The Impact of Leber Hereditary Optic Neuropathy on the Quality of Life of Patients and Their Relatives: A Qualitative Study

Background: Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by severe bilateral vision loss and chronic visual impairment. The objective of this study was to comprehensively explore the impact of LHON on the lives of patients and their relatives at the time of diagnosis and now. Methods: Qualitative study design with 8 focus group interviews conducted in France, Germany, the United Kingdom, and the United States, involving 17 individuals with m.11778G>A mutation and their relatives. Separate focus groups for patients and their relatives were facilitated by a moderator in French, German, or English. Qualitative analysis of interviews using a pre-defined analytical framework. Results: Participants reported feeling devastated by the diagnosis of LHON after a lengthy and worrisome diagnostic journey. Patients were frustrated by the loss of autonomy, which also affected their relatives. Participants described challenges across several domains: physical capabilities, emotional well-being, interpersonal relationships, work and studies, finances, and recreational activities. Access to disability allowances, vision aids, and funded or subsided idebenone varied by country, resulting in unequal financial impact. Patients are hopeful for therapy that would restore autonomy and improve their ability to enjoy a fulfilling life, while alleviating the demands placed on their relatives. Conclusions: The impact of LHON extends beyond vision-related activity limitations. Addressing the psychosocial impact of LHON and helping patients and their relatives adapt and cope with vision loss are vital. As part of this, an accurate and timely diagnosis is important to enable early intervention. Further investigation of specific unmet needs is required.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD The Impact of Leber Hereditary Optic Neuropathy on the Quality of Life of Patients and Their Relatives: A Qualitative Study Benson S. Chen, MD, Erik Holzinger, MBA, Magali Taiel, MD, Patrick Yu-Wai-Man, MD, PhD Background: Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by severe bilateral vision loss and chronic visual impairment. The objective of this study was to comprehensively explore the impact of LHON on the lives of patients and their relatives at the time of diagnosis and now. Methods: Qualitative study design with 8 focus group interviews conducted in France, Germany, the United Kingdom, and the United States, involving 17 individuals with m.11778G.A mutation and their relatives. Separate focus groups for patients and their relatives were facilitated by a moderator in French, German, or English. Qualitative analysis of interviews using a pre-defined analytical framework. Results: Participants reported feeling devastated by the diagnosis of LHON after a lengthy and worrisome diagnostic journey. Patients were frustrated by the loss of autonomy, which also affected their relatives. Participants described challenges across several domains: physical capabilities, emotional well-being, interpersonal relationships, work and studies, finances, and recreational activities. Access to disability allowances, vision aids, and funded or subsided idebenone varied by country, resulting in unequal financial impact. Patients are hopeful for therapy that would restore John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit (BSC, PY-W-M), Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit (BSC and PY-W-M), Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; GroupH (EH), London, United Kingdom; GenSight Biologics (MT), Paris, France; Moorfields Eye Hospital NHS Foundation Trust (PY-W-M), London, United Kingdom; and Institute of Ophthalmology (PY-W-M), University College London, London, United Kingdom. P. Yu-Wai-Man is a consultant for GenSight Biologics. M. Taiel is a GenSight Biologics employee. E. Holzinger is director of groupH. The remaining authors have 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 Benson S. Chen, MD, Neurology Unit Level 5, “A” Block, Box 165, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom; E-mail: [e-mail] 316 autonomy and improve their ability to enjoy a fulfilling life, while alleviating the demands placed on their relatives. Conclusions: The impact of LHON extends beyond visionrelated activity limitations. Addressing the psychosocial impact of LHON and helping patients and their relatives adapt and cope with vision loss are vital. As part of this, an accurate and timely diagnosis is important to enable early intervention. Further investigation of specific unmet needs is required. Journal of Neuro-Ophthalmology 2022;42:316–322 doi: 10.1097/WNO.0000000000001564 © 2022 by North American Neuro-Ophthalmology Society L eber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial disease characterized by severe bilateral vision loss during young adult life (1,2). The m.11778G.A mutation, accounting for 70% of LHON cases, is associated with the poorest visual prognosis and the lowest probability of spontaneous visual recovery (3,4). Most patients meet the legal criteria for blindness within 1 year, and the majority remain chronically visually impaired without any spontaneous improvement (1). It is well established that traditional metrics of visual function do not fully capture the experience of individuals with visual disability (5). Increasing awareness of the importance