ORRT

Introduction

Vision and visual acuity are crucial for everyday life. These are essential for maintaining mental well-being, and their impairment may lead to the onset of disorders like depression and anxiety [1-5]. Fuchs endothelial corneal dystrophy (FECD) is a genetic, bilateral corneal disease affecting approximately 7.33% of the global population [6-8]. With increasing age, the degeneration of corneal endothelial cells leads to their destruction. In a healthy state, these cells actively pump water out of the cornea, enabling light to pass through the transparent cornea almost unimpeded. However, if these cells are impaired, water accumulates in the cornea, causing stromal oedema and, over time, epithelial oedema and scarring. The progressive loss of endothelial cells in FECD thus leads to progressive visual impairment in affected patients. Keratoplasty with endothelial replacement (DMEK) is usually performed to restore or improve vision. In some cases, a gas bubble must be reintroduced into the anterior chamber of the eye within the first few days after surgery to re-adapt a dehiscent endothelial lamella. This process is known as rebubbling. Mental health conditions such as depression and anxiety disorders are becoming increasingly prevalent worldwide, representing a significant issue for affected individuals, their families, and society as a whole  [9,10]

The lifetime prevalence of generalized anxiety disorder is estimated between 4.7% and 7.3% in different populations [11-14]. A recent German population-based revealed that 18.5% of the subjects presented with symptoms consistent with anxiety disorders, as indicated by elevated scores on the GAD-7 questionnaire [15]. Additionally, there is significant comorbidity with depression, which has a lifetime prevalence of approximately 15-18% in Germany [1, 9-11,16]. Anxiety disorders in particular are often undetected. Various studies have already described the association between reduced visual acuity in various eye diseases and the increased prevalence of depressive and anxiety symptoms [1,4,3,17]. However, to date, no study has focused on these psychological disorders specifically in the context of patients with FECD. It also remains unclear whether endothelial transplantation in one or both eyes results in a reduced prevalence of depressive and anxiety symptoms. To address this, we collected scores from validated questionnaires for depressive symptoms (PHQ-9 and HADS), anxiety symptoms (GAD-7 and HADS), and health-related quality of life (SF-12). Demographic and FECD-specific clinical data were also collected to investigate correlations within these parameters.

This prospective, validated questionnaire-based, cross-sectional study aims to evaluate the extent of depressive and anxiety symptoms in patients with FECD, and to compare these parameters in patients who have undergone surgery with those who have not. Furthermore, the study intends to identify specific factors associated with these psychological disorders and to uncover possible gaps in care for affected patients.

Patients and methods

Between August 2020 and February 2023, 155 patients were informed about the study during their consultation in our Cornea Department at Cologne University Hospital, immediately prior to their examination. The patients were given full information about the study and its possible consequences, and their written informed consent was obtained. This study was conducted by the Department of Ophthalmology at the University of Cologne in Germany. It was performed in accordance with the principles of the Declaration of Helsinki and was approved by the University of Cologne's Institutional Review Board (approval number 19-1665). This study was also performed independently of previous studies.

Inclusion and exclusion criteria

Inclusion criteria comprised an age of >18 years, sufficient proficiency in the German language, and a confirmed clinical diagnosis of FECD, irrespective of prior ocular surgery. Exclusion criteria included inability to provide informed consent and the presence of ocular comorbidities other than cataract, the latter being almost universally observed within the target cohort.

Demographic and Clinical variables

Researchers asked patients face-to-face questions using a standardized three-section questionnaire [18]:

Section 1 of the survey asked for general demographic data, e.g. age, gender, ethnicity, current relationship status, highest educational qualification, occupation, occupational disability and the urge to change or quit one's occupation due to FECD.

Section 2 requested potential pre-diagnosed depression or anxiety disorders, and whether they already had undergone psychotherapeutic or pharmacological treatment. Furthermore, risk factors associated with FECD were documented, including age over 40 years, female sex, familial history, and the presence of conditions such as hypertension, diabetes mellitus, and smoking [8]. In addition, data were collected regarding previously conducted endothelial transplants and the best corrected visual acuity (BCVA) before and after surgery.

