Continuing Education Activity

Dry eye syndrome (DES), also referred to as dry eye disease (DED) or keratoconjunctivitis sicca (KCS), encompasses multifactorial ocular surface pathology causing discomfort and visual disturbances. Understanding the complexity of tear film composition and dysfunction is pivotal in assessing patients presenting with dry eyes. This activity delves into the tear film's structure, comprising lipid, aqueous, and mucin layers, impacting tear stability and ocular surface health. It navigates the nomenclature nuances, differentiating between DES and DED, acknowledging their broader clinical implications and comprehensive categorizations according to the 2017 Tear Film and Ocular Surface Society Dry Eye Workshop II report.

Emphasizing the importance of an interprofessional approach, this session highlights the roles of various specialists, including ophthalmologists, optometrists, and researchers, in diagnosing and managing dry eyes. Diagnostic methods encompass ocular examinations, tear film assessment, and symptom evaluation to determine suitable treatments, ranging from lubricating eye drops to antiinflammatory agents or surgical interventions based on underlying causes and disease severity. With evolving research, this activity underscores the shift towards a more intricate understanding of DED, focusing on inflammation, meibomian gland dysfunction, and environmental influences, aiming to refine patient care strategies for improved outcomes in this prevalent ocular condition.

Objectives:

• Identify diverse etiological factors contributing to dry eye syndrome (DES), including environmental triggers, systemic conditions, aging, medication side effects, and ocular surface irregularities.
• Differentiate between various presentations of DES, distinguishing between evaporative and aqueous-deficient subtypes based on clinical signs and symptoms.
• Implement personalized treatment plans for patients with DES, integrating artificial tears, lubricating eye drops, punctal plugs, oral supplements, and lifestyle modifications tailored to individual needs.
• Implement interprofessional team strategies for improving care coordination and communication to advance the treatment of DES and improve patient outcomes.

Introduction

Dry eyes, also known as dry eye syndrome (DES), dry eye disease (DED), ocular surface disease (OSD), dysfunctional tear syndrome (DTS), and keratoconjunctivitis sicca (KCS), are among the most common reasons for a visit to an eye doctor.[1][2] The definition of a dry eye according to the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop II (DEWS II) is, "Dry eye is a multifactorial 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 inflammation and damage, and neurosensory abnormalities play etiologic roles."[3]

The tear film is approximately 2 to 5.5 µm thick over the cornea and comprises 3 main components.[4][5] These components (lipid, aqueous, and mucin) are often described as layers, although this may oversimplify the tear film milieu.[6][7]

The tear film is approximately 2 to 5.5 µm thick over the cornea. It is composed of 3 main components, often described as layers (although this may be an oversimplification of the tear film milieu):[4][5]

1. Lipid layer: The most superficial layer; produced by the meibomian glands of the eyelids and functions to reduce the evaporation of tears [8]
2. Aqueous layer: The middle layer and the thickest component of the tear film; produced by the lacrimal glands, located in the orbits and the accessory lacrimal glands (glands of Krause and Wolfring) in the conjunctiva. Aqueous fluid contains water, metabolites, electrolytes, peptides, proteins, etc.[9]
3. Basal layer: Composed of mucins, or glycoproteins; predominantly produced by conjunctival goblet cells.[10] Mucins enhance the spread of the tear film over the corneal epithelium through the regulation of surface tension.[11]

Nomenclature and Terminology

DES and DED relate to a common ocular illness in which there is insufficient lubrication and moisture on the eye's surface. Numerous symptoms, such as dryness, irritation, burning, redness, and blurred vision, can be brought on by this illness. Even though the names are frequently used interchangeably, DED refers to a more comprehensive understanding of the disorder. It can be confusing because different medical practitioners and researchers use different terminologies.

DES

This term is frequently used informally to refer to inadequate tear production or poor tear quality, which causes ocular pain and associated symptoms. Patients and medical professionals frequently use it to characterize the disease.

DED

The multifaceted character of the ailment is better described by the more inclusive term DED. It recognizes that evaporative dry eye, aqueous deficit, and mixed etiologies are some underlying causes of dry eye, a complex and heterogeneous disease. DED covers a broader spectrum of clinical manifestations and causes.

Classification

DES is a broader term that emphasizes symptoms and a decline in tear quantity or quality rather than focusing on underlying causes in detail. DED acknowledges that the disorder has several facets and different subtypes. The 2017 TFOS DEWS II report offers a thorough categorization and in-depth explanation of dry eye illness.[3] Inflammation, neurosensory abnormalities, and environmental triggers are just a few of the contributing elements the report considers when classifying DED into aqueous-deficient and evaporative subtypes.

Diagnosis and Treatment

Diagnostic procedures and therapies for DES and DED are comparable. A thorough eye exam that includes tests for tear film quality and quantity, a review of the ocular surface, and an evaluation of the patient's stated symptoms is frequently required for diagnosis. Artificial tears, lubricating eye drops, dietary changes, antiinflammatory drugs, and, in extreme circumstances, procedures or operations may all be used as treatments. The underlying cause and severity of the condition determine the best course of action.

Research

Over time, dry eye research has advanced, and our understanding of the condition has become more complex. In contemporary medical literature and research investigations, the term DED is used more frequently to reflect this thorough understanding. Inflammation, meibomian gland dysfunction, and the effect of the environment on the ocular surface have all been studied in recent DED studies. Researchers hope to advance patient care by utilizing the term DED to cover various contributing factors.

