FormalPara Key Summary Points

We emphasize the limited education on sickle cell retinopathy that our patient received, and the impact of sight loss on our patient’s daily activities and mental health, especially in the context of a disease that often progresses suddenly.

Sight loss may have a unique impact on quality of life in people with sickle cell disease.

We summarize the low-quality evidence for routine retinal screening for sickle cell retinopathy.

We highlight the limited evidence for interventions that prevent sight loss due to sickle cell retinopathy, and the crucial need for further research in this area.

Introduction

Sickle cell disease (SCD) is estimated to affect almost 8 million people globally, mostly affecting people of sub-Saharan African, Asian, Middle Eastern, and Eastern Mediterranean descent [1]. Globally, over 500,000 babies were born with SCD in 2021 [1].

SCD is a genetic condition whereby a mutation in the hemoglobin gene results in a change from the normal biconcave shape of red blood cells to a sickle crescent shape. This renders the red blood cells unable to transit through small blood vessels, resulting in vaso-occlusion that can result in episodes of severe pain, end-organ damage, and reduced life expectancy compared to the general population. Despite a well-defined pathophysiological process underpinning the disease, the symptom profile widely varies across persons.

SCD research is well recognized to be underfunded [2], with few available therapeutic options. However, in the last two decades, there has been an increase in available treatment and more novel therapies, at various stages of development [3]. In 2023, the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the US Food and Drug Administration (FDA) historically approved gene-editing therapy for SCD, in addition to the FDA approving another gene therapy using a more traditional approach [4, 5]. Both therapies were highly effective in clinical trials, showing a complete resolution of vaso-occlusive crises for at least 12 months in more than 90% of patients treated [6]. However, while genetic therapies cannot reverse end-organ complications already sustained, they do hopefully signal a step-change with regards to research prioritization and funding for this globally highly prevalent disease.

Quality of life (QOL) is now established as a significant concept and target for health outcomes in the practice of medicine. Understanding QOL is important to gain insight into the range of problems that can affect patients, and improve symptom relief and delivery of care [7]. Visual impairment is well recognized to have a significant impact on QOL, particularly as it can interfere with social interactions, activities of daily living, and independence [8].

Ocular manifestations of SCD can involve many important structures within the eyes, with the most common sight-threatening manifestation being proliferative sickle cell retinopathy (PSCR). Prevalence estimates of PSCR vary between 14 and 43%, depending on factors such as age, genotype, and research setting, with up to 12% suffering irreversible sight loss [9, 10]. Despite the first published description of SCD in 1910 by Herrick [11] and classification of sickle cell retinopathy (SCR) in 1971 [12], there remain significant knowledge gaps limiting our ability to prevent sight loss in these patients. In addition, there are no published insights into the impact of sight loss on QOL in SCD. This underpins the low level of recognition and understanding of the potential impact of visual impairment in the context of SCD.

To understand, and further validate, the need for research into visual impairment in SCD, it is important to highlight its impact on the quality of life of those affected. Chanel Taylor, who lives with SCD and is chronically affected by the complications of SCR, was interviewed by ophthalmology consultant and researcher Christiana Dinah (CD).

Chanel Taylor is in her late 30s and has the HbSC genotype. She was diagnosed with sickle cell retinopathy (SCR) in 2020, and since then her condition has progressed (Fig. 1). Despite management by ophthalmologists, she has now had to make significant adjustments to her daily life due to the condition and the impact on her vision. We discuss her experiences of SCR, interactions with eye care services, and the overall impact of SCR on her QOL.

Fig. 1
figure 1

Timeline of Chanel’s experience with symptomatic proliferative sickle cell retinopathy

Full size image

This paper focuses on the perspectives and experiences of a single individual, an example of what might be termed an instrumental case study [13], whereby a single case is explored in its full complexity in order to provide illustrative insights into a broader issue. Such an approach has previously been used in ophthalmology to illustrate the complex, unique experiences of individuals living with geographic atrophy [14, 15] and diabetic macular ischemia [16]. Analysis of Chanel’s experience of SCR is interwoven with insights derived from the relevant literature on SCD and its ocular manifestations.

