PanOph

Dry Eye Disease

Cornea

1. Clinical Analogy & TFOS DEWS II Framework

CLINICAL ANALOGY
  • Think of the tear film as a SOAP BUBBLE on the eye. A perfect soap bubble needs: (1) Water (aqueous) for volume, (2) Soap/surfactant (mucin) to spread and adhere to the glass surface, and (3) An oil layer (lipid) on top to prevent evaporation. In Dry Eye, ANY disruption to these three components - too little water (aqueous deficiency), bad soap (mucin deficiency), or a leaky oil cap (lipid layer deficiency/MGD) - makes the bubble unstable and prone to BREAKING (tear film instability = low TBUT). When the bubble breaks repeatedly, the glass (cornea) gets damaged - this is what we measure as staining, and the eye FEELS dry, gritty, and irritated. The body then tries to over-compensate → reflex tearing → paradoxical watering in dry eye!els dry, gritty, and irritated. The body then tries to over-compensate → reflex tearing → paradoxical watering in dry eye!els dry, gritty, and irritated. The body then tries to over-compensate → reflex tearing → paradoxical watering in dry eye!

2. Definition & Epidemiology

TFOS DEWS III Definition (2025)

  • Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors.
Exam pearl
  • Multifactorial - No single cause; multiple overlapping mechanisms
  • Loss of homeostasis - Not just "less tears"; the entire tear film ecosystem is dysregulated
  • Ocular symptoms required - A positive dry eye disease diagnosis requires symptoms and signs; signs without symptoms warrant assessment for reduced corneal sensitivity or predisposition to dry eye disease
  • Neurosensory abnormalities - Recognized etiological role; neuropathic pain is a differential diagnosis when symptoms outweigh signs

Epidemiology

ParameterData
Global Prevalence• 5–50% • Wide variation due to diagnostic criteria
Indian Prevalence• 18.4% in a hospital-based Indian study • Not attributable to the Andhra Pradesh Eye Disease Study
Age peak• Prevalence increases with age • Gradual rise from approximately 50 years • More marked increase beyond 80 years • Estimates vary by diagnostic criteria
Gender• Female prevalence is generally higher than male prevalence • Approximately 1.3–1.5 times the prevalence in men in studies combining symptoms and signs • Variability by age and diagnostic criteria
Post-menopausal women• Recognized risk context • Hormonal associations are complex • Not universally the highest-risk group
Contact lens wearers• Approximately 50% reported dry eye disease symptoms in one study • Estimates vary with population, symptoms versus signs, lens type and diagnostic criteria
Screen users• Visual-display-associated dry eye disease is an important emerging category • Reduced blink frequency and incomplete blinking may contribute to tear evaporation, tear-film instability, epithelial damage and symptoms
Post-refractive surgery• Dry eye is common, but reported rates vary by procedure, diagnostic criteria and follow-up • One LASIK study reported chronic dry eye persisting for at least 6 months in 20% of eyes • Corneal nerve injury and reduced corneal sensitivity contribute alongside other mechanisms

3. TFOS DEWS II - Conceptual Framework

Core MechanismConsequenceClinical Marker
• Tear film instability• Rapid tear breakup• Tear breakup time (TBUT) < 10 seconds
• Tear hyperosmolarity• Epithelial inflammation/damage• Osmolarity ≥ 308 mOsm/L
• Ocular surface inflammation• Mucin 5AC (MUC5AC) loss • Goblet cell damage• Conjunctival staining
• Neurosensory abnormalities• Symptom–sign dissociation • Consider neuropathic ocular pain• No single clinical marker
• Loss of homeostasis• Perpetuating vicious cycle• No single clinical marker

4. TFOS DEWS II Classification

A. Aqueous Deficient Dry Eye (ADDE)

  • Sjögren syndrome-associated dry eye: primary Sjögren syndrome with anti-Sjögren syndrome-related antigen A (anti-Ro/SSA) and anti-Sjögren syndrome-related antigen B (anti-La/SSB) antibodies.
  • Secondary Sjögren syndrome associated with rheumatoid arthritis, systemic lupus erythematosus, or systemic sclerosis.
  • Autoimmune lacrimal-gland destruction.
  • Lymphocytic infiltration of the lacrimal gland.
  • Non-Sjögren aqueous-deficient dry eye: lacrimal-gland disease, including sarcoidosis, lymphoma, and human immunodeficiency virus (HIV) infection.
  • Lacrimal-gland obstruction or cicatricial conjunctivitis in Stevens–Johnson syndrome, ocular cicatricial pemphigoid, and trachoma: mixed-phenotype dry eye.
  • Reflex hyposecretion in familial dysautonomia (Riley–Day syndrome).
  • Reflex hyposecretion in neurotrophic keratitis with impaired corneal sensory innervation, including ophthalmic-division trigeminal involvement.
  • Drug-induced aqueous-deficient dry eye: antihistamines, anticholinergics, and antidepressants.
  • Isotretinoin is a risk factor for meibomian gland dysfunction and evaporative dry eye.

B. Evaporative Dry Eye (EDE) - COMMON; PROPORTIONS VARY

Intrinsic (Lid/Meibomian gland related):

  • Meibomian gland dysfunction (MGD) (LEADING cause of dry eye disease (DED) overall)
  • Blepharitis
  • Low blink rate (video display terminal (VDT) use, Parkinson's, reading)
  • Lagophthalmos

Extrinsic (Ocular surface related):

  • Vitamin A deficiency (goblet cell loss → mucin deficiency)
  • Ocular surface disease (Allergy - tear-film instability)
  • Contact lens wear (increased evaporation)
  • Preservative toxicity (benzalkonium chloride (BAC) in eye drops)

Key Classification Concept

  • In clinical practice, dry eye disease often has mixed aqueous-deficient and evaporative components. The predominant mechanism helps guide the primary therapeutic approach, while all relevant contributing factors should be considered.
  • The Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) presents aqueous-deficient and evaporative dry eye as overlapping categories on a continuum rather than mutually exclusive entities.
  • The two mechanisms can reinforce one another: in aqueous-deficient dry eye, reduced tear-film thickness may impair tear-film lipid-layer spreading and produce a secondary evaporative component; conversely, severe evaporative dry eye may reduce corneal sensitivity and reflex lacrimal secretion, producing secondary aqueous deficiency.

5. Pathophysiology - The Core Mechanisms

Step 1: Initiating Events

  • Any triggering factor (meibomian gland dysfunction (MGD), autoimmune, nerve damage, environment) initiates tear film instability.
  • Evaporation increases → Tear hyperosmolarity develops (> 308 milliosoles per liter (mOsm/L) or intereye difference ≥ 8 milliosoles per liter (mOsm/L)).

Step 2: Hyperosmolarity - The Central Driver

  • Hyperosmolar tears activate mitogen-activated protein kinase (MAPK) pathways, including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), in epithelial cells
  • Nuclear factor kappa B (NF-κB) signaling induces interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9)
  • Matrix metalloproteinase-9 (MMP-9) cleaves tight-junction proteins, including occludin and zonula occludens-1 (ZO-1), contributing to epithelial-barrier disruption
  • Goblet-cell loss reduces mucin 5AC (MUC5AC), the gel-forming mucin, contributing to mucin deficiency and reduced lubrication
  • Mucin 1 (MUC1), mucin 4 (MUC4), and mucin 16 (MUC16) form part of the ocular-surface glycocalyx; reduced glycocalyx mucin expression can impair wettability, but changes in individual transmembrane mucins are inconsistent

Step 3: Inflammation - Amplification Loop

  • T-helper cell 1 (Th1) and T-helper cell 17 (Th17) responses contribute to ocular-surface inflammation; CD4-positive T-cell infiltration occurs in the conjunctiva and is associated with lacrimal-gland infiltration in experimental dry eye disease.
  • Interferon-gamma (IFN-γ) from T-helper cell 1 (Th1) → Goblet-cell loss and squamous metaplasia.
  • Interleukin-17 (IL-17) → Corneal epithelial damage and barrier disruption; matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-3 (MMP-3) upregulation; decreased conjunctival goblet-cell density.
  • Dendritic-cell activation → Antigen presentation → Perpetuates autoimmune loop, especially in Sjögren syndrome.
  • Substance P and calcitonin gene-related peptide (CGRP) are neuropeptides expressed by corneal nerves and may contribute to post-laser in situ keratomileusis (LASIK) dry eye/neuroepithelial syndrome; they also provide trophic support for corneal epithelial maintenance and healing.