Psychometric Questionnaires

Section 3 contained German versions of four standardized and established questionnaires, which were used to evaluate depressive and anxiety symptoms, and health-related quality of life. The Patient Health Questionnaire (PHQ-9) was used to screen for depressive disorders. This short, frequently validated questionnaire examines the nine criteria set out in the Diagnostic and Statistical Manual of Mental Disorders (DSM) in terms of their occurrence within the past two weeks [19,20]. Scores range from 0 (“not at all”) to 3 (“nearly every day”) and the total score corresponds to mild, moderate, moderately severe or severe depressive symptoms at 5, 10, 15 and 20 points, respectively [19,20]. The Generalized Anxiety Disorder (GAD-7) questionnaire is a valid and efficient tool for assessing anxiety disorder symptoms [12,21]. Seven DSM criteria are queried with regard to their occurrence within the past two weeks, with scores ranging from 0 (“not at all”) to 3 (“nearly every day”) [12, 21]. The scores are added up and correspond to minimal, mild, moderate or severe anxiety disorder symptoms at 5, 10, 15 or 21 points, respectively [12,21].

In addition to the well-established PHQ-9 and GAD-7 instruments, this study also used the Hospital Anxiety and Depression Scale (HADS), which was specifically developed for the psychological screening of patients with somatic illnesses [22]. The HADS contains seven questions on the categories of anxiety and depression, respectively, with scores ranging from 0 to 3 points [22,23]. Adding the points separately results in separate scores for depressive and anxiety symptoms of 0-7 points (“normal”), 8-10 points (“borderline abnormal”) and 11-21 points (“abnormal”) [22,23]. In contrast to the PHQ-9 and GAD-7, somatic items such as sleep disorders or changes in appetite were deliberately omitted to avoid confounding with physical illnesses. This is useful for the study group surveyed, which consists predominantly of older people, most of whom have general illnesses, in order to ensure a differentiated assessment of psychological stress, independent of physical symptoms. The Short Form Health Survey (SF-12) is an abbreviated version of the SF-36. It uses twelve items to calculate a score that assesses the respondent's general physical and mental condition [24]. A higher physical composite score (PCS) or mental composite score (MCS) indicates a better health-related quality of life. The average value for the general population is 50, with a standard deviation of 10 points [25]. The SF-12 is significantly more efficient in clinical practice, while still reflecting the results of the SF-36 very accurately [24].

 Statistical analyses

All statistical analyses were performed using commercial software (SPSS version 30.0 for Mac; SPSS, Inc., Chicago, IL). Kolmogorov–Smirnov and Shapiro–Wilk tests were performed to analyze the normal distribution of all scores graphically and statistically and showed that the distribution was not normal (p value < 0.001 for all instruments in both tests). Differences in best corrected visual acuity (BCVA) before and after surgery were calculated by using Wilcoxon test (p value < 0.001). To investigate factors related to PHQ-9 and GAD-7 scores,

Single linear regression models were performed, analyzing the following explanatory variables:

Depression and anxiety scoring without somatic context (HADS); physical (SF-12 PCS) and general mental health condition (SF-12 MCS); age; gender (male vs. female); highest educational degree; relationship status (single or not); body mass index (BMI); FECD-specific risk factors; and transplantation status (whether surgery was performed, or not). All p values from the regression analysis < 0.05 were classified as statistically significant. Statistically significant explanatory variables (patients’ age and FECD-specific risk factors) were examined in a further linear regression in relation to all completed questionnaires (PHQ-9, GAD-7, HADS, SF-12) at the same significance level. To compare the evaluated questionnaire scores according to whether surgery was performed on no eye, one eye, or both eyes, Mann-Whitney U tests were performed.