Sickle Cell Retinopathy

“On the 1st of January 2020… I woke up and my eyes were blurry; they usually are for a while in the morning but after rubbing my eyes I then realized, wow, I actually can’t see…I couldn’t tell anybody what I was going through because of the shock. I was just kee** quiet, thinking OK, maybe it would go away”. (Quote 1, Fig. 1)

“When I got to the doctor’s surgery, the doctor examined my eye and he wrote me a letter and he said, ‘Chanel, you should have come and seen me straight away. This is serious. Go to A&E [Accident and Emergency].’ He wrote a note for me to go to A&E. I remember reading ‘Dear colleague, see this person’ and I cried.” (Quote 2)

Sickle cell retinopathy (SCR) is more common in individuals with HbSC, occurring as early as 8 years of age compared to 13 years of age in HbSS [17, 18]. Goldberg described 5 stages of sickle cell retinopathy in 1971 [12]. These stages are:

Stage 1: Arterial occlusion.

Stage 2: Arterio-venous anastomosis.

Stage 3: Sea-fan retinal neovascularization.

Stage 4: Vitreous hemorrhage.

Stage 5: Retinal detachment.

Stages 1–3 are asymptomatic but classically well defined and easily identified on dilated slit-lamp indirect funduscopy and with ultrawide fundus photography and/or ultrawide fluorescein angiography. Stages 3–5 are termed proliferative sickle cell retinopathy (PSCR). Progression to stage 4 (vitreous hemorrhage) is typically sudden and heralded by floaters or sudden awareness of loss of vision. Retinal detachment, which can be rhegmatogenous or tractional (stage 5) is also insidious, and despite advances in retinal detachment surgery and improved anatomical outcomes, median visual acuity after surgery remains suboptimal [19]. This is why identifying precursor lesions through annual screening is a well-established approach in some countries [20,21,22], with sectorial laser photocoagulation applied adjacent to areas of detected active sea-fan lesions (stage 3) to prevent vitreous hemorrhage and/or retinal detachment.

Education and Awareness

In A&E, Chanel was confirmed to have sustained a vitreous hemorrhage due to PSCR (stage 4). Indeed, Chanel refers to the “shock” (Quote 1) of suddenly experiencing visual symptoms and highlights the urgency with which her care team responded (Quote 2).

“I didn’t get any (education). No one gave me information that this may occur. That this may happen. So…my first experience is me waking up and having that vision loss. That’s my experience till now.” (Quote 3)

“I remember in the night (when the symptoms began), I was googling vision loss and sickle cell. It was not like I saw the words “vision loss in sickle cell”; [instead] it said “retinopathy”. Then I started to read the information and I was like, ‘Oh I’ve lost my vision’.” (Quote 4)

Chanel had been attending annual retinal examinations at her hospital eye clinic for years but did not understand what was being assessed or that she was at risk of sudden visual loss. The literature suggests that there are several barriers that prevent patients from receiving adequate educational support for their condition. Over 2000 peer-reviewed studies have shown that healthcare information is often not easily accessible to sickle cell patients and the language used is often difficult to understand and above the average reading levels of most adults [23].

It is noteworthy that the general practitioner in Quote 2 told Chanel “You should have come and seen me straight away. This is serious”, striking a clear note of urgency and severity. Nevertheless, Quote 3 illustrates that no medical professional had explained to Chanel how SCD could affect her vision. Examining these two quotations side-by-side makes clear that there is a significant gap in patient education about SCR, given the suddenness and urgency of ocular complications that can arise. In the absence of education, Chanel had to search for information herself about the ocular consequences of SCD; this points to the importance of ensuring information online is easily understandable and accessible, as well as the importance of sufficient ‘offline’ information for patients to help improve the patient experience. As described by Gbedemah et al., online content about sickle cell retinopathy is fairly difficult to read and of substandard quality [24].

Screening for Sickle Cell Retinopathy

Natural history studies have demonstrated that more than 30% of sea-fan lesions autoinfarct without any blinding complications [10, 17], and vitreous hemorrhage mostly clears within 3 months [17]. This, in addition to relative rarity in comparison to other retinovascular diseases such as diabetic retinopathy and retinal vein occlusions in European countries like the UK, may contribute to the lack of awareness and poor patient education Chanel reports.

