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.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Severe Leber Hereditary Optic Neuropathy Plus Disease in a Middle-Aged Man Faith A. Birnbaum, MD, Sidney M. Gospe III, MD, PhD 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. Department of Ophthalmology (FAB, SMG), Duke University Medical Center, Durham, North Carolina. The authors report no conflicts of interest. Address correspondence to Sidney M. Gospe III, MD, PhD, Department of Ophthalmology, Duke University Medical Center, Duke Eye Center, 2351 Erwin Road, Durham, NC 27710; E-mail: [e-mail] Birnbaum and Gospe: J Neuro-Ophthalmol 2021; 41: e715-e717 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). e715 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Abnormal findings on initial workup. A. Optos color fundus photographs of the right (OD; left side) and left (left OS; right side) optic discs, showing possible temporal pallor in both eyes. B. Optical coherence tomography peripapillary retinal nerve fiber layer analysis showing borderline temporal thinning in both eyes. C. Ganglion cell layer (GCL) analysis of the right and left eye showing diffuse macular GCL thinning bilaterally, with an average volume of 0.74 and 0.76 mm3, respectively. D. Sagittal T2 MRI of the spine showing hyperintensity of the spinal cord from the cervical region to T9 (between yellow arrows). Disc herniation is incidentally noted at T4/T5 (white arrow). The combination of this patient’s genotype, demographics, visual outcome, and extensive spine pathology makes this a highly atypical case of LHON. Whereas point mutations at 3 mitochondrial DNA loci—positions 11778, 14484, and 3460—account for over 95% of LHON cases (2), our patient’s rare 3635 G.A mutation has not previously been reported in the United States. The link between this specific mutation and LHON was first identified in 2001 in a Russian family (3), and its pathogenicity has since been confirmed in a Han Chinese population and in cell culture (4). Another unusual feature in our patient was the late onset of vision loss. Usually LHON-related vision loss occurs in younger adults in their twenties or thirties, with 95% of cases occurring before age 50 (2). Our patient excepted, this seems to be no different with the 3635 G.A mutation; in the Han Chinese study, the average age of onset within 9 pedigrees ranged from 14 to 30 years of age, with an overall mean of 20.2 years (4). Our patient’s progressive vision loss to NLP in both eyes is also highly atypical for LHON, which often leaves peripheral vision relatively spared due to lower susceptibility of retinal ganglion cell axons outside the papillomacular bundle. Although examples of visual outcomes of NLP are rare in the literature, it should be noted that one large e716 series documented bilateral NLP vision in 4 of 107 LHON patients (5). NLP vision has not previously been associated with the 3635 G.A mutation; in the Chinese series, vision loss was typically profound (visual acuity , 0.05 in the both eyes) but did exhibit some improvement with time (final visual acuity 0.3 to 0.1) in 5 of the 9 probands (4). Finally, whereas most LHON patients present with isolated optic neuropathy, systemic manifestations may coexist, a presentation termed LHON-Plus. Among possible extraocular manifestations are central nervous system white matter lesions, myopathy, cardiac conduction anomalies, and peripheral neuropathy. Although multiple sclerosis–like white matter lesions may cause significant neurological morbidity in LHON-Plus, cases with longitudinally extensive spine lesions masquerading as NMO are quite rare; the absence of aquaporin-4 antibodies and the predilection for the dorsal columns (as opposed expansile transverse spinal cord involvement) can help to distinguish these cases from bona fide NMO (6). This case illustrates the importance of considering LHON in patients with acute bilateral optic neuropathy and white matter disease. Despite this patient’s highly atypical presentation, the genetic confirmation of LHON and rejection of the diagnosis of seronegative NMO allowed Birnbaum and Gospe: J Neuro-Ophthalmol 2021; 41: e715-e717 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Longitudinal progression of profound optic atrophy. A. Color fundus photographs showing optic disc pallor of both eyes 4 months after initial presentation. B and C. Optical coherence tomography peripapillary retinal nerve fiber layer analysis of the right eye (B) and left eye (C). The black tracings show progressive RNFL thinning at 4 months (top panel) and 9 months (bottom panel) after initial presentation. Gray tracings depict RNFL thickness on initial presentation. him to be spared from aggressive and likely futile chronic immunosuppression. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. M. Gospe; b. Acquisition of data: S. M. Gospe; c. Analysis and interpretation of data: F. A. Birnbaum, and S. M. Gospe. Category 2: a. Drafting the manuscript: F. A. Birnbaum; b. Revising it for intellectual content: S. M. Gospe. Category 3: a. Final approval of the completed manuscript: F. A. 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