of the patient voice in ophthalmology has resulted in the proliferation of patient-reported outcome measures (PROMs), questionnaires that capture the patient experience. Some PROMs are generic and can be used to compare the health status or views of individuals across different disease groups. Other PROMs are condition specific, for example, the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) is a PROM designed to measure the quality of life (QoL) of individuals with ophthalmic disorders (6). In order for PROMs to be effective in clinical practice and research, they have to capture the disease characteristics that matter to the patient (5). Chen et al: J Neuro-Ophthalmol 2022; 42: 316-322 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Participant eligibility criteria (1) Confirmed diagnosis of LHON with the 11778G.A mutation; (2) chronic disease, ideally 12–18 mo or more since second eye involvement; (3) psychologically sound, able, and willing to participate in constructive discussion within a group setting. LHON, Leber hereditary optic neuropathy. Previous studies using PROMs to determine the impact of LHON on the QoL of affected individuals have focused on vision-related activity limitation and the emotional impact of vision loss (7–10). Little is understood about the impact of LHON on interpersonal relationships, work and education, and finances of affected individuals. The overall objective of the study was to explore the impact of LHON on patients’ and their relatives’ lives at the time of diagnosis and now. METHODS This was a qualitative study involving individuals harboring the m.11778G.A LHON mutation and their relatives from 4 countries (France, Germany, the United Kingdom, and the United States). Focus group interviews were conducted as part of a market research study sponsored by GenSight Biologics, and independently designed and conducted by groupH, a health care market research and analytics firm. The design and conduct of the study complied with the European Pharmaceutical Market Research Association and British Healthcare Business Intelligence Association guidelines. The 4 countries were selected because all have established networks of individuals with LHON and were where previous LHON studies have been conducted. Potential participants were recruited from patient support networks and screened for eligibility (Table 1). Eight face-to-face focus groups lasting 3 hours on average were conducted in Paris, Munich, London, and New York. Purposive sampling was used to select eligible participants for focus groups using specific sampling criteria (Table 2) to ensure a diverTABLE 2. Purposive sampling criteria for focus group interviews Inclusion of $1 female participant with LHON; $1 participant diagnosed with LHON before the age of 20 yr; $1 participant diagnosed in their 20s; $1 participant diagnosed over the age of 30 yr; participants with and without a known family history of LHON; and participants from rural and urban areas LHON, Leber hereditary optic neuropathy. Chen et al: J Neuro-Ophthalmol 2022; 42: 316-322 sity of views. Neuro-ophthalmologists in the 4 countries helped to identify additional patients who fulfilled underrepresented sampling criteria. Written informed consent was obtained from all participants. Three separate moderators facilitated each focus group in the local language. The moderators, who did not have any prior knowledge of LHON, used a semistructured interview guide. Moderators and participants were masked to the study sponsor. All study documentation was written to avoid perception that participation would result in access to clinical trials or treatments. All discussions were audio and video recorded for further analysis without input from the sponsor. Secondary analysis of the focus group interviews was independently conducted by 2 authors (B.S.C. and P.Y.W.-M.), using a prespecified analytical framework that included deductive codes organized into categories (See Supplemental Digital Content, Data File, http://links. lww.com/WNO/A572) (11). This was deemed by the Research Governance Office and the Psychology Research Ethics Committee (University of Cambridge) to involve secondary use of collected data, and ethics approval was not required. RESULTS Seventeen patients with LHON were recruited, with a median age of 34 years (interquartile range, 24–56 years) (Table 3). Four patients were female. All patients had bilateral eye involvement and a median duration of 43 months (interquartile range, 19–80 months) since second eye involvement. Three patients were students in tertiary education, and 9 were in full- or part-time employment. Seventeen participants were included in the relatives’ group, which consisted of 10 mothers (asymptomatic carriers), one father, 3 wives, and 3 husbands of the LHON participants recruited into the study. Key findings for each section of the discussion, including a selection of illustrative quotes, are summarized in Table 4. Despite residing in different countries, participants with LHON and their relatives described similar experiences in the 4 areas of focus in this study: (1) experience leading to the point of diagnosis; (2) impact of their condition on various aspects of life; (3) perceptions about treatment; and (4) expectations toward future therapies. Experience Leading to the Point of Diagnosis Patients typically first saw an ophthalmologist in the United States, Germany, and France or an optometrist in the United Kingdom with