Etiology

DED is usually classified into 2 major nonmutual exclusive etiology groups, which include evaporative dry eye and aqueous-deficiency dry eye.[12] Excessive evaporation from the ocular surface can occur due to a reduced muco-aqueous component in the tear film, whereas aqueous deficiency is due to reduced production, usually based on underlying autoimmune or systemic conditions. Mixed cases of the 2 types can also be found in patients with dry eyes.[13]

Numerous potential etiologies may contribute to the development of DED, and many cases may be multifactorial.[14] These include local ocular factors, systemic diseases, sociodemographic factors, environmental conditions, and iatrogenic causes such as medications or surgeries.[15] Potential causes or factors associated with dry eye include:

• Systemic medications: 

  • Antihistamines
  • Antihypertensive
  • Anxiolytics/benzodiazepines
  • Diuretics
  • Systemic hormones
  • Nonsteroidal antiinflammatory drugs
  • Systemic or inhaled corticosteroids
  • Anticholinergic medications
  • Isotretinoin (causes meibomian gland atrophy)
  • Antidepressants [16]
• Topical medications: Including glaucoma drops or preservative toxicity from eye drops containing preservatives [17][18]
• Skin diseases: On or around the eyelids, such as rosacea or eczema [19]
• Meibomian gland dysfunction: A common comorbidity with thickening and erythema of the eyelids and inadequate or altered secretions of meibomian glands [20] 
• Ophthalmic surgery: 

  • Refractive surgery
  • Cataract surgery
  • Keratoplasty
  • Lid surgery [21]
• Chemical or thermal burns: Those that scar the conjunctiva [22]
• Ocular allergies  [23]
• Decreased androgen levels: Ocuuring with menopause and other conditions [24]
• Computer or device usage: This may lead to decreased blinking when looking at the screen.[25]
• Excess or insufficient dosages of vitamins: Particularly vitamin A deficiency; can lead to xerophthalmia and the appearance of Bitot spots on the conjunctiva in severe cases [26]
• Decreased sensation in the cornea: Due to:

  • Long-term contact lens wear
  • Herpes virus infections
  • Other causes of a neurotrophic cornea [27]
• Graft-versus-host disease  [28]
• Autoimmune systemic diseases: 

  • Sjogren syndrome
  • Graves' ophthalmopathy
  • Connective tissue disorders such as:

    • Rheumatoid arthritis
    • Lupus
    • Thyroid disease [29]
• Systemic conditions that increase the risk factors of dry eye:

  • Diabetes [30]
  • Xerophthalmia [31]
  • Hereditary diseases [32]
  • Gut dysbiosis [33]
  • Multiple sclerosis [34]
  • Nerve damage pathologies [35] 
• Environmental factors: Including exposure to irritants such as:

  • Chemical fumes
  • Cigarette smoke
  • Strong winds
  • High temperature
  • Pollution
  • High altitude
  • Low humidity [36][37]
• Behavioral habits: 

  • Smoking [38] 
  • Alcohol [39]
  • Poor sleep [40]
  • Unhealthy diet [41]
  • Dislipidemia [42] 

Epidemiology

Dry eye is more common in women than men (due to female hormonal effects on the lacrimal and Meibomian glands and ocular surface) and has an increased prevalence with age.[43] Studies have shown that female gender is a risk factor in developing dry eye, with a prevalence that ranges from 12% to 22%.[15] The prevalence of DED worldwide varies depending on the diagnostic criteria employed, which ranges from approximately 5% to 50% in population-based studies.[13]

DES has been shown to be as high as 70% in visual terminal users.[43][44]  In general, it is more common in Black individuals and Asian populations when compared with White individuals,[45] although geographic, climatic, and environmental variations may also be significant factors.[43][46] Evaporative dry eye is considered the most common subtype of DED. There may be discordance between dry eye signs and symptoms, with signs being more prevalent and variable than symptoms.[43]

Pathophysiology

Dry eye has traditionally been classified into 2 categories: aqueous deficient and evaporative.[3][47] These 2 categories, however, are not mutually exclusive, and numerous patients have a combination of these mechanisms of DED.

Aqueous Tear Deficiency

This category of dry eye is characterized by inadequate tear production. The predominant causes consist of Sjogren Syndrome (primary or secondary); diseases, inflammation, or dysfunction of the lacrimal gland; obstruction of the lacrimal gland; and systemic drugs (ie, decongestants, antihistamines, diuretics, beta-blockers, etc).[48]

Evaporative Dry Eye

This category of dry eye is characterized by increased tear film evaporation and a deficiency in the lipid portion of the tear film. In this case, the quantity of tears produced is normal; however, the quality of tears causes excessive evaporation. This alteration is most frequently caused by meibomian gland dysfunction. 

Meibomian Glands

Meibomian glands line the eyelid margins and secrete oils that become the lipid layer of the tear film and reduce the evaporation of tears. Meibomian gland dysfunction may be caused by inadequate secretion due to atrophy, dropout of the glands, or obstruction of the gland orifices. Other major causes of increased tear evaporation include poor blinking (low rate, incomplete lid closure), lid aperture disorders, vitamin A deficiency, contact lens use, and environmental factors (low humidity, high airflow).  

Tear Film

A hallmark of DED is hyperosmolarity of the tear film,[49] which may damage the ocular surface directly or indirectly by inciting inflammation, tear film instability, epitheliopathy, and ocular surface neurosensory abnormality.[50] The normal osmolarity of the tear film is usually less than 300 mOsm/L, which has been reported to be as high as 360 mOsm/L in patients with DED.[51]

Hyperosmolarity of the tear film leads to a cascade of signaling events that releases inflammatory mediators (ie, tumor necrosis factor, cytokines, alarmins, interleukin 1 and 6, etc.). It leads to damage to the ocular surface, which may further decrease tear film stability, leading to self-perpetuation of the disease in a vicious cycle.[52][53] Apart from hyperosmolarity, other factors may initiate this pathologic cycle, including ocular surface inflammation caused by conditions such as allergic eye disease, topical preservative toxicity, or xerophthalmia.[54] 

History and Physical

DED may lead to a number of symptoms, ranging from mild to severe[51]:

• Stinging, burning, or a feeling of pressure in the eyes 
• A sandy, gritty, or foreign body sensation
• Epiphora, or tearing, is a symptom that is often counterintuitive. This is due to dryness leading to pain or irritation that results in intermittent excess tearing or epiphora.
• Pain is a broad term, and sharp and dull pain can be described as localized to some part of the eye, behind the eye, or even around the orbit.
• Redness is a common complaint and is often made worse by the rebound effect of vasoconstrictors found in many over-the-counter eye drops designed to reduce redness. Vasoconstrictors may decrease redness for the short term by constricting the vessels of the episclera but can have a rebound effect and increased redness after the drops wear off in a relatively short time period. 
• Blurry vision, particularly intermittent blurry vision, is a common complaint and may also be described as glare or haloes around lights at night.
• Vision fluctuation and difficulties in reading
• A sensation of heavy eyelids or difficulty opening the eyes 
• Excessive blinking
• Eyelid twitching
• Dryness is a common problem for contact lens wearers, and irritation may make contact lenses uncomfortable or even impossible to wear.
• Tired eyes (closing the eyes may provide relief to some individuals with dry eyes)
• Inability to cry in severe DED

Evaluation

There is no single gold standard sign or symptom for diagnosing DED. Evaluation of symptoms and signs of DED is recommended, as signs may be present without symptoms and vice-versa. 

Symptoms

A verbal history allows the nonscripted elicitation of dry eye symptoms. In addition, many questionnaires have been developed to screen for symptoms of DED. Using a validated questionnaire allows accurate quantification of symptoms as a screening tool and monitoring for progression and response to treatments. Several questionnaires exist, such as the Ocular Surface Disease Index (OSDI),[55] Dry Eye Questionnaire (DEQ-5),[56] and Symptoms Analysis in Dry Eye (SANDE),[57] and others, which may help assess dry eye symptoms. Many questionnaires also include questions about subjective visual function or disturbances that may be attributable to dry eye.[58]

Tear Stability

Tear film breakup time 

Tear film breakup time (TBUT) is the interval between a complete blink and the first break in the tear film. This is most often performed in the clinic using a slit lamp microscope after instilling sodium fluorescein stain to enhance the visibility of the tear film. A cutoff of fewer than 10 seconds for the appearance of a patch in the tear film is often considered consistent with DED. Alternatively, a noninvasive tear breakup time can be measured without fluorescein using instrumentation that evaluates the reflections of patterns or rings from the tear film or interferometry to assess for the appearance of discontinuity of the lipid layer after a blink. Studies have shown corneal hyperalgesia in eyes with a shorter TBUT.[59]  

Tear Volume 

Tear Meniscus Assessment

Assessment of the tear meniscus is performed at the slit lamp by judging the inferior tear film meniscus height. This technique is simple to perform but is subject to poor intervisit repeatability.[60] Instrumentation has been developed for more objective measurement of the tear film meniscus but is not currently widely available in most clinics. 

Schirmer Test

A Schirmer paper strip is folded at the notch with the shorter end hooked over the lateral lid margin to avoid cornea irritation while the patient rests with closed eyes.[61] The Schirmer I test is performed without topical anesthetic to measure basic and reflex tearing with less than 5 to 10 mm (depending on cutoff used) of wetting after 5 minutes of diagnostic of aqueous deficiency. Alternatively, a topical anesthetic can be administered. Then, residual fluid blotted from the inferior fornix before performing testing to measure basic secretion with less than 5 to 10 mm of wetting is considered diagnostic for aqueous deficiency.[62]  

Phenol Red Test

Like Schirmer testing, a cotton thread dyed with phenol red is hooked over the temporal eyelid into the sulcus for 15 seconds while the patient rests with closed eyes.[63] When wet, the thread turns red with cutoff values ranging from less than 10 to 20 mm used clinically. 

Ocular Surface Assessment

Fluorescein Staining

Fluorescein staining allows the assessment of corneal damage. A minimal volume of fluorescein is instilled into the tear film with optimal viewing 1 to 3 minutes later. Greater than five spots of staining are considered positive results, with various grading scales, such as the Oxford grading scale, also used.[64][65]

Lissamine Green Staining 

Lissamine allows the assessment of conjunctival and lid margin damage and, to a lesser extent, corneal damage. Greater than nine spots is a positive result.[64] Lid wiper epitheliopathy, or staining of the lid margin, can be performed with a positive result as 2 mm or more staining in length or greater than 25% in sagittal width.[66]

Conjunctival Redness

Conjunctival redness, or hyperemia, is not specific to DED as this may result from any stimulus that results in conjunctivitis, including infective, allergic, chemical, or mechanical etiologies. Grading is generally determined subjectively by slit lamp examination, although some devices with automated grading or digital photography can also be used.[67] 

Tear Film Assays

Tear film Osmolarity

Elevated osmolarity and increased variability of osmolarity of the tears are characteristics of DED. Osmolarity values typically increase with disease severity. Various cutoff values have been reported, with 308 mOsm/L used as a threshold to diagnose mild-to-moderate disease, whereas 316 mOsm/L has been used as a cutoff for more severe disease.[58] Studies have shown that high osmolarity levels can lead to proinflammatory effects on the ocular surface, with the secretion of inflammatory cytokines and metalloproteinases that can cause chronic epithelium dysfunction and induce apoptosis.[68]

Matrix Metalloproteinases

These proteases are found in the tears of individuals with dry eyes. Matrix metalloproteinase-9 (MMP-9) levels can be tested using a point-of-care test.[69]    

Eyelid Evaluation

Blepharitis

Evaluation of the eyelids is a crucial part of the evaluation to determine any factors contributing to DED. The evaluation includes assessment for anterior blepharitis and demodex blepharitis, which are frequent comorbidities of DED.[70]

Lid Wiper Epitheliopathy

The portion of conjunctiva along the lid margin that contacts the ocular surface to spread tears has been termed the "lid wiper."[71] Lid wiper epitheliopathy, or staining of the lid wiper with fluorescein or lissamine green, may be seen more commonly in individuals with DED, presumably due to increased friction between the lid and ocular surface.