Step 4: Nerve Damage & Sensory Changes

  • Corneal nerves (sub-basal plexus) - the cornea is the most densely innervated tissue in the human body, with approximately 7,000 epithelial nociceptors/mm²; corneal innervation is approximately 300–600 times greater than in skin.
  • In laser refractive surgery-associated dry eye disease: corneal nerve damage impairs the cornea-blink reflex and ocular-surface–lacrimal-gland neural loop, reducing reflex tearing and increasing tear-film instability; reduced blinking may further increase evaporation.
  • Central sensitization → Allodynia, hyperalgesia (neuropathic pain)
  • Corneal nerve damage → reduced trophic support for the epithelium, including reduced neuromediators such as substance P and disruption of growth-factor signaling; substance P acts synergistically with insulin-like growth factor 1 to support corneal epithelial healing.
  • In vivo confocal microscopy - enables noninvasive assessment of sub-basal corneal nerve morphology and nerve-fiber density.

6. Tear Film Anatomy & Layers

LayerThicknessCompositionSourceFunctionDeficiency Causes
Lipid (Outer)• Approximately 20–160 nanometres (0.02–0.16 micrometres); variable rather than fixed• Polar lipids, including phospholipids • Non-polar lipids, including wax esters and cholesteryl esters• Meibomian glands (primary) • Zeis glands• Retards evaporation • Reduces surface tension • Contributes to tear-film stability• Meibomian gland dysfunction • Blepharitis • Rosacea • Isotretinoin use
Aqueous (Middle)• Historically described as approximately 6–8 micrometres and forming most of the tear film • Modern studies describe a variable aqueous-mucin layer; total precorneal tear-film thickness is approximately 3–5 micrometres in some measurements• Water 98% • Proteins, including lactoferrin, lysozyme, and immunoglobulin A • Electrolytes • Growth factors, including epidermal growth factor and nerve growth factor• Main lacrimal gland: major contributor to aqueous tears and reflex secretion • Accessory glands of Krause and Wolfring: contribute to aqueous tear secretion, including basal secretion • Exact relative contribution is uncertain• Antimicrobial activity • Oxygen supply • Waste removal • Optical clarity• Sjögren syndrome • Lacrimal gland disease • Neurotrophic involvement of the trigeminal nerve (cranial nerve V)
Mucin (Inner)• 0.2–0.5 micrometres• Gel-forming: MUC5AC, mainly from goblet cells • Membrane-bound: MUC1, MUC4, and MUC16 from epithelial cells• Conjunctival goblet cells: MUC5AC • Corneal and conjunctival epithelium: membrane-tethered mucins• Wettability, converting the hydrophobic cornea to hydrophilic • Lubrication • Glycocalyx barrier• Vitamin A deficiency • Stevens–Johnson syndrome • Ocular cicatricial pemphigoid • Benzalkonium chloride toxicity

7. Tear Film - Viva Pearls

  • The tear film is NOT truly trilaminar - modern concept (Willcox et al. 2017) considers it a BIPHASIC model:
  • Lipid phase
  • Mucin-aqueous gel phase (as aqueous and mucin are intimately mixed)
  • Lactoferrin is an AQUEOUS phase protein.
  • Levels are reduced in aqueous-deficient dry eye.
  • Useful diagnostic marker; one study reported 1.89 ± 0.70 mg/mL in normal controls versus 1.04 ± 0.80 mg/mL in a dry-eye group.
  • Mucin 16 (MUC16) forms part of the glycocalyx.
  • Its loss contributes to epithelial barrier breakdown.
  • Meibomian glands: approximately 25–40 upper lid, 20–30 lower lid.
  • Holocrine secretion.
  • Androgen-regulated.
  • Accessory lacrimal glands: Krause: about 40 upper, 6–8 lower; Wolfring: 2–5 upper lid, 1–3 lower lid.
  • Accessory lacrimal glands contribute to tear secretion and are assumed to respond similarly to reflex stimulation.
  • The main lacrimal gland is the chief source of lacrimal tears.

8. The Vicious Cycle of DED

The Vicious Cycle (TFOS DEWS II)

  1. TRIGGERING FACTOR (meibomian gland dysfunction (MGD) / autoimmune disease / nerve damage / environmental factors) ↓ TEAR FILM INSTABILITY
  2. Tear-film breakup contributes to tear hyperosmolarity ↓ tear osmolarity of 308 mOsm/L or higher is a sensitive threshold for early dry eye disease ↓ activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) ↓ increased interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9)
  3. GOBLET CELL LOSS (mucin 5AC (MUC5AC) ↓) + EPITHELIAL DAMAGE ↓ MORE TEAR INSTABILITY + INFLAMMATORY CYCLE
  4. ↓ LACRIMAL GLAND DYSFUNCTION (reflex hyposecretion) ↓ MORE AQUEOUS DEFICIENCY
  5. Tear hyperosmolarity and epithelial injury stimulate corneal nerve endings; with progressive dry eye disease, corneal sensitivity may become impaired and subepithelial nerve density may decrease ↓ reduced blinking and reduced trophic support ↓ ESTABLISHED CHRONIC
  6. DRY EYE DISEASE (DED) (perpetuating cycle)
Exam pearl
  • Breaking Points for Therapeutic Intervention:
  • Artificial tears/lubricants → Decrease tear osmolarity and increase ocular-surface moisture/lubrication
  • Anti-inflammatories (Cyclosporine A (CsA), Lifitegrast) → Break the inflammatory amplification loop
  • Lid therapy → Address meibomian gland dysfunction (MGD) (evaporation control)
  • Autologous serum → Trophic factors for nerve healing and epithelial repair
  • Punctal plugs → Retain tears; treat ocular-surface inflammation before occlusion
  • Cenegermin → Treat neurotrophic keratitis; not established as a treatment for dry eye disease

9. Clinical Features

Symptoms
Symptoms
SymptomMechanismNotes
• Dryness / Foreign body sensation• Reduced lubrication • Ocular-surface epithelial damage• Symptom associated with dry eye disease
• Burning / Stinging• Hyperosmolarity • Inflammatory mediators• Associated with dry eye disease
• Paradoxical tearing / Watering• Reflex hypersecretion from ocular-surface irritation• May present as watery eyes in dry eye disease
• Photophobia• Corneal nerve sensitization • Epitheliopathy• May occur in dry eye disease • Not specific for a neurotrophic component
• Blurred vision (fluctuating)• Tear-film instability or breakup • Ocular-surface irregularity• Blinking refreshes the tear film and may improve the visual disturbance
• Worse with screen use / reading• Reduced blink rate • Tear-film instability • Increased evaporative stress• Recognized contributor to video display terminal (VDT)-related dry eye symptoms
• Worse in air-conditioned / windy environments• Increased tear evaporation or instability• Environmental triggers
• Contact lens intolerance• Contact-lens-related tear-film instability • Impaired wettability • Increased evaporation• May occur with contact-lens-related dry eye symptoms
• Morning symptoms• Reduced tear production during sleep • Nocturnal lagophthalmos• Afternoon-worst symptoms are nonspecific and should not alone suggest allergy

