Authors: Maria Miura, Takenori Inomata, Masahiro Nakamura, Jaemyoung Sung, Ken Nagino, Akie Midorikawa-Inomata, Jun Zhu, Keiichi Fujimoto, Yuichi Okumura, Kenta Fujio, Kunihiko Hirosawa, Yasutsugu Akasaki, Mizu Kuwahara, Atsuko Eguchi, Hurramhon Shokirova, Akira Murakami
Categories: Review, Cataract surgery, Characteristics, DED, Dry eye disease, MGD, Meibomian gland dysfunction, Meta-analysis, Prevalence, Risk factors, Systematic review
Source: Ophthalmology and Therapy
Dry eye disease (DED) after cataract surgery is associated with various risk factors, while causing a wide range of heterogeneous symptoms including decreased quality of vision. This systematic review and meta-analysis aimed to determine the prevalence and characteristics of DED after cataract surgery. We searched PubMed and EMBASE and included studies on patients with DED after cataract surgery, between January 2011 and June 2020. Study-specific estimates (DED prevalence rates after cataract surgery in patients without preexisting DED) were combined using one-group meta-analysis in a random-effects model. We included 36 studies published between 2013 and 2020. We included nine of these in the meta-analysis of DED prevalence after cataract surgery. Overall 37.4% (95% CI 22.6–52.3; 206/775) of patients without preexisting DED developed DED after cataract surgery. The risk factors for DED after cataract surgery included age, female sex, systemic diseases, systemic medications, psychiatric conditions, preexisting DED, meibomian gland dysfunction, preservatives in eye drops, surgery techniques, and lifestyle. DED severity peak occurred 1 day postoperatively and persisted for at least 1–12 months following cataract surgery; therefore, consistent follow-up for DED is warranted for at least 1 month after cataract surgery. Topical administration of preservative-free diquafosol tetrasodium solution and preoperative meibomian gland treatment were effective in preventing and treating DED following cataract surgery. As more than one-third of patients develop DED after cataract surgery, careful DED management and treatment is needed after cataract surgery to improve satisfaction and vision quality.
Keywords: Cataract surgery, Characteristics, Dry eye disease, Meta-analysis, Prevalence, Risk factors, Systematic review, DED, MGD, Meibomian gland dysfunction
Cataract surgery is an increasingly prevalent ophthalmic procedure owing to an aging society [1, 2]. Although it yields excellent results in most patients, some develop postoperative disorders, such as dry eye disease (DED) [3–5], with symptoms including dryness, foreign body sensation, and ocular fatigue [6, 7]. This negatively impacts the quality of vision (QOV) and work productivity and has economic repercussions [8], warranting preventative and management strategies for DED after cataract surgery [9].
The pathogenesis of DED after cataract surgery remains unclear, resulting in a lack of evidence-based, established treatment [9]. Moreover, there have been no systematic or large-scale studies on DED following cataract surgery in individuals without preexisting DED to comprehensively elucidate its risk factors, duration, and treatment.
This systematic review and meta-analysis aimed to summarize the current evidence to identify the prevalence, characteristics, perioperative risk factors, treatment, and preventative measures for DED after cataract surgery.
DED prevalence after cataract surgery was assessed by reviewing systematically evaluated and characterized studies focusing on risk factors, duration, treatment, and DED management after cataract surgery. From the relevant studies, we extracted pre- and postoperative results of DED examinations, including Ocular Surface Disease Index (OSDI) [10–12], tear film breakup time (TFBUT), Schirmer’s I test, corneal fluorescein staining (CFS), tear meniscus height (TMH), tear osmolarity values (TOV) [13], severity peak, and postoperative disease duration. In reports of multiple severity peaks regarding different parameters, the parameter with the most peaks was chosen. Priority was given to subjective symptoms (i.e., OSDI) for any inter-parameter differences.
We retrieved all articles published between January 1, 2011 and June 9, 2020 by combining the search terms [cataract AND (dry eye) NOT (review)] in key electronic bibliographic databases (PubMed, EMBASE). The search was conducted in June 2020. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines [14]. Table 1 presents the inclusion and exclusion criteria. The search results were compiled using EndNote X9.3.2 software (Clarivate Analytics, Philadelphia). To maintain the quality standards for reporting systematic reviews and meta-analyses of observational studies [15], the retrieved articles were screened by two researchers (M.M. and T.I.) who independently assessed eligible full-text articles through consensus.