While SCR meets most of the criteria for a population screening program [25], there are no national screening guidelines in the UK, largely due to the lack of robust evidence on the risk–benefit profile of the available interventions [26].

Sector laser photocoagulation and intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy are the only interventions widely employed in the management of stage 3 PSCR. With regards to sector laser photocoagulation, there have only been three randomized controlled trials comparing this intervention versus observation. Two of these trials were conducted over 30 years ago, and the most recent was 15 years ago [27]. While a systematic review of the results shows that laser photocoagulation is effective in preventing visual loss and vitreous hemorrhage, regression of sea-fan lesions was only significant in younger patients with flat lesions; furthermore, many eyes in the trial that received laser developed new sea-fan lesions elsewhere. Therefore, it was concluded that the studies were likely underpowered to demonstrate non-inferiority of laser, compared to observation for regression of sea-fan lesions and development of new sea-fan lesions in the timeframe of 32 to 47 months in which they were conducted. In addition to a high risk of bias, this means the certainty of the evidence for laser photocoagulation from these trials is low.

Furthermore, while there are case series demonstrating successful treatment of stage 3 and 4 PSCR with intravitreal anti-VEGF therapy, there are no randomized controlled trials of any of these agents in the management of PSCR.

Thus, high-quality evidence is crucially needed to advance our understanding of the epidemiology of SCR, and the underlying mechanisms, in order to develop efficacious therapies that are acceptable to those affected.

Life Changes

There is no published account of the impact of sight loss on quality of life in patients with SCD. Chanel here begins to share what most concerned her when she suddenly developed visual impairment, and the impact the diagnosis of irreversible sight loss has in the context of SCD:

“My main fear and concern was I wasn’t going to be able to drive…I started driving when I was 18…driving means a lot to me because I suffer from post-traumatic stress disorder and anxiety, so public transport and people hasn’t always been nice to me…you know, even just wanting to have a seat or wearing the badge, means people just look at you, but with driving, even though it was tiring to drive, it was you know, very convenient… It would make it easier for me to engage with disabled services (spaces).” (Quote 5)

“I used to work with children in a care home, so I used to stay overnight, and what I used to do is make sure my shifts are at a time where I’m driving in the daytime and then I’m leaving, I leave in the morning. This is so I’m not driving at night-time because there have been a few instances where I was driving on a motorway, driving at night and I’m literally blinking. I’m like oh wow, I can’t see at all... So, I stopped driving at night.” (Quote 6)

Quote 5 clearly illustrates that driving was both convenient in Chanel’s everyday life and supported her mental well-being. Quote 6 suggests that even before Chanel experienced significant sight loss from PSCR, she noticed problems with driving at night. As she also has sickle cell maculopathy, which has been shown to reduce retinal sensitivity [28], it is not clear whether difficulties driving at night were due to or compounded by sickle cell maculopathy. Our research group has held focus groups discussing the impact of sickle cell retinopathy on quality of life, and many focus-group participants reinforced the importance of driving in the context of SCD. People with SCD may suffer from mobility impairment, and anxiety to travel, due to complications of their condition, such as avascular necrosis of the hip and acute vaso-occlusive episodes, which can be triggered by the ever-changing external environment and psychological stressors. The literature amalgamated with Chanel’s testimony highlights the importance of the controlled and comfortable environment that driving can provide. Therefore, maintaining adequate visual acuity in order to safely and legally manage this task is paramount for many.

Rizio et al. [29] attempted to identify the impact of vaso-occlusive crisis in people with SCD and its association with health-related quality of life and work productivity. The study highlighted the significant burden on the person’s emotional state and social functioning, as well as significant impact within the workplace, with a reported increase in absenteeism and impairment of work productivity. However, there is currently no literature on the impact of sight impairment on these parameters within the SCD patient cohort. This lack of research means workplaces are also unaware of the burden, and often refuse or find it difficult to accommodate, as Chanel goes on to explain:

“Currently I work with a section of the health service in the public sector and even just reasonable adjustments at the air con and things like that make a difference. Sometimes I’m at the reception (at work), I have my area where I do things, but I don’t put things on my left hand side because I will probably knock it off (left temporal vision affected due to retinal detachment). But some of my colleagues say, you need to put this here, we need to put this there…and I have to keep explaining... ‘Are you aware that I’m partially sighted?’ But still if I’ve left my desk a certain way for me to work, it is often moved around again…So I feel like I’m battling, and I’m fighting with my employers and colleagues just trying to make things easier for me and more manageable” (Quote 7).