Meibomian Gland Evaluation

The evaluation of the meibomian gland structure can be performed with meibography.[72] Although the outline of meibomian glands can be seen at the slit lamp or with a penlight by transilluminating the everted eyelid, enhanced visualization is obtained using infrared imaging systems to perform meibography. Inspection of the meibomian gland orifices along the eyelid margin can be performed to detect external obstructions of orifices. Meibomian gland function can be assessed by evaluating meibum quantity, quality, and expressibility.[58]  Expressibility is assessed by applying digital pressure along the eyelid margin with a clear meibum easily expressed from the normal eyelid. Themeibum is turbid or viscous in meibomian gland dysfunction and is not easily expressed.  

Eyelid Blink and Closure

Incomplete blinking and nocturnal lagophthalmos can result in DED. Blink assessment can be performed with or without a microscope or video recording equipment.[73] Lagophthalmos can be estimated by having the patient gently close their eyes and assessing for incomplete closure.

Evaluation for Systemic Disease

Numerous systemic diseases may cause DED, particularly primary Sjogren syndrome and secondary Sjogren syndrome caused by other autoimmune conditions such as rheumatoid arthritis, lupus, progressive systemic sclerosis, and dermatomyositis.[54] Other systemic abnormalities such as Parkinson's disease, androgen deficiency, thyroid disease, and diabetes have also been associated with DED.

Evaluation for systemic disease causing secondary dry eye may be warranted if an underlying condition is suspected. A review of systems is indicated to screen for underlying systemic diseases. Sjogren syndrome may also involve the salivary glands leading to dry mouth and predisposing to periodontal disease, and other mucous membranes may be affected, such as vaginal, gastric, and respiratory mucosae.[74] Laboratory testing for Sjogren syndrome (antibodies to Ro/SS-A or La/SS-B), rheumatoid factor, and antinuclear antibodies.[75] Referral to a rheumatologist may be indicated, and some cases of Sjogren syndrome may require a salivary gland biopsy by an oral surgeon.

Treatment / Management

Treatment of DES is performed in a step-wise approach that may vary depending on the severity of the disease.[13] 

Initial approaches include:

• Education about the condition
• Modification of the environment

  • Eliminating direct high airflow or fans
  • Reducing screen time
  • Taking frequent screen breaks
  • Using a humidifier 
• Identification and elimination of offending topical and systemic agents
• Topical ocular lubricants
• Lid hygiene (warm compresses and lid scrubs)
• Oral essential fatty acid supplements

Therapy aims to decrease signs and symptoms, restore ocular surface homeostasis, and enhance quality of life.[76]

The next step of treatment options includes

• Preservative-free ocular lubricants
• Reversible punctal occlusion (punctal plugs)
• Night-time ointment or moisture goggles
• Device-assisted heating or expression of the meibomian glands
• Intense pulsed light therapy
• Topical anti-inflammatory medications (corticosteroids, cyclosporine, lifitegrast)
• Oral antibiotics (macrolide or tetracycline).[51] 

Further treatment options include:

• Serum eye drops
• Oral or topical secretagogues
• Therapeutic contact lenses
• Amniotic membrane grafting
• Surgical punctal occlusion
• Tarsorrhaphy

Differential Diagnosis

Many conditions may evoke symptoms similar to those caused by DED.[58] Some conditions may also be associated with or lead to DED, such as allergic conjunctivitis, cicatricial conjunctivitis, filamentary keratitis, and neurotrophic keratitis. Identifying the underlying primary condition in these cases is key to reducing the progression of the disease and worsening of dry eye.

Differential diagnosis for DED include:

• Conjunctivitis (allergic, viral, bacterial, parasitic/chlamydial)
• Anterior blepharitis
• Demodex blepharitis
• Cicatricial conjunctivitis (Stevens-Johnson Syndrome, mucous membrane pemphigoid)
• Bullous keratopathy
• Contact lens–related keratoconjunctivitis
• Eyelid malposition (entropion, ectropion) or abnormality (trichiasis) leading to ocular surface disease
• Keratitis (interstitial, filamentary, contact lens–related, neurotrophic)

Prognosis

There are minimal published data describing the natural history of treated and untreated DED.[43] DED is often considered chronic, with periods of exacerbation due to intermittent contributing factors. Postsurgical dry eye (such as following cataract surgery or refractive surgery) often improves with time, possibly related to the regeneration of corneal nerves or reduction of ocular inflammation.[77]

Complications

Complications from DED range from mild to severe. Mild-to-moderate DED causes symptoms detailed above, including ocular irritation or visual disturbances. More severe diseases can result in corneal complications, including infectious keratitis, ulceration, and scarring, which may cause subsequent loss of vision.[78][79] Although causation has not been established, several nonocular associations exist with DED, including depression, sleep and mood disorders, dyslipidemia, and migraine headaches.[80][81]

Deterrence and Patient Education

Patients should be educated regarding environmental or behavioral modifications that can be performed to reduce DED. For example, fans, air conditioners, or heating vents may worsen DED. Blinking awareness training or taking intermittent breaks may reduce the dry eye effects of staring at digital devices. Artificial tears should be promoted, while contact lens use can preferably be limited. Patients may also be educated regarding dietary factors influencing DED, including supplementation with essential fatty acids.

Enhancing Healthcare Team Outcomes

The primary care provider, ophthalmic nurse, and pharmacist should educate patients on the prevention and basic treatments of dry eyes by limiting screen time, blinking often, using artificial tears, and keeping the home environment cool and moist. Eye care providers should work with patients' primary care providers or rheumatologists to investigate possible underlying systemic diseases in cases where an underlying systemic disease is suspected.