Two independent reviewers (M.M. and T.I.) extracted the data from eligible articles using standardized data extraction sheets and then cross-checked the results. Inter-reviewer disagreements were resolved through discussions with a third reviewer (J.S.). The following data were first author name, publication date, study type, country, sample size, follow-up time after cataract surgery, and definition of DED. The following characteristics were assessed in patients with DED after cataract age, sex, ocular findings, DED prevalence, peak of DED severity, and duration of DED after cataract surgery. Ocular findings were assessed on the basis of the OSDI, TFBUT, CFS, Schirmer’s I test, TMH, TOV, and presence of meibomian gland dysfunction (MGD). Figure 1a summarizes the selection process used for identifying the published studies.
Fig. 1 a Flowchart of the systematic review—PRISMA flow diagram. b DED prevalence after cataract surgery. Forest plot of the prevalence rates of DED after cataract surgery in patients without preexisting DED. For each study, the symbol size corresponds to the sample size. DED dry eye disease, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Study-specific estimates (prevalence rates of DED after cataract surgery) were combined through one-group meta-analysis in a random-effects model using OpenMetaAnalyst version 12.11.14 (available from http://www.cebm.brown.edu/openmeta/) [16]. Subgroup analyses were performed using studies that reported on each specific outcome.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
The database search identified 280 articles (Fig. 1a). Three additional articles were selected from the reference lists of the included articles [17–19] and reviewed on the basis of their title and abstract. A total of 247 articles were excluded because of low relevance or article type (clinical guidelines, consensus documents, reviews, systematic reviews, and conference proceedings). Finally, 36 articles were included in the systematic review, nine of which were included in the meta-analysis to estimate the prevalence of DED after cataract surgery in patients without preexisting DED.
Table 2 presents the results of the included studies that were published between November 12, 2013, and June 3, 2020. The details include study type, country, sample size, follow-up time after cataract surgery, definition of DED, and DED-related clinical metrics such as OSDI and TFBUT.
Table 2 presents DED prevalence in patients without preexisting DED. Among 775 patients without preexisting DED in nine identified studies [6, 18, 20, 23, 30, 32, 37, 50, 51], 206 (26.6%) individuals developed DED after cataract surgery.
A one-group meta-analysis of the nine studies reporting on DED prevalence after cataract surgery [6, 18, 20, 23, 30, 32, 37, 50, 51] yielded a 37.4% prevalence rate (206/775; 95% CI 22.6–52.3; Fig. 1b).
Table 2 summarizes the severity peak and duration of DED after cataract surgery. Although early postoperative ocular surface changes began to recover within a month of cataract surgery [38], most studies reported that DED parameters, including subjective symptoms, TFBUT, CFS, tear secretion volume, and MGD, did not recover to baseline values by the end of the study, indicated as “> (study period).” The peaks of DED severity usually occurred 1 week after cataract surgery, although the reported values ranged from 1 month to more than 1 year [6, 17, 19–23, 26, 27, 29–35, 37, 40, 41, 44, 57, 58]. Notably, eight out of the 22 articles that reported severity peak at 1 month postoperatively had their first measurement at 1 month [22, 26, 29–31, 35, 43, 46]. Several studies showed varying persistence of DED and ocular surface abnormalities ranging from 2 week to 12 months after cataract surgery [17, 18, 20, 21, 26, 29, 33, 35, 40, 44, 46, 51, 55, 56, 58], possibly preceded by a higher than baseline OSDI, short TFBUT, and MGD at 1 month postoperatively [35]. Corneal denervation or a higher TFBUT score induced by cataract surgery returned to baseline levels within 1–3 months of surgery [17, 59]. Jun et al. [46] reported that preservative-free diquafosol showed better efficacy regarding meibum quality at 1 and 3 months after cataract surgery than preservative-containing diquafosol or preservative-free hyaluronate.
Accurately recognizing the individual risk factors and initiating perioperative intervention is critical for patients with preexisting DED, particularly for those with minimal signs or symptoms. This section discusses the reported risk factors (Table 3) and prevention/intervention strategies (Table 4) for DED after cataract surgery.
Older age and female sex were associated with DED after cataract surgery [18, 25, 30, 34, 37, 55]. Notably, Kohli et al. [37] showed that individuals above the age of 60 years had worse OSDI, Schirmer test results, TFBUT, CFS, and TMH at 2 weeks post-cataract surgery. Prolonged exposure to visual display terminals, particularly in developed countries, is of concern for the increasing global DED prevalence [61–66]. Villani et al. [51] suggested that the use of computers might exacerbate DED after cataract surgery, advising minimal visual display terminal use during recovery.