subsequent referral to a hospitalbased general ophthalmologist. Getting an appointment with an ophthalmologist was difficult for patients in France due to long waiting times, and it was relatively faster for participants in the United States. However, patients in the United States were seen by at least 3 clinicians including 317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution several general ophthalmologists before referral to a neuroophthalmologist. The diagnosis of LHON was ultimately made by a neuro-ophthalmologist and confirmed by genetic testing. The average time from onset of symptoms to final diagnosis for patients who did not have a known family history of LHON varied by country: 3–4 months in the United States, 5–7 months in Germany, 3–12 months in France, and 1–4 months in the United Kingdom and was longer for female patients. Participants used strong and emotive words to describe how they felt when they were diagnosed, with many feeling “devastated” after a long diagnostic journey characterized by uncertainty. Impact of Leber Hereditary Optic Neuropathy on Various Aspects of Life Vision loss resulted in the loss of independence. Driving was frequently mentioned by patients. While a few patients tried to retain their independence using public transport or taxis to travel, others were very reliant on family to travel with them. Patients also relied on the support of others for everyday tasks, such as choosing clothes, going shopping, and making meals. A few younger male patients, in the United Kingdom and the United States, remained stoic and stated that they just got on with life and tried not to let their visual impairment get in the way. There was agreement among patients that classifying themselves as “blind” or “(visually) disabled” had been difficult to come to terms with. The psychological impact of LHON was described by patients in different phases. At the time of diagnosis, all patients described symptoms of depression or anxiety, including disbelief. During the postdiagnosis period, all talked about constantly feeling frustrated and impatient at not being able to do the things they previously used to. TABLE 3. Characteristics of 17 individuals with LHON and m.11778G.A mutation Characteristic Sex Male Female Current age, yr Age at diagnosis, yr ,20 yr 20–30 yr .30 yr Family history of LHON Country of residence France Germany UK USA n (%) or Median (IQR) 13 4 34 28 5 5 7 10 (76.5%) (23.5%) (24–56) (19–40) (29.4%) (29.4%) (41.2%) (58.8%) 4 4 5 4 (23.5%) (23.5%) (29.4%) (23.5%) IQR, interquartile range; LHON, Leber hereditary optic neuropathy; n, number of patients. 318 Some UK patients described feeling helpless and “useless” as individuals. Patients felt mentally and physically fatigued by having to keep a constant vigilance to what was happening around them. Relatives also described feelings of stress and concern for the LHON patient. Mothers of LHON patients felt guilty that they had transmitted the mutation to their child, and they expressed concern that their other children could develop symptoms. Vision loss impacted on interpersonal relationships. Patients developed an “unwanted” but necessary relationship with their partner or parents, and some felt that they were holding back their relatives and taking away their independence. Patients from the United Kingdom in particular felt guilty for their families having to do much more for them. Relationships with friends were also strongly impacted. Some patients had lost several friends because they were often viewed as a burden to them. Interactions with strangers were also described as difficult because patients required to be in close proximity when asking for information or assistance. Patients also perceived that people, in general, felt uncomfortable talking to someone with visual impairment. Some level of work or study was maintained by most patients since diagnosis. Younger patients who were studying had to reconsider their studies in the light of vision loss. Most patients who were working at the time of diagnosis talked about being “lucky” to have kept their job with the same employer or found an employer who accepted their disability. A few patients in the United Kingdom and Germany were unsure how long they would be able to keep their job. The impact on relatives’ work appeared to be minimal in the United States, Germany, and France. However, a minority of relatives in those countries, and the relatives in the United Kingdom, had to reduce their working hours or put their careers on hold to support their affected family member. The impact of LHON on personal income and budget varied between participants, depending on circumstances relating to their employment and the availability of subsidized pharmacological treatments and visual aids. Some participants kept the same level of income, yet others experienced a reduction in income as a consequence of reduced job activity. For French participants, a reduction in income was offset by a governmental disability monthly allowance. Participants from the United Kingdom reported access to an equivalent allowance, but it was a “pittance.” The financial impact of LHON also included the purchase of medications and visual aids, particularly for participants in countries where idebenone or visual aids were not fully subsidized or reimbursed. Perceptions About Treatment Treatment with idebenone was discussed with most patients after their diagnosis. Eight participants (2 American, 2 