Results

Demographic and clinical data

Among the 155 patients diagnosed with FECD who participated in this study, 140 met the inclusion criteria and agreed to participate in the study. The average age of these patients was 67.82 years, with 42 men and 98 women taking part (Table 1).

Regarding ethnicity, 139 participants self-identified as European, while one participant self-identified as Asian. Overall, 73.5% were married or in a committed relationship; 19 patients were widowed and 18 are single. 59.3% of respondents had completed an apprenticeship, while nearly 22.9% had a university degree. Thirteen patients had a secondary school degree and three had either a high school degree or no degree. In line with the age group studied, most patients were retired (63.6%), while 39 were employed full-time or part-time, four were self-employed and one was in training. Two patients were unemployed and five did not provide information on this question. Five patients (3.5%) had changed jobs or become unable to work due to FECD. Of the 140 patients surveyed, 17 (12.1%) reported having been diagnosed with depression, while three (2.1%) reported having been diagnosed with an anxiety disorder. In terms of treatment, six people (4.2%) were receiving psychotherapy, six (4.2%) were taking medication, and a further six (4.2%) were receiving a combination of both. Only one person diagnosed with depression was not receiving pharmacological or psychological treatment.

Patients were grouped according to the surveyed risk factors for FECD, including age over 40 years, female sex, family history and conditions such as hypertension, diabetes mellitus and smoking. Fifty-four patients (38.6%) had one or two risk factors; more than half of all patients (56.4%) had three or four risk factors; and seven patients (5%) had five or six risk factors. The BCVA for diagnosed FECD with no previous transplantation was 0.48 ± 0.18 for the right eye and 0.47 ± 0.19 for the left eye. Following transplantation, regardless of whether DMEK or triple DMEK was performed, visual acuity improved significantly, reaching 0.76 ± 0.24 for the right eye (p value < 0.001, Wilcoxon test) and 0.79 ± 0.23 for the left eye (p value < 0.001).

Table 1: Demographics and clinical data of 140 patients with FECD.

Depressive and anxiety symptoms are elevated in FECD patients

The mean PHQ-9 and HADS depression scores for all FECD patients were within the normal range (PHQ-9: 3.39 ± 3.61; HADS: 2.82 ± 2.75) [20,22]. According to the PHQ-9, 99 patients (70.7%) had no depressive symptoms, while 29.3% showed symptoms (scoring 5-27). Of those patients, 30 (21.4%) had mild depressive symptoms, nine (6.4%) had moderate depressive symptoms, two (1.4%) had moderately to severe depressive symptoms, and none had severe depressive symptoms (Table 2).

The anxiety symptom scores for all FECD patients were also within the normal range for the GAD-7 (2.94 ± 3.39) [21] and HADS anxiety (3.76 ± 3.61) [22] scales. According to the GAD-7, 105 patients (75%) had no anxiety symptoms, while 25% showed anxiety symptoms (scoring 5-21). Of those patients, 28 (20%) had mild anxiety symptoms, five (3.6%) had moderate anxiety symptoms, and two (1.4%) had severe anxiety symptoms (Table 2).

The assessment of physical and mental condition, collected using the SF-12 questionnaire, was within the normal range at 47.09 ± 10.38 (PCS) and 52.78 ± 8.9 (MCS) [24,25].

Table 2: Questionnaire scores in 140 FECD patients without and with depression (A) or anxiety (B) symptoms (mean ± SD and range).

Age and clinical risk factors affect psychological symptoms in FECD patients

The linear regression models for explanatory variables in relation to PHQ-9 or GAD-7 scores demonstrated a highly significant association with the other questionnaires surveyed (p values < 0.001 in each case; linear regression, exception: PCS in relation to GAD-7, p = 0.043; Table 3). Among the other tested variables, age showed a significant negative correlation with a p value of 0.013 for the PHQ-9 and a p value of < 0.001 for the GAD-7. The same association was also identified in the linear regression model with regard to age for the HADS scores (depression score p value = 0.01, anxiety score p value = 0.013). Consequently, younger patients, irrespective of somatic comorbidities associated with psychological disorders, displayed a substantial increase in depressive and anxiety symptoms.