10. Signs - Slit Lamp Examination

  • Lid margin: Meibomian orifice plugging, irregular or distorted lid margin, increased vascularity, and telangiectasia are findings associated with Meibomian Gland Dysfunction (MGD).
  • Tear meniscus: Reduced tear meniscus height (TMH) < 0.2 mm (normal 0.2–0.3 mm). Low meniscus = aqueous-deficient dry eye (ADDE).
  • Tear Break-Up Time (TBUT) with fluorescein: < 10 sec is a commonly used abnormal reference threshold. Tear Break-Up Time (TBUT) alone does not reliably distinguish aqueous-deficient from evaporative or Meibomian Gland Dysfunction (MGD)-associated dry eye.
  • Conjunctival staining: Rose bengal or lissamine green may be used for ocular-surface staining, particularly conjunctival and lid-margin damage. Grade staining with the Oxford or van Bijsterveld system.
  • Corneal staining: Fluorescein staining demonstrates corneal epithelial damage, typically with punctate staining most prominent in the interpalpebral zone. The pattern and location may provide clues to alternative or coexisting causes, including contact-lens-related disease and superior limbic keratoconjunctivitis (SLK).
  • Filamentary keratitis: Fine strands of degenerated epithelial cells and mucus attached to the cornea at one or both ends; aqueous-deficient dry eye is the most common associated ocular condition.
  • Superficial punctate keratopathy (SPK): Fluorescein may demonstrate punctate epithelial keratopathy or erosions, typically most prominently in the interpalpebral zone. The distribution of staining may provide an etiologic clue but is not, by itself, specific for aqueous-deficient dry eye, evaporative dry eye, or Meibomian Gland Dysfunction (MGD).
  • Tear film debris: Mucous strands, meibum particles in tear film
  • Blink rate: Normal spontaneous blink rate is reported as 10–15 blinks/min, with substantial variation by conditions. Blink rate falls during visual display terminal (VDT) or computer work and may be reduced in Parkinson disease.
  • Conjunctival/corneal sensitivity: Corneal sensitivity is reduced or absent in neurotrophic keratopathy and is often reduced in dry eye, particularly aqueous-deficient disease. Inflammatory dry eye may cause sensitization and other altered sensory responses; sensitivity is variable and is not reliably normal or increased.

11. Diagnostic Tests - Complete Battery

CLINICAL ANALOGY
  • Think of DED diagnosis like diagnosing heart failure: No single test is diagnostic. Just as you use BNP + Echo + CXR + clinical features together, in DED you combine: Symptoms (OSDI) + TBUT + Osmolarity + Staining + Schirmer. Each test measures a DIFFERENT aspect of the pathophysiology.
TestNormal ValueDry eye disease (DED) CutoffMeasuresPearls
Ocular Surface Disease Index (OSDI)Score 0–12 (normal)≥ 13 (positive symptom screen)• Validated 12-item subjective symptom tool. • Measures symptom severity.• Score 0–100. • Common symptom bands: normal 0–12; mild 13–22; moderate 23–32; severe 33–100. • Interpret with objective homeostasis markers.
Fluorescein tear break-up time> 10 seconds< 10 seconds. < 5 seconds with smaller, controlled fluorescein volumes.• Measures tear-film stability.• Fluorescein may reduce measured tear-film stability. • When both tests are performed, standardize the sequence and generally perform tear break-up testing before Schirmer testing. • Do not use staining-pattern associations as definitive diagnostic rules.
Non-invasive tear break-up timeUse the validated reference range for the device and protocol.Use the validated, instrument-specific cutoff.• Measures tear-film stability without fluorescein. • Avoids fluorescein-related measurement artifact.• Do not present 7.8 seconds as universal. • Do not label it the gold standard for evaporative dry eye.
Schirmer test I without anesthesiaThresholds are not absolute.≤ 10 mm/5 minutes. ≤ 5 mm/5 minutes indicates more severe aqueous deficiency.• Estimates stimulated reflex tear flow. • Is not a pure basal-secretion test.• Standardize testing conditions. • Eyes closed may reduce variability. • Do not require upward gaze.
Schirmer test with topical anesthesiaInterpret with the clinical context.< 3 mm/5 minutes is highly diagnostic of aqueous-deficient dry eye. 3–10 mm/5 minutes is equivocal.• Estimates basal tear secretion. • No nasal stimulation.• Nasal stimulation is a separate reflex-secretion variant. • These variants are not routine core diagnostic tests.
Phenol red thread test (PRT; Zone-Quick)Interpret wetting length using the validated cutoff for the protocol.Published thresholds vary around 9–10 mm/15 seconds.• Indirectly estimates resting tear volume. • Performed for 15 seconds.• The pH-sensitive thread changes from yellow to red when moistened by tears. • Less likely than Schirmer testing to induce substantial reflex tearing. • Generally better tolerated than Schirmer testing.
Tear osmolarityNot a universal normal/cutoff pair.≥ 308 mOsm/L in either eye or interocular difference > 8 mOsm/L.• Measures tear-film hyperosmolarity. • Hyperosmolarity is a core etiologic feature of dry eye disease.• Values increase and become more variable with disease severity. • Interpret alongside symptoms, tear-film stability, and ocular-surface staining. • Do not describe it as a definitive single diagnostic marker.
Lissamine green stainingRecord using a specified grading system.No universal dry-eye cutoff. Do not treat any staining as diagnostic.• Assesses conjunctival and lid-margin epithelial damage. • Stains epithelial cells with damaged cell membranes, irrespective of mucin status.• Less toxic and better tolerated than rose bengal. • Do not call it a goblet-cell marker.
Rose bengal stainingRecord using a specified grading system.Van Bijsterveld score > 3.5 is a grading-based threshold, not a universal standalone cutoff.• Stains cells unprotected by mucin or glycocalyx and dead or degenerated cells.• It is irritating. • Lissamine green has largely replaced it.
Fluorescein staining of the corneaNo staining is recorded as grade 0.Record using a specified grading system, such as the Oxford scale (0–5). Do not use any staining as a universal dry-eye cutoff.• Indicates superficial epithelial compromise. • May reflect disruption of tight junctions or defective glycocalyx.• Distribution may provide etiologic clues. • Distribution is not diagnostic of a dry-eye subtype.
Infrared meibographyUse a specified grading system, such as a 0–3 meiboscore.No universal percentage-dropout cutoff.• Non-invasive assessment of meibomian-gland morphology and dropout.• Interpret with lid-margin assessment and gland expressibility. • Do not diagnose meibomian gland dysfunction from meibography alone.
In vivo confocal microscopyUse device-, analysis-, and population-specific reference values.No validated universal cutoff for sub-basal nerve density.• Non-invasive cellular imaging. • Can assess corneal epithelial and sub-basal nerve changes and conjunctival cellular features.• Reduced sub-basal nerve density may occur in dry eye disease. • Do not present a universal cutoff or a clinical gold-standard claim for nerve damage.
Matrix metalloproteinase-9 (MMP-9) / InflammaDryNegative.Approximately > 40 ng/mL is positive.• Point-of-care tear inflammatory-marker assay.• Reported sensitivity and specificity are approximately 85% and 94%, respectively, but vary by population and disease severity. • Interpret with the clinical examination. • Do not use a positive result alone to direct cyclosporine therapy.
Lactoferrin levelNo universal normal value.No universal cutoff; published values vary by assay and population.• Tear-film biomarker related to lacrimal-gland function. • Levels may be reduced in aqueous-deficient dry eye.• Available commercially but less commonly used in routine practice than tear osmolarity or matrix metalloproteinase-9 testing.
Tear meniscus heightUse the validated reference range for the instrument and protocol.≤ 0.20 mm may indicate aqueous-deficient dry eye.• Indirectly assesses the tear reservoir and tear volume. • Optical coherence tomography (OCT), including anterior-segment optical coherence tomography (OCT), provides rapid, non-invasive measurement.• Findings may correlate with Schirmer testing. • Interpretation is device- and technique-dependent.

