Diagnostic methods for managing dry eyes

Abstract

BACKGROUND

Dry eye disease (DED) represents a multifactorial condition characterized by ocular discomfort and visual disturbances. The management of DED relies heavily on accurate diagnosis to tailor effective treatments. Diagnostic approaches encompass both subjective and objective assessments.

AIM

To review the diagnostic methods used in the process of dry eye disease management.

METHODS

A comprehensive review of diagnostic approaches for dry eye was performed using scientific databases. Studies published within the last four years were considered. Studies were excluded if a full text was absent or the article was not written in English. Articles were assessed for relevancy, and a total of 107 studies were selected. The selection method used a systematic methodology, which guaranteed an exhaustive assessment of the diagnostic techniques reported in current literature. The study adheres to principles for systematic reviews ensuring dependability and accuracy. The studies were assessed for emphasize on both novel traditional and diagnostic methods for dry eye disease management.

RESULTS

Key objective tests include tear break-up time, which evaluates tear film stability; fluorescein and lissamine green staining, which assess ocular surface damage and inflammation; tear osmolarity measurement, indicative of tear film quality; and tear volume assessment via Schirmer's test, which evaluates tear production. Advanced imaging techniques such as optical coherence tomography and meibography offer detailed anatomical insights into the ocular surface and meibomian glands, aiding in the diagnosis of underlying structural abnormalities. Moreover, emerging technologies such as matrix metalloproteinase-9 testing and inflammatory biomarkers provide additional diagnostic precision, particularly in identifying inflammatory components of DED.

CONCLUSION

Integrating a combination of subjective and objective diagnostic tools allows clinicians to comprehensively assess the condition, tailor treatment plans, and monitor therapeutic efficacy. Continued advancements in diagnostic technologies promise to enhance our understanding and management of this prevalent ocular condition.

Key Words: Dry eye syndrome; Diagnostic methods; Tear film stability; Ocular surface; Meibomian glands

Core Tip: Keratoconjunctivitis sicca, or dry eye disease (DED), is a common ocular illness with different incidence rates worldwide. The complicated etiology of DED involves tear film instability and can cause pain, decreased vision, and ocular surface damage. Evaporative and aqueous-deficient dry eye have different causes. Differentiating between these types is often required for appropriate diagnosis and effective therapy. A detailed diagnosis is needed as Sjögren's syndrome, an autoimmune condition, is connected to a type of DED. Recent advances aim to standardize diagnosis and improve therapy by addressing the causes of DED.

INTRODUCTION

Dry eye disease (DED), also known as dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS), is a common ocular condition affecting millions globally, with prevalence rates ranging from 5% to 50%[1-3]. This multifactorial disease of the ocular surface causes discomfort and visual disturbances[4] and is more likely to be encountered in primary care settings rather than secondary or tertiary centers[5]. The tear film, which consists of mucin, aqueous, and lipid layers[6], can become unstable due to disruptions in the normal anatomy or physiology of these layers. This instability may result from qualitative or quantitative abnormalities in the tear film’s aqueous, lipid, and mucin layers.

The 2017 DEWS II report redefined DED as “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles”[7]. Ongoing Delphi analyses aim to enhance understanding of DED and establish a standardized framework for its diagnosis and management[8].

DED can result from reduced tear secretion by the lacrimal glands, increased tear evaporation, or the production of poor-quality tears. This tear instability can lead to ocular surface inflammation, damage, and abnormal nociception[9]. Symptoms include burning, foreign body sensations, blurred vision, and redness, which can cause discomfort and reduce work efficiency and quality of life[10]. Complications may include conjunctival scarring or corneal issues that can impair vision[11].

