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BCLA CLEAR - Contact lens complications

      Abstract

      Contact lens-related complications are common, affecting around one third of wearers, although most are mild and easily managed. Contact lenses have well-defined anatomical and physiological effects on the ocular surface and can result in other consequences due to the presence of a biologically active material. A contact lens interacts with the tear film, ocular surface, skin, endogenous and environmental microorganisms, components of care solutions and other antigens which may result in disease specific to contact lens wear, such as metabolic or hypersensitivity disorders. Contact lens wear may also modify the epidemiology or pathophysiology of recognised conditions, such as papillary conjunctivitis or microbial keratitis. Wearers may also present with intercurrent disease, meaning concomitant or pre-existing conditions unrelated to contact lens wear, such as allergic eye disease or blepharitis, which may complicate the diagnosis and management of contact lens-related disease.
      Complications can be grouped into corneal infection (microbial keratitis), corneal inflammation (sterile keratitis), metabolic conditions (epithelial: microcysts, vacuoles, bullae, tight lens syndrome, epithelial oedema; stromal: superficial and deep neovascularisation, stromal oedema [striae/folds], endothelial: blebs, polymegethism/ pleomorphism), mechanical (corneal abrasion, corneal erosion, lens binding, warpage/refractive error changes; superior epithelial arcuate lesion, mucin balls, conjunctival epithelial flaps, ptosis, discomfort), toxic and allergic disorders (papillary conjunctivitis, solution-induced corneal staining, incomplete neutralisation of peroxide, Limbal Stem Cell Deficiency), tear resurfacing disorders/dry eye (contact lens-induced dry eye, Meibomian gland dysfunction, lid wiper epitheliopathy, lid parallel conjunctival folds, inferior closure stain, 3 and 9 o'clock stain, dellen, dimple veil) or contact lens discomfort. This report summarises the best available evidence for the classification, epidemiology, pathophysiology, management and prevention of contact lens-related complications in addition to presenting strategies for optimising contact lens wear.

      Keywords

      Abbreviations

      ADDE
      aqueous deficient dry eye
      CIE
      corneal infiltrative events
      CLADE
      contact lens-associated dry eye
      CLD
      contact lens discomfort
      CLIDE
      contact lens-induced dry eye
      CLPC
      contact lens-induced papillary conjunctivitis
      CLPU
      contact lens-related peripheral ulcers
      DED
      dry eye disease
      EDE
      evaporative dry eye
      ECP
      eye care practitioner
      IVCM
      in vivo confocal microscopy
      LSCD
      limbal stem cell deficiency
      LWE
      lid-wiper epitheliopathy
      MGD
      meibomian gland dysfunction
      MK
      microbial keratitis
      PHMB
      polyhexamethylene biguanide
      PMMA
      polymethylmethacrylate
      SICS
      solution-induced corneal staining
      SiHy
      silicone hydrogel
      TBUT
      tear film break-up time
      TFOSDEWS II
      tear film and ocular surface dry eye workshop II

      1. Introduction

      Contact lens-related complications are common, with one third of wearers surveyed in the USA reporting having experienced a red or painful eye requiring emergency eye care [
      • Cope J.R.
      • Collier S.A.
      • Rao M.M.
      • Chalmers R.
      • Mitchell G.L.
      • Richdale K.
      • et al.
      Contact lens wearer demographics and risk behaviors for contact lens-related eye infections--United States, 2014.
      ]. A similar proportion of wearers derived from eyecare practices reported experiencing a complication arising from lens wear [
      • Donshik Pc
      • Ehlers Wh
      • Anderson Ld
      • Suchecki Jk
      Strategies to better engage, educate, and empower patient compliance and safe lens wear: compliance: what we know, what we do not know, and what we need to know.
      ]. Forty three percent of asymptomatic wearers present with clinically observed ocular surface signs, which may predispose them to contact lens-related complications [
      • Chen E.Y.
      • Myung Lee E.
      • Loc-Nguyen A.
      • Frank L.A.
      • Parsons Malloy J.
      • Weissman B.A.
      Value of routine evaluation in asymptomatic soft contact lens wearers.
      ]. Complications may result in a reduction in wear time, discontinuation from contact lens wear or a need for emergency eye care. Severe complications may result in vision loss and in significant cost and morbidity [
      • Keay L.
      • Edwards K.
      • Dart J.
      • Stapleton F.
      Grading contact lens-related microbial keratitis: relevance to disease burden.
      ].
      Contact lens-related complications differ from other ocular surface conditions in several ways. Contact lenses can have well-defined anatomical and physiological effects the ocular surface and can result in other consequences due to the presence of a biologically active material [
      • Dart J.K.
      The epidemiology of contact lens related diseases in the United Kingdom.
      ]. A contact lens interacts with the tear film, ocular surface, skin, endogenous and environmental microorganisms, components of care solutions and other antigens which may result in disease specific to contact lens wear, such as metabolic or hypersensitivity disorders. For the same reasons, contact lens wear may alter the epidemiology or pathophysiology of recognised conditions, such as contact lens induced papillary conjunctivitis (CLPC) or microbial keratitis (MK). Wearers may also present with intercurrent disease, meaning concomitant or pre-existing conditions unrelated to contact lens wear, such as allergic eye disease or blepharitis, which may complicate the diagnosis and management of contact lens-related disease.
      This report summarises the best available evidence for the classification, epidemiology, pathophysiology, management and prevention of contact lens-related complications in addition to presenting strategies for optimising contact lens wear.