13. TFOS DEWS Diagnostic Algorithm (Simplified)

TFOS DEWS Diagnostic Algorithm (Simplified)
TFOS DEWS Diagnostic Algorithm (Simplified)
StepCriterionResult
1. Symptoms• Ocular Surface Disease Index (OSDI) ≥ 13 • OR 5-Item Dry Eye Questionnaire (DEQ-5) ≥ 6• Required before dry eye disease (DED) diagnostic confirmation
2. Homeostasis markers (≥1 required with a positive symptom screen)• Reduced non-invasive break-up time, with a method-dependent positive cut-off up to 10 seconds • OR fluorescein break-up time < 10 seconds • OR osmolarity ≥ 308 milliosmoles per litre (mOsm/L) in either eye • OR interocular difference > 8 milliosmoles per litre (mOsm/L) • OR positive ocular-surface staining • >9 conjunctival lissamine-green spots • OR >5 corneal fluorescein spots• Confirms dry eye disease (DED) when a positive symptom screen is accompanied by ≥1 positive homeostasis marker
3. Additional tests for subtype or mechanism• Schirmer/tear-volume assessment for aqueous deficiency • Meibography for meibomian gland dysfunction (MGD) assessment • Selected tests such as matrix metalloproteinase-9 (MMP-9) assessment may evaluate ocular-surface inflammation • In-vivo confocal microscopy (IVCM) may evaluate ocular-surface damage at a cellular level • In-vivo confocal microscopy (IVCM) remains an emerging technique that is not widely adopted for routine diagnosis• Supports subtype or mechanism assessment • Not equivalent routine triaging tests
4. Sub-classification• Predominantly aqueous-deficient or predominantly evaporative disease, with a mixed spectrum • Use tear-volume assessment, meibomian gland dysfunction (MGD)/lipid-layer findings, and their severity • A low Schirmer result supports aqueous deficiency but does not define it alone • Meibomian gland dysfunction (MGD) features and deficient lipid-layer findings support an evaporative bias • Reduced tear volume supports an aqueous-deficient bias • Dry eye disease (DED) exists on a spectrum between these categories• Informs management
5. Severity and treatment selection• Assess symptom burden together with subtype features • Include meibomian gland dysfunction (MGD)/lipid-layer findings • Include non-invasive tear-volume or stability measures • Use ocular-surface staining systems such as the Oxford scheme as supportive clinical measures• Informs treatment selection • No standalone validated severity algorithm

14. DEWS Severity Grading

DEWS Severity Grading (2007 four-level framework)
DEWS Severity Grading (2007 four-level framework)
FeatureGrade 1 (Mild)Grade 2 (Moderate)Grade 3 (Severe)Grade 4 (Very Severe)
• Discomfort• Mild/episodic under environmental stress• Moderate/episodic or chronic (stress or no stress)• Severe/frequent/constant (without stress)• Severe/disabling/constant
• Vision• None or episodic mild fatigue• Annoying/activity-limiting episodic• Annoying/chronic and/or constant, limiting activity• Constant +/- disabling
• Injection• None/mild• None to mild• +/-• +/++
• Staining (corneal)• None/mild• Variable• Marked central• Severe punctate corneal erosions
• Lid/Meibomian• Meibomian gland dysfunction (MGD) variable• Meibomian gland dysfunction (MGD) variable• Frequent• Trichiasis/keratinization/symblepharon
• Tear breakup time (TBUT)• Variable• ≤ 10• ≤ 5• Immediate
• Schirmer (mm/5min)• Variable• ≤ 10• ≤ 5• ≤ 2
• Treatment trigger• Education • Environmental/dietary modification • Eliminate offending systemic medications • Artificial tears/gels/ointments • Eyelid therapy• If inadequate: anti-inflammatory therapy • Tetracyclines when indicated • Punctal plugs • Secretagogues • Moisture-chamber spectacles• If inadequate: serum • Contact lenses • Permanent punctal occlusion• If inadequate: systemic anti-inflammatory agents • Surgery

15. Management Algorithm

Stepwise Management - Tear Film & Ocular Surface Society Dry Eye Workshop II / American Academy of Ophthalmology Preferred Practice Pattern

STEP 1 (Initial management)

  • Patient education: frequent screen breaks and blink-awareness training
  • Environmental modification: humidifiers, avoid direct air-conditioning vents, moisture chamber spectacles/goggles
  • Identify and, under clinician guidance, potentially modify or eliminate offending systemic and topical medications (antihistamines, antidepressants, diuretics)
  • Dietary: omega-3 fatty acid supplementation; the Dry Eye Assessment and Management (DREAM) trial found no significant benefit over placebo
  • Lid hygiene for meibomian gland dysfunction: warm compresses and lid massage; optimal duration is not definitively established, and at least 40°C refers to the palpebral conjunctiva/gland temperature

STEP 2 (Mild–Moderate: Grade 1–2)

  • Preservative-free artificial tears as needed; frequency individualized to symptoms, signs, and treatment burden.
  • Lipid-containing artificial tears may be considered when meibomian gland dysfunction (MGD) or lipid deficiency contributes to evaporative dry eye disease (DED).
  • Lid hygiene or lid scrubs if blepharitis is present; consider a short course of topical antibiotic therapy selectively, rather than routine long-term use alone.
  • Tetracyclines: Doxycycline may be considered for selected meibomian gland dysfunction (MGD) or blepharitis; dosing and duration are individualized because the optimal regimen has not been established. It has antimicrobial and anti-inflammatory effects.
  • Punctal plugs if needed, after ocular-surface inflammation is controlled; effectiveness is more established for aqueous-deficient dry eye disease than for evaporative dry eye disease (DED).

Escalation Options (TFOS DEWS II)

  • Step 2: Topical cyclosporine A 0.05% (Restasis) twice daily or cyclosporine A 0.1% (Ikervis) once daily at bedtime; treatment duration and reassessment are individualized
  • Step 2: Lifitegrast 5% (Xiidra) twice daily - lymphocyte function-associated antigen-1 (LFA-1) antagonist
  • Step 2: Short-term topical steroids: fluorometholone (FML) or loteprednol × 2–4 weeks (bridge therapy)
  • Step 3: Autologous serum tears (typically 20%; 50–100% also used) - vitamins, fibronectin, and growth factors such as epithelial growth factor and nerve growth factor
  • Step 3: Moisture-chamber spectacles / scleral lenses; therapeutic contact lenses (CL), including silicone-hydrogel bandage lenses

STEP 4 (Advanced/severe dry eye disease; if previous options are inadequate)

  • If previous options are inadequate, consider:
  • Topical corticosteroid for longer duration
  • Amniotic membrane grafts (PROKERA - cryopreserved amniotic membrane)
  • Surgical punctal occlusion
  • Other surgical approaches, such as tarsorrhaphy or salivary-gland transplantation
  • Cenegermin-bkbj 0.002% (Oxervate) - recombinant human nerve growth factor indicated for neurotrophic keratitis
  • Systemic: oral secretagogues, such as pilocarpine or cevimeline, may increase tear production in selected patients with Sjögren-associated dry eye disease and residual glandular function.

16. Severe Dry Eye Management

  • For severe dry eye disease, individualize management according to disease severity and the contributing etiologies; multiple appropriate treatments may be used concurrently.
  • Treat ocular-surface inflammation before considering punctal occlusion; use punctal plugs judiciously because their use in active inflammation is controversial.
  • Tear osmolarity greater than 340 milliosmoles per liter (mOsm/L) may indicate severe tear-film hyperosmolarity, and an intereye difference greater than 8 milliosmoles per liter (mOsm/L) may indicate tear-film instability; select treatment based on the complete clinical assessment and contributing etiologies.
  • In vivo confocal microscopy may demonstrate corneal-nerve alterations in dry eye disease, but sub-basal nerve density alone does not establish a neuropathic component or determine treatment. Consider cenegermin for neurotrophic keratitis in accordance with its indication.
  • Prosthetic replacement of the ocular surface environment (PROSE) devices are specialized scleral lenses that may provide visual rehabilitation and ocular-surface support in severe cicatricial or inflammatory dry eye disease; use should be individualized.