German, 1 French, and 3 in United Kingdom) were still Chen et al: J Neuro-Ophthalmol 2022; 42: 316-322 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 4. Summary of key findings from focus group interviews Section Category Life before Experience disease leading to the point of diagnosis Findings Participants were leading active and full lives, with plans for the future Most patients had never heard of LHON and were not aware of their family history Most relatives in Europe were unaware of the risk of immediate family member suffering from vision loss; US relatives were more aware Symptoms before diagnosis Initially blurred vision or vision loss, but not sudden. Often assumed to be nothing serious The persistent vision loss in the first eye became concerning for some patients, even more so when the second eye became affected The cause of vision loss was unknown to most participants, even some patients with a known family history Diagnosis Long diagnostic journey, beginning with an assessment by an ophthalmologist or optometrist depending on country Diagnosis ultimately made by a neuro-ophthalmologist, often after seeing several physicians Participants felt devasted by diagnosis Visual Impact of perception LHON on various aspects of life Blurred vision due to the loss of central vision and the need to use the remaining peripheral vision make identification of people, objects and situations challenging Illustrative Quotations “Before, everything was fine, I was spending all my time on videogames, even during the evenings . My plan for the future was having a job related to videogames such as a designer, a producer or even a professional player.” “Just before it started, me and my husband took over the company of my brother—we had our own company, we had 2 children, and many plans for the future.” “We had no idea about this disease. Then when I got diagnosed, we worked out where it had come from by going through the family tree with the doctors.” “I had noted that my vision was decreasing. I thought it was due to my job as I was doing welding. I did not really pay attention to it, then my vision was less and less good while I was driving, red traffic lights, stuff like this, I was more and more questioning myself, it was weird this sudden change.” “At first, we thought he was joking, or we didn’t take it seriously quite honestly, he said he thought there was something wrong and we said ‘well stop drinking so much and start living a slightly more decent lifestyle and perhaps you’ll be able to see better.” “Obviously, my brother had it since he was much younger but I never considered I could get it—I was a female and much older. There’s a curve indicating the most at risk patients and I’m not even on the curve!” “I called the ophthalmologists to get an appointment, but I was given one only 3 mo later. When I noted that things were not improving and even worsening, I went to an optician’s to ask if he could provide glasses to read things at work, that I could use before I see the ophthalmologist. He checked my vision and he told me to go to the emergency [department].” “So we were devastated, totally devastated, and I just felt like our whole world had collapsed there and then, we just didn’t believe it was going to be that, it’s a rare thing anyway, nobody in the family, we’d looked up about it and just decided that it couldn’t possibly be that. Obviously it was.” “In the center I only see a white area.” “Like it s always very bad weather—grey and few colors.” “Living in a pixelated world.” Using different analogies, patients were able to paint a very vivid picture of life with LHON “Like having your 2 fists in front of your face and you are just able to see around.” “Like having to use your imagination all the time, in terms of what things look like.” Physical impact Except for fatigue experienced by patients and their relatives, patients did not report any physical symptoms While relatives may accept the fact that their family member is “disabled,”, this is not a term patients feel comfortable using to describe themselves “I guess we are more tired because we constantly have to focus our attention on things.” “It s a constant fight, you re at 300% all the time. Very exhausting. I often feel tired.” “Disabled .. that is a term which I found very difficult to come to terms with.” “We used to all go skiing together and he would rather die than put on the blind thing and ski so he doesn’t want to ski which means we don’t do ski trips with the family.” Relatives adapted family activities to ensure the patient did not feel left out Psychological impact The psychological impact of their diagnosis was described by patients as different phases The different phases extended from feelings of concern prior to the diagnosis; anxiety, depression, denial, and panic at the time of diagnosis; and feelings of dependency, frustration, uselessness in the period since diagnosis Concern, anxiety, depression, and frustration are also feelings commonly experienced by relatives Impact on The relationship between patients and their relatives relationships became closer but was sometimes difficult for patients to bear LHON impacted on every type of family relationship, including parents, partners, siblings, and children Relationships with friends, acquaintances, and even strangers were affected “Before, I was concerned because I had the feeling I was becoming blind. After the diagnosis, I used to stay at home, I did not want to go out. I