The association between DED after cataract surgery and diabetes mellitus was reported [51]. Sajnani et al. [18] evaluated the epidemiology of persistent postsurgical pain (PPP), which manifested as DED-like symptoms for 6 months postoperatively. Autoimmune disorders, non-ocular chronic pain disorder, and use of antihistamines, anti-reflux medication, antidepressants, anxiolytics, and anti-insomnia medication were reported as risk factors for PPP; hormone replacement therapy, thyroid malfunction, psychiatric conditions, and systemic medication were also reported as risk factors for postoperative DED [51].
Two studies [27, 50] reported correlations between preexisting DED and DED after cataract surgery. These studies suggest that preexisting DED may lead to more severe DED postoperatively. Traditional DED metrics that may predict DED after cataract surgery included TFBUT [30, 35, 51], higher CFS [30, 51], conjunctivochalasis [51], Schirmer’s I test score [51], and TOV [25]. Additionally, the Ocular Surface Frailty Index (OSFI), developed for DED symptom-onset after cataract surgery [51], might aid in predicting ocular surface symptoms with OSFI ≥ 0.3. Lid-parallel conjunctival folds and ocular allergy predicted DED to some extent [51].
MGD affects tear-film stability and is strongly associated with DED [67]; the accelerated tear-evaporation rate and the subsequent tear hyperhidrosis in MGD likely trigger DED development [35, 43, 51, 52, 68]. Clinically, this is observed as MGD aggravated by cataract surgery, with a positive correlation between MGD and DED-related indicators including postoperative TFBUT and CFS [52]. Conversely, a Chinese trial [43] has shown that preoperative MGD management might allow effective and optimal alleviation of obstructive-MGD and DED induced by cataract surgery.
Preservative-containing topical eye drops for intraoperative or postoperative use, including benzalkonium chloride, may cause ocular surface damage stemming from epithelial cell injury and apoptosis and reduced goblet cell density [69, 70]. Jee et al. [22] compared the efficacy of preservative-free versus preservative-containing sodium hyaluronate 0.1% and fluorometholone 0.1% eye drops after cataract surgery. The preservative-free group showed superior DED-related metrics, impression cytology findings, goblet cell count, tear interleukin-1β and tumor necrosis factor-α levels, and catalase and superoxide dismutase levels at 2 months postoperatively. Further, a Korean study reported that compared with preservative-containing diquafosol, preservative-free diquafosol 3% showed better efficacy in treating DED after cataract surgery [46].
Kato et al. [31] observed the negative effects of topical non-steroidal anti-inflammatory drugs (NSAIDs) after cataract surgery on conjunctival goblet cell density, raising concerns about DED with prolonged topical NSAID administration. Interestingly, topical rebamipide, widely used to prevent oral NSAID-induced gastric mucosal damage [71], counteracts the reduction of conjunctival goblet cell density induced by diclofenac [31].
Artificial tears and sodium hyaluronate 0.1% are common first-line treatments for DED [66, 72]; however, treatments are shifting toward more complex and effective topical drops [73]. Diquafosol tetrasodium solution is reportedly effective for DED treatment after cataract surgery with comparative benefits over artificial tears or sodium hyaluronate 0.1% [29, 30, 33, 46].
Addition of trehalose to sodium hyaluronate also effectively reduces DED symptoms and improves clinical outcomes (TFBUT, OSDI) after cataract surgery, possibly owing to its propensity for deep hydration, lipid and protein stabilization, protection against oxidative insult, and epithelial cell recovery [45]. Fogagnolo et al. [54] reported improvements in TFBUT and OSDI with antioxidant solution usage for 2 weeks pre- and postoperatively, implicating antioxidants in protecting ocular surface homeostasis from surgical invasions. Oral lactoferrin [23] and omega-3 fatty acid [60] (over-the-counter supplements established as effective adjuvants for DED treatment) have also been implicated in the management of DED after cataract surgery.
Increased duration of surgery and longer phacoemulsification time may be risk factors for postoperative DED, compounded by increased microscopic light exposure [37]. Further, femtosecond laser-assisted cataract surgery is among the reported risk factors for DED after cataract surgery [6, 40, 44, 74], likely owing to peri-conjunctival injury caused by the femtosecond laser suction ring.
These results suggest that light filters, short surgery duration, adequate irrigation, and soft manipulation of the ocular surface tissue may minimize surgery-related complications [20]. Use of an ophthalmic viscosurgical device—normally used to prevent intraocular tissue damage during cataract surgery—on the ocular surface has shown protective effects for a week postoperatively with significant improvements in TFBUT, corneal ocular staining score, and OSDI [48]. Administration of hydroxypropyl methylcellulose on the corneal surface also results in improved clinical outcomes related to tear film and ocular surface health [32].