Chanel’s experience highlights the challenges she faces as she describes having to “battle” and “fight” to manage within the workplace with a non-visible disability. She experiences the burden herself, even though it is incumbent on UK employers to make reasonable adjustments for people with visual impairment under the legal terms of the UK’s Equality Act 2010 [30]. However, there is often a distinct lack of reasonable adjustments for disabled people in general within the UK workplaces, with around three-quarters of employees like Chanel reporting negative experiences obtaining reasonable adjustments [31].

Experience with the Eye Service

Chanel attended one of the few hospital eye clinics that does provide screening for SCR in the UK:

“You know, they (ophthalmologists) would ask if there’s any problem, and I’ll say I’ll see floaters sometimes when I wake up or at night-time as well. So I did, you know, mention that I had a little bit of vision difficulty before the incident, but again it was kind of dismissed. And I guess in their eyes, they didn’t see anything challenging for them that needed treatment. I guess they were like ‘OK, everything’s fine, everything’s fine’. But now when I look at it, I just feel like you can’t have a yearly appointment, they have to be more frequent or tailored for some” (Quote 8).

“When I was seen in the eye clinic (January 2020), they told me I had suffered a bleed in my eye and that they were going to do laser surgery. Then they changed their mind. And it was back and forth, back and forth with the decision. So in the end they decided we’ll have to wait and see. It was the wait and see game. During this time, I struggled at work with blurred vision in one eye, struggled navigating stairs and struggled at work. It was only in 2021 (one year later), when they decided my retina was detaching and to go with the surgery” (Quote 9)

Downes et al. [17] describe vitreous hemorrhage occurring rarely and clearing within 3 months in all cases. However, there are many reports of non-clearing vitreous hemorrhage in the context of SCR which invariably require vitrectomy to restore vision. In addition, vitreous hemorrhage can be complicated by retinal detachment, necessitating vitrectomy as well.

There are no contemporary publications reporting on the proportion of vitreous hemorrhages associated with SCR that clear spontaneously, nor the likelihood and risk factors for progressing to retinal detachment in this scenario. Of note, 72 of 108 eyes (66.7%) from a recent retrospective series of patients with SCR in Lagos, Nigeria received treatment with intravitreal anti-VEGF, vitrectomy and or sector laser photocoagulation for vitreous hemorrhage in isolation and achieved a mean gain of > 5 lines, with a mean follow-up of 21.3 months [32]. Practice patterns in the US also revealed 16.8% of surgeons use anti-VEGF for vitreous hemorrhage in this context, although there are no randomized controlled trials of anti-VEGF therapy for this indication [33]. Therefore, spontaneous clearance of vitreous hemorrhage is not inevitable, and these eyes need to be monitored closely. Further research is required to determine the proportion that clear spontaneously, the average time to clearance, the optimal time to intervene in a non-clearing vitreous hemorrhage in the context of SCR, and the role of intravitreal anti-VEGF in isolation or combined with vitrectomy.

Chanel was offered surgery to correct her vision and discussed the outcome:

“I have been told my retina is back in place but my vision is not likely to improve. If I had the option again now to have surgery or not have surgery, I probably wouldn’t have opted for the surgery because I could see at least, even though it was blurry and I know it sounds so silly but with the vision that I had, I was able to do my eyelashes myself. It’s just simple little things. I can’t see anything… I can’t do my lashes. I have to get them done. But it’s just like I said, it’s just the small thing that matters the most.” (Quote 10)

Visual loss in PSCR is commonly due to vitreous hemorrhage (VH), macula-threatening tractional and/or rhegmatogenous retinal detachment (TRD/RRD), epiretinal membrane (ERM), and macular hole [9].

