Geographic atrophy – Signs, symptoms, and quality of life

Geographic atrophy (GA) is a prevalent cause of vision loss among elderly and is associated with a significant loss of function. We reviewed the current literature to assess the effect of GA on patients' daily lives and well‐being. We record and organize the signs, symptoms, and impacts that are important in life with GA. Further, we examined the impact of GA on vision‐related quality of life. The main complaint among patients was difficulties regarding daily tasks, especially reading and other near activities. However, a large proportion of patients also reported fear, frustration, and anxiety as salient symptoms with large impact. Many patients do not have adequate information about their condition as well as the prognosis. The most commonly used measure of patient‐reported outcome measure (PROM) is the National Eye Institute Visual Function Questionnaire (VFQ), that reflects the severity of impact on 12 subscales, from where near activities, general vision, mental health, and role difficulties had the lowest scores. Longitudinal studies of GA and the impact of low‐vision rehabilitation efforts on health‐related quality of life are sparse but suggest a significant improvement on several items. PROM is included in clinical trials, and so far, no drug has shown to improve the functional outcome in terms of PROM.


| I N T RODUC T ION
Late-stage dry AMD is termed geographic atrophy (GA) and is characterized by expanding atrophic lesions in the outer retina, causing irreversible damage to visual function.In the early stages of AMD, patients will describe no or subtle changes to visual function.The earliest sign of deteriorating visual function affects tasks performed at low luminance levels.Persons might report difficulties with seeing in dim or low-contrast surroundings -they will need more light when reading, typing, or sewing (Cocce et al., 2018).The same is reported by patients with GA, as they often experience visual deterioration involving low-light vision and reduced contrast sensitivity.Further, patients with GA suffer from dense, irreversible scotomas in the central visual field, eventually causing more severe problems with reading or recognizing details and faces (Fleckenstein et al., 2018).Best corrected visual acuity can be misleading as GA often presents with parafoveal lesions that deeply affect night vision, contrast sensitivity, and reading speed, while the person might still have a good visual acuity when measured on a chart due to foveal sparing (Sadda et al., 2016).
At the later stages of GA, when the atrophic lesion involves the foveal region, the patient will experience further deterioration in visual function, with limits in key aspects of daily life and self-maintenance (Holz et al., 2014).GA is associated with loss of functions and daily activities as well as a massive negative influence on quality of life (Morga et al., 2023).Understanding the experience of patients with GA is key in fulfilling the role of a health professional, both in counselling, but also in evaluating efficacy of new treatment options and rehabilitation initiatives.
A lot of resources are spent in both the public and private healthcare sectors, by charities, support networks, and organizations to diminish the detrimental effect of GA on daily life, self-maintenance, and quality of life.However, little is known about the effect of these initiatives.The U.S. Food and Drug Administration and the European Medicines Agency recommend including patient experience in clinical trials (DeMuro et al., 2013;U.S. Food and Drug Administration, 2020).
The objective is to review the current knowledge of the effect of GA on patients' daily life and well-being.We wish to better understand challenges in daily life and adapted coping strategies, to qualify counselling and evaluate relevant changes in healthcare initiatives provided.

