Introduction

Dry eye disease (DED) is one of the most common chronic ocular complaints presented to the Ophthalmic clinic. The prevalence worldwide is high, and ranges from 5 to 50 percent in different parts of the world [1]. Patients present with a range of symptoms like ocular surface irritation, itching, redness, watering, stinging pain, foreign body sensation and intermittent visual blurring [2]. These symptoms often result in difficulty driving, working on a computer, watching television, and reduced reading speed [3]. Thus, DED can negatively affect quality of life (QOL) and visual function [4].

Dry eye has been defined by the Tear Film and Ocular Surface Society (TFOS) in Dry Eye Workshop II (DEWS II) as a multi-factorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface in-flammation and damage, and neurosen-sory abnormalities play etiological role [5]. The tear film comprises three layers—mucin, aqueous, and lipid—spanning from the corneal surface to the air interface [6]. Secreted mainly by the lacrimal glands, the aqueous layer of tear film provides oxygen and nutrients to the cornea [6]. The lipid layer is secreted by the meibomian glands and plays an important role in preventing excessive evaporation of tears from the eye [7]. DED is classified as either aqueous-deficient or evaporative [8]. Aqueous–deficient DED is a result of lacrimal gland dysfunction, while evaporative DED, present in over 85% of cases, arises from meibomian gland dysfunction, leading to a deficient lipid layer and excessive tear evaporation [8, 9].

Diagnosis of DED commonly involves questionnaires assessing symptoms, as well as clinical evaluations, such as slit-lamp examination, ocular surface staining (fluorescein, lissamine green, or rose bengal), tear film breakup time (TBUT), Schirmer test, and meibomian gland function assessment using interferometry [10]. Ocular Surface Disease Index (OSDI) and Standard Patient Evaluation of Eye Dryness Questionnaire (SPEED) are two of the commonly used quality-of-life questionnaires used to assess patients with dry eye disease [11, 12]. The OSDI questionnaire consists of questions relating to 5 ocular symptomatic domains, 4 vision-related domains, and 3 domains related to environmental triggers [13]. On the other hand, the SPEED questionnaire focuses on the presence, frequency, and severity of four common (dryness/ grittiness/ scratchiness; soreness/ irritation; burning/ watering and eye fatigue) subjective symptoms experienced by patients [12, 14].

Common DED treatments include over-the-counter lubricants to supplement the aqueous or lipid tear film layers [15–17]. Newer therapies like the LipiFlow Thermal Pulsation System (LipiFlow, Tear Science, Johnson and Johnson, Santa Ana, Ca) and the MiBoFlo Thermoflo treatment system (MiBo Medical, Dallas, TX) have been shown by us and others to improve meibomian gland function and thus improve the lipid layer quality of the tear film, providing long term relief (up to 6 months) to patients with evaporative dry eye [18–22]. These heat-based therapies deliver heat to the meibomian glands which softens the inspissated lipids and enables their extrusion by using gentle ocular massage.

However, the presence of other ocular diseases, such as age-related macular degeneration (AMD), may confound symptom improvement measured by QOL questionnaires. AMD, a leading cause of central vision loss in the United States, shares overlapping visual symptoms with DED, such as difficulty with driving, performing detailed tasks, and navigating [23–25]. Studies have shown that AMD, even in the mild and intermediate stages, significantly impairs visual function particularly in low contrast, low luminance, and glare environments [26]. For this reason we aimed to determine whether the severity of AMD impacts QOL improvements in patients treated for DED.

Methods

This retrospective study was conducted at the Department of Ophthalmology, University of California San Diego (UCSD), Shiley Eye Institute on data from records of 203 eyes of 102 patients suffering from evaporative dry eyes who came to dry eye clinic and received thermotherapy in the form of LipiFlow or MiBoFlo. 40 eyes from 22 of these patients were included since they had dry AMD disease which was stable through the course of dry eye treatment. One of these patients was monocular with Phthisis bulbi in one eye. Three eyes were excluded from the study due to the presence of neovascular AMD (nAMD). Active nAMD is associated with fluctuating visual outcomes caused by retinal fluid accumulation and its subsequent resolution following anti-VEGF therapy. These changes in vision would confound our results, as the improvement in quality-of-life (QOL) questionnaire scores could not be attributed solely to dry eye treatment. Our study aimed to isolate the impact of dry eye treatment on QOL while ensuring that the underlying retinal pathology remained stable over the course of treatment. This stability was not achievable in eyes with active nAMD, where changes in vision due to the retinal disease and its treatment would introduce variability unrelated to dry eye therapy. Institutional Review Board approval from UCSD was obtained for the review of patients’ charts and images (UCSD IRB #120516). Scores for quality-of-life assessments on two standardized questionnaires were recorded before treatment and 6-months after treatment using the Ocular Surface Disease Index (OSDI) and the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaires [27].