No statistically significant associations were identified with regard to gender, highest educational degree, single (or not), BMI, or transplantation status.

Table 3: Linear regression of explanatory variables in relation to PHQ-9 and GAD-7.

Furthermore, a highly significant association was identified between FECD-specific risk factors and the PHQ-9 score (p value < 0.001), with a slight tendency observed in the GAD-7 score (p value = 0.088). Consequently, additional analyses were conducted using linear regression, with the risk factors for FECD serving as the dependent variable (Table 4).

Table 4: Linear regression of psychological scores in terms of clinical risk factors for FECD.

A significant positive correlation was discovered among patients with depressive symptoms (PHQ-9, p value < 0.001 and HADS depression score, p value = 0.004) according to the presence of increasing risk factors. In patients exhibiting anxiety symptoms, this significant correlation was less prominent (GAD-7, p value = 0.088 and HADS anxiety score, p value = 0.043). Furthermore, with the increase of risk factors, which also include health-restricting items such as hypertension, diabetes mellitus, and smoking, there was a decrease in the physical and mental condition of the patients. A highly significant negative association was identified for the physical composite score (PCS) of the SF-12 (p = 0.001). A tendency towards significant negative association was observed for the mental composite score (MCS) of the SF-12 (p = 0.079). A notable finding was the absence of a correlation between the risk factors for FECD and the patients' age (p value = 0.851). Consequently, an increase in risk factors for FECD is associated with an increase in depressive and anxiety symptoms, as well as a decrease in physical and mental health. There is no statistically significant correlation between patients age and the number of risk factors.

Epithelial transplantation has no influence on psychological symptoms

To investigate the potential impact of epithelial transplantation on anxiety and depressive symptoms, patients were compared according to whether or not they had undergone transplantation after being diagnosed with FECD. The following three groups were formed: “transplantation of no eye”; “transplantation of one eye”; “transplantation of two eyes.” When comparing the groups mentioned above, no significant influence on the scores collected to measure anxiety and depressive symptoms could be demonstrated (p value > 0.05 in each case, Table 5). Thus, a successful transplant, regardless of whether one or both eyes were operated, has no influence on the psychological setting of the patients. The transplantation of one or even both eyes also had no significant influence on the physical and mental condition of the patients (SF-12 score, p value > 0.05 in each case, Mann-Whitney-U test, Table 5).

Table 5: Epithelial transplantation has no influence on psychological scores.

Discussion

This study provides significant results for the following four key statements regarding patients with FECD:

(1)    Depressive and anxiety symptoms are underdiagnosed in surveyed FECD patients. Therefore, these patients should undergo psychological screening in clinical practice to detect and treat relevant disorders early on.

(2)    Younger patients with FECD have an increased prevalence of depressive and anxiety symptoms. This patient group should be specifically targeted for appropriate psychological screening in clinical practice.

(3)    The more FECD-specific risk factors patients have, the more severe their depressive and anxiety symptoms are, and the more impaired their physical and mental health is. This highlights the need for interdisciplinary treatment of affected patients, who require not only good ophthalmological care, but also reliable general practitioners.

(4)    After guideline-based therapy using epithelial transplantation, BCVA increases significantly, while no influence on depressive and anxiety symptoms or on physical and mental condition could be demonstrated. Thus, in addition to ophthalmological rehabilitation through transplantation, the psychological setting of patients must be addressed and treated separately.