| SY M P TOM S A N D SIGNS
Elderly people with loss of vision experience difficulties with daily activities (Moore & Miller, 2003;Stanford et al., 2009).However, a lot of investigations performed include all types of causes of visual impairment and are not exclusively concerning the effect of GA.The specific impact of GA on daily life is therefore not well described.Most studies report the impact of advanced AMD and do not differentiate between GA from neovascular AMD (Bennion et al., 2012;Taylor et al., 2016).A few studies have applied a holistic approach to capture and organize the signs, symptoms, and impacts that are important in GA.
Carlton et al. ( 2019) did interviews with nine British elderly persons with GA with different severity of GA.Firstly, they report that patients had little understanding of the mechanisms of GA.Some assumed it was a part of natural ageing, others thought it was due to excess reading, or a consequence of their cataract surgery.However, they were all aware that the prognosis was poor, but that they were unlikely to go completely blind.The impact of GA on activities fell into two categories: management of activities of daily living and reading.Even though magnifying aid is helpful, patients described that their reading speed was so slow that they gave up on reading books and newspapers.Also, reading signs, bus tables, prices, and sell-by dates is a real struggle.Some persons seek help among others, but many do not like to be dependent on others.
Many patients did not have adequate information about their condition as well as the prognosis.Patients felt that there was little information given and that the information was given with complex terminology, only adding to confusion.Most relied on information from friends and family.This problem with lack of information is also found by others in qualitative studies of patients with AMD (Boxell et al., 2017;Burton et al., 2013).Patients described the paradox that they were referred rapidly to the eye clinic by their general practitioner or their optician, only to be informed that nothing could be done.This referral raised false hope and resulted in frustration.Further, patients experience that they are told to seek help at their ophthalmologist if they experience deteriorating vision, albeit no help is provided when they do.This description reflects very well the need for further information about the disease's natural history and the risk of worsening in development of neovascular AMD.Burton et al. (2013) and Boxell et al. (2017) found that patients experienced a poor provision of low-vision support in the UK, which was not the case in the more recent study by Carlton et al. (2019), where all participants were aware of where to find practical support, and felt they had access to glasses and aids supplied by opticians or low-vision clinics.Hassell et al. (2006) also found that the majority of their study population had not used low-vision rehabilitation, despite the need and availability.All of the participants interviewed by Carlton et al. (2019) mentioned the need for a support group with fellow patients, to discuss their condition and daily struggles, and with a health professional to provide information.Anger, frustration, and fear have previously been linked to AMD and vision loss (Cimarolli et al., 2012;Owsley et al., 2006).Importantly, the findings were reflected equally in patients with better and patients with worse visual acuity.The qualitative interviews highlight the need to ensure that information is provided so that patients gain knowledge about organizations, charities, and support networks that they can benefit from, which might reduce the psychosocial effects of GA (Boxell et al., 2017).Morga et al. (2023) performed concept elicitation interviews with patients with GA to determine salient symptoms and impacts of GA (Figure 1).A symptom or impact was considered salient if it was mentioned by 50% of the 19 patients, and the average rating of how disturbing the symptom was more than 5 on a scale from 0 to 10.The salient symptoms with the largest impact were found to be directly associated with sight -poor light adaptation, blurred vision, sensitivity to light, defective F I G U R E 1 Interviews with patients have allowed studies to capture and organize the signs and symptoms that are important in living with geographic atrophy (GA).Daily activities are described as becoming more difficult after development of GA, and many find that they are increasingly dependent on family, friends, and professionals.The lack of abilities and dependency is reflected in frustration and fear of worsening.Further, patients are in several studies found to have little knowledge of the disease's cause and natural history, likely increasing the psychological impact.colour vision, progressive visual loss, restricted visual field, poor contrast vision, difficulties in reading and driving.But other salient symptoms with large impact were more general such as worrying about disease and future, frustration, limited activities, stress, anxiety, and dependency on others.
The individual's experience of disease and loss of abilities is believed to be deeply affected by the social and cultural context.Therefore, it is important that the lived experience of GA could vary greatly across ethnicities and cultures (Reeves et al., 2008).To accommodate this fact, Sivaprasad et al. (2019) performed interviews of 16 patients with GA across three countries -United States, United Kingdom, and Germany -regarding their experiences and challenges associated with their disease.
For all countries, the most dominant negative impact in daily activities was reading, driving, watching television, recognizing faces, and household activities.The most prevalent emotional impact was fear/worry about the future, and frustration/irritability.Further, Sivaprasad et al. (2019) report that 10 of 16 patients report a significant negative impact on finance, meaning expenses for visual aid, vitamins, etc.
Taylor et al. ( 2020) identified various themes similar to Morga et al. (2023) when interviewing patients from the UK with dry AMD in terms of functional and psychological impacts of diagnosis, visual loss, and coping strategies.Interestingly, only eight of the 27 participants had GA, and the majority of patients had intermediate AMD with a good visual acuity.This suggests that the psychological impact of disease might to some extent be caused by the diagnosis awareness more than the loss of visual function.
Only a few studies explored the lived experience of people suffering from GA, and even less is known about the impact of disease in developing countries.Madheswaran et al. (2021) performed interviews with 10 participants in India with bilateral GA and BCVA ≤6/60 in the better-seeing eye, corresponding to legal blindness.Their findings were similar to studies of industrialized countries, as the challenges of patients fell into four categories: Challenges in activities in daily living (reading, driving); lifestyle and socialization (cooking, recognizing faces); psychological implications (fear of worsening, depression); Strategies to overcome challenges (listening instead of seeing TV and books, moving closer, more light, decreased self-independence).The use of low-vision devices was not common, and participants reported that these were not supportive enough to meet their challenges.
Charles Bonnet syndrome (CBS) is a condition characterized by development of complex visual hallucinations in patients with significant loss of vision, no cognitive impairment, and no psychiatric disease.The hallucinations are typically clear, well-defined, organized images (Jan & Del Castillo, 2012).CBS is thought to be due to the deafferentation of the cerebral cortex's visual association areas.Patients have minimal or no control of the hallucinations, and they are often unrecognized or misdiagnosed as early dementia or psychosis (El Haj et al., 2017).We performed a meta-analysis of the prevalence and found an overall prevalence of CBS of 15.8% in persons with AMD.However, among visitors to visual rehabilitation centres the prevalence of CBS was 31.6%.Hence, we find that CBS is rather common in patients with late-stage AMD (Niazi et al., 2020).
Little is known about the condition in patients with GA, but we have found it to be prevalent in late neovascular AMD among Danish patients (Singh & Sørensen, 2012).In the cohort, we found that CBS was most prevalent in patients with atrophic lesions in their eyes with neovascular AMD.Therefore, it is reasonable to assume that it occurs to persons with GA as well.CBS is an important symptom to uncover, as only 15% of a cohort with CBS had told their ocular health professional about these symptoms, and 50% of people with CBS described the symptoms as causing them severe or moderate stress (Vukicevic & Fitzmaurice, 2008).