The SPEED questionnaire was scored between 0 to 28, adding scores from the frequency of symptoms on a 0–3 scale and severity of symptoms on a 0–4 scale. The symptoms assessed in the standardized questionnaire included:1. dryness/ grittiness/ scratchiness; 2. soreness/ irritation; 3. burning/ watering and 4. eye fatigue.

In the OSDI questionnaire, the frequencies of dry eye symptoms were assessed in items 1–5, the effect on daily living tasks in items 6–9 and environmental conditions that may trigger the symptoms in items 10–12. Each question was graded on a scale from 0 to 4. The total OSDI score was calculated by multiplying the sum of scores by 25 and dividing by the number of questions answered [27].

Total scores ranged from 0 to 100, with higher scores indicating worse dry eye symptoms for both questionnaires. Items 6–9 included reading, driving at night, working on a computer/ ATM and watching TV. Due to their direct relation to visual functioning, these were the ones we suspected would be affected by dry AMD disease. Hence, the 6-month post- treatment scores were subtracted from the pretreatment scores for total OSDI scores, SPEED scores and OSDI items 6–9 scores.

The difference between visual acuity before treatment and 6 months after treatment was also recorded. Snellen visual acuity was converted to ETDRS letters to facilitate calculation.

For dry AMD grading, color fundus photographs and raster Optical Coherence Tomography (OCT) scans were analyzed. These were obtained on the on the Optos Ultra-widefield (UWF™) Retinal Imaging Device and Heidelberg Spectralis imaging as part of routine evaluation.

Dry AMD was classified as early, intermediate, and late. Early AMD was defined by presence of numerous small (<63 microns) or intermediate (≥63 to <125 microns) drusen. Intermediate AMD was defined as either extensive drusen of small or intermediate size, or any drusen of large size (≥125 microns). Late AMD was defined by the presence of geographic atrophy [28].

The color fundus photographs and OCT scans pretreatment were compared with those taken 6-months after treatment to ensure no concurrent retinal changes occurred that could potentially confound the results of our study.

Results

The average age of patients in our study was 75.9 years. A total of 26, 9, and 5 eyes in our study group had early dry, intermediate and late dry AMD respectively.

For each of the eyes in our study, the retinal disease was stable over the 6-month study period. This stability was demonstrated by macular OCT findings, which showed no changes when compared between pretreatment and 6 months post-treatment.

The mean (± SD) visual acuity, measured in ETDRS letters, was 66.6 ± 22.2 at pretreatment and 66.3 ± 22.4 at 6 months post-treatment. There was no significant change in visual acuity over the treatment period.

All treated eyes had statistically significant improvement (p<0.01) in QOL scores across all the questionnaires studied (Table 1).

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Table 1. Overall improvement with dry eye treatment across all groups.

https://doi.org/10.1371/journal.pone.0318733.t001

For the early dry AMD group, the mean pre-treatment total OSDI score, OSDI items 6–9 score and SPEED scores were 47.57, 6.58 and 17.57 respectively. For the intermediate dry AMD group, the mean scores were 47.66, 8 and 12.11 respectively. For the late dry AMD group, the scores were 71.11, 10.2 and 18.6 respectively. The mean improvement in total OSDI score with treatment (pretreatment minus 6-month post treatment) was 14.82, 14.56, and 13.61 for early, intermediate, and late dry AMD patients whereas the improvement in OSDI scores for items 6 to 9 was 1.85, 2.89 and 1.8 for the respective groups. The mean improvement for SPEED scores with treatment (pretreatment minus 6-month post treatment) for the patients was 6.07, 4.78, and 9.6 for early, intermediate, and late dry AMD. (see Table 2). No significant difference was found between the score improvements in early, intermediate, or late dry AMD groups at p<0.05 (Table 2), showing that QOL improved with dry eye treatment irrespective of the severity of dry AMD (see Fig 1).

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Fig 1. Improvements in dry eye symptoms across AMD subgroups.

https://doi.org/10.1371/journal.pone.0318733.g001

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Table 2. Change in dry eye questionnaire scores with 3 AMD groups.

https://doi.org/10.1371/journal.pone.0318733.t002

This bar chart illustrates the score improvement across three AMD subgroups (Early, Intermediate, and Late AMD) following dry eye treatment. It compares improvements for the OSDI, OSDI (6–9), and SPEED questionnaires. Overlay Boxes highlight the overall mean improvement, standard deviation (SD), and statistical significance (p-value) for all AMD classes combined. The translucent boxes visually encompass all three AMD subgroups for each questionnaire. Significant improvements (p < 0.001) are observed across all groups, reflecting the positive impact of dry eye treatment regardless of AMD stage.