People with reduced vision face multiple challenges in life, including an increased risk of depression and anxiety disorders [1-3]. Working with those questionnaires it should be noted, that both PHQ-9 and GAD-7 evaluate and grade severity of depressive or anxiety symptoms and neither score provides any information about the genesis of the examined disorders or equals a medical diagnosis made by a psychiatrist [12,19-21]. Compared to the general German population, which has a rate of elevated depressive symptoms of 20.76%, our patient group had a significantly higher rate of depressive symptoms with 29.7% (41 patients) [1,9,10,11,16,26]. Although most patients (30 out of 41) have mild symptoms, nine have moderate symptoms, and two have moderate-to-severe symptoms. The study also revealed a discrepancy between the general German population and the study group with regard to anxiety disorder symptoms. As indicated by the elevated GAD-7 scores, 18.5% of the German population exhibited pronounced anxiety symptoms compared to 25% (35 patients) of the examined patients demonstrating significant elevations [11-15].

However, only 12.1% reported suffering from diagnosed depression and 1.4% suffering from diagnosed anxiety disorder, there seems to be a mismatch with significantly more patients affected by the disease specific symptoms. 

In all statistical calculations, the PHQ-9 and the depression score of HADS as well as the GAD-7 and the anxiety score of HADS were aligned. A high burden on the surveyed patients due to somatic complaints would have led to differences here, allowing the focus to be placed on the psychological burden of the patients. The available data on patients with FECD even exceed the increased prevalence of depressive symptoms in visually impaired patients of up to 24% reported by Schuster et al. [4]. This substantial discrepancy between the prevalence in the general population and in cohorts with impaired visual function underscores the necessity of psychological screening in patients with FECD. Since depression and anxiety disorders and symptoms impose a significant psychological and socioeconomic burden, early screening and, if necessary, intervention, are advisable [27,28].

In addition to the increased risk of depressive and anxiety symptoms in general, we were also able to demonstrate a significant negative correlation with patients' age. Interestingly, we found that symptoms of depression and anxiety increased when patients were younger. However, other studies have shown that the highest lifetime prevalence of depression is among 60- to 69-year-olds, which roughly corresponds to the average age of our FECD patients and thus does not correspond to our younger patients [29-31]. Furthermore, other studies have described an increase in lifetime depression prevalence in older age groups in German cohorts [32,33,34].

This contrast could perhaps be explained by the circumstance that younger patients have had the disease for a shorter period of time and have therefore had less time to come to terms with and maybe accept it. Other studies have shown that the rate and severity of depression decrease with time since diagnosis [18,35]. Furthermore, younger patients may exhibit increased symptoms of psychological disorders due to impaired visual function if they are still working or planning to start a family [36,37]. As diagnoses of impaired visual function become more common with age, older people are maybe more familiar with reduced vision [5]. Younger people with a first diagnosis of FECD may have received their first diagnosis of a vision-threatening disease. Regardless of the possible causes, it is important for ophthalmologists to pay particular attention to symptoms of depression and anxiety in younger patients with FECD. For example, special attention should be paid to age in brief screenings to identify affected individuals early and refer them for targeted pharmacological, psychotherapeutic, or combined therapy.

In addition to the significant correlation between increased depressive and anxiety symptoms and FECD, a linear regression model demonstrated that psychological symptoms increase with an elevated number of FECD-specific risk factors, such as age over 40, female sex, family history, and the presence of hypertension, diabetes mellitus, and smoking. The more risk factors a patient has, the more likely they are to be diagnosed with FECD [8] and experience symptoms of depression and anxiety. At the same time, physical and mental health decline as risk factors increase. Since the risk factors of being over 40 years old, being female, and having a positive family history cannot be influenced, the risk factors of having hypertension, diabetes mellitus, and being a smoker become more important. On one hand, ophthalmologists should ask about these risk factors and take them into account in psychological screenings. On the other hand, interdisciplinary cooperation with the general practitioner should be emphasized. Additionally, patients should be educated on the significant role of these risk factors in causing depression, anxiety disorders, and impaired visual function due to various disorders, including FECD. As multiple studies have shown, reducing the risk of FECD, depression, and anxiety disorders further leads to a reduction in individual morbidity and mortality [38,39].

