Leber's Hereditary Optic Neuropathy in Older Individuals Because of Increased Alcohol Consumption During the COVID-19 Pandemic

Backgeber's hereditary optic neuropathy (LHON) is a disorder affecting oxidative phosphorylation in mitochondria. A majority of affected patients are men of 15 to 35 years of age. Phenotypic penetrance of this condition is only 50% in man and 10% in women and increases if the cellular energy demands go up, with the most common risk factors being smoking and alcohol use. Methods: Revi of clinical features of 3 patients who were diagnosed with LHON in their sixth decade of life after doubling their alcohol intake during the recent COVID-19 pandemic. Results: All 3 pa ents were older than the age of 50 when they developed severe sequential visual loss. All have at least doubled their alcohol intake for at least 4 weeks preceding visual loss, and 2 who were smokers increased the number of cigarettes consumed daily because of the stress and boredom during the lockdowns triggered by the pandemic. Conclusions: Significant increase in substance abuse in the general population during the recent lockdowns to combat the COVID-19 pandemic is well documented. We report 3 patients older than the age of 50, one of them a woman, who developed severe bilateral visual loss due to LHON after doubling their alcohol consumption and increasing number of cigarettes smoked daily during the pandemic. Clinicians are reminded to consider LHON in the differential diagnosis when encountering older patients with bilateral sequential visual loss and to specifically inquire about alcohol use and cigarette smoking in these patients.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Leber’s Hereditary Optic Neuropathy in Older Individuals Because of Increased Alcohol Consumption During the COVID-19 Pandemic Kirill Zaslavsky, MD, PhD, Edward A. Margolin, MD Background: Leber’s hereditary optic neuropathy (LHON) is a disorder affecting oxidative phosphorylation in mitochondria. A majority of affected patients are men of 15 to 35 years of age. Phenotypic penetrance of this condition is only 50% in man and 10% in women and increases if the cellular energy demands go up, with the most common risk factors being smoking and alcohol use. Methods: Review of clinical features of 3 patients who were diagnosed with LHON in their sixth decade of life after doubling their alcohol intake during the recent COVID-19 pandemic. Results: All 3 patients were older than the age of 50 when they developed severe sequential visual loss. All have at least doubled their alcohol intake for at least 4 weeks preceding visual loss, and 2 who were smokers increased the number of cigarettes consumed daily because of the stress and boredom during the lockdowns triggered by the pandemic. Conclusions: Significant increase in substance abuse in the general population during the recent lockdowns to combat the COVID-19 pandemic is well documented. We report 3 patients older than the age of 50, one of them a woman, who developed severe bilateral visual loss due to LHON after doubling their alcohol consumption and increasing number of cigarettes smoked daily during the pandemic. Clinicians are reminded to consider LHON in the differential diagnosis when encountering older patients with bilateral sequential visual loss and to specifically inquire about alcohol use and cigarette smoking in these patients. Journal of Neuro-Ophthalmology 2021;41:316–320 doi: 10.1097/WNO.0000000000001333 © 2021 by North American Neuro-Ophthalmology Society Departments of Ophthalmology and Vision Sciences (KZ, EM), University of Toronto, Toronto, Canada; and Department of Medicine (EM), Division of Neurology, University of Toronto, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, University of Toronto, Department of Ophthalmology and Visual Sciences, Department of Medicine, Division of Neurology Chief of Service, Neuro-Ophthalmology, 801 Eglinton Avenue, West, Suite 301, Toronto ON M5N 1E3; E-mail: [e-mail] 316 L eber’s hereditary optic neuropathy (LHON) causes severe bilateral visual loss and is typically diagnosed in men in their second and third decades of life. It occurs secondary to mutations affecting complex I of the mitochondrial respiratory chain. Penetrance of the disease in men is around 50% and 10% in women. It is believed that increased energy demands on mitochondria because of smoking and binge drinking can contribute to phenotypic expression