      1.1 Scope of the report

      This report will consider only contact lens-related complications per the definition below and where possible, recent evidence will be prioritised. The effects of contact lens wear on the anatomy and physiology of the eye and medical and speciality indications for contact lens wear are outside of the scope of the report and are covered elsewhere.

      1.2 Definition of a contact lens complication

      A contact lens complication is considered to be an event caused by contact lens wear, which is generally symptomatic, causing the wearer to seek care, or requiring intervention, such as an interruption to contact lens wear or pharmacological intervention.

      1.3 Classification of complications

      Several approaches have been proposed in order to classify contact lens -related complications, including classification based on anatomical location, presumed aetiology and severity of the condition. Each approach may be suitable for different applications.

      1.3.1 Anatomical location

      Contact lens complications have been classified according to anatomical location [
      • Efron N.
      Contact Lens complications.
      ,
      • Stamler J.F.
      The complications of contact lens wear.
      ], which is a useful approach in systematically evaluating the physiological effect of contact lenses on each of the ocular structures. This can be helpful from a teaching perspective. However, this approach does not inform the pathogenesis and may not be helpful in managing or preventing the complication.

      1.3.2 Presumed aetiology

      Categorisation by presumed aetiology can be helpful for treatment as well as management and prevention of adverse events. For example, to assist in managing sterile corneal infiltrates, an approach based on presumed aetiology has been described, where corneal infiltrates were classified as traumatic, viral, allergic, preserved solution-related, contact lens fitting-related, due to coated lenses, toxic vapours or idiopathic [
      • Josephson J.E.
      • Caffrey B.E.
      Infiltrative keratitis in hydrogel lens wearers.
      ]. This method has also been used in a broader range of complications, classfied as patient-, contact lens - or care-related events, in an attempt to support their management [
      • Stenson S.
      Complications of soft contact lenses.
      ].
      A similar approach was used in a series of epidemiological studies where complications were classified as either ‘ulcerative’ (microbial keratitis) or ‘non-ulcerative’. The latter group were categorised into six divisions based on presumed aetiology: sterile keratitis, toxic and hypersensitivity, metabolic, mechanical, tear resurfacing and other contact lens related events [
      • Dart J.K.
      The epidemiology of contact lens related diseases in the United Kingdom.
      ,
      • Radford C.F.
      • Minassian D.
      • Dart J.K.
      • Stapleton F.
      • Verma S.
      Risk factors for nonulcerative contact lens complications in an ophthalmic accident and emergency department: a case-control study.
      ,
      • Stapleton F.
      • Dart J.
      • Minassian D.
      Nonulcerative complications of contact lens wear. Relative risks for different lens types.
      ]. Most recently, this has been modified to four categories, based on microbial challenge, hypoxia, mechanical and toxicity challenges to the ocular surface due to contact lens wear [
      • Zimmerman A.B.
      Contemporary contact lens complications.
      ].
      One of the difficulties with classification approach is where more than one mechanism may be involved in the pathophysiology of the condition. For example, the presentation of CLPC is thought to be primarily due to a mechanical stimulus in silicone hydrogel (SiHy) lenses and is localised to the region corresponding to the lens edge. Conversely for hydrogel contact lenses, protein deposition and subsequent denaturation, the stimulus is likely to be antigenic and the response inflammatory, manifesting as a generalised palpebral response [
      • Skotnitsky C.
      • Sankaridurg P.R.
      • Sweeney D.F.
      • Holden B.A.
      General and local contact lens induced papillary conjunctivitis (CLPC).
      ].
      While it is clear that MK and sterile infiltrates have different underlying pathophysiology, there is an argument to suggest that there is significant overlap in their clinical signs and that they form a “continuum” of conditions that includes microbial and sterile events [
      • Efron N.
      • Morgan P.
      Rethinking contact lens associated keratitis.
      ]. Challenges with this approach include that a binary approach (sterile or microbial) is required to determine management strategy, and a range of clinical presentations are described by one descriptor, such as “generalized or localized conjunctival redness”, which limits the diagnostic value of this analysis. This is an inherent problem of retrospective datasets, where diagnostic criteria are not pre-defined and prospectively collected.