17. Pharmacological Agents - Detailed

Pharmacological Agents - Detailed
Pharmacological Agents - Detailed
DrugClass / MOADoseKey Facts / Exam Pearls
• Cyclosporine A (Restasis 0.05% Ikervis 0.1%)• Calcineurin-inhibitor immunomodulator • Suppresses T-cell/interleukin-2 (IL-2)-mediated inflammation • Associated with reduced conjunctival epithelial apoptosis and preservation or recovery of goblet-cell density• Restasis 0.05%: 1 drop in each eye twice daily (BD), approximately 12 hours apart • Ikervis 0.1%: 1 drop in each affected eye once daily at bedtime • Assess response over several months• Food and Drug Administration (FDA) approval package for Restasis New Drug Application (NDA) 21-023 lists October 10, 2003. • Benefit develops gradually and may require several months. • Ocular burning/stinging is common. • Avoid presenting a universal 3–6-month minimum regimen.
• Lifitegrast (Xiidra 5%)• Lymphocyte function-associated antigen-1 (LFA-1) antagonist • Binds leukocyte lymphocyte function-associated antigen-1 (LFA-1) and blocks lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) interaction • May inhibit T-cell adhesion to intercellular adhesion molecule-1 (ICAM-1) and inflammatory cytokine secretion; blocking lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) signaling may reduce T-cell activation and migration.• 5% twice daily (BD)• Initially approved in the United States in 2016. • Improves dry-eye signs and/or symptoms. • Dysgeusia is characteristic. • Efficacy is supported by OPUS trials.
• Loteprednol (Lotemax 0.5%)• Retrometabolically designed corticosteroid • Lower propensity for clinically significant intraocular-pressure (IOP) elevation than prednisolone acetate • Limited systemic absorption occurs after topical ophthalmic administration• 0.5% four times daily (QID) when clinically appropriate as short-term bridge therapy• If used for 10 days or longer, monitor intraocular pressure (IOP). • Prolonged corticosteroid use may increase the risk of secondary ocular infection. • Lotemax SM is a submicron ophthalmic gel containing loteprednol etabonate 0.38%.
• Doxycycline• Tetracycline antibiotic • Anti-inflammatory and anti-metalloproteinase activity, including matrix metalloproteinase-9 (MMP-9) inhibition or reduction • Do not describe inhibition of meibum-lipolytic enzymes as an established mechanism• Regimen-dependent; published regimens range from sub-antimicrobial dosing to higher doses for approximately 4–12 weeks or longer• Adjunctive therapy for inflammatory, persistent, or refractory meibomian gland dysfunction (MGD), particularly with ocular rosacea. • Do not present 50–100 mg once daily for exactly 3 months as a universal regimen.
• Omega-3 fatty acids (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA])• Biologically plausible anti-inflammatory effects • Influence inflammatory mediator/eicosanoid pathways • Experimental and observational studies suggest effects on meibomian and tear-film lipid composition• No universally established supplementation regimen for dry eye disease (DED)• DREAM Trial (New England Journal of Medicine [NEJM] 2018): 3 g/day eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) was not superior to olive-oil placebo after 12 months. • Clinical benefit of routine supplementation remains uncertain; do not state categorically that it reduces meibum viscosity.
• Autologous serum tears (AST)• Contains biologically active components including epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-β), vitamin A, and fibronectin • May support epithelial maintenance, healing, and nerve-related trophic effects• Patient-derived preparation • Commonly 20%; higher concentrations such as 50–100% have also been studied • Dosing is protocol-dependent, commonly several times daily• Not a conventional commercially manufactured eye drop. • May be used in selected severe or persistent ocular-surface disease, including Sjögren syndrome and postoperative ocular-surface disease. • Storage and handling depend on the compounding protocol; −20°C storage for up to approximately 3 months is reported. • Umbilical-cord serum is an allogeneic alternative.
• Cenegermin (Oxervate 0.002%)• Recombinant human nerve growth factor • Supports corneal innervation and integrity and may promote epithelial healing• 0.002% • 1 drop 6 times/day at 2-hour intervals for 8 weeks• Indicated for the treatment of neurotrophic keratitis; pivotal studies evaluated patients with neurotrophic persistent epithelial defects or corneal ulcers. • European Medicines Agency (EMA) describes moderate or severe disease corresponding clinically to stage 2–3; Food and Drug Administration (FDA) labeling states neurotrophic keratitis without specifying Mackie stage. • REPARO trial provides relevant evidence. • Not routine therapy for ordinary dry eye disease (DED) or post-laser-assisted in situ keratomileusis (LASIK) neuropathic dry eye without neurotrophic keratitis.
• Pilocarpine (oral)• Muscarinic/parasympathomimetic agonist • Stimulates residual exocrine secretion• 5 mg four times daily (QID) orally in selected patients• May be used in Sjögren syndrome to help increase tear production and improve ocular dryness. • Cholinergic adverse effects include sweating, flushing, urinary frequency, gastrointestinal symptoms, and increased lacrimation. • Cevimeline 30 mg three times daily (TDS) is an alternative muscarinic agonist used in Sjögren syndrome; comparative tolerability versus pilocarpine is not established here.
• Sodium hyaluronate artificial tears (preservative-free [PF], various %)• Viscoelastic, water-retaining polymer • Increases tear-film viscosity and thickness and supports ocular-surface coating and residence time • May interact with cluster of differentiation 44 (CD44) to promote epithelial migration or repair• Concentration and dosing vary by product and clinical need • Published regimens include approximately 4–8 times daily; some patients require more frequent use• Commonly used artificial-tear ingredient. • Higher concentrations may increase tear-film stability or residence time, but 0.3% is not universally superior. • Preservative-free (PF) preparations are preferred with frequent dosing or moderate-to-severe disease. • Carbomer gels may be used as longer-acting, higher-viscosity lubricants when clinically appropriate; bedtime use depends on the specific formulation and patient needs.
• Hydroxypropyl guar (HP-Guar) (Systane Ultra)• pH-/borate-sensitive gelling agent • Forms a protective, mucomimetic or mucin-like layer on the ocular surface • Increases retention of lubricant demulcents• As needed; formulation-dependent • Do not assume every Systane Ultra formulation is preservative-free• May be useful for ocular-surface lubrication. • Systane Ultra contains polyethylene glycol 400 and propylene glycol as lubricant demulcents, with hydroxypropyl guar (HP-Guar) as an inactive gelling agent. • Polyethylene glycol (PEG) and propylene glycol are not lipid components.
MCQ

A 35-year-old woman with Sjögren syndrome dry eye disease is using ciclosporin 0.05% twice daily for 3 months but has persistent burning and an Ocular Surface Disease Index (OSDI) score of 38. Schirmer I testing is 3 mm/5 min. Which option best addresses the marked aqueous deficiency and ocular-surface support among those listed, after reassessment of inflammation and treatment response?

18. Punctal Plugs & Surgical Options

Punctal Plugs
Punctal Plugs
TypeMaterialDurationIndicationComplications
Temporary (dissolvable)• Collagen-based • Product-specific absorbable materials vary• 1–16 weeks (collagen-based)• Trial before permanent occlusion • Post-refractive surgery• Self-dissolving • Complications can occur
Intracanalicular plugs (SmartPlug)• Thermosensitive acrylic • Becomes shorter and thicker at body temperaturePermanent• Dry eye symptoms relieved by punctal occlusion • May be used after ocular surgery• Migration • Difficult removal • Canaliculitis
Punctal plugs (visible/silicone)• Silicone • Polymethyl methacrylate (PMMA)Permanent (removable)• Moderate–severe dry eye disease • Sjögren syndrome • Post-laser-assisted in situ keratomileusis (LASIK)• Extrusion • Lacrimation • Canaliculitis • Pyogenic granuloma at punctum
Thermal cautery (permanent occlusion)• Diathermy • ThermalPermanent• Unable to retain or tolerate punctal plugs • Severe dry eye disease with recurrent plug extrusion • Sjögren syndrome-associated dry eye disease (partial occlusion may be used)• Intended to provide permanent occlusion • Recanalization may occur; repeat treatment may be required • Consider temporary punctal occlusion before permanent closure when feasible
Exam pearl
  • Punctal occlusion during active ocular-surface inflammation is controversial because it may prolong the presence of pro-inflammatory cytokines; treat the inflammation before occlusion with cyclosporine A (CsA) and/or steroids.
  • Punctal occlusion may be performed at either the lower or upper punctum; available evidence does not establish a universal lower-first sequence or a 70% drainage proportion.
  • If insufficient, add upper plug.
  • SmartPlug advantages: intracanalicular placement with minimal foreign-body sensation and a lower chance of extrusion; however, complications including canaliculitis, dacryocystitis, epiphora, and discomfort may occur.
  • SmartPlug removal may be possible with lacrimal irrigation, but a lodged or complicated plug can be difficult to remove and may require canaliculotomy.
  • Thermal cautery - if you cauterize too aggressively, it can extend into the horizontal canaliculus causing permanent epiphora.
  • Freeman plug = the classic silicone punctal plug (dumbbell-shaped).