The primary roles of the aqueous component of the tear film are to lubricate the surface of the eye, remove unwanted objects or contaminants, and provide nourishment to the cornea, which lacks blood vessels (such as oxygen, inorganic salts, proteins, and glucose)[12]. Consequently, when these glands are not functioning properly, there is a decrease in the production of necessary fluids and other important substances required to maintain and protect the surface of the eye. This leads to dry eye and possibly severe damage to the eye's surface[13]. Dry eye is a prevalent ocular condition, with an estimated prevalence of 14% to 33% in adults, which tends to increase with age[14]. It is often accompanied by other ocular conditions, such as impaired vision[15]. The variation in the occurrence and frequency of dry eye in different regions of the world has been attributed, in part, to interracial variances across populations[16]. The preservation of clear vision and ocular comfort relies on the integrity and stability of the air-tear film interface, which serves as the principal refractive surface of the eye[17]. The more severe symptoms of DED are linked to reduced job productivity and activity levels, both when comparing different individuals (cross-sectionally) and over time within the same person (intra-individually)[18].

DED is a diverse disorder with multiple poorly understood subcategories, broadly classified into aqueous-deficient and evaporative DED. Five distinct subgroups have been identified, each exhibiting substantial differences in demographics, symptoms, clinical signs, and associations with systemic diseases[19]. These include: (1) Sjögren’s syndrome-related DED; (2) Non-Sjögren aqueous deficit; (3) Intrinsic evaporative DED; (4) Extrinsic evaporative DED, and (5) Mixed mechanism DED, aiding clinicians in implementing tailored treatment strategies[20,21]. Meibomian gland dysfunction (MGD) accounts for approximately 60% of DED cases, leading to a deficiency in tear film lipids and causing intrinsic evaporative DED. Conversely, extrinsic evaporative DED stems from environmental factors such as contact lens wear or ocular surface disorders. Sjögren’s syndrome and other autoimmune conditions also play a significant role in aqueous-deficient DED[19]. The diagnosis of DED relies on meibography, lipid layer thickness evaluation, and evaporimetry, which help differentiate between subtypes and guide appropriate management[21].

Primary Sjögren's Syndrome (PSS) is a persistent condition characterized by symptoms of dryness in the mouth and eyes, as well as discomfort, exhaustion, anxiety, and despair. The Newcastle Sjögren's Stratification Tool may classify PSS patients based on the severity pattern of five significant symptoms[22]. Research revealed a higher prevalence of primary Sjögren syndrome in women compared to males. This condition is characterized by increased dryness, positive autoantibodies[23,24], and a higher likelihood of co-occurring primary biliary cholangitis (PBC) in adults. The presence of PSS influences the clinical characteristics of PBC[25]. Oral dryness is a prominent characteristic of Sjögren syndrome, a condition linked to a higher likelihood of developing oral disorders and a worse quality of life-related to oral health[26]. Sjögren's syndrome dry eye (SSDE) is a specific form of dry eye that differs from non-SSDE (NSSDE). It is a subtype of Sjögren's disease characterized by dry eye symptoms. Timely detection of SSDE is crucial as it might lead to significant complications. Nevertheless, differentiating between SSDE and NSSDE[27,28] remains challenging due to the same clinical signs.

KCS, sometimes referred to as NSSDE, is a prevalent disorder marked by persistent dryness and irritation of the eyes. NSSDE, in contrast to Sjögren's syndrome, has no connection to an autoimmune illness that impacts tear-producing glands[29]. Alternatively, it can be attributed to many causes, such as environmental influences, hormone fluctuations, certain drugs, and natural aging[30]. Common symptoms of this condition include enduring dryness, a sensation of grittiness, and a burning feeling in the eyes. Additionally, individuals may have impaired vision and heightened sensitivity to light. Possible treatment modalities encompass the administration of artificial tears, prescription drugs, and modifications in lifestyle, such as using humidifiers and evading arid surroundings[31]. Sjögren's syndrome is associated with digestive[32], dental[33-35], cardiovascular[36-39], and renal health consequences[40,41]. DED can also arise as a result of other ocular/systemic disorders such as thyroid eye disease[42] and fibromyalgia[43]. Views on the management of dry eye can diverge significantly[44], even among a specific subset of people. Extensive research conducted in India found that 39.62% of dry eye patients had evaporative dry eye, whereas 34.7% had aqueous deficient dry eye[45].

The successful management of DED depends on the precise diagnosis of the condition to determine the root cause and use the most suitable treatment method[46,47]. This study examines the existing diagnostic procedures for DED, including their advantages and disadvantages. It also discusses new approaches that are being developed and have the potential to enhance the diagnosis and treatment of DED.

