Disulfiram-Induced Optic Neuropathy: A Case Series and Review of Literature

Clinical Correspondence Disulfiram-Induced Optic Neuropathy: A Case Series and Review of Literature Sydney R. Roston, BS, Andrew R. Carey, MD T oxic optic neuropathy is well described with medications including ethambutol, amiodarone, tumor necrosis factor-a inhibitors, and linezolid. Toxic optic neuropathy may also be attributed to disulfiram.1–3 Disulfiram, approved for use in alcohol dependence, inhibits acetaldehyde dehydrogenase, an enzyme crucial to alcohol metabolism.4 Alcohol consumed in the presence of a therapeutic dose of disulfiram cannot be metabolized, resulting in nausea, facial flushing, tachycardia, and diaphoresis, discouraging alcohol consumption.4 The clinical manifestation and mechanism of disulfiram toxic optic neuropathy are poorly characterized.5 English language reports have identified 3 cases of disulfiram-induced toxic optic neuropathy that varied in the duration of disulfiram use before visual symptom presentation from 10 weeks to 3 years.1–3 All 3 cases showed improvement in visual acuity within 1 month after cessation of disulfiram.1–3 Here, we present 2 additional cases of suspected disulfiram-induced toxic optic neuropathy to further characterize the clinical presentation and prognosis. Case #1: A 53-year-old man with a history of multiple sclerosis (MS) presented with loss of vision in the setting of disulfiram use. The patient’s MS was diagnosed 13 years before his recent illness and was currently managed on teriflunomide. He had no recently documented MS exacerbations, specifically no optic neuritis. The patient was also taking buspirone, sertraline, combination emtricitabine and tenofovir disoproxil fumarate for pre-exposure prophylaxis, and 250 mg of disulfiram. He developed bilateral, simultaneous, slowly progressive over 9 months, painless decreased central vision after 24 months of disulfiram therapy. Disulfiram was discontinued by an outside physician 1 year after the onset of decreased vision. University of Minnesota Medical School (SRR), Minneapolis, Minnesota; and Wilmer Eye Institute (ARC), Johns Hopkins School of Medicine, Baltimore, Maryland. A. R. Carey has relationships with Horizon Therapeutics and Springer Publishing, neither of which pertain to this work. The other author reports no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Andrew R. Carey, MD, NeuroOphthalmology Division, Wilmer Eye Institute, 600 N. Wolfe Street, Maumenee Building, 2nd Floor, Baltimore, MD 21287; E-mail: [e-mail] doi: 10.1097/WNO.0000000000002067 © 2023 by North American Neuro-Ophthalmology Society Roston and Carey: J Neuro-Ophthalmol 2024; 44: e599-e601 The patient presented to our institution for a second opinion. At this time, best-corrected visual acuity (BCVA) was counting fingers in each eye. Intraocular pressure (IOP) was 9 in the right eye and 8 in the left eye mm Hg. Color vision on Ishihara color plates was 1/11 in both eyes (OU). Examination revealed a left relative afferent pupillary defect (RAPD) and bilateral optic disc temporal pallor. Automated perimetry visual field testing demonstrated bilateral central scotoma (diameters of 20° in the right eye and 15° in the left eye) to size V stimulus. Optical coherence tomography (OCT) of the optic nerve showed normal peripapillary retinal nerve fiber layer thickness of 87 in the right eye and 85 in the left eye microns. However, OCT shows symmetric bundle thinning greater supero-temporally compared with infero-temporally and severe diffuse inner plexiform layer (GC-IPL) thinning (Fig. 1A). Of note, the macula was decentered in the right eye and could not be corrected, but the GC-IPL was clearly thinned. MRI of the brain was unremarkable for a lesion to explain the patient’s vision loss; in particular, there was no enhancement or compression of the optic nerves and no increased T2 signal. The differential diagnosis included toxic optic neuropathy and Leber Hereditary Optic Neuropathy. The patient deferred genetic testing, electing to wait for potential spontaneous visual improvement. At the six-month follow-up visit, his BCVA was improved to 20/200 in both eyes, color vision of 5/14 in the right eye and 2/14 in the left eye, and there was a decrease in the diameter of the central scotoma OU. Most recently, 28 months after initial presentation to neuro-ophthalmology, BCVA was 20/100 in the right eye and 20/80 in the left eye. Color vision was 7/13 in the right eye and 6/13 in the left eye. OCT demonstrated a slow decline in the RNFL thickness with broadening of the bundle defects (see Supplemental Digital Content, Supplemental Data 1, http://links.lww. com/WNO/A797). Ganglion cell layer thickness had reached a floor effect at presentation (54 mm). Visual field findings showed continued improvement in the central scotomas. Case #2: A 58-year-old man with type 1 diabetes and hypothyroidism presented with vision loss in the setting of disulfiram use. His medications at the time of symptom onset were insulin, rosuvastatin, levothyroxine, and 250 mg daily of disulfiram. He developed bilateral, simultaneous, painless decreased vision after 12 months of disulfiram therapy. Examination by an outside ophthalmologist 2 weeks after the onset of visual symptoms reported. BCVA was e599 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Zeiss cirrus optical coherence tomography from case 1: Retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layers (GC-IPL) at initial presentation to our institution showing OU supero-temporal and infero-temporal nerve fiber bundle thinning (OD with saccade artifact through superior margin of disc) and diffuse & GC-IPL thinning (right eye with superior decentration artifact). 