of the disease (1–3). Recent lockdowns to combat the COVID19 pandemic have changed substance consumption habits with approximately 30% of individuals increasing their alcohol intake and 10% increasing smoking (4). We describe 3 cases of LHON diagnosed between April and August of 2020 in individuals older than 50 years of age, 2 of whom began smoking more and all of whom reported doubling their average daily alcohol intake during the pandemic. As countries navigate the COVID-19 pandemic and its economic ramifications, prevention of substance abuse–related health sequelae should be prioritized. CASE 1 A 53-year-old man noticed decreased vision in both for 6 weeks. He had a history of osteoporosis but did not take any medications regularly. There was no family history of vision loss. He admitted to drinking one bottle of wine each night for the past many years and had 40 years of 1 pack per day smoking. He stated he increased his drinking to 2 bottles a night and started smoking at least 10 more cigarettes a day for the preceding 4 months since the beginning of the COVID-19 pandemic. The visual acuity was 20/200 in each eye, there was no relative afferent pupillary defect (RAPD), and automated 24-2 SITA-Fast visual fields demonstrated a cecocentral scotoma in each eye. Although peripapillary optical coherence tomography (OCT) was normal, ganglion cell analysis of the macular complex demonstrated nasal thinning in each eye (Fig. 1). Neurological examination demonstrated abnormal Zaslavsky and Margolin: J Neuro-Ophthalmol 2021; 41: 316-320 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution cerebellar testing and marked essential tremor. He was admitted to the hospital for thiamine infusion. MRI of the brain and orbits with contrast was demonstrated mild generalized brain atrophy and microangiopathic white matter changes but was otherwise unremarkable. Vitamin B12 and folate levels were normal. Sequencing of the entire mitochondrial genome revealed 14484/ND6 T.C mutation at homoplasmy. He started taking idebenone 900 mg a day and entered a rehabilitation hospital for treatment of alcoholism. Ten months later, his examination was unchanged. CASE 2 A 51-year-old man noticed progressive worsening of vision in both eyes over 1 month. He had no other accompanying neurological symptoms. He was otherwise healthy and did not take any medications. There was no family history of vision loss. He smoked half a pack of cigarettes a day for the past many years and admitted to drinking at least 3–4 hard liquor drinks a day. He doubled his alcohol intake and admitted to smoking 5–10 cigarettes more per day since the beginning of the COVID-19 pandemic 2 months ago. The visual acuity was 20/40 and 20/125, and there was no RAPD. FIG. 1. Late-onset Leber’s hereditary optic neuropathy in cases 1 and 2 (A) visual field testing (automated 24-2 SITA-Fast algorithm) reveals bilateral cecocentral scotomas (B) ganglion cell analysis demonstrating predominantly nasal thinning of the ganglion cell and inner plexiform layers surrounding the fovea bilaterally; all measurements in mm (C) color fundus photographs demonstrating slight temporal pallor in Case 2. Zaslavsky and Margolin: J Neuro-Ophthalmol 2021; 41: 316-320 317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Formal visual fields demonstrated cecocentral scotoma in each eye (left greater than right). Peripapillary OCT was normal in each eye, but ganglion cell analysis of the macular complex demonstrated binasal thinning. There was very slight temporal pallor of both optic nerves on ophthalmoscopy (Fig. 1). MRI of the brain and orbits with contrast was unrevealing. When examined 2 weeks later, vision deteriorated to 20/100 and 20/400, there was still no RAPD, and cecocentral scotomas have become denser in each eye. Sequencing of entire mitochondrial genome revealed 11778/ND4 G.A mutation at homoplasmy. Treatment with 900 mg of idebenone commenced and patient reported stopping smoking as well as any alcohol consumption. Eight months later, his examination was unchanged. CASE 3 A 60-year-old woman presenting with worsening vision in the right eye over 4 weeks followed by the left eye over 2 weeks. She had a remote history of endometrial ablation over 5 years ago, benign thyroid nodules which were followed by regular neck ultrasounds, and anxiety. She was taking lorazepam nightly. She quit smoking 15 years ago and denied drinking alcohol other than occasionally. The