MATERIALS AND METHODS

The authors searched the PubMed database using “Diagnostic methods in managing dry eyes” as keywords, as shown in Table 1.

Table 1 Search components and resulting algorithms.

Search component	Keywords used
Diagnostic	"diagnosis" [MeSH Terms] OR "diagnosis" [All Fields] OR "diagnostic" [All Fields] OR "diagnostical" [All Fields] OR "diagnostically" [All Fields] OR "diagnostics" [All Fields]
Method	"methods" [All Fields] OR "methods" [MeSH Terms] OR "methods" [All Fields] OR "method" [All Fields] OR "methods" [MeSH Subheading] AND "manage" [All Fields]
Manage	"manage" [All Fields] OR "managed" [All Fields] OR "managements" [All Fields] OR "managements" [All Fields] OR "manager" [All Fields] OR "managers" [All Fields] OR "managers" [All Fields] OR "manages" [All Fields] OR "managing" [All Fields] OR "management" [All Fields] OR "organization and administration" [MeSH Terms] OR ("organization" [All Fields] AND "administration" [All Fields]) OR "organization and administration" [All Fields] OR "management" [All Fields] OR "disease management" [MeSH Terms] OR ("disease" [All Fields] AND "management" [All Fields]) OR "disease management" [All Fields])
Dry eye syndromes	("dry eye syndromes" [MeSH Terms] OR ("dry" [All Fields] AND "eye" [All Fields] AND "syndromes" [All Fields]) OR "dry eye syndromes" [All Fields] OR ("dry" [All Fields] AND "eye" [All Fields]) OR "dry eye" [All Fields])) AND ((ffrft[Filter]) AND (2020: 2024[pdat])).

Records that were not in the English language, lacked full text, and/or not relevant were further excluded as shown in the PRISMA[47] flowchart below in Figure 1. The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist (Figure 1).

Figure 1 PRISMA guideline showing retrieved records stratification.

RESULTS

The search string initially returned 914 records. Articles published more than 4 years ago and those not in English were excluded, leaving 199 records. Additionally, articles that were not available as free full text and lacked abstracts were excluded. This filtering process resulted in 199 articles, which were then retrieved by the authors. One publication was excluded because it had been retracted, another two on the basis of language, and 89 publications were not used because they were out of scope. A total of 107 publications were included in this review. A spread of the number of papers included as segregated by year of publication is shown in Figure 2[48-53].

Figure 2 Distribution of records used by year.

DISCUSSION

Some of the diagnostic methods reviewed are shown in Table 2. Accurate diagnosis and management of dry eye are essential for improving patient quality of life[54]. While objective measurements are crucial for diagnosing and managing DED, subjective evaluations provide valuable insights into the patient's experience[55]. Subjective evaluations, which include patient-reported symptoms and standardized questionnaires, are critical components in the diagnostic process[56].

Table 2 Diagnostic methods for dry eye curated from sampled records.

Method	Ref.	Sample size	Diagnostic rubric
American-European consensus group classification criteria	Lee et al[48]	187 serum samples of age matched females	Authors suggest peptides treated with malondialdehyde increase the formation of autoantibodies, suggesting that they have diagnostic utility for primary Sjögren's Syndrome
Existing data analyses	Acar-Denizli et al[49]	12084 patients with ESSDAI scores	Combination patterns of two antibodies-anti-Ro/SSA and anti La/SSB was used to define Sjogrens syndrome
Machine learning algorithm using routine healthcare data	Dros et al[50]	1411 primary Sjögren's Syndrome patients and 929179 non-primary Sjögren's Syndrome patients	The task entailed employing logistic regression and random forest models for the purpose of categorizing patients. The models used characteristics such as age, gender, medical conditions, symptoms, medication prescriptions, and visits to general practitioners
Diagnostic criteria by Japanese research committee on severe cutaneous adverse reaction	Sotozono et al[51]	94 Stevens-Johnson syndrome and toxic epidermal necrolysis patients with severe ocular complications	The diagnostic criteria for ocular involvement in instances of Stevens-Johnson syndrome and toxic epidermal necrolysis include particular ocular abnormalities, such as the creation of pseudo-membranes and defects in the epithelium. These symptoms are regarded to be high-risk indicators for ocular complications
DryEyeRhythm mobile app	Inomata et al[52]	4454 individuals	The diagnostic rubric involved assessing subjective symptoms reported by the participants via the DryEyeRhythm app. The DryEyeRhythm is a mobile application that facilitates real-time monitoring of DED symptoms, allowing for remote symptom tracking and prompt intervention
Ultrasonographic techniques (grayscale and color Doppler sonography) and contrast-enhanced ultrasonography	Xu et al[53]	161 patients with primary Sjögren's Syndrome and 66 non primary Sjögren's Syndrome patients	The diagnostic approach entailed assessing the ultrasonographic characteristics of the parotid and submandibular glands. Ultrasonographic methods, encompasses grayscale and Doppler imaging, to evaluate lacrimal gland structure and vascularity in patients with DED