In cases of primary or secondary Sjogren syndrome, treatment of the underlying disorder is often needed to treat the ocular manifestations adequately. Early identification and management of patients with dry eyes are imperative in reducing ocular symptoms and irreversible complications. Caring for patients with dry eyes necessitates a collaborative approach among healthcare professionals to ensure patient-centered care and improve overall outcomes. Health professionals involved in the care of these patients should possess the essential clinical skills and knowledge to diagnose and manage dry eye syndrome accurately.

A strategic approach involving evidence-based strategies to optimize treatment plans and minimize adverse effects is equally crucial. Each healthcare professional must know their responsibilities and contribute their unique expertise to patients' care plans, fostering a multidisciplinary approach. Effective interprofessional communication is paramount, allowing seamless information exchange and collaborative decision-making among the team members. Care coordination is pivotal in ensuring a patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety.

By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance in managing focal onset seizures. The interprofessional team approach with all clinicians, nursing staff, and pharmacists communicating openly and sharing information is optimal for addressing patients with dry eyes syndrome. 

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007 Apr;5(2):75-92. [PubMed: 17508116]

2.

Huang R, Su C, Fang L, Lu J, Chen J, Ding Y. Dry eye syndrome: comprehensive etiologies and recent clinical trials. Int Ophthalmol. 2022 Oct;42(10):3253-3272. [PMC free article: PMC9178318] [PubMed: 35678897]

3.

Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols JJ, Tsubota K, Stapleton F. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017 Jul;15(3):276-283. [PubMed: 28736335]

4.

King-Smith PE, Fink BA, Hill RM, Koelling KW, Tiffany JM. The thickness of the tear film. Curr Eye Res. 2004 Oct-Nov;29(4-5):357-68. [PubMed: 15590483]

5.

King-Smith PE, Fink BA, Fogt N, Nichols KK, Hill RM, Wilson GS. The thickness of the human precorneal tear film: evidence from reflection spectra. Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3348-59. [PubMed: 11006224]

6.

Chen Q, Wang J, Tao A, Shen M, Jiao S, Lu F. Ultrahigh-resolution measurement by optical coherence tomography of dynamic tear film changes on contact lenses. Invest Ophthalmol Vis Sci. 2010 Apr;51(4):1988-93. [PMC free article: PMC2868399] [PubMed: 19933178]

7.

Willcox MDP, Argüeso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, Papas EB, Rolland JP, Schmidt TA, Stahl U, Suarez T, Subbaraman LN, Uçakhan OÖ, Jones L. TFOS DEWS II Tear Film Report. Ocul Surf. 2017 Jul;15(3):366-403. [PMC free article: PMC6035753] [PubMed: 28736338]

8.

Peng CC, Cerretani C, Braun RJ, Radke CJ. Evaporation-driven instability of the precorneal tear film. Adv Colloid Interface Sci. 2014 Apr;206:250-64. [PubMed: 23842140]

9.

Zhou L, Beuerman RW. Tear analysis in ocular surface diseases. Prog Retin Eye Res. 2012 Nov;31(6):527-50. [PubMed: 22732126]

10.

Mantelli F, Mauris J, Argüeso P. The ocular surface epithelial barrier and other mechanisms of mucosal protection: from allergy to infectious diseases. Curr Opin Allergy Clin Immunol. 2013 Oct;13(5):563-8. [PMC free article: PMC3858173] [PubMed: 23974687]

11.

O'Neil EC, Henderson M, Massaro-Giordano M, Bunya VY. Advances in dry eye disease treatment. Curr Opin Ophthalmol. 2019 May;30(3):166-178. [PMC free article: PMC6986373] [PubMed: 30883442]

12.

Fjaervoll K, Fjaervoll H, Magno M, Nøland ST, Dartt DA, Vehof J, Utheim TP. Review on the possible pathophysiological mechanisms underlying visual display terminal-associated dry eye disease. Acta Ophthalmol. 2022 Dec;100(8):861-877. [PMC free article: PMC9790214] [PubMed: 35441459]

13.

Craig JP, Nelson JD, Azar DT, Belmonte C, Bron AJ, Chauhan SK, de Paiva CS, Gomes JAP, Hammitt KM, Jones L, Nichols JJ, Nichols KK, Novack GD, Stapleton FJ, Willcox MDP, Wolffsohn JS, Sullivan DA. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017 Oct;15(4):802-812. [PubMed: 28797892]

14.

Qian L, Wei W. Identified risk factors for dry eye syndrome: A systematic review and meta-analysis. PLoS One. 2022;17(8):e0271267. [PMC free article: PMC9390932] [PubMed: 35984830]

15.

I Y Hasan ZA. Dry eye syndrome risk factors: A systemic review. Saudi J Ophthalmol. 2021 Apr-Jun;35(2):131-139. [PMC free article: PMC8982940] [PubMed: 35391807]

16.

Paulsen AJ, Cruickshanks KJ, Fischer ME, Huang GH, Klein BE, Klein R, Dalton DS. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol. 2014 Apr;157(4):799-806. [PMC free article: PMC3995164] [PubMed: 24388838]

17.

Chang CJ, Somohano K, Zemsky C, Uhlemann AC, Liebmann J, Cioffi GA, Al-Aswad LA, Lynch SV, Winn BJ. Topical Glaucoma Therapy Is Associated With Alterations of the Ocular Surface Microbiome. Invest Ophthalmol Vis Sci. 2022 Aug 02;63(9):32. [PMC free article: PMC9434984] [PubMed: 36036910]

18.

Andole S, Senthil S. Ocular Surface Disease and Anti-Glaucoma Medications: Various features, Diagnosis, and Management Guidelines. Semin Ophthalmol. 2023 Feb;38(2):158-166. [PubMed: 35915557]

19.

Sobolewska B, Schaller M, Zierhut M. Rosacea and Dry Eye Disease. Ocul Immunol Inflamm. 2022 Apr 03;30(3):570-579. [PubMed: 35226588]

20.