| FRAILTY IN GEOGRAPHIC ATROPHY AND VISUAL IMPAIRMENT
The impact of GA on visual function and daily functions is described above.However, the impact of visual impairment goes beyond day-to-day activities.Older adults with loss of visual function have worse physical and cognitive functioning, and is linked with an increased risk of comorbidity (Crews et al., 2006), disability (Lam et al., 2013), and mortality (Christ et al., 2014;Palbo et al., 2023).
Frailty is a geriatric syndrome defined as an increased vulnerability to adverse outcomes following stressors.It is described as a result of age-related multisystem dysregulation and decreased physical reserve (Fried et al., 2004).Fried et al. (2001) proposed five frailty criteria: weakness, slow walking speed, low physical activity, self-reported exhaustion, and unintentional weight loss.
The direct association between GA and frailty is lacking, but near vision impairment, which is a key feature in GA is an individual risk factor of frailty.Importantly, older adults who reported difficulty with near vision tasks had greater odds of being frail than individuals with objectively measured impaired near vision -defined as visual acuity worse than 20/40 (Varadaraj et al., 2019).This is especially relevant in patients with GA where visual acuity is a poor measurement of visual function due to foveal sparing, but deeply affected contrast sensitivity and reading speed (Sadda et al., 2016).
Falls are a massive public health issue as approximately 28-35% of people 65 and older fall annually, with 37.3 million falls per year worldwide requiring medical attention and each year an estimated 684 000 individuals die from falls globally (World Health Organization, 2021).It is well known that falls among elderly are linked to visual impairment and AMD (Dhital et al., 2010;Reed-Jones et al., 2013;Wood et al., 2011).However, Garrigan et al. (2022) found that it was not investigated if treatment for AMD had an effect on falls and mobility.Ophthalmologic research outcomes beyond visual parameters are warranted to include patient-centred, functional measures.