DED: Dry eye disease; ESSDAI: European league against rheumatism Sjogren's syndrome disease activity index.

Patient-reported symptoms and questionnaires

The diagnosis of DED is based mostly on the symptoms stated by the patient, as this gives direct insight into their experience. These symptoms include various discomforts, such as dryness, burning, stinging, grittiness, and vision problems[57]. Patients frequently complain of a chronic feeling of dryness or not enough tears, which can be made worse by external conditions like wind or low humidity[58]. Patients may also complain of these symptoms after prolonged screen time, which results in digital strain[59].

Clinical visits usually entail comprehensive patient discussions to assess these symptoms. Inquiries concerning symptoms' onset, length, frequency, and severity are among the detailed qualitative data collected. These data are essential for modifying treatment regimens to meet each patient's needs and tracking the long-term efficacy of treatments[60]. A thorough medical history is needed, as studies suggest a relationship between the white blood cell population and the symptoms experienced in DED patients[61]. Barrio-Cortes et al[62] concluded that other comorbidities positively correlated to the likelihood of patients presenting for treatment.

Ocular surface disease index

The ocular surface disease index (OSDI) is a questionnaire designed to measure the severity of dry eye symptoms and their impact on daily activities. It covers three main areas: Environmental triggers, visual function, and ocular symptoms[63]. The questionnaire consists of twelve questions, each scored from 0 to 4, with higher scores indicating more severe symptoms[64]. The total OSDI score ranges from 0 to 100 and helps track symptom progression and treatment effectiveness[65]. Table 3 below provides more comprehensive information on the OSDI questionnaire[63-65].

Table 3 Ocular surface disease index questionnaire and scoring system¹.

Category	Questions	Scoring (0-4)
Ocular symptoms	Dryness, grittiness, discomfort	0 (None) to 4 (Severe)
Visual function	Blurred vision, difficulty reading	0 (None) to 4 (Severe)
Environmental factors	Wind sensitivity, air conditioning	0 (None) to 4 (Severe)

¹The ocular surface disease index score is calculated as: Total score = (Sum of responses) × 25/number of questions answered, giving a 0-100 range.

Standard patient evaluation of eye dryness

The standard patient evaluation of eye dryness (SPEED) questionnaire, developed by Korb and Blackie, is a tool used to quickly assess and track the symptoms of DED. It consists of eight questions evaluating the frequency and severity of symptoms such as dryness, grittiness, soreness, irritation, burning, watering, and eye fatigue[66]. Patients rate their symptoms on a scale from 0 to 4, with a total score ranging from 0 to 28. This standardized method helps healthcare providers monitor symptom progression and identify triggers, making it easier to diagnose and manage DED[67]. Its simplicity and efficiency make it useful in both clinical settings and research studies. Table 4 below provides more comprehensive information on the SPEED questionnaire[66,67].

Table 4 Standard patient evaluation of eye dryness questionnaire¹.

Question type	Symptoms evaluated	Scoring (0-4)
Frequency	Burning, grittiness, fatigue	0 (Never) to 4 (Constant)
Severity	Discomfort level	0 (None) to 4 (Severe)

¹The total standard patient evaluation of eye dryness score (0-28) provides a measure of symptom burden, aiding in dry eye disease diagnosis.