Bilgic AA, Kocabeyoglu S, Dikmetas O, Tan C, Karakaya J, Irkec M. Influence of video display terminal use and meibomian gland dysfunction on the ocular surface and tear neuromediators. Int Ophthalmol. 2023 May;43(5):1537-1544. [PubMed: 36239837]

21.

Al Sabti K, Zechevikj S, Raizada S. Evaluation of lipid layer tear film changes after femtosecond small incision lenticule extraction. Ther Adv Ophthalmol. 2022 Jan-Dec;14:25158414221129534. [PMC free article: PMC9554113] [PubMed: 36246953]

22.

Napoli PE, Nioi M, Iovino C, Sanna R, d'Aloja E, Fossarello M. Ocular surface and respiratory tract damages from occupational, sub-chronic exposure to fluorspar: case report and other considerations. Int Ophthalmol. 2019 May;39(5):1175-1178. [PubMed: 29594792]

23.

Suárez-Cortés T, Merino-Inda N, Benitez-Del-Castillo JM. Tear and ocular surface disease biomarkers: A diagnostic and clinical perspective for ocular allergies and dry eye disease. Exp Eye Res. 2022 Aug;221:109121. [PubMed: 35605673]

24.

Truong S, Cole N, Stapleton F, Golebiowski B. Sex hormones and the dry eye. Clin Exp Optom. 2014 Jul;97(4):324-36. [PubMed: 24689906]

25.

Talens-Estarelles C, García-Marqués JV, Cerviño A, García-Lázaro S. Dry Eye-Related Risk Factors for Digital Eye Strain. Eye Contact Lens. 2022 Oct 01;48(10):410-415. [PubMed: 36155946]

26.

Chakraborty U, Chandra A. Bitot's spots, dry eyes, and night blindness indicate vitamin A deficiency. Lancet. 2021 Jan 16;397(10270):e2. [PubMed: 33453784]

27.

Altinbas E, Elibol A, Fıratlı G, Ayhan C, Celebi ARC. Assessment of risk factors on eye dryness in young adults using visual display device in both contact lens wearers and non-wearers. Int Ophthalmol. 2023 Feb;43(2):441-450. [PMC free article: PMC9362648] [PubMed: 35920942]

28.

Trindade M, Rodrigues M, Pozzebon ME, Aranha FJP, Colella MP, Fernandes A, Fornazari DO, de Almeida Borges D, Vigorito AC, Alves M. A plethora of ocular surface manifestations in a multidisciplinary ocular graft-versus-host disease unit. Sci Rep. 2022 Sep 23;12(1):15926. [PMC free article: PMC9508128] [PubMed: 36151252]

29.

Choudhry HS, Hosseini S, Choudhry HS, Fatahzadeh M, Khianey R, Dastjerdi MH. Updates in diagnostics, treatments, and correlations between oral and ocular manifestations of Sjogren's syndrome. Ocul Surf. 2022 Oct;26:75-87. [PubMed: 35961534]

30.

Zou X, Lu L, Xu Y, Zhu J, He J, Zhang B, Zou H. Prevalence and clinical characteristics of dry eye disease in community-based type 2 diabetic patients: the Beixinjing eye study. BMC Ophthalmol. 2018 May 10;18(1):117. [PMC free article: PMC5946388] [PubMed: 29747621]

31.

Feroze KB, Kaufman EJ. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 17, 2023. Xerophthalmia. [PubMed: 28613746]

32.

Palma JA, Norcliffe-Kaufmann L, Fuente-Mora C, Percival L, Mendoza-Santiesteban C, Kaufmann H. Current treatments in familial dysautonomia. Expert Opin Pharmacother. 2014 Dec;15(18):2653-71. [PMC free article: PMC4236240] [PubMed: 25323828]

33.

Moon J, Yoon CH, Choi SH, Kim MK. Can Gut Microbiota Affect Dry Eye Syndrome? Int J Mol Sci. 2020 Nov 10;21(22) [PMC free article: PMC7697210] [PubMed: 33182758]

34.

Khanna RK, Catanese S, Emond P, Corcia P, Blasco H, Pisella PJ. Metabolomics and lipidomics approaches in human tears: A systematic review. Surv Ophthalmol. 2022 Jul-Aug;67(4):1229-1243. [PubMed: 35093405]

35.

Andersen HH, Yosipovitch G, Galor A. Neuropathic symptoms of the ocular surface: dryness, pain, and itch. Curr Opin Allergy Clin Immunol. 2017 Oct;17(5):373-381. [PMC free article: PMC5995578] [PubMed: 28858914]

36.

Tandon R, Vashist P, Gupta N, Gupta V, Sahay P, Deka D, Singh S, Vishwanath K, Murthy GVS. Association of dry eye disease and sun exposure in geographically diverse adult (≥40 years) populations of India: The SEED (sun exposure, environment and dry eye disease) study - Second report of the ICMR-EYE SEE study group. Ocul Surf. 2020 Oct;18(4):718-730. [PubMed: 32783926]

37.

van Setten G, Labetoulle M, Baudouin C, Rolando M. Evidence of seasonality and effects of psychrometry in dry eye disease. Acta Ophthalmol. 2016 Aug;94(5):499-506. [PubMed: 27105776]

38.

Md Isa NA, Koh PY, Doraj P. The Tear Function in Electronic Cigarette Smokers. Optom Vis Sci. 2019 Sep;96(9):678-685. [PubMed: 31479023]

39.

Magno MS, Daniel T, Morthen MK, Snieder H, Jansonius N, Utheim TP, Hammond CJ, Vehof J. The relationship between alcohol consumption and dry eye. Ocul Surf. 2021 Jul;21:87-95. [PubMed: 34029755]

40.

Yu X, Guo H, Liu X, Wang G, Min Y, Chen SS, Han SS, Chang RT, Zhao X, Hsing A, Zhu S, Yao K. Dry eye and sleep quality: a large community-based study in Hangzhou. Sleep. 2019 Oct 21;42(11) [PubMed: 31310315]

41.