| PAT I E N T-R EPORT ED A N D PAT I EN T-R ELEVA N T OU TCOM E M EA SU R E S
Patient-reported outcome measures (PROMs) are frequently used and recommended to assess the impact of disease in clinical practice and clinical trials (Braithwaite et al., 2019).A PROM is a tool designed to demonstrate an effect of an impact or intervention.The measured effect can be either beneficial or harmful, and PROM plays an increasingly important role in assessment of therapies and health technology (Whittal et al., 2021).As previously described, patients with sight-affecting diseases have a large variety of experiences, and therefore the developers often design PROM tools to measure multiple concepts, such as difficulties in performing daily activities, worries about vision, difficulties in social events, etc.Once a PROM has been developed, it is important to evaluate to which extent content of the instrument is valid for a particular population.
Questionnaire-based methods have been widely applied in monitoring AMD, and the most frequently used PROM is the National Eye Institute Visual Function Questionnaire (NEI VFQ-25).The Visual function questionnaire was developed at the National Eye Institute, Bethesda, Maryland, USA (Mangione & Berry, 1998).Initially, the questionnaire comprised 51 questions but was reduced to 25 questions, which made it more suitable for use in daily clinical practice.The NEI VFQ-25 is a PROM instrument first published in 2001, which consists of 25 items evaluating the impact of visual impairment on health-related quality of life.It is designed to capture the 'status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else' (U.S. Food and Drug Administration, 2009).It contains 25 items and additional 14 items are optional in the VFQ-39 (Lindblad & Clemons, 2005;Mangione et al., 2001).Each of the subscales is scored on a 0-100 scale in which 100 indicates the best possible and 0 the worst possible function.
We localized 12 reports of cross-sectional measures of patients with GA, and no other retinal disease (Table 1).Not surprisingly, the lowest score was concerning near activities, except from one study (Patnaik et al., 2021).Driving also had a very low score, however, it was only reported by four studies, possibly since driving was not relevant among participants in the other studies.Other items that had low scores were general vision, role difficulties, general health, and mental health.Items such as dependency, social functioning, peripheral vision, colour vision, and ocular pain had the overall highest scores.Interestingly, Holm et al. (2023) found that categories near activity, general vision, and dependency were even lower in patients with GA and cardiovascular disease.This highlights the fact that PROM is not necessarily specific to the disease that we wish to measure.
The majority of studies of vision-related quality of life is not specifically concerning GA but involve other stages of AMD as well.In a study by Brown et al. (2006), it was found that cases with AMD with milder vision loss (20/20-20/40) experienced a 17% decline in their quality of life.However, persons with severe vision loss due to AMD (<20/800) were reported to have a 60% decline in quality of life, similar to that of a catastrophic stroke or end-stage cancer.Further, they found that patients were found to have quality-of-life impairment ranging from 96% to 750% greater than that estimated by their treating ophthalmologist.
More recently, development of The Functional Reading Independence Index has been shown to reflect severity of GA, as the index decreased in patients with GA and lesion enlargement during a period of 18 months (Kimel et al., 2016).Therefore, it is a valuable tool to monitor GA, as it likely reflects the same difficulties as one of the most affected NEI-VFQ items near activities.

| V I SUA L R EH A BI LI TAT ION
The British focus group interviewed by Carlton et al. (2019) was getting informal support, mainly from spouses and grown-up children.For those without family members nearby, friends, and neighbours provided invaluable support.All participants in this group had access to hospital eye clinics and low-vision clinics.Also, some had sought help from charitable organizations for social support and were also very satisfied with the help provided.However, the accessibility to low-vision support and rehabilitation, and the focus group interviewed by Madheswaran et al. (2021) found rehabilitation efforts and aid devices to be lacking.
A few studies investigated the effect of visual rehabilitation, Nekolova et al. (2023) showed that implantation of a magnifying add-on lens implant followed by intensive visual rehabilitation for 20 days had a significant positive effect on performing near activities and upturns in mental health symptoms related to vision.It is unclear if the effect was caused by rehabilitation or implantation of the magnifying lens.The results of Erginturk Acar et al. (2023) suggest that surgery might not be necessary, as a larger group of patients with GA who underwent visual rehabilitation and used low-vision aid devices showed significant improvements in near and distance activities, social functioning, mental health, role difficulties, and dependency subscale scores on the NEI-VFQ-25.They conclude that low-vision patients with GA should be included in low-vision rehabilitation programs as soon as possible.

| CONC LUSIONS
Geographic atrophy is a prevalent disease among the elderly population, and has deep impacts on daily activities, especially concerning reading and other near activities, but also driving and recognizing details and faces.Further, disease is closely linked to anxiety, fear of the future and progression of disease, and frustration over lack of independence.Qualitative research demonstrates that patients are unaware of the disease's cause and course (Figure 1).However, many develop coping strategies and have a support network in their daily life.
Longitudinally studies of GA and the impact of low-vision rehabilitation efforts on health-related quality of life are sparse but suggest a significant improvement on several items measured on VFQ.
Development of local complement inhibition provides hope for the many patients affected by GA.Pegcetacoplan inhibits complement C3 and has shown to be efficient in reducing growth of the atrophic lesion (Goldberg et al., 2022).More recently, avacincaptad pegol has shown as an emerging therapy, also with probable benefits on anatomical endpoints (Khanani et al., 2023).So far, no medical treatments have shown to better the functional outcome or PROM, but long-term data are awaited.

AC K NO W L E DGE M E N T S
None.

F U N DI NG I N FOR M AT ION
None.

T A B L E 1
Studies reporting patient reported outcome measures from patients with geographic atrophy using the Visual Function Questionnaire 25.Values are given in each subscale as items are scored from 0 to 100, where 0 is the worst possible and 100 is the best possible function.Values are presented as mean and standard deviation.Last column presents the weighted average from each subscale.