McMonnies dry eye questionnaire

The McMonnies questionnaire is a diagnostic tool used to evaluate the severity and frequency of dry eye symptoms and identify risk factors[68]. It asks about environmental triggers and systemic conditions to help clinicians understand the underlying causes. Higher total scores indicate a greater likelihood of DED, aiding in diagnosis and treatment planning, which may include artificial tears, lifestyle changes, or other therapies to improve the patient's quality of life[69]. Table 5 below provides more comprehensive information on the McMonnies questionnaire[68,69].

Table 5 McMonnies questionnaire¹.

Question type	Symptoms evaluated	Scoring (0-4)
Risk factors	Age, sex, contact lens use, medications, systemic diseases (e.g., Sjögren’s)	Yes/No responses (Binary)
Symptoms frequency	Dryness, grittiness, burning, excessive tearing	0 (Never) to 3 (Frequent)
Symptom severity	Eye discomfort, irritation, redness	0 (None) to 3 (Severe)
Triggers	Environmental factors (wind, air condition, smoke), screen time impact	Yes/No responses (Binary)

¹The total McMonnies score (0-45) helps assess dry eye disease severity, with higher scores (≥ 14) indicating significant dry eye disease.

Subjective assessments are essential in diagnosing DED, although they require supplementation with objective metrics for precision. The OSDI and SPEED questionnaires offer symptomatic insights but should not serve as the exclusive diagnostic criterion. The OSDI and SPEED questionnaires are mostly diagnostic, evaluating symptom load. The McMonnies questionnaire is primarily designed for screening, but the DryEyeRhythm app facilitates the longitudinal tracking of symptoms. Clinicians must choose instruments according to the specific therapeutic purpose.

Objective measures-tear film stability, ocular surface integrity, and tear production

Proteomic indicators and exosomal biomarkers are recent means of objectively assessing tear film stability in dry eye treatment[70,71]. Although there are many high-end means of objectively assessing individuals with dry eyes, with each method having a specific level of specificity and sensitivity, the gold standard still remains the tear film ocular surface algorithm[72].

In the future, a workup on the particular microbes present in the anterior segment will help control inflammation and ocular surface complications from DED[73].

Tear break-up time, which evaluates tear film stability

Tear break-up time (TBUT) assesses tear film stability by the application of fluorescein dye. A TBUT of less than 10 seconds indicates tear instability. The flowchart image below in Figure 3 illustrates the steps in measuring TBUT. Following a case-control study carried out by Pu et al[74], it was observed that assessing first non-invasive TBUT, average non-invasive TBUT, tear meniscus height, and meibomian gland assessment showed a correlation between the onset of obstructive sleep apnea and the onset of DED[74-76]. Ocular surface temperature reduces following phacoemulsification cataract surgery, partly due to instability of the tear film[77], potentially disrupting the tear film (Figure 3).

Figure 3 Tear break-up time diagnostic flowchart. TUBT: Tear break-up time.

Fluorescein, rose bengal, and lissamine green staining, which assess ocular surface damage and inflammation

Ocular staining scores evaluate corneal damage utilizing fluorescein or lissamine green dyes, with grading determined by staining intensity. Ocular staining score has been found to have a higher degree of sensitivity and specificity when compared to other dry eye diagnostic parameters[78]. Sahlu et al[79] conducted a cross-sectional study and observed a significant drop in TBUT and corneal staining in glaucoma patients, especially those on multiple drops[79,80].

Using parameters like the Schirmer test score, Corneal staining score, and worse composite DED sign score as criteria for gender prevalence of complaints and in premenopausal and post-menopausal women, the result was in favor of premenopausal women compared to those that have reached menopause[81]. Software assessment of corneal staining, compared to individual objective assessment, shows more accuracy and is deemed fit to be used for monitoring purposes[82-84].

Tear osmolarity measurement, indicative of tear film quality

It was found in the DREAM study that there is no significant relationship between tear osmolarity in a patient with dry eyes and DED symptoms, so changes in tear film osmolarity cannot be regarded as a causal factor for the development or worsening of dry eyes[85,86]. A controlled environment chamber technique can be used in the assessment of dry eye complaints and symptoms, as it allows researchers to manipulate the testing location while observing tear parameters[87]. The OcuSense TearLab osmometer is a digital device that measures tear osmolarity from a very small sample. García et al[88]showed that this osmometer had good reproducibility indices and as such, can be very handy in DED diagnosis.