García-Marqués JV, Talens-Estarelles C, García-Lázaro S, Wolffsohn JS, Cerviño A. Systemic, environmental and lifestyle risk factors for dry eye disease in a mediterranean caucasian population. Cont Lens Anterior Eye. 2022 Oct;45(5):101539. [PubMed: 34789408]

42.

Choi HR, Lee JH, Lee HK, Song JS, Kim HC. Association Between Dyslipidemia and Dry Eye Syndrome Among the Korean Middle-Aged Population. Cornea. 2020 Feb;39(2):161-167. [PubMed: 31517720]

43.

Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, Na KS, Schaumberg D, Uchino M, Vehof J, Viso E, Vitale S, Jones L. TFOS DEWS II Epidemiology Report. Ocul Surf. 2017 Jul;15(3):334-365. [PubMed: 28736337]

44.

Fjaervoll H, Fjaervoll K, Magno M, Moschowits E, Vehof J, Dartt DA, Utheim TP. The association between visual display terminal use and dry eye: a review. Acta Ophthalmol. 2022 Jun;100(4):357-375. [PubMed: 34697901]

45.

Tan LL, Morgan P, Cai ZQ, Straughan RA. Prevalence of and risk factors for symptomatic dry eye disease in Singapore. Clin Exp Optom. 2015 Jan;98(1):45-53. [PubMed: 25269444]

46.

Saxena R, Srivastava S, Trivedi D, Anand E, Joshi S, Gupta SK. Impact of environmental pollution on the eye. Acta Ophthalmol Scand. 2003 Oct;81(5):491-4. [PubMed: 14510797]

47.

Rolando M, Cantera E, Mencucci R, Rubino P, Aragona P. The correct diagnosis and therapeutic management of tear dysfunction: recommendations of the P.I.C.A.S.S.O. board. Int Ophthalmol. 2018 Apr;38(2):875-895. [PMC free article: PMC5932107] [PubMed: 28397148]

48.

Sheppard J, Shen Lee B, Periman LM. Dry eye disease: identification and therapeutic strategies for primary care clinicians and clinical specialists. Ann Med. 2023 Dec;55(1):241-252. [PMC free article: PMC9809411] [PubMed: 36576348]

49.

Dunn JD, Karpecki PM, Meske ME, Reissman D. Evolving knowledge of the unmet needs in dry eye disease. Am J Manag Care. 2021 Mar;27(2 Suppl):S23-S32. [PubMed: 33856159]

50.

Shetty R, Sethu S. Newer paradigms in dry eye disease research. Indian J Ophthalmol. 2023 Apr;71(4):1064. [PMC free article: PMC10276670] [PubMed: 37026231]

51.

Mohamed HB, Abd El-Hamid BN, Fathalla D, Fouad EA. Current trends in pharmaceutical treatment of dry eye disease: A review. Eur J Pharm Sci. 2022 Aug 01;175:106206. [PubMed: 35568107]

52.

Henrioux F, Navel V, Belville C, Charnay C, Antoine A, Chiambaretta F, Sapin V, Blanchon L. Inflammation of Dry Eye Syndrome: A Cellular Study of the Epithelial and Macrophagic Involvement of NFAT5 and RAGE. Int J Mol Sci. 2023 Jul 04;24(13) [PMC free article: PMC10341472] [PubMed: 37446230]

53.

Garrigue JS, Amrane M, Faure MO, Holopainen JM, Tong L. Relevance of Lipid-Based Products in the Management of Dry Eye Disease. J Ocul Pharmacol Ther. 2017 Nov;33(9):647-661. [PMC free article: PMC5655476] [PubMed: 28956698]

54.

Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, Knop E, Markoulli M, Ogawa Y, Perez V, Uchino Y, Yokoi N, Zoukhri D, Sullivan DA. TFOS DEWS II pathophysiology report. Ocul Surf. 2017 Jul;15(3):438-510. [PubMed: 28736340]

55.

Asiedu K, Kyei S, Mensah SN, Ocansey S, Abu LS, Kyere EA. Ocular Surface Disease Index (OSDI) Versus the Standard Patient Evaluation of Eye Dryness (SPEED): A Study of a Nonclinical Sample. Cornea. 2016 Feb;35(2):175-80. [PubMed: 26655485]

56.

Akowuah PK, Adjei-Anang J, Nkansah EK, Fummey J, Osei-Poku K, Boadi P, Frimpong AA. Comparison of the performance of the dry eye questionnaire (DEQ-5) to the ocular surface disease index in a non-clinical population. Cont Lens Anterior Eye. 2022 Jun;45(3):101441. [PubMed: 33836971]

57.

Martin R, Emo Research Group Comparison of the Ocular Surface Disease Index and the Symptom Assessment in Dry Eye Questionnaires for Dry Eye Symptom Assessment. Life (Basel). 2023 Sep 21;13(9) [PMC free article: PMC10532939] [PubMed: 37763343]

58.

Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, Gupta PK, Karpecki P, Lazreg S, Pult H, Sullivan BD, Tomlinson A, Tong L, Villani E, Yoon KC, Jones L, Craig JP. TFOS DEWS II Diagnostic Methodology report. Ocul Surf. 2017 Jul;15(3):539-574. [PubMed: 28736342]

59.

Tagawa Y, Noda K, Ohguchi T, Tagawa Y, Ishida S, Kitaichi N. Corneal hyperalgesia in patients with short tear film break-up time dry eye. Ocul Surf. 2019 Jan;17(1):55-59. [PubMed: 30125664]

60.

Nichols KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. Cornea. 2004 Apr;23(3):272-85. [PubMed: 15084861]

61.

Schulze K, Großjohann R, Paul S, Bossaller L, Tost F. [Schirmer's test and strip meniscometry : Comparative consideration in the diagnostics of dry eye]. Ophthalmologe. 2021 Jun;118(6):561-568. [PubMed: 33146774]

62.