      1.3.3 Severity

      Several models of classification of sterile keratitis (or corneal infiltrative events, CIE) have been proposed based on disease severity and impact. Corneal infiltrates may be described as severe or non-severe events based on their signs and symptoms [
      • Sweeney D.F.
      • Jalbert I.
      • Covey M.
      • Sankaridurg P.R.
      • Vajdic C.
      • Holden B.A.
      • et al.
      Clinical characterization of corneal infiltrative events observed with soft contact lens wear.
      ], however a contrary view suggested that these different categories of sterile inflammatory events were not distinguishable clinically [
      • Baum J.
      • Donshik P.C.
      Corneal infiltrates associated with soft contact lens wear.
      ].
      In summary, while multiple classification systems have been proposed, each with their respective advantages and disadvantages, for the purposes of this report an approach based on likely aetiology has been used. This supports a pragmatic approach to management and prevention. Corneal infection (microbial or ulcerative keratitis) is differentiated from the less serious non-ulcerative events “non-ulcerative” are further categorised into six sub-groups: sterile keratitis, toxic/hypersensitivity, metabolic, mechanical, tear resurfacing and other contact lens related events (Table 1).
      Table 1Classification of contact lens-related disorders (adapted from Stapleton et al, 1992 [
      • Stapleton F.
      • Dart J.
      • Minassian D.
      Nonulcerative complications of contact lens wear. Relative risks for different lens types.
      ]).
      Classification Contact Lens-Related Disorders
      ClassificationDisorderSymptomsProbable originsCorneal signsConjunctival signs
      InfectionMicrobial keratitisRapid onset and progression of pain, redness, and dischargeBreach of ocular surface defence due to tear stagnation or microtrauma [
      • Fleiszig S.M.
      The Glenn A. Fry award lecture 2005. The pathogenesis of contact lens-related keratitis.
      ]; infection, inflammation and necrosis of corneal tissue
      Epithelial ulcer with underlying stromal infiltrate; Pseudomonas aeruginosa common and associated with fulminating course; adherent mucous; gross corneal oedemaCiliary injection
      InflammationSterile keratitisDiscomfort, redness, and dischargeInflammatory response in absence of infecting organism; factors include delayed hypersensitivity to thiomersal [
      • Mondino B.J.
      • Brawman-Mintzer O.
      • Boothe W.A.
      Immunological complications of soft contact lenses.
      ], tight lenses [
      • Zantos S.G.
      Management of corneal infiltrates in extended-wear contact lens patients.
      ] and hypersensitivity to bacteria [
      • Josephson J.E.
      • Caffrey B.E.
      Infiltrative keratitis in hydrogel lens wearers.
      ] or bacterial toxins [
      • Phillips A.J.
      • Badenoch P.R.
      • Grutzmacher R.
      • Roussel T.J.
      Microbial contamination of extended-wear contact lenses: an investigation of endotoxin as a cause of the acute ocular inflammation reaction.
      ]; in overnight-wear soft CLs, poor tear exchange causes build-up of trapped cellular/metabolic debris
      Like those of marginal keratitis; small peripheral self-limiting subepithelial infiltrates, with/without overlying epithelial defectHyperaemia
      Metabolic EpithelialMicrocystsNoneImpaired metabolic activity; thought to be cellular debris; seen in 85% to 100% of users of overnight-wear soft low Dk [
      • Humphreys J.A.
      • Larke J.R.
      • Parrish S.T.
      Microepithelial cysts observed in extended contact-lens wearing subjects.
      ,
      • Holden B.A.
      • Sweeney D.F.
      • Vannas A.
      • Nilsson K.T.
      • Efron N.
      Effects of long-term extended contact lens wear on the human cornea.
      ]; Spike occurs following high Dk refitting [
      • Holden B.A.
      • Sweeney D.F.
      The significance of the microcyst response: a review.
      ]