Surgical Options for Severe DED

  • Tarsorrhaphy (lateral): Reduces palpebral aperture, evaporation, and corneal exposure. Used in lagophthalmos-related exposure keratopathy and neurotrophic keratopathy. Temporary or permanent.
  • Amniotic Membrane Transplantation: PROKERA (cryopreserved) or AmnioTek. Anti-inflammatory, promotes epithelial healing. Sutured or ring-device. Indication: Severe persistent epithelial defect in dry eye disease, filamentary keratitis.
  • Conjunctival/Limbal Stem Cell Transplant: For severe ocular surface disease with limbal stem cell deficiency (chemical burns, Stevens-Johnson syndrome). Restores corneal surface.
  • Scleral Contact Lenses: Large-diameter lenses that vault over cornea, filled with preservative-free saline. Creates constant fluid reservoir. Non-surgical option for severe dry eye disease. Indication: Sjogren syndrome, Stevens-Johnson syndrome, graft-versus-host disease, post-laser-assisted in situ keratomileusis dry eye disease.
  • Parotid duct transposition: Parotid duct transferred to the lower conjunctival fornix. Severe aqueous-deficient dry eye disease; limited evidence. Complications: gustatory reflex epiphora, blepharitis, and keratitis from excessive secretion.
  • Botulinum toxin injection (upper lid): Creates temporary partial ptosis, functioning as temporary tarsorrhaphy → reduces exposure and evaporation. Used for persistent epithelial defects and severe dry eye disease refractory to medical treatment and punctal occlusion.

19. Post-LASIK DED

  • Mechanism: Laser-assisted in situ keratomileusis (LASIK) flap creation transects sub-basal corneal nerve fibers, and stromal ablation damages deeper stromal nerves.
  • Reduced corneal sensation disrupts the cornea–blink reflex and the ocular surface–lacrimal gland neural loop, reducing tear secretion and neurotrophic-factor supply.
  • Laser-assisted in situ keratomileusis (LASIK) may reduce aqueous tear secretion through corneal denervation and may worsen evaporative dry eye through reduced blinking and adverse effects on meibomian gland function.
  • Risk factors:
  • Pre-existing dry eye disease is the most important preoperative risk factor.
  • Larger flap diameter and greater ablation depth increase postoperative dry eye risk.
  • Hyperopic laser-assisted in situ keratomileusis (LASIK) causes greater denervation because peripheral corneal nerve density is higher than central corneal nerve density.
  • Prevention: Preoperative dry eye disease should be treated aggressively to optimize the ocular surface before laser-assisted in situ keratomileusis (LASIK).
  • Small-incision lenticule extraction (SMILE) has a less pronounced effect on corneal innervation than laser-assisted in situ keratomileusis (LASIK) and is associated with less postoperative dry eye disease (Denoyer et al. 2015).
  • Management:
  • Preservative-free artificial tears should be used aggressively.
  • Autologous serum and scleral lenses may be used for severe ocular-surface disease.
  • Cenegermin is indicated for neurotrophic keratitis with a persistent epithelial defect (PED), rather than for every persistent epithelial defect (PED) after laser-assisted in situ keratomileusis (LASIK).
  • Recovery: Corneal nerve regeneration occurs over months to years; the extent and timing of recovery are variable, and nerve morphology may remain below preoperative levels.

20. Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)

Stevens Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)
  • Mechanism: Immune-mediated ocular surface inflammation and scarring can cause conjunctival goblet-cell loss with reduced mucin 5AC (MUC5AC)-related mucin support.
  • Mechanism: The same process can cause cicatricial conjunctivitis and meibomian gland orifice/gland damage, producing severe tear-film instability.
  • Acute phase: Pseudomembranous conjunctivitis and epithelial defects may lead to conjunctival scarring and symblepharon.
  • Acute phase: Severe or persistent ocular surface injury may subsequently cause limbal stem-cell deficiency.
  • Dry eye disease (DED) type: MIXED - mucin deficiency from goblet-cell loss, aqueous deficiency from lacrimal gland ductal obstruction/scarring, evaporative deficiency from meibomian gland/lid-margin disease, and exposure from lagophthalmos related to cicatricial lid changes.
  • Acute management: Amniotic membrane transplantation should be considered urgently in clinically significant acute ocular Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), preferably early in the acute phase.
  • Acute management: Reported protocols commonly treat within 4–7 days of the index day, with earlier treatment favored to reduce scarring complications including symblepharon.
  • Acute management: Systemic corticosteroid evidence is equivocal.
  • Chronic management: Scleral contact lenses may be used for selected patients with chronic ocular surface disease, particularly for ocular-surface protection and lid-margin keratinization; they are not universal first-line treatment.
  • Mucin secretagogues: Diquafosol and rebamipide are mucin secretagogues with evidence in dry eye disease; their use in Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)-related dry eye should be individualized because Stevens–Johnson syndrome/toxic epidermal necrolysis-specific evidence is not established.
  • Chronic management: Fornix reconstruction with symblepharon release may be considered for cicatricial disease.
  • Chronic management: Selected eyes with limbal stem-cell deficiency may require specialized ocular-surface reconstruction, including limbal stem-cell transplantation after surface stabilization.
  • Severe cases: Severe cicatrizing ocular surface disease can profoundly affect quality of life and vision; coordinated multidisciplinary care is often required.

21. Sjogren Syndrome DED

  1. Primary Sjögren syndrome: Anti-Ro/Sjögren syndrome-related antigen A (SSA), anti-La/Sjögren syndrome-related antigen B (SSB), and antinuclear antibody (ANA) may be positive. In the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria, anti-Ro/Sjögren syndrome-related antigen A (SSA) is the weighted serologic item; antinuclear antibody (ANA) and isolated anti-La/Sjögren syndrome-related antigen B (SSB) are not weighted items. Lymphocytic infiltration of lacrimal and salivary glands.
  2. Secondary Sjögren syndrome: Associated with rheumatoid arthritis (RA) (most common), systemic lupus erythematosus (SLE), scleroderma, and primary biliary cholangitis (PBC).
  3. Classification criteria: 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria (score ≥4 classifies primary Sjögren syndrome). Includes: anti-Sjögren syndrome-related antigen A (SSA)/Ro positivity (3 points), lip biopsy focal lymphocytic sialadenitis with focus score ≥1 focus per 4 mm² (3 points), ocular staining score ≥5 or van Bijsterveld score ≥4 in at least one eye (1 point), Schirmer ≤5 mm/5 min (1 point), and unstimulated whole salivary flow rate ≤0.1 mL/min (1 point).
  4. Dry eye disease (DED) here is aqueous-deficient dry eye disease (ADDE) predominantly. Schirmer typically <5 mm. Lactoferrin markedly reduced.
  5. KEY: Ocular dryness (xerophthalmia or keratoconjunctivitis sicca) is reported in approximately 93% of patients with Sjögren syndrome. Often the presenting complaint to ophthalmology BEFORE diagnosis of Sjögren syndrome!
  6. Management: Topical cyclosporine A (CsA) is an anti-inflammatory treatment option; autologous serum; oral pilocarpine/cevimeline; systemic hydroxychloroquine may be used for appropriate systemic manifestations of Sjögren syndrome under rheumatology care.