This is the systematic review and meta-analysis to comprehensively present DED prevalence after cataract surgery that included 775 individuals from nine articles [6, 18, 20, 23, 30, 32, 37, 50, 51]. We observed that 37.4% (95% CI 22.6–52.3; 206/775) of patients without preexisting DED developed DED postoperatively, highlighting the importance of perioperative DED management in addressing postoperative patient dissatisfaction and decreased QOV. The global DED prevalence is 5–50% [75]; inclusion of cataract surgery-related DED may expand it to half of the global population. Thus, a thorough and effective DED assessment during the perioperative period of cataract surgery is warranted [8, 62].
The major mechanisms underlying DED pathogenesis include tear-film instability and ocular surface inflammation [47, 76–80]. We observed that DED after cataract surgery was weakly and strongly associated with tear secretion (Schirmer’s I test) and TFBUT, respectively [22, 29, 30, 35, 44, 52]. Additionally, postoperative upregulation of inflammatory mediators contributes to DED development [27, 77–81], which simultaneously alters subjective perception and sensitivity of the ocular surface nerve plexuses [82]. This might be attributed to the surgical procedure itself and/or preservatives in postsurgical eye drops, both of which contribute to inflammation and tear-film instability [37, 83, 84]. Larger corneal wounds [84], longer microscopic exposure times [21, 37], and greater phacoemulsification energy [37] increase the likelihood of DED after cataract surgery, including the persistent decrease of conjunctival goblet cells despite an uncomplicated phacoemulsification [59, 84].
MGD is closely related to DED pathology [35, 43, 52], and Han et al. [21] reported persistent MGD after cataract surgery without accompanying structural changes even in patients without preexisting MGD. A Japanese study [56] focused on TFBUT patterns in patients with DED after cataract surgery, observing a random break pattern that was predominant during the postoperative period, which is a common feature in evaporative DED and is often associated with MGD [85]. Therefore, owing to potential comorbidity, MGD should be preoperatively evaluated in all patients regardless of preexisting DED [21, 26, 35, 52].
Additionally, we investigated the risk factors for DED after cataract surgery, which were consistent with the characteristics reported by epidemiological studies on DED in the elderly [86]. Patients with traditional DED risk factors [8, 63–65] may present with DED after cataract surgery; therefore, preventative measures should be considered. Other non-ocular risk factors include various systemic diseases, systemic medications, and psychiatric conditions. Notably, diabetes mellitus is among the systemic risk factors for DED [87], likely affected by tear hyperosmolarity and tear-film instability resulting from dysfunction of lacrimal functional units and the ocular surface. The effects of hyperglycemia on the lacrimal gland functional unit components are systematically transmitted via neural connections, resulting in abnormal tear production and composition, both of which contribute to DED [8]. Ultrasonic energy produced during phacoemulsification can cause free radical formation [88], which may compound the damage. Although the exact underlying mechanisms remain unclear, other systemic diseases and treatments damage the conjunctiva, lacrimal glands, goblet cells, and peripheral nerve innervations, predisposing the affected population to DED after cataract surgery.
There is a recent consensus regarding the concomitant role of neurogenic stress and ocular surface inflammation on DED pathogenesis [8]. Additionally, DED is associated with other chronic pain conditions and may alter the genetic susceptibility for depression [65, 89]. Patients with DED usually present with chronic pain syndromes, which are associated with increased severity of subjective DED symptoms, even with comparable objective ocular surface signs [90]. Anxiety disorders and usage of anxiolytics, antidepressants, or sleep medication are also associated with DED after cataract surgery [18]. Extrapolating the psychogenic effects on ocular sensations, it is possible that only the subjective indicators are elevated for specific populations, although further studies are required to validate the hypothesis. The relationship between surgical techniques and DED after cataract surgery was also analyzed. Studies have reported a correlation of DED examination values with microscopic light exposure time [37] and phacoemulsification energy used [37]; surgeons should strategize to minimize both factors in patients with preoperative DED or risk factors.
Pathological changes and inflammatory kinetics preceding DED after cataract surgery are crucial when determining postoperative treatment and management. DED severity after cataract surgery tends to peak around 1 week postoperatively [6, 19, 20, 32, 34, 40–42, 44, 45, 52–54]. Notably, numerous studies reported postoperative follow-ups scheduled after 1 week and 1 month, and the true peak of DED symptoms most likely lies within this time period. Kasetsuwan et al. [20] proposed that the timeline of corneal neuron regeneration and DED symptom exacerbation within 1 postoperative month may be correlated. As new neurite cells emerge, there is a stark increase in neural growth factors at 25 days postoperatively, indicative of sub-epithelial corneal axon regeneration. Khanal et al. [91] reported that alterations in corneal neuronal plexuses and a postoperative decrease in the blink rate reduced corneal sensitivity and feedback. Moreover, the authors reported recovery of tear functions within 1 postoperative month, supporting the existence of a DED peak within 1 week and 1 month postoperatively. Notably, this result also coincides with the observed increased tear evaporation up to 1 month postoperatively, associated with usage of benzalkonium chloride preservatives [92].