visual acuity was counting fingers in each eye, and there was no RAPD. Both optic nerves demonstrated temporal pallor on ophthalmoscopy. Formal visual fields were black in each eye. Peripapillary OCT was normal in each eye, but ganglion cell analysis of the macular complex demonstrated diffuse thinning bilaterally. MRI of the brain and orbits with gadolinium demonstrated high T2 signal in intracanalicular and intracranial portions of both optic nerves which did not enhance after gadolinium administration (Fig. 2). Sequencing of entire mitochondrial genome revealed 11778/ND4 G.A mutation at homoplasmy. On the follow-up visit, when asked again about smoking and alcohol consumption, patient denied smoking but admitted to drinking 4 shots of whiskey nightly for the past many years which she doubled in the past 8 weeks after the start of the COVID-19 pandemic. She also recalled that her brother, who was estranged from the family, lost vision in both eyes in his late teens. Treatment with 900 mg of idebenone was initiated, and the patient entered the alcoholics anonymous program. Examination 10 months later was unchanged. DISCUSSION LHON is the most common maternally transmitted disease with a prevalence of 1 in 30,000 and a carrier rate of 1 in 350. Mutations in mtDNA are the most frequently identified cause (2), although recently nuclear DNA mutations in NDUFAF5 and DNAJC30 were described (5,6). Most cases are diagnosed in men between the age of 10–30 years with less than 10% of patients presenting after 50 years of age (7). The spectrum of disease is wide and is believed to be secondary to interaction between genetic background and environmental influences. It has been previously demonstrated 318 that tobacco smoking and heavy alcohol drinking significantly increase the risk of developing LHON (8–10). Penetrance is variable, with 50% in men and 10% in women, and the reasons for male predilection are poorly understood. The recurrence risk of disease in siblings of affected probands is 20% or less and is highest for those of female probands (11), suggesting a higher biological threshold for developing LHON in women. A protective effect of estrogens has been postulated, as affected women have a later disease onset, 17b-estradiol increases mitochondrial biogenesis in vitro, and retinal ganglion cells express estrogen receptors (12,13). It is possible that menopause was an additional trigger to alcohol for late-onset LHON in Case 3. The capacity for mitochondrial biogenesis and the ability to mount an efficient response to oxidative stress seem central to the incomplete penetrance of LHON. These features likely depend on yet undiscovered modifier loci that buffer environmental toxicity (1). For example, relative to affected patients with LHON with the same mutations, unaffected LHON carriers have higher mtDNA copy number, and their cells exhibit more robust compensatory responses on exposure of cigarette smoke concentrate (14). Strikingly, recent observations from 2 large separate cohorts link later age of onset (50+) with significantly greater cumulative exposure to smoking. Although confounded by survivor and patient selection biases, together these data suggest that patients with older onset harbor modifier genes that provide relative protection from developing LHON but are ultimately unable to withstand the severity of environmental insult over time (1,15). Both smoking and alcohol increase oxidative stress by interfering with mitochondrial function (14,16). Critically, although cumulative alcohol intake per year is increased 2-fold in affected individuals relative to controls, maximum weekly consumption of alcohol is increased nearly 7-fold, suggesting that binge drinking plays a significant influence in LHON pathogenesis (7). Therefore, lifestyle intervention to cease smoking and reduce alcohol intake, specifically binge drinking, is an important preventative measure for susceptible individuals. It is thus possible that the patients in our case series who were all older than a typical patient with LHON would not have developed LHON had their substance consumption during the pandemic. Lockdown to combat the spread of infectious disease can worsen psychological distress because of increased social isolation, financial stress, and uncertainty about the future (17). The concomitant interruption of support programs and addiction services may also contribute to increase in alcohol misuse, particularly