22. Graft-versus-Host Disease (GvHD) DED

  • After allogeneic hematopoietic stem-cell transplantation. Donor immune-cell interactions with host antigens injure the lacrimal glands and conjunctiva.
  • Type: Severe dry eye disease with lacrimal-gland, conjunctival, and meibomian-gland involvement; cicatricial changes may occur. Ocular involvement is reported in 60–90% of patients with graft-versus-host disease.
  • Chronic ocular graft-versus-host disease is the most common ocular form; it can cause lacrimal-gland fibrosis and conjunctival scarring.
  • Management: Topical cyclosporine A + scleral lenses + autologous serum eye drops. Coordinate systemic immunosuppression, including tacrolimus or mycophenolate mofetil, with the transplant team according to systemic graft-versus-host disease activity; do not state that donor serum is preferred.
  • National Institutes of Health ocular graft-versus-host disease score (0–3): Grade 3 = severe dry-eye symptoms significantly affecting activities of daily living; special eyewear may be required to relieve pain, and the patient may be unable to work because of ocular symptoms or have vision loss caused by keratoconjunctivitis sicca.

23. Contact Lens-Associated DED (CLDED)

Contact Lens Associated DED (CLDED)
  • Contact lens-induced dry eye (CLIDE) symptoms are reported by about 40% of soft contact lens wearers.
  • Contact lenses split the tear film.
  • Contact lenses alter lipid-layer spread and tear-film stability.
  • Contact lenses increase evaporation.
  • Contact lenses may cause friction-related conjunctival changes and reduced goblet-cell density.
  • Lens-related tear-film effects and comfort depend on the material, design, fit, and wearing schedule.
  • Silicone hydrogel contact lenses have higher oxygen permeability than hydrogel contact lenses.
  • The effects of silicone hydrogel contact lenses on the tear film and lipid layer are material-specific.
  • Management: Consider daily disposable contact lenses.
  • Management: Use preservative-free, contact-lens-compatible lubricating or rewetting drops.
  • Management: Reduce or modify wearing time as needed.
  • Management: Confirm product-specific compatibility before using any drop with contact lenses.

24. Key Comparison Tables

ADDE vs. EDE vs. Mixed
ADDE vs. EDE vs. Mixed
FeatureAqueous-deficient dry eye diseaseEvaporative dry eye disease (meibomian gland dysfunction dominant)Mixed dry eye disease
Prevalence• No fixed prevalence figure supported • Aqueous-deficient and evaporative mechanisms frequently overlap• Evaporative component more common• Frequent overlap of aqueous-deficient and evaporative mechanisms
Schirmer I• ≤ 5 millimetres/5 minutes supports severe aqueous deficiency • Interpret with the clinical context• May be normal (≥ 10 millimetres/5 minutes) • Reflex tearing can mask subtle reductions in tear volume• Variable
Tear breakup time• Low (< 10 seconds) • Threshold is not specific to this subtype• Low (< 10 seconds) • < 5 seconds may apply with smaller, controlled fluorescein volumes • Threshold is not specific to this subtype• Low (< 10 seconds)
Osmolarity• Elevated• Elevated• Elevated
Staining pattern• May provide an etiological clue • No defining subtype-specific pattern established• May provide an etiological clue • No defining inferior one-third corneal pattern established• Variable
Lid margin• Assess for meibomian gland dysfunction signs • A normal lid margin is not a defining feature• Assess for meibomian gland dysfunction signs• Assess for both aqueous-deficient and evaporative findings
Meibography• Meibomian gland changes may be less pronounced than in evaporative dry eye disease • Interpret with other clinical parameters• Meibomian gland changes may be more pronounced • Do not apply a fixed greater-than-25% gland-dropout threshold• Variable • Interpret with other clinical parameters
Treatment approach• Tailor treatment to the predominant mechanism • Cyclosporine or other anti-inflammatory therapy for inflammatory aqueous-deficient disease • Autologous serum for severe ocular-surface disease • Oral pilocarpine for selected Sjögren syndrome-associated disease• Warm compresses and lid hygiene for meibomian gland dysfunction • Lipid-containing lubricants • Doxycycline selectively for refractory meibomian gland dysfunction or rosacea• Combination treatment when aqueous-deficient and evaporative components overlap
Common causes• Lacrimal-gland disease, including Sjögren syndrome• Meibomian gland dysfunction • Blink abnormalities • Mucin deficiency • Contact-lens wear• Overlapping aqueous-deficient and evaporative etiologies • Post-laser-assisted in situ keratomileusis or other iatrogenic disease • Symptoms become more common with age
CsA vs. Lifitegrast - Head-to-Head
CsA vs. Lifitegrast - Head-to-Head
ParameterCyclosporine A (Restasis/Ikervis)Lifitegrast (Xiidra)
Mechanism of action• Calcineurin inhibitor • Blocks T-cell interleukin-2 (IL-2)• Lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) blocker • Blocks T-cell homing
Concentration• 0.05% (Restasis) • 0.1% (Ikervis)• 5%
United States Food and Drug Administration approval• 2003• 2016
Onset of action• 3–6 months• As early as 2 weeks (symptom improvement) • Faster than cyclosporine A in separate trials
Dosing• Twice daily • 1 drop in each eye approximately 12 hours apart• Twice daily • 1 drop in each eye approximately 12 hours apart
Unique side effect• Ocular burning• Dysgeusia (altered taste) • Eye irritation
Treats signs• Yes (staining, goblet cells)• Yes (staining primarily)
Treats symptoms• Improves symptoms • Restasis indication: increases tear production• United States Food and Drug Administration approved for symptoms too
Trial evidence• Multiple randomized controlled trials• OPUS-1 • OPUS-2 • OPUS-3 • SONATA
Best for• Inflammatory dry eye disease • Sjögren disease–associated dry eye• Dry eye disease with signs and symptoms
Schirmer I vs. II vs. PRT - Exam Differentiation
Schirmer I vs. II vs. PRT - Exam Differentiation
TestAnaesthesiaStimulationMeasuresNormalDry eye disease (DED) Cutoff
Schirmer INone• Filter paper insertion can induce reflex tearing• Basal secretion • Reflex secretion • Total tear secretion≥ 10 mm/5 min (historical; method-dependent)< 10 mm/5 min (historical; method-dependent)
Schirmer II• Topical anaesthesia• Nasal mucosa stimulation• Reflex secretion only≥ 10 mm/5 min (method-dependent)< 5 mm/5 min (method-dependent)
Basic secretion test (Schirmer with topical local anaesthesia)• Topical anaesthesia• No deliberate stimulation• Approximation of basal secretion • Topical anaesthesia may not abolish all reflex components≥ 5 mm/5 min (method-dependent)< 5 mm/5 min (method-dependent)
Phenol Red Thread (PRT)None• Designed to minimise reflex stimulation• Indirect estimate of resting tear volume • Not a direct measurement of total secretion≥ 10 mm/15 sec (historical; method-dependent)< 10 mm/15 sec (historical; method-dependent)
Notes
  • Numerical values are commonly used historical or clinical thresholds; they are not universally standardised and should be interpreted in relation to test methodology and the clinical context.

25. Landmark Trials & Evidence

Trial NameYearInterventionKey Finding
Dry Eye Assessment and Management (DREAM)2018• Omega-3 3g/day vs. olive-oil placebo• NO significant difference in Ocular Surface Disease Index (OSDI) between omega-3 and placebo at 12 months
OPUS-1, OPUS-2, OPUS-3 (lifitegrast trials)2014, 2015, 2017 (publication years)• Lifitegrast 5% twice daily (BD) vs. vehicle• OPUS-1 significantly improved inferior corneal staining and eye-dryness symptoms • OPUS-2 significantly improved Eye Dryness Score (EDS) but did not significantly reduce inferior corneal staining • OPUS-3 significantly improved Eye Dryness Score (EDS)
SONATA (lifitegrast safety)2016 (publication year)• Lifitegrast 5% twice daily (BD) for 360 days• Appeared safe and well tolerated over 360 days, with no unexpected adverse events or serious ocular treatment-emergent adverse events reported • Dysgeusia (change in taste) was the most common nonocular treatment-emergent adverse event • Common ocular events included instillation-site irritation and instillation-site reaction
Cyclosporine A trialsMultiple studies• Cyclosporine A 0.05% plus preservative-free artificial tears vs. preservative-free artificial tears alone• Significant increase in goblet-cell density • Reduced corneal and conjunctival staining • Improved Schirmer scores
REPARO (cenegermin)2018, Ophthalmology• Recombinant human nerve growth factor at 10 and 20 μg/mL, including the 0.002% (20 μg/mL) formulation • Six times daily for eight weeks• Complete corneal healing at eight weeks occurred in 72.0% of cenegermin-treated participants vs. 33.3% of vehicle-treated participants
Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II)2017, The Ocular Surface (entire issue)• Comprehensive update on dry eye disease (DED) definition, pathophysiology, diagnostics, and management• Redefined dry eye disease (DED) and included neurosensory abnormalities in its conceptualization • Identified tear-film osmolarity as an important diagnostic measure and tear-film hyperosmolarity as a central feature, but not as a standalone or universally definitive biomarker • Proposed staged, stepwise management as an organizational tool to be adapted to individual patient factors