It should be noted that a higher score in the SPEED as well the OSDI questionnaire indicates worse subjective symptoms of dry eye. Thus, a negative value obtained when subtracting the 6-month post-treatment scores with pretreatment scores indicated improvement of DED. All the mean differences in scores we studied after treatment were improvements, meaning they were all negative scores.

To improve the robustness of our study findings, we conducted an additional analysis that classified the eyes into early and non-early AMD groups. Eyes with intermediate and late dry AMD were classified together and compared to eyes with early dry AMD for this analysis.

For the early dry AMD group, the mean total OSDI score, item 6–9 OSDI score, and SPEED score were 47.57, 6.58 and 17.57 respectively. For the non-early dry AMD group, these mean scores were 56.04, 8.78 and 14.42 respectively.

The total OSDI score improvement 6 months after treatment were 14.82 and 14.22 while OSDI 6–9 item score improvement were 1.85 and 2.5 respectively for the early and non-early AMD groups. The SPEED questionnaire score improvement for the respective groups were 6.07 and 6.5.

Like the previous analysis with three groups, there was no significant difference between improvement of total OSDI, OSDI 6–9 or SPEED question scores for the early and non-early dry AMD groups (p<0.05). Here again, dry eye treatment improved the symptomatic outcomes for all treated patients irrespective of the grade of dry AMD disease.

Discussion

Both AMD and dry eye disease contribute to visual symptoms including visual blurring, compromised night driving, reading speed and comprehension. Our study demonstrates that visual functioning improved following dry eye treatment, even in the presence of different stages of AMD pathology. It is logical that vision QOL improves across all three subgroups of AMD and that there seems to be no difference between the ability to improve QOL between AMD stages.

We observed a mean improvement of 6.2 in the SPEED questionnaire scores and 14.6 in the OSDI scores across all stages of AMD, however, there was only a small difference among the AMD stages. Since no significant differences were detected between early, intermediate, and late AMD groups, our findings suggest that dry eye treatment provides meaningful benefits to patients regardless of retinal disease stage. Separating the subjects into two groups—early and non-early AMD—provided a valuable supportive analysis, further demonstrating that the stage of AMD did not impact the response to dry eye management.

Our study is under powered to assess magnitude of QOL improvement after treatment across these subgroups. Indeed, a power analysis shows that a much larger study would be required with approximately 1000 eyes subdivided equally in each of the three subgroups to show if one AMD group had improvement more than the others.

It is possible that even with a larger sample size, our findings would retain the clinical significance of dry eye treatment in improving QOL across this population. Future research should aim to address these limitations through prospective study designs with larger, more diverse populations and a combination of subjective and objective outcome measures. Additionally, exploring the interplay between other retinal diseases and dry eye treatment outcomes could further advance our understanding of holistic eye care, particularly in populations with complex ocular comorbidities.

The most common form of dry eye treatment has traditionally been the use of topical lubricants. However, barriers such as the need for daily application, intolerance to preservatives, reduced dexterity in elderly individuals, and recurring costs can limit their lubricant effectiveness as does the short half-life of most lubricants instilled onto the ocular surface [29–33]. Therapies based on thermal expression of lipids from meibomian glands improves the physiology of the tear film and reduces lipid layer dysfunction and may eliminate or reduce the need for frequent eye drop use. Thus, their acceptance by patients is also likely to be better.

While our study demonstrates the benefits of treating dry eye disease in patients with AMD, several limitations should be acknowledged. First, the retrospective nature of the study may have introduced selection bias due to reliance on available clinical records and completed questionnaires. Second, subjective assessments like SPEED and OSDI are susceptible to patient perception and recall bias. Finally, the relatively small sample size limits the ability to determine differences amongst AMD groups.

Our study is unique in examining the relationship between AMD severity and the outcomes of dry eye treatment using validated quality-of-life (QOL) questionnaires, such as SPEED and OSDI. While prior research has demonstrated the benefits of managing ocular surface disease, none have investigated these effects in patients with coexisting retinal pathologies. 22 Our study demonstrates that improvements in QOL with dry eye treatment occur consistently across all stages of AMD. These findings highlight the importance of addressing treatable ocular conditions, even in the presence of advanced retinal disease.

Since both AMD and dry eye disease tend to affect the elderly population, it is common for AMD patients presenting to retina clinics to also have coexisting dry eye disease. Our results suggest that managing a patient’s dry eye can lead to meaningful improvements in vision related QOL, even in the presence of AMD. Thus, reduction in central vision by AMD does not preclude the need to treat dry eye and such treatment may enhance patient QOL and satisfaction.