for individuals with alcohol addiction. Coupled with redistribution and reprioritization of health services, these factors can delay diagnosis and management of health-related sequelae from substance use. In addition, patients suffering health consequences from alcohol misuse may be less likely to seek care in a timely manner during the COVID-19 pandemic. Alarm about the rising tide of alcohol-related illness has been raised in other fields, such as hepatology and addiction psychiatry (17,18). Zaslavsky and Margolin: J Neuro-Ophthalmol 2021; 41: 316-320 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Late-onset Leber’s hereditary optic neuropathy in case 3 (A) visual field testing (automated 24-2 SITA-Fast algorithm) reveals bilateral cecocentral scotomas (B) ganglion cell analysis demonstrating diffuse thinning of the ganglion cell and inner plexiform layers surrounding the fovea bilaterally; all measurements in mm (C) color fundus photographs demonstrating temporal pallor (D) nonenhancing T2/FLAIR hyperintensity of bilateral optic nerves on MRI brain and orbits (red arrows). Across multiple countries, nationwide surveys show bidirectional changes in substance use, most pronounced for alcohol consumption, during the recent lockdowns to prevent the spread of COVID-19 (4,18,19). In a recent survey, 18% of Canadians self-reported increased alcohol intake (25% among those aged 35–54) during the lockdown (20). The main reasons cited were boredom, lack of regular schedule, and stress. A silver lining is that 12% reported decreased alcohol intake primarily because of decreased opportunities to socialize and motivation to maintain good health in case they get infected. It remains to be determined whether these short-term changes in alcohol consumption will persist or worsen as countries grapple with long-term effects of the global economic crisis and navigate the second wave of the COVID-19 pandemic. Alcohol consumption increased after the global financial crisis in 2008 and largely remained at that level (17). Compounding the psychological distress from bankruptcy, job loss, and economic hardship is the possibility of further social isolation secondary to mitigation measures to combat COVID-19. Together with regulatory changes that have increased access to alcohol during the pandemic, these factors create an environment where alcohol use and its health-related consequences can continue to rise, unless checked by careful public health policy. Zaslavsky and Margolin: J Neuro-Ophthalmol 2021; 41: 316-320 We presented a case series of 3 older patients who suffered bilateral visual loss because of the new diagnosis of LHON in the context of significantly increased alcohol and smoking consumption during the recent lockdown to combat the COVID-19 pandemic. The long-term burden of alcohol and substance use-related harm needs to be carefully considered as policies are implemented to mitigate the spread of COVID-19 and the associated economic stress. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Margolin and K. Zaslavsky; b. Acquisition of data: E. Margolin and K. Zaslavsky; c. Analysis and interpretation of data: E. Margolin and K. Zaslavsky. Category 2: a. Drafting the manuscript: E. Margolin and K. Zaslavsky; b. Revising it for intellectual content: E. Margolin and K. Zaslavsky. Category 3: a. Final approval of the completed manuscript: E. Margolin and K. Zaslavsky. References 1. Carelli V, d’Adamo P, Valentino ML, La Morgia C, Ross-Cisneros FN, Caporali L, Maresca A, Polosa PL, Barboni P, De Negri A, Sadun F, Karanjia R, Salomao SR, Berezovsky A, Chicani F, Moraes M, Moraes Filho M, Belfort R Jr, Sadun A. Parsing the 319 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. differences in affected with LHON: genetic versus environmental triggers of disease conversion. Brain. 2016;139:e17. Kisilevsky E, Freund P, Margolin E. Mitochondrial disorders and the eye. Surv Ophthalmol. 2020;65:294–311. Wallace DC, Lott MT. Leber hereditary optic neuropathy: exemplar of an mtDNA disease. In: Pharmacology of Mitochondria [Internet]. Singh H, Sheu S-S, eds. Cham: Springer International Publishing, 2017:339–376. (Handbook of Experimental Pharmacology; vol. 240). Vanderbruggen N, Matthys F, Van Laere S, Zeeuws D, Santermans L, Van den Ameele S, Crunelle CL. Self-reported alcohol, tobacco, and cannabis use during COVID-19 lockdown measures: results from a web-based survey. Eur Addict Res. 2020;26:309–315. Mansukhani SA, Mehta DG, Renaud DL, Whealy MA, Chen JJ, Bhatti MT. Nuclear DNA mutation causing a phenotypic leber hereditary optic neuropathy plus. Ophthalmology. 