26. Emerging Therapies - Frontiers of DED

Therapy / interventionDetails
Diquafosol tetrasodium (P2Y2 purinergic receptor agonist)• 3% ophthalmic solution. • Promotes fluid and mucin secretion at the ocular surface. • Japanese dosage: one drop six times daily. • Japanese indication: dry eye. • Specific Korean approval and subgroup indications require separate supporting evidence.
Rebamipide (2% ophthalmic suspension)• Mucin-secretagogue treatment for dry eye. • Approved for dry eye in Japan. • Phase 3 clinical evaluation was conducted in Japan. • Mucin-related ocular-surface effects have been reported. • United States phase 3 status and the specific corneal reactive-oxygen-species claim require separate verification.
Isunakinra (formerly EBI-005)• Topical interleukin-1 receptor inhibitor. • Blocks interleukin-1 signaling at the ocular surface. • Evaluated in a phase 1b/2a randomized trial in moderate-to-severe dry eye disease. • The study findings supported further evaluation; phase 3 status is not established by the reviewed source.
Tanfanercept (tumor-necrosis-factor inhibitor)• Topical engineered tumor-necrosis-factor-receptor-1 fragment. • 0.25% formulation evaluated twice daily in an exploratory phase 2 dry eye trial. • Reported improvements in signs and symptoms favoring treatment. • The study was not powered for confirmatory statistical testing. • Tumor necrosis factor is an inflammatory mediator in dry eye disease; the specific hyperosmolar-epithelium production claim requires separate evidence.
OC-01 (varenicline nasal spray)• Nicotinic acetylcholine receptor agonist. • Activates the trigeminal parasympathetic pathway and increases basal tear production. • ONSET-1 and ONSET-2 trials demonstrated significant Schirmer-test improvements. • United States Food and Drug Administration approved TYRVAYA for dry eye disease in 2021.
Perfluorohexyloctane (MIEBO; formerly NOV03)• Semifluorinated alkane ophthalmic solution. • Forms a monolayer at the air–liquid interface of the tear film and is expected to reduce evaporation. • GOBI and MOJAVE phase 3 trials showed improvement in dry eye disease signs and symptoms in patients with clinical signs of meibomian gland dysfunction. • United States Food and Drug Administration approved MIEBO in 2023 for treatment of the signs and symptoms of dry eye disease. • Water-free formulation; not direct lipid replenishment.
Intense Pulsed Light (IPL)• Non-pharmacological treatment for selected meibomian gland dysfunction. • Uses device-specific wavelengths and treatment protocols; repeated sessions are commonly studied. • May be combined with meibomian gland expression. • Randomized studies report improvements in tear breakup time and Ocular Surface Disease Index. • Proposed effects include improvement of meibomian gland function and reduction of lid-margin vascular or inflammatory features; exact mechanisms vary by device and remain incompletely established.
Thermal Pulsatile Therapy (LipiFlow)• Vectored thermal pulsation system that applies heat and pulsatile pressure to the inner eyelid surfaces and meibomian glands. • Typically delivered as a single 12-minute in-office treatment. • Comparative studies have evaluated LipiFlow against warm-compress protocols. • Treatment intervals should be individualized; routine annual repetition is not established as a universal recommendation.
PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem)• Custom-fit scleral-lens device. • Vaults the cornea and creates a fluid reservoir over the ocular surface. • Used for severe ocular-surface disease, including Stevens–Johnson syndrome, graft-versus-host disease, and Sjögren syndrome. • Can protect the corneal epithelium from eyelid trauma and evaporation. • Requires specialized fitting and training.
Stem Cell Therapy for Lacrimal Gland• Experimental/investigational therapy. • Allogeneic adipose-derived mesenchymal stem-cell injection into the lacrimal gland has been evaluated for severe aqueous-deficient dry eye disease associated with Sjögren syndrome. • A 2024 double-blinded randomized trial reported improvement in subjective and objective tear-film measures after lacrimal-gland injection. • Symptom improvement also occurred with vehicle, and several objective changes were not significantly different between groups. • Potential immunomodulatory and regenerative approach; not currently standard dry-eye-disease treatment.

27. MCQ Traps & Viva Questions

MCQ

A patient presents with severe watering from both eyes. On examination, Tear break-up time (TBUT) = 4 seconds, Schirmer test = 3 mm, fluorescein staining of inferior cornea. What is the MOST likely diagnosis?

MCQ

Which staining dye specifically stains cells DEVOID of mucin protection (not dead cells)?

MCQ

The leading cause of Dry Eye Disease in clinic- and population-based studies is considered to be:

MCQ

A patient with Sjögren syndrome-associated dry eye disease (SS-DED) requires punctal plug insertion. What should be done before inserting the plugs when active ocular-surface inflammation is present?

MCQ

Q: Lifitegrast 5% (Xiidra) received United States Food and Drug Administration approval in 2016 for dry eye disease - which is TRUE about its mechanism?

MCQ

Q: Which of the following is approved by the United States Food and Drug Administration for the treatment of neurotrophic keratitis, including post-herpetic and post-laser-assisted in situ keratomileusis neuropathic dry eye disease?

28. Viva Extension Questions

Oral-exam Q&A
Q1

If a patient has OSDI = 40 but Schirmer = 15 mm and TBUT = 12 sec and NO staining - how do you classify and manage this?

Q2

What is the role of androgens in DED, and which drug commonly prescribed in dermatology causes DED by androgen antagonism?

Q3

A 28-year-old woman 3 months post-SMILE (not LASIK) presents with DED symptoms. How does SMILE differ from LASIK in nerve preservation?

Q4

What is the significance of INTEREYE OSMOLARITY DIFFERENCE > 8 mOsm/L even if both eyes are individually < 308 mOsm/L?

Q5

What is the specific immunopathology in Sjogren Syndrome lacrimal gland, and which antibody is more SPECIFIC vs. more SENSITIVE?

29. Advanced Consultant-Level Extension Question

Consultant-level oral-exam question

Question A 45-year-old female rheumatology patient with confirmed Primary Sjogren Syndrome (anti-SSA+, lip biopsy confirmed) is referred to you with: • OSDI score: 72/100 (severe) • Schirmer I: 1 mm bilaterally (profound ADDE) • TBUT: 2 seconds (lipid deficiency also present) • Corneal staining: Oxford Grade IV (central dense staining with filaments) • Conjunctival staining: Grade 3 (van Bijsterveld, lissamine green) • Tear osmolarity: 342 mOsm/L (R), 336 mOsm/L (L) • MMP-9 (InflammaDry): Strongly positive • Meibography: 40% gland dropout bilateral (significant MGD also) • Corneal sensitivity (Cochet-Bonnet): Reduced bilaterally (5 cm, normal > 6cm) • IVCM: Sub-basal nerve density 12.4 mm/mm2 (severely reduced; normal >25) • She has failed: PF AT Q1H, CsA 0.05% × 6 months, punctal plugs (extruded) She has been prescribed oral pilocarpine by rheumatology but is not on systemic immunosuppression. She reports debilitating photophobia and is unable to drive. QUESTION: As her senior ophthalmologist, outline your comprehensive 3-month and 12-month management plan with scientific justification, addressing each pathophysiological component. Include at least 5 specific therapeutic decisions with mechanistic reasoning, and state ONE experimental/emerging therapy you would consider enrolling her in, explaining the scientific rationale.

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