did not want to see others.” “I already had thoughts about suicide—but I block them. It s an up and down all the time. If you let yourself go while down, you re lost.” “My son was panicking at the beginning. He could not bear staying in the dark. He was calling his girlfriend several times a night.” “It s very hard for everyone in the family—it s rather surviving than living. We feel so sorry about our son. He s not going to school, is at home all the time, has no friends. And this at the age of 13, it s really terrible” “His mother turned away from him. She actively avoids contacts—she does not want to have to deal with this condition. This is really heavy” “I always said I prefer I have LHON than my daughters. What a misery for a mother to transmit this shit to her children!” “It clearly changed the relationship to my husband. On one hand, it’s a positive change, much more intense than before. But on the other hand, it sometimes feels like I have a third child now. I need to take care of him all the time, and that s terrible for him.” “In terms of the social aspect, I have found that generally people are uncomfortable talking to someone that has a vision impairment. They don’t want to say the wrong thing so they avoid any interaction which obviously makes it much harder for me.” “His friends are seeing him less often as they have to drive him. I clearly now have to do the taxi for him given he cannot drive any longer.” Chen et al: J Neuro-Ophthalmol 2022; 42: 316-322 319 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Section Category Findings Impact on work/ Some level of work or study was maintained by most studies patients, but the impact varied from patient to patient The impact of LHON was not as significant for most relatives, while others had to adjust their professional commitments or even stop working to take care of the patient Illustrative Quotations “When I was going through all those interviews I was going for higher paying jobs and now I have had to settle for less. There is certainly a gap between what I could have made and what I am earning now.” “Although my company have been really supportive, and I’ve kept on the same level and everything like that, I do muddle through a lot . I’m only there because of the support they’ve given me. There’s a lot of functions in my job that I simply can’t do, and I am maintaining the current role just because of the familiarity and I don’t want that to change at the moment” “I was in line for the Practice Manager role and they held it for me when my son was first diagnosed. But, as time has gone on and I’ve had to take more and more time off work, it’s not fair for them to keep waiting for me—so I told them that I wouldn’t take the job, even though it was more money and more responsibility and something which I really wanted.” Impact on recreation Most patients had to give up activities which they had previously enjoyed during their spare time “I have to tell my wife what is happening on TV when we “watch” a film on TV.” “I stopped going to the cinema when my son was no longer able to go there—I cannot imagine myself being there while he cannot do it.” Financial impact LHON can directly or indirectly reduce personal income “I get idebenone from America but, unfortunately, you have to pay VAT and customs, and related to work and impact on the household budget when you get hit with everything . it’s quite a lot of money.” it comes to purchasing medications or visual aids “I was an actor, but I can’t really do much now. I’ve done a minimal amount of work that involves me doing things where I can either take her along, or I can do for the day and Most relatives did not experience a direct impact commute. But I certainly wouldn’t do anything like theatre which would mean I’d have to on their income go round the country and live away from home. I’m looking at the end game now of what we do in 5 yr time. We live hand to mouth really.” Perceptions about treatment Quality of life scales The NEI-VFQ-25 was viewed as the most relevant and comprehensive scale, but the VF-14 was regarded as a good alternative, especially in the United States, United Kingdom, and Germany “I think both have pros and cons—VF-14 is a bit simple, but easily filled in. VFQ-25 is much more detailed but overall too long. You get bored and tired when filling in all these questions. After a while, just stop trying to rate each individual aspect diligently —you just chose something in the middle to get it done quickly. I don t think it s a good tool for a clinical trial where one would have to complete this again and again.” Current therapies Most patients were offered idebenone by their LHON specialist after they were diagnosed. Views about the efficacy of idebenone were mixed, a few noticed some efficacy while most did not observe any specific benefit “My doctor in America he just said be patient, because nothing is happening, and then when I went back last time he said that . he was using words like remarkable, and he thinks it’s because of that, it’s got a little bit better. I don’t know yet.” Most patients admitted they have tried alternative and complementary treatments Most patients had support via low-vision specialists and some purchased adapted visual aids “My husband is on idebenone—Actually, there is no worsening, neither any improvement. I would say this a stabilisation.” “I am, taking Idebenone for half year now, I do not feel it helped my vision so far. But I feel to sleep better, no