Surgery for retinal detachment due to PSCR is challenging, with studies reporting rates of iatrogenic breaks over 30% and limited visual gain [34, 35], which was also Chanel’s experience as described in Quote 10.

Even with ever smaller gauge vitrectomy which has improved fluidics, and is associated with lower surgical trauma and intraoperative complications as low as 9%, a recent large retrospective case series reported no statistically significant difference between mean post-operative best corrected visual acuity (BCVA) and pre-operative BCVA [19]. In fact, the mean-post-operative BCVA remained below 6/60 and only 23.7% of patients achieved driving vision or better (≥ 6/12). Okonkwo et al. [32] also report poor post-operative outcomes in eyes with tractional retinal detachment with PSCR in their Nigerian series. However, they report maintenance of good vision in eyes with stage 3 PSCR with or without pre-retinal hemorrhage treated with sector laser photocoagulation ± intravitreal anti-VEGF.

These findings underscore the need to predict and identify eyes with PSCR at risk of progressing before they sustain vitreous hemorrhage or retinal detachment. Considering Chanel’s account, vitreous hemorrhages appear to have a significant impact on vision-related quality of life, including mental health and social functioning, even if many ultimately self-resolve in time. In addition, in those who develop retinal detachment, there is a high risk of permanent, irreversible visual loss.

Surgical Management

“Before surgery, I had a pre-assessment which was about a week before. During the pre-assessment I was informed of what to expect on the day, this also gave me an opportunity to also ask questions. Although I thought I was fully informed on what to expect, I was still apprehensive, anxious and nervous as to how I would feel on the day.” (Quote 11)

“…having expectations of the surgery working and the possibility of having my sight restored. My thought process in time and at different stages, marinated the possibility and the probability of not having sight restored 100%. I wasn’t sure how I was going to feel.” (Quote 12)

Quotes 11 and 12 suggest that Chanel was well informed and given space to ask questions, but still approached the procedure with uncertainty and anxiety. There are indications that patient decision aids, informational tools that help clinicians and patients decide together on how to treat chronic or surgical conditions, can support patients’ decision-making and help them avoid decisional regret [36].

“Once I reached the theatre room, my body froze although I was present, everything went numb, I kept telling myself to pay attention and to listen to the instructions given and to focus…The surgeon was so attentive and making sure he was communicating with me and asking how I felt and if I could feel any pain, at one point I remember raising my hand to indicate that I could feel some discomfort. More anesthetic was administered, shortly after that I don’t remember much.” (Quote 13)

Building and maintaining trust and rapport between healthcare staff and patients is imperative in the management of anxiety and to ensure a good experience throughout the healthcare process [37]. Chanel’s experience as discussed in Quote 13 chimes with the experiences of patients who have undergone high-stakes glaucoma surgery [38], where transparent, caring and empathetic communication from the surgeon helped reduce anxiety attributable to the surgery.

“I wish I had some form of support or aftercare team to speak to… as for me, I don’t have family around me that I can go to for support. Mentally and emotionally, it’s extremely difficult to decipher and process my experience, especially when it’s unexpected” (Quote 14).

Chanel’s closing statement may echo the concerns for many suffering with visual impairment due to SCR. In line with Chanel’s perspective, broader research suggests that psychological support following surgery would be valued by ophthalmology patients, who may feel especially vulnerable after surgery [38].

Conclusions

With SCR, there unfortunately remain more questions than answers. However, recent advances in retinal imaging, improved laser and surgical techniques, and increasing public and political awareness may mean we are on the cusp of tangible improvements in our understanding and management of this disease. Certainly, the ophthalmology community needs to develop improved ways of better communicating what is known about SCR to those living with SCD. More work needs to be done to raise awareness of the potential impact of visual impairment in people with SCD across institutions, including workplaces and educational establishments. Insights gained from engaging those affected by SCR will inform the direction and prioritization of research, in order to address the significant unmet needs that continue to persist. There is great hope that the burgeoning pipeline of therapeutics for SCD will consequently result in increased research into end-organ complications, including SCR.