by a month-long course of oral doxycycline, without improvement in vision or lower extremity sensation. On follow-up 4 months later, his visual acuity had decreased to hand-motion bilaterally. Prominent temporal optic disc pallor and temporal RNFL thinning had developed in the interim (Fig. 2). Full-field electroretinography was entirely normal in both eyes, with the exception of profoundly decreased photopic negative responses indicative of retinal ganglion cell dysfunction. Serum copper and arsenic were normal on repeat testing. Mitochondrial DNA (mtDNA) testing revealed a homoplasmic 3635 G.A pathological variant in the ND1 subunit of complex I. It was therefore concluded that the bilateral optic atrophy and spinal cord pathology represented Leber Hereditary Optic Neuropathy (LHON) Plus disease. Unfortunately, despite initiating treatment with idebenone 300 mg 3 times daily, the patient’s vision loss progressed to no light perception (NLP) over the subsequent 5 months with profound diffuse RNFL thinning bilaterally (Fig. 2B, C). Department of Ophthalmology (FAB, SMG), Duke University Medical Center, Durham, North Carolina.