idea whether that s an effect of the drug. Also, I m worried to stop it, because I fear that my vision might then deteriorate.” “I tried everything—I saw an acupuncturist, an hypnotist, a sophrologist, yoga .. It did not really had an impact on the disease, but those experiences allow to think about yourself.” “I am going to have another low vision evaluation in the next 3 mo (hopefully) to see which CCTV is the best one for me (I want to purchase one) and see if there are any other optical instruments that might be of use to me.” Expectations toward future therapies Patients in every country just wished to be able to do the simple things most of us take for granted “I would like to be able to identify a shop in the street, to know if it is a butcher or a baker.” The ideal treatment should restore autonomy and improve patients’ ability to enjoy a fulfilling social life and recreation “I would like to see her/his eyes, I would like to recognise who this person is.” “Even a small improvement in your ability to see people and see things around you, to make a practical difference to everyday life and bring reading to things you take for granted. Even something that offered an improvement could make a huge difference if it allowed you to go from a level of being functionally blind to getting back everyday life skills and socialising and being able to recognise and see people around you.” “To be able to drive would help so much. To be able to recognise people right away would be nice so that I didn’t have people coming up to me saying you walked right past me the other day without saying anything. People see a blind person and feel pity for them right away so it would be great if that social perception could be changed.” LHON, Leber hereditary optic neuropathy; NEI-VFQ-25, National Eye Institute Visual Function Questionnaire-25; VF-14, visual function index. 320 Chen et al: J Neuro-Ophthalmol 2022; 42: 316-322 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution taking idebenone. Half of these participants self-purchased idebenone because it was not funded or they were not participating in an expanded access program. Patients who were no longer taking idebenone discontinued the drug mainly because of the lack of efficacy, rather than the cost. Most patients admitted trying alternative approaches recommended by relatives and friends or what they had read online, including ailments for good vision. Some had purchased supplements, including co-enzyme Q10, flax oil, and vitamin C. A few participants had sought input from acupuncturists, hypnotists, and “healers” with little benefit. Most patients were referred to a low vision service, but only some found it beneficial for learning to adjust to their visual impairment. Some patients had purchased aids to facilitate their daily activities, including handheld magnifiers and ZoomText (Freedom Scientific, Clearwater, FL) screen magnifier and screen reader. Most patients used accessibility options on their smartphone or television, if they owned one, such as VoiceOver for Apple devices. Expectations Toward Future Therapies Patients in every country wished to be able to do simple things most of us take for granted. Participants agreed that besides a cure, the ideal therapy should restore autonomy and improve their ability to enjoy a fulfilling social life and recreation. Common requests included driving again, moving alone in the street, going shopping, using a mobile phone properly, or any daily task involving going out and identifying places or things. Patients discussed being able to recognize people, particularly friends and family, without feeling like a burden. Most patients admitted that going from “unable to do” to “can do with difficulty” would be a big improvement. A few participants, especially those in the United Kingdom, also imagined more preventative treatments to prevent disease progression, prevent asymptomatic carriers from becoming symptomatic, or prevent transmission of the mutation. CONCLUSIONS This study is the first to explore the impact of LHON on patients and their relatives in 4 different countries. Loss of autonomy and inability to independently perform tasks or fulfil previous roles was frequently reported by patients. The psychological impact of LHON was felt by all participants in multiple areas of life, including emotional well-being, work and education, and social life. Despite residing in countries with different health care and social welfare systems, patients and their relatives all described financial challenges due to reduction in income and/or costs associated with treatments. Previous studies on the experience of individuals with LHON have focused on vision-related activity limitation and emotional response to vision loss (7–10). Two studies using the Visual Function Index (VF-14) questionnaire found that patients with LHON had the lowest VF-14 scores compared with other previously studied ophthalmic disorders (7,8). In a Chen et al: J Neuro-Ophthalmol 2022; 42: 316-322 Chinese LHON cohort, VF-14 scores improved over 3 years after second eye involvement, but this did not correlate with visual acuity of the better seeing eye (8). The social and psychological impact of vision loss are not assessed by the VF-14 (12). Although both are assessed by the NEI-VFQ-25 (6), the psychometric properties of the VF-14 and NEI-VFQ-25 when used by individuals with LHON, have not been reported previously. Accurate measurement of QoL can only be