2021;128:628–631. Stenton SL, Sheremet NL, Catarino CB, Andreeva NA, Assouline Z, Barboni P, Barel O, Berutti R, Bychkov I, Caporali L, Capristo M, Carbonelli M, Cascavilla ML, Issa PC, Freisinger P, Gerber S, Ghezzi D, Graf E, Heidler J, Hempel M, Heon E, Yulya S, Javasky E, Kaplan J, Kopajtich R, Kornblum C, Kovacs-Nagy R, D Krylova T, Kunz WS, La Morgia C, Lamperti C, Ludwig C, Malacarne PF, Maresca A, Mayr JA, Jana M, Nevinitsyna TA, Palombo F, PodeShakked B, Shmelkova MS, Tim M, Tagliavini F, Tzadok M, Amelievan der Ven T, Vignal-Clermont C, Wagner M, Zakharova E, Nino VZ, Rozet JM, Carelli V, Tsygankova PG, Klopstock T, Wittig I, Prokisch H. Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy. J Clin Invest. 2021;131:e138267. Dimitriadis K, Leonhardt M, Yu-Wai-Man P, Kirkman MA, Korsten A, De Coo IF, Francis Chinnery P, Klopstock T. Leber’s hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients. Orphanet J Rare Dis. 2014;9:158. Chalmers RM, Harding AE. A case-control study of Leber’s hereditary optic neuropathy. Brain. 1996;119:1481–1486. Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros PA, Sadun F, DeNegri AM, Andrade R, Moraes M, Angelo Passos, Kjaer P, Pereira J, Lucia Valentino M, Schein S, Belfort R. Extensive investigation of a large Brazilian pedigree of 11778/ haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2003;136:231–238. Kirkman MA, Yu-Wai-Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock Thomas, Francis Chinnery P. Gene–environment interactions in Leber hereditary optic neuropathy. Brain. 2009;132:2317–2326. Kerrison JB, Miller NR, Hsu F-C, Beaty TH, Maumenee IH, Smith KH, Savino PJ, Stone EM, Newman NJ. A case-control study of tobacco and alcohol consumption in leber hereditary optic neuropathy. Am J Ophthalmol. 2000;130:803–812. 320 12. Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, RossCisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, Sadun A, d’Amati G, Carelli V. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain. 2011;134:220–234. 13. Giordano C, Iommarini L, Giordano L, Maresca A, Pisano A, Valentino ML, Caporali L, Liguori R, Deceglie S, Roberti M, Fanelli F, Fracasso F, Ross-Cisneros FredN, D’Adamo P, Hudson G, Pyle A, Yu-Wai-Man P, Chinnery P, Zeviani M, Salomao SR, Berezovsky A, Belfort R Jr, Ventura D, Moraes M, Moraes Filho M, Barboni P, Sadun F, De Negri A, Sadun AA, Tancredi A, Mancini M, d’Amati G, Polosa P, Cantatore P, Carelli V. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy. Brain. 2014;137:335–353. 14. Giordano L, Deceglie S, d’Adamo P, Valentino ML, La Morgia C, Fracasso F, Roberti M, Cappellari M, Petrosillo G, Ciaravolo S, Parente D, Giordano C, Maresca A, Iommarini L, Dotto VDel, Ghelli AM, Salomao SR, Berezovsky A, Belfort R Jr, Sadun AA, Carelli V, Polosa PL, Cantatore P. Cigarette toxicity triggers Leber’s hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways. Cell Death Dis. 2015;6:e2021. 15. Yu-Wai-Man P, Hudson G, Klopstock T, Chinnery PF. Reply: parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion. Brain. 2016;139:e18. 16. Song B-J, Akbar M, Abdelmegeed MA, Byun K, Lee B, Yoon SK, Hardwick JP. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 2014;3:109–123. 17. Rehm J, Kilian C, Ferreira‐Borges C, Jernigan D, Monteiro M, Parry CDH, Sanchez ZilaM, Manthey J. Alcohol use in times of the COVID 19: implications for monitoring and policy. Drug Alcohol Rev. 2020;39:301–304. 18. Kim JU, Majid A, Judge R, Crook P, Nathwani R, Selvapatt N, James L, Manousou P, Thursz M, Dhar A, Lewis H, Vergis N, Lemoine M. Effect of COVID-19 lockdown on alcohol consumption in patients with pre-existing alcohol use disorder. Lancet Gastroenterol Hepatol. 2020;5:886–887. 19. Chodkiewicz J, Talarowska M, Miniszewska J, Nawrocka N, Bilinski P. Alcohol consumption reported during the COVID-19 pandemic: the initial stage. Int J Environ Res Public Health. 2020;17:4677. 20. NANOS Research. COVID-19 and Increased Alcohol Consumption: NANOS Poll Summary Report [Internet]. Canadian Centre on Substance Use and Addiction, 2020. Available at: https://www.ccsa.ca/covid-19-andincreased-alcohol-consumption-nanos-poll-summary-report. Zaslavsky and Margolin: J Neuro-Ophthalmol 2021; 41: 316-320 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.