20/100 in the right eye and 20/80 in the left eye. IOP was indicated to be 12 mm Hg OU. Ishihara color vision was 0/12 in the right eye and 1/12 in the left eye. Pupils were equally reactive with no RAPD. Examination revealed bilateral optic disc temporal pallor. OCT demonstrated bilateral temporal RNFL thinning (average 72 in the right eye & 69 in the left eye microns) with diffuse and severe ganglion cell layer thinning (Fig. 2A, B). Automated perimetry testing demonstrated decreased foveal threshold bilaterally and a supratemporal scotoma in the left eye (see Supplemental Digital Content, Supplemental Data 2, http://links.lww.com/WNO/A798). MRI of the brain was unremarkable. MRI of the orbits demonstrated slight enhancement of the right optic nerve compared with the left. Electroretinogram was normal in both eyes. Visual evoked potential testing demonstrated a small response bilaterally and a delayed p-100 peak by 40–50 milliseconds. Disulfiram was discontinued 6 weeks after the onset of symptoms. FIG. 2. Case 2 initial presentation: (A) Heidelberg SPECTRALIS optical coherence tomography (OCT) of the optic nerve showing temporal thinning OU. B. Heidelberg SPECTRALIS OCT of the macula ganglion cell showing severe diffuse thinning. e600 Roston and Carey: J Neuro-Ophthalmol 2024; 44: e599-e601 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Four weeks later, he presented to our institution—10 weeks after symptom onset. BCVA improved to 20/40 in the left eye and 20/50 in the left eye. IOP was 10 in the right eye and 11 in the left eye mm Hg. Pupils were equally reactive without an RAPD. Color vision was 1.5/13 in the right eye and 3/13 in the left eye. Examination revealed trace bilateral optic disc temporal pallor. Laboratory testing was unremarkable for lyme, syphilis, aquaporin 4 antibody, myelin oligodendrocyte glycoprotein IgG, biotinidase, ceruloplasmin, vitamin B12, copper, folate, methylmalonic acid, vitamin B1, and gamma glutamyl transferase. Mitochondrial genome sequencing and focused nuclear panel (GeneDx, Gaithersburg, MD) was negative for a genetic etiology such as Leber Hereditary Optic Neuropathy. These cases better characterize the clinical picture of disulfiram toxic optic neuropathy. In contrast to the rapid recovery noted in previously reported cases, our cases showed a gradual improvement, perhaps related to the duration of continued exposure after onset of vision impairment. In addition, the availability of OCT findings, which are lacking in the literature, helps to characterize the condition. The patients presented here share features with nutritional optic neuropathy and Leber Hereditary Optic Neuropathy, suggesting a mitochondrial etiology of disulfiram toxicity. Disulfiram was shown to crosslink sulfhydryl groups of intermembrane proteins in the mitochondria of rat liver tissue, inhibiting oxidative phosphorylation.5 Roston and Carey: J Neuro-Ophthalmol 2024; 44: e599-e601 Further studies are indicated to determine the mechanism of disulfiram optic neuropathy and whether a dosedependent relationship exists. These additional reports of disulfiram optic neuropathy heighten awareness of this disease entity. STATEMENT OF AUTHORSHIP Conception and design: S. R. Roston, A. R. Carey; Acquisition of data: S. R. Roston, A. R. Carey; Analysis and interpretation of data: S. R. Roston, A. R. Carey. Drafting the manuscript: S. R. Roston, A. R. Carey; Revising the manuscript for intellectual content: S. R. Roston, A. R. Carey. Final approval of the completed manuscript: S. R. Roston, A. R. Carey. REFERENCES 1. Kulkarni RR, Pradeep AV, Bairy BK. Disulfiram-induced combined irreversible anterior ischemic optic neuropathy and reversible peripheral neuropathy: a prospective case report and review of the literature. J Neuropsychiatry Clin Neurosci. 2013;25:339–342. 2. Orakzai A, Guerin M, Beatty S. Disulfiram-induced transient optic and peripheral neuropathy: a case report. Ir J Med Sci. 2007;176:319–321. 3. Norton AL, Walsh FB. Disulfiram-induced optic neuritis. Trans Am Acad Ophthalmol Otolaryngol. 1972;76:1263–1265. 4. Stokes M, Abdijadid S. Disulfiram. In: StatPearls. Treasure Island, FL: StatPearls Publishing. 2022. 5. Kuroda MA, Cuéllar A. Deleterious effects of disulfiram on the respiratory electron transport system of liver mitochondria. Int J Biochem. 1993;25:87–91. e601 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.