      Reverse illumination irregular 15-50um discrete bodies. As reach surface of cornea, exhibit negative stainingNone
      VacuolesNoneMost common in low Dk overnight wear; non reversed illumination suggests fluid filled [
      • Zantos S.G.
      Cystic formations in the corneal epithelium during extended wear of contact lenses.
      ]
      Round intraepithelial 20-50 μm bodies with distinct margins; seen in conjunction with microcystsNone
      Bullae
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Mechanical
      Pain and epiphora when coalesceHypoxia with possible mechanical component, non-reversed illumination suggest fluid filled [
      • Zantos S.G.
      Cystic formations in the corneal epithelium during extended wear of contact lenses.
      ].
      Oval, greater than 40 μm bodies that tend to coalesceNone
      Tight lens syndromeOverwear, starting in morning after overnight anoxia; vision usually affectedLens tightening precipitated by osmolarity changes causing altered lens parametersStromal oedema and epithelial stainingCiliary injection and limbal indentation
      Epithelial oedemaBlurred vision after wear or adaptation to rigid corneal lens [
      • Cox I.G.
      • Holden B.A.
      Can vision loss be used as a quantitative assessment of corneal edema?.
      ]
      Hypoxia causing central corneal clouding [
      • Lambert S.R.
      • Klyce S.D.
      The origins of Sattler’s veil.
      ]; osmotic changes due to hypotonic reflex tearing [
      • Cox I.G.
      • Holden B.A.
      Can vision loss be used as a quantitative assessment of corneal edema?.
      ].
      Dull corneal reflex from central epithelial oedema; diffuse oedema with reflex tearingNone
      StromalSuperficial and deep neovascularisationNone unless lipid keratopathy results from deep vessels, where vision may be lostHypoxia causing stromal softening and release of vasogenic mediatorsSuperficial/deep stromal vessels; lipid keratopathy associated with deep vesselsIf active, associated limbal hyperaemia
      Stroma/ oedema (striae/folds)Blurred vision in some casesOsmolarity changes causing increased corneal-swelling pressure [
      • Polse K.A.
      • Mandell R.B.
      Etiology of corneal striae accompanying hydrogel lens wear.
      ]
      Striae occur when 5–6 % and folds when 10 % oedema [
      • Kame R.T.
      Clinical management of hydrogel-induced edema.
      ]
      None
      EndothelialEndothelial blebsNoneHypoxic stress [
      • Holden B.A.
      • Williams L.
      • Zantos S.G.
      The etiology of transient endothelial changes in the human cornea.
      ]
      Black zones in mosaic, occur on CL insertion, transient [
      • Zantos S.G.
      • Holden B.A.
      Transient endothelial changes soon after wearing soft contact lenses.
      ]
      None
      Polymegethism/ pleomorphismNoneChronic hypoxia [
      • Holden B.A.
      • Sweeney D.F.
      • Vannas A.
      • Nilsson K.T.
      • Efron N.
      Effects of long-term extended contact lens wear on the human cornea.
      ]
      Increased size and irregularity of endothelial cellsNone
      MechanicalCorneal abrasionSudden onset of pain and epiphora; resolves in hoursTrauma caused during CL insertion or removal; foreign bodies trapped behind CL; deposits on CL; poor CL fittingLinear or sharply circumscribed epithelial defectHyperaemia
      Corneal erosionPain, redness, light sensitivity, blurred vision, and tearingMechanical injury; overnight wear [
      • Markoulli M.
      • Papas E.
      • Cole N.
      • Holden B.
      Corneal erosions in contact lens wear.
      ]; Gram negative bacterial CL contamination [
      • Willcox M.D.
      • Naduvilath T.J.
      • Vaddavalli P.K.
      • Holden B.A.
      • Ozkan J.
      • Zhu H.
      Corneal erosions, bacterial contamination of contact lenses, and microbial keratitis.
      ]
      Circumscribed epithelial defect; mild stromal oedemaHyperaemia
      Lens bindingPain, redness, light sensitivity, blurred vision, and tearingMore frequent with rigid corneal lenses, orthoK and high modulus soft CL overnight wear [
      • Markoulli M.