Tear volume assessment via Schirmer's test, evaluating tear production

The Schirmer’s test evaluates tear volume using a wettable strip inserted into the lower fornix. Tortuous meibomian gland and a high composite score for features of the meibomian gland was associated with longer TBUT and longer length on the Schirmer strip[89]. The Schirmer test is the most common test for tear quantity and it is a tool for verifying/standardizing other tear volume testing techniques[90,91].

In cases of aqueous-deficient DED, Schirmer's test and tear osmolarity assessments are the most pertinent. In evaporative DED, meibography and lipid layer thickness assessment are essential. The prognostic evaluation is enhanced by OCT-based monitoring of tear meniscus height and in vivo confocal microscopy for assessing nerve injury.

Advanced imaging techniques

In vivo, confocal microscopy is a great tool for assessing neurosensory changes that occur in eyes with DED[92]. These imaging techniques in DED management are more objective and provide real-time documentation of parameters both now and in the near future[93]. There is an emergence in the use of protein microarray technology in the management of ocular surface disease caused or worsened by diabetes[94]. Tracking field failure has been found to increase the severity of dry eyes, suggesting that the reduced lubrication occasioned by DED affected eye movement[95,96]. The use of app-based software in diagnosing dry eyes is, however, gaining more ground and has been found to offer as much information as the traditional diagnostic technique[97].

Optical coherence tomography

Epithelial thickness profile range and Epithelial irregularity factor obtained by using ultra-high OCT have been found to correlate with patient's complaints and symptoms, viz a viz, there is a direct relationship between symptoms and these two parameters[98]. There seems to be a significant difference in corneal morphology parameters when using Pentacam and the anterior segment OCT as measuring tools[99]. The most reliable method of assessing the tear meniscus height is the use of OCT, followed by the regular slit lamp examination. However, comparing tear meniscus height with lid margin thickness or number of lashes is not a reliable method as shown by research work[100].

The DryEyeRhythm app, an innovative tool developed by Juntendo University, serves as a sophisticated mechanism for the monitoring and management of dry eye symptoms. Utilizing the smartphone's camera for conducting a blink assessment, coupled with a concise questionnaire, users are afforded the capability to determine their dry eye score within a brief duration of approximately five minutes[52]. The application further enables users to systematically track daily lifestyle variables, including stress levels and sleep patterns, thereby elucidating the relationship between these factors and dry eye symptoms. The anonymized data collected via the app significantly contributes to dry eye research, facilitating advancements in early detection and treatment strategies[84].

Color Doppler imaging (CDI) has emerged as a valuable diagnostic tool in the assessment of ocular blood flow abnormalities associated with DED. By employing this non-invasive ultrasound technique, clinicians can visualize and quantify blood flow in the ophthalmic vessels, including the central retinal artery and posterior ciliary arteries[53]. CDI facilitates the detection of hemodynamic changes that may contribute to the pathophysiology of dry eye, such as reduced blood flow velocity and altered resistivity indices[53]. This advanced imaging modality offers a promising approach for early diagnosis and monitoring of DED, potentially leading to more effective therapeutic interventions and improved patient outcomes

Meibography

Meibography employs infrared imaging to visualize the morphology of meibomian glands. Atrophy and gland loss correspond with the severity of DED. With this technique, the lower lid is everted and imaged. The image generated is then assessed and graded to account for any dilation, or atrophy blockage in the meibomian glands. This technique offers detailed anatomical insights into meibomian glands, aiding in diagnosing underlying structural abnormalities[101]. By capturing detailed images, meibography helps identify blockages or atrophy in these glands, which are essential for producing the lipid layer of the tear film that prevents tear evaporation. When combined with other dry eye tests, such as TBUT, osmolarity tests, and questionnaires like the OSDI, meibography provides a comprehensive understanding of a patient’s dry eye condition[102]. The use of the noninvasive keratograph, tear meniscus height, and bulbar injection, when compared to other clinical evaluation techniques such as the Schirmer test, etc., showed no correlation between the two techniques using the ocular surface disorder score[103]. In the detection of underlying issues, it has been found that there is a correlation between the onset of anterior segment endothelial anomalies in patients with dry eye.