achieved if the selected PROM is psychometrically sound. Further research is required to determine if currently available PROMs have appropriate content coverage for the issues that participants in our study have described. Modification of current PROMs or development of a LHON-specific PROM may be required. The experiences of participants in our study mirror those with other rare diseases (13,14). Although the physical and somatic constraints and limitations are inherently related to specific diseases, the impact of disease on emotional and social adjustment, and overall well-being and health is common in all diseases. However, having a rare genetic condition does not necessarily entail poor QoL (13). Challenges within each disease should be managed and tailored to everyday life, to minimize their psychological impact (14). Factors, such as psychological well-being, coping, and illness perceptions, may serve as potent targets for intervention. Early intervention to train LHON patients in visual aid technologies, to prevent declining academic achievement or loss of work, has been suggested as way of reducing the severity of psychological suffering (9). Efforts must be made to address the financial barriers that prevent patients from accessing such interventions. Relatives of affected patients shouldered the psychological burden of LHON in our study. Mothers of LHON patients expressed their sense of guilt at having transmitted the condition, despite there being no question of moral culpability. This was evident in discussions regarding expectations of future therapies, where mitochondrial donation and mitochondrial replacement therapy were mentioned by mothers, as a method of preventing transmission of the mutation. Parental guilt and blame, particularly for mothers, has been widely reported for a number of inherited conditions (15,16). Genetic counselling, addressing risks of transmission and reproductive options, is a key support service that should be provided to LHON families (9). A key strength of this study was the qualitative methodology. We gained an in-depth understanding of the experiences of participants through focus groups without relying on preexisting PROMs or preconceived ideas of the impact of LHON on QoL. Focus groups are less threatening to many research participants, and this environment is helpful to discuss perceptions, opinions, and thoughts (17). Another strength of the study was the double masking of moderators and participants to the study sponsor to minimize bias. Although purposive sampling criteria ensured a diverse representation of participants, only patients with the m.11778G.A mutation were included. Race and socioeconomic status were not included as sampling criteria, potentially affecting the generalizability of the results. Further studies are required to determine 321 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution if the experiences of participants in our study differ from other LHON patients. The impact of LHON extends beyond vision-related activity limitations. Addressing the psychosocial impact of LHON by helping patients and their relatives adapt and cope with vision loss are vital. An accurate and timely diagnosis, as part of this, is important to enable early intervention, including provision of visual aids, genetic counselling, psychological support, and occupational therapy. Financial barriers that limit access to treatments must be addressed. Patients are hopeful for a treatment that restores some of the autonomy and social life they enjoyed before and that alleviates the burden they feel they are placing on family and friends. In the meantime, further investigation of specific unmet needs is important. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: B. S. Chen, E. Holzinger, and P. Yu-Wai-Man; b. Acquisition of data: E. Holzinger and M. Taiel; c. Analysis and interpretation of data: B. S. Chen and P. Yu-Wai-Man. Category 2: a. Drafting the manuscript: B. S. Chen and P. Yu-WaiMan; b. Revising it for intellectual content: B. S. Chen, E. Holzinger, M. Taiel, and P. Yu-Wai-Man. Category 3: a. Final approval of the completed manuscript: B. S. Chen, E. Holzinger, M. Taiel, and P. YuWai-Man. ACKNOWLEDGMENTS The authors thank the study participants for their contributions and Mr. Russell Wheeler for reviewing the manuscript. B. S. Chen is recipient of the CambridgeRutherford Memorial Scholarship awarded by the Royal Society Te Ap arangi—Rutherford Foundation and the Cambridge Commonwealth, European and International Trust, and also the Aotearoa New Zealand Fellows Research Entry Scholarship awarded by the Royal Australasian College of Physicians (RACP). P. Yu-Wai-Man is supported by an Advanced Fellowship Award (NIHR301696) from the United Kingdom National Institutes of Health Research (NIHR) and a Clinician Scientist Fellowship Award (G1002570) from the United Kingdom Medical Research Council (MRC). P. Yu-Wai-Man also receives funding from Fight for Sight (United Kingdom), the Isaac Newton Trust (United Kingdom), Moorfields Eye Charity (GR001376), the Addenbrooke’s Charitable Trust, the National Eye Research Centre (United Kingdom), the International Foundation for Optic Nerve Disease (IFOND), the NIHR as part of the Rare Diseases Translational Research Collaboration, the NIHR Cambridge Biomedical Research Centre (BRC1215-20014), and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. 322 REFERENCES 1. 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