DED duration after cataract surgery is clinically important. Studies have reported a wide range of DED duration, from 1 months to more than 1 year [17, 18, 20, 21, 26, 29, 33, 35, 40, 44, 46, 51, 55, 56, 58]. Further, some studies have reported that surgery-induced invasive corneal changes recover within 1–3 months [17, 59]. The long-term effects of DED after cataract surgery remain unclear as most patients, particularly after successful bilateral cataract surgery, require follow-up for only a few months. While further studies are needed, the results show that consistent follow-up for DED is necessary for at least 1 month after cataract surgery.
Postoperative eye drops should be carefully selected owing to variable efficacy and the presence of preservatives. Several studies have suggested a correlation between preservatives and DED after cataract surgery [22, 46], advising preservative-free treatment options for surgery recipients. Considering the multifactorial pathophysiology of DED and the wide-ranging effects of cataract surgery on the ocular surface, future strategies for addressing DED after cataract surgery require surgeons to gain a better understanding of treatment and prevention methods.
This review has several limitations. First, only a few included studies had a follow-up period of more than 1 year, which limited the analysis of long-term effects. Second, approximately three-quarters of the included articles were published in Asian countries, which partially limits the generalizability of the findings. Third, the criteria and dry eye examination techniques for DED diagnosis have not been standardized across countries and practices, and the included studies showed inconsistencies in their diagnostic standards. Future studies should consider further standardization of the diagnostic criteria and generalizability of the study results through the inclusion of participants of different ethnic groups, longer observation periods, and use of standardized guidelines for DED diagnosis, such as those proposed by the Tear Film & Ocular Surface Society [47] and the Asia Dry Eye Society [76].
This study comprehensively analyzed DED prevalence and characteristics after cataract surgery. It presents a concise and up‐to‐date description of the risk factors, prevention, and treatments. Our findings contribute to generating increased awareness among physicians, researchers, and the general population regarding DED after cataract surgery and encourage the development of effective preventative and treatment strategies.
The authors thank all members of the Department of Ophthalmology, Juntendo University Graduate School of Medicine for their critical comments on this manuscript.
This work was supported by JSPS KAKENHI Grant Numbers JP20KK0207 (Takenori Inomata) and JP21K20998 (Atsuko Eguchi). The journal’s Rapid Service Fees were funded by the authors.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Concept and Takenori Inomata. Acquisition, analysis, or interpretation of All authors. Drafting of the Maria Miura, Takenori Inomata, and Jaemyoung Sung. Critical revision of the manuscript for important intellectual All authors. Statistical Maria Miura, Takenori Inomata, Masahiro Nakamura, and Akie Midorikawa-Inomata. Administrative, technical, or material Maria Miura, Takenori Inomata, Ken Nagino, Akie Midorikawa-Inomata, Jun Zhu, Keiichi Fujimoto, Yuichi Okumura, Kenta Fujio, Kunihiko Hirosawa, Yasutsugu Akasaki, Mizu Kuwahara, Atsuko Eguchi, and Hurramhon Shokirova. Supervision: Akira Murakami.
Dr. Takenori Inomata reported receiving a grant from Johnson & Johnson Vision Care, Inc, Hogy Medical Co, Ltd, SEED Co, Ltd, Santen Pharmaceutical Co, Ltd, Alcon Japan Ltd, Lion Ltd, InnoJin Co, Ltd; personal fees from Santen Pharmaceutical Co, Ltd, outside the submitted work. Dr. Akira Murakami reported receiving grants from Eisai Co, Ltd, Kowa Ltd, Novartis Pharma K.K., HOYA Corporation, ROHTO Pharmaceutical Co, Ltd, Alcon Japan Ltd, AMO Japan K.K., Otsuka Pharmaceutical Co, Ltd, SEED Co, Ltd, Senju Pharmaceutical Co, Ltd, Novartis Pharma K.K., Pfizer Japan Inc, and Santen Pharmaceutical Co, Ltd; personal fees from Johnson & Johnson Vison Care, Kowa Ltd, and Lion Ltd, outside the submitted work. No other disclosures were reported.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
All data relevant to the study are included in the article.
All data relevant to the study are included in the article.