Matrix metalloproteinase-9 testing

Inflammatory biomarkers testing provide additional diagnostic precision, particularly in identifying inflammatory components of DED[104,105]. The ability to assess matrix metalloproteinase-9 can be a helpful tool in measuring response to treatment and monitoring the course of disease in cases of dry anophthalmic socket syndrome[104]. It was found that both patients with DED without Sjogren disease and those with Sjogren disease, with positive metalloproteinase-9, showed lower tear secretion and high tear osmolarity compared to those with negative metalloproteinase-9[106].

Artificial intelligence and DED diagnosis

Artificial intelligence (AI) algorithms evaluate ocular images to identify early biomarkers of DED, improving diagnostic precision and efficiency. Deep learning algorithms, particularly deep transfer learning is said to be a new way of automatically analyzing inflammatory markers in the diagnosis and management of DED[107]. As an example, machine learning models have been shown to identify an increase or upregulation of tear proteins, in cases of DED of Sjogren origin or KCS[108,109]. These advancements in DED diagnostics enables better sensitivity in comparison to traditional methods.

Besides the use of AI in tear protein analysis as discussed earlier, it has also been integrated into immunoassay-based diagnostic techniques like the Chemiluminescent immunoassay and the Siemens immunonephelometric assay, which are close to precise methods for detecting immunoglobulins in related diseases and PSS[110]. There is an increased demand for the standardization of Schirmer’s strip production, processing of tear fluid, and analyte concentration normalization, and AI is primed to step in to ensure consistency and reproducibility in diagnostic protocols[111].

In addition to these efforts, AI models also support in clinical decision-making to assist eye care practitioners in the diagnosis of DED. For instance, Chatzaki et al[112] successfully developed an electronic tool for training primary eye care providers on accurate diagnosis of DED with commendable success with a 97.2% reported usability score[112].

To guarantee a methodical approach in diagnosing DED, the subsequent sequence is advised

Symptom evaluation: Employ validated questionnaires like the OSDI or SPEED to ascertain the intensity and frequency of symptoms.

Assess tear film stability: Perform TBUT and measure tear osmolarity to determine tear film integrity.

Ocular surface staining: Employ fluorescein and lissamine green staining to identify corneal injury.

Tear volume assessments: Conduct Schirmer’s test to evaluate tear production.

Imaging techniques: Meibography for assessing meibomian gland functionality and OCT for measuring tear meniscus.

Confirmatory and prognostic assessment: Employ in vivo confocal microscopy for nerve examination and tear film proteomics for inflammatory biomarkers.

Management strategies, comparison of treatment plan: Current and future frontiers

DED therapy includes artificial tears, anti-inflammatory medications, punctal occlusion, and lifestyle adjustments. Recent therapeutics encompass regenerative medicine and biologics. Approved treatments encompass artificial tears, cyclosporine A, lifitegrast, and punctal plugs. Innovative therapies like regenerative eye drops and mesenchymal stem cell treatment are still in the experimental phase. Recent trials indicate that biologic medicines aimed at inflammation (e.g., IL-1 inhibitors) may surpass traditional anti-inflammatories in severe DED.

In the use of artificial tears as a DED therapy, the use of ocular lubricant for individuals with reflex tearing usually improves their complaints[113]. However, the use of orthokeratology lenses has been found to have little or no effect on tear film stability[114].

The addition of tear supplements to steroid and non-steroidal anti-inflammatory drugs following cataract surgery has been found to lessen DED symptoms post-operatively[115-117]. Water-free topical cyclosporin 0.1%, when used in comparison to a vehicle, had an earlier therapeutic effect on the ocular surface[118-120]. Hydroxyquinoline, when combined with cyclosporine, improved the Schirmer score and significantly reduced surface inflammation[121]. Topical spironolactone helps in the production of the lipid layer of tear film, which helps to reduce surface inflammation in cases of graft vs host disease[122]. Placebos have been employed to measure the intervention's efficacy in treating dry eyes[123].