Brott NR, Zeppieri M, Ronquillo Y. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 24, 2024. Schirmer Test. [PubMed: 32644585]

63.

Miyasaka K, Kazama Y, Iwashita H, Wakaiki S, Saito A. A novel strip meniscometry method for measuring aqueous tear volume in dogs: Clinical correlations with the Schirmer tear and phenol red thread tests. Vet Ophthalmol. 2019 Nov;22(6):864-871. [PubMed: 30900351]

64.

Whitcher JP, Shiboski CH, Shiboski SC, Heidenreich AM, Kitagawa K, Zhang S, Hamann S, Larkin G, McNamara NA, Greenspan JS, Daniels TE., Sjögren's International Collaborative Clinical Alliance Research Groups. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's Syndrome International Registry. Am J Ophthalmol. 2010 Mar;149(3):405-15. [PMC free article: PMC3459675] [PubMed: 20035924]

65.

Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003 Oct;22(7):640-50. [PubMed: 14508260]

66.

Korb DR, Herman JP, Greiner JV, Scaffidi RC, Finnemore VM, Exford JM, Blackie CA, Douglass T. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005 Jan;31(1):2-8. [PubMed: 15665665]

67.

Schulze MM, Ng A, Yang M, Panjwani F, Srinivasan S, Jones LW, Senchyna M. Bulbar Redness and Dry Eye Disease: Comparison of a Validated Subjective Grading Scale and an Objective Automated Method. Optom Vis Sci. 2021 Feb 01;98(2):113-120. [PubMed: 33534379]

68.

Guzmán M, Miglio M, Keitelman I, Shiromizu CM, Sabbione F, Fuentes F, Trevani AS, Giordano MN, Galletti JG. Transient tear hyperosmolarity disrupts the neuroimmune homeostasis of the ocular surface and facilitates dry eye onset. Immunology. 2020 Oct;161(2):148-161. [PMC free article: PMC7496787] [PubMed: 32702135]

69.

Kaufman HE. The practical detection of mmp-9 diagnoses ocular surface disease and may help prevent its complications. Cornea. 2013 Feb;32(2):211-6. [PubMed: 22673852]

70.

Sędzikowska A, Tarkowski W, Moneta-Wielgoś J, Grzyliński K, Tarkowski G, Młocicki D. Effect of ocular demodicosis on the stability of the tear film and the tear break up time. Sci Rep. 2021 Dec 21;11(1):24296. [PMC free article: PMC8692470] [PubMed: 34934108]

71.

Korb DR, Greiner JV, Herman JP, Hebert E, Finnemore VM, Exford JM, Glonek T, Olson MC. Lid-wiper epitheliopathy and dry-eye symptoms in contact lens wearers. CLAO J. 2002 Oct;28(4):211-6. [PubMed: 12394549]

72.

Yasar E, Kemeriz F, Gurlevik U. Evaluation of dry eye disase and meibomian gland dysfunction with meibography in seborrheic dermatitis. Cont Lens Anterior Eye. 2019 Dec;42(6):675-678. [PubMed: 30922551]

73.

Shew W, Muntz A, Dean SJ, Pult H, Wang MTM, Craig JP. Blinking and upper eyelid morphology. Cont Lens Anterior Eye. 2022 Dec;45(6):101702. [PubMed: 35599140]

74.

Akpek EK, Bunya VY, Saldanha IJ. Sjögren's Syndrome: More Than Just Dry Eye. Cornea. 2019 May;38(5):658-661. [PMC free article: PMC6482458] [PubMed: 30681523]

75.

Apaydın H, Koca Bicer C, Feyza Yurt E, Abdulkadir Serdar M, Dogan İ, Erten S. Elevated Kynurenine Levels in Patients with Primary Sjögren's Syndrome. Lab Med. 2023 Mar 07;54(2):166-172. [PubMed: 36053233]

76.

Morthen MK, Magno MS, Utheim TP, Snieder H, Hammond CJ, Vehof J. The physical and mental burden of dry eye disease: A large population-based study investigating the relationship with health-related quality of life and its determinants. Ocul Surf. 2021 Jul;21:107-117. [PubMed: 34044135]

77.

Chao C, Golebiowski B, Stapleton F. The role of corneal innervation in LASIK-induced neuropathic dry eye. Ocul Surf. 2014 Jan;12(1):32-45. [PubMed: 24439045]

78.

Li M, Gong L, Sun X, Chapin WJ. Anxiety and depression in patients with dry eye syndrome. Curr Eye Res. 2011 Jan;36(1):1-7. [PubMed: 21174591]

79.

Ayaki M, Kawashima M, Negishi K, Tsubota K. High prevalence of sleep and mood disorders in dry eye patients: survey of 1,000 eye clinic visitors. Neuropsychiatr Dis Treat. 2015;11:889-94. [PMC free article: PMC4386766] [PubMed: 25848288]

80.

Aldaas KM, Ismail OM, Hakim J, Van Buren ED, Lin FC, Hardin JS, Meyer JJ. Association of Dry Eye Disease With Dyslipidemia and Statin Use. Am J Ophthalmol. 2020 Oct;218:54-58. [PMC free article: PMC8034500] [PubMed: 32413410]

81.

Ismail OM, Poole ZB, Bierly SL, Van Buren ED, Lin FC, Meyer JJ, Davis RM. Association Between Dry Eye Disease and Migraine Headaches in a Large Population-Based Study. JAMA Ophthalmol. 2019 May 01;137(5):532-536. [PMC free article: PMC6512290] [PubMed: 30844042]

Disclosure: Mark Golden declares no relevant financial relationships with ineligible companies.

Disclosure: Jay Meyer declares no relevant financial relationships with ineligible companies.

Disclosure: Marco Zeppieri declares no relevant financial relationships with ineligible companies.

Disclosure: Bhupendra Patel declares no relevant financial relationships with ineligible companies.