Surgical treatment for FECD patients using epithelial transplantation significantly improves BCVA. Interestingly, successful transplantation did not result in a notable reduction in symptoms of depression or anxiety, regardless of whether one or both eyes were treated. Similarly, no influence on physical or mental condition could be demonstrated. These findings underscore the unique challenges faced by ophthalmologists treating FECD patients, as improving visual acuity alone is not sufficient for comprehensive patient care. Thus, the increased rate of depressive and anxiety symptoms in FECD patients appears to be less associated with visual function. It is possible that the general risk profile of hypertension, diabetes mellitus, and smoking is much more likely to be the cause, as these factors themself are strongly associated with an increased prevalence of depression and anxiety disorders [40-42]. This is also probable because, in comparison to patients with cataracts, who also exhibit elevated symptoms of anxiety and depression and an impaired BCVA, their psychological burden is demonstrably reduced after surgery [43,44,45]. In addition, individuals diagnosed with glaucoma or age-related macular degeneration (AMD) are also more prone to manifest depressive and anxiety symptoms to a greater extent than the general population, as shown by Pan et al. analyzing a total of 67 studies [46]. In such cases, the primary objective of treatment shifts from achieving substantial BCVA enhancement to preserving the existing BCVA. This approach contrasts with the treatment strategies employed in conditions such as FECD or cataracts. The findings imply that the elevated prevalence of depression and anxiety may be attributable to a combination of factors, beyond the scope of BCVA alone, as all these vision-impairing diseases have a significant impact on the psychological burden. It underscores the necessity to consider the patient comprehensively and to address comorbidities with a comparable level of emphasis, aiming to enhance their quality of life.

One limitation of this study is the lack of data on potential changes in the pre- and post-epithelial transplantation questionnaire scores. Surveying depression and anxiety scores before and after surgery in the same patient could provide a more precise depiction of symptom dynamics. Additionally, the cross-sectional design of the study has led to a limitation in the derivation of causality of the presented data. The usage of screening questionnaires is highly validated, can easily be used by non-psychiatrists, and is timely effective. In the context of a large study group, as depicted in this paper, they serve as a highly advantageous instrument. However, it should be noted that these methods are inferior to diagnostic structured interviews, which are significantly more precise and capable of differentiating symptoms from diagnoses. In terms of visual function, subjective visual function would be an interesting parameter to consider in addition to objective BCVA. After all, each patient experiences their disease and visual impairment differently, so subjective perception could be useful when it comes to psychological disorders such as depression and anxiety. According to the available literature, this study is the first to assess the psychological burden experienced by patients with FECD. Further studies are necessary to thoroughly examine the psychological challenges confronting these patients.

In summary, the cohort of patients with FECD examined in this study showed significantly higher rates of depressive and anxiety symptoms than the general German population. This suggests an underdiagnosis of these conditions in clinical practice. This rate is even higher among younger patients and those with more FECD-specific risk factors. Therefore, it is recommended that a standardized psychological screening should be implemented in routine clinical care for these patients. Interdisciplinary collaboration with general practitioners is essential to address FECD- and morbidity- and mortality-specific risk factors. Close cooperation with psychiatrists and psychologists is also necessary, because FECD patients have an increased psychological burden that is not significantly improved by surgery.

Acknowledgements

Conflict of interest

The authors did not receive support from any organization for the submitted work and do not have relevant financial or non-financial interests to disclose.

Funding statement

This project was partially funded by the Köln Fortune project (project number 180/2023), the Rotation Program for clinician scientists of the Medical Faculty at the University of Cologne and the Collaborative Research Consortium 1607 (SFB 1607/1 2024, Project number 501530074) of the Department of Ophthalmology, University of Cologne.

Author contributions

LHM, ACR and CN contributed to the study conception and design. SJF collected the data. CN and PZ analyzed the data. CN wrote the article. PAWMR, SJF, JW, MS, PZ and ACR provided revisions. All authors approved the final manuscript.

Data Availability

Data generated during this study are available from the corresponding author on reasonable request.

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