Treating dry eyes with hyaluronic acid and Ginkobiloba eye drops significantly improves the symptoms of DED[124]. There is, however, no significant difference in the prolonged use of omega-3 fatty acids compared with those who discontinued their usage at some point[125-127]. Research has shown that Lacrimera drops improve dry eye treatment, using TBUT, Schirmer analysis, and corneal staining as parameters, and it has been found to have a high-level regeneration time that can be sustained for about a month after use[128]. Semi-fluorinated alkane eye drops improve symptoms of dry eyes in patients who underwent cataract surgery[129]. A similar outcome was achieved when a mirrored demographic was treated with sodium hyaluronate and dexpanthenol-containing eye drops also after cataract extraction[130].

Current studies on recombinant growth factors have been shown to give good symptom relief in the treatment of dry eyes[131]. The management of conjunctivochalasis is an important antidote in managing patients with dry eyes, especially those using high-frequency radio wave electrosurgery[132]. The use of contact lenses has been found to reduce inflammatory cell numbers on the ocular surface, thereby presenting a possible future management strategy for dry eyes[133] as it enhanced corneal nerve health while reducing activated/mature corneal inflammatory cell numbers, delivering a safe and promising new treatment for moderate-to-severe DED. Loteprenol-tobramycin combination drops have shown some promise in mitigating DED symptoms and progression, lending a voice to the characterization of DED and the inflammatory process[134].

In studies by Moon et al[135], autologous epithelial growth factor ointment successfully reduced areas of epithelial damage. Punctual cauterization using heat treatment can be helpful when dealing with severe, potentially scarring dry eyes[136]. In a similar vein, mesenchymal stem cells show promise in managing Sjorgen syndrome[137,138] due to their ability to stimulate nuclear factor id3. A summary of some of the methods used to manage dry eyes is shown in Table 6.

Table 6 Management of dry eyes.

Category	Ref.	Management tool	Details description
Management strategies	Akpek et al[118]	Topical cyclosporine 0.1%	A water-free cyclosporine formulation that improves the ocular surface in moderate-to-severe dry eye
	Fogagnolo et al[124]	Hyaluronic acid and ginkgo biloba drops	Effective in improving symptoms, especially post-cataract surgery
	Wirta et al[131]	Recombinant human nerve growth factor	Promising in treating moderate-to-severe dry eye by enhancing corneal nerve regeneration
	Hu et al[138]	Mesenchymal stem cells	Shows promise in managing Sjögren's syndrome, potentially aiding in ocular surface repair
Surgical options	Wang et al[136]	Punctal cauterization	Heat treatment that is useful for severe dry eye, particularly in preventing scarring
	Ji et al[139]	High-frequency radiowave electrosurgery	Improves conjunctivochalasis, reducing symptoms and improving management outcomes
Post-COVID-19 Considerations	Castillo et al[144]	Telehealthcare	Utilized to mitigate DED-linked ocular morbidity, particularly relevant post-COVID-19

DED: Dry eye disease; COVID-19: Coronavirus disease 2019.

Post coronavirus disease 2019 considerations in DED diagnosis and management

The SARS-CoV-2 virus has forever changed the face of medicine and healthcare as we knew it[139-141]. In China and Italy for example, research has shown that the coronavirus disease 2019 (COVID-19) exacerbated symptoms in patients with rheumatoid related conditions, which are in themselves linked to DED[140-143]. The IMPULSE study carried out in Spain recommended that tele-healthcare can be utlized to mitigate DED-linked ocular morbidity[144]. Brito-Zerón et al[145] also reported a positive correlation between DED and exacerbation of COVID linked morbidities.

This paper was limited to reviewing records in the search pool published not older than 2020. A wider search criterion may have yielded more data to sample.

CONCLUSION

In conclusion, the effective management of DED begins with an accurate diagnosis. Integrating a combination of subjective and objective diagnostic tools allows clinicians to comprehensively assess the condition, tailor treatment plans, and monitor therapeutic efficacy. Continued advancements in diagnostic technologies promise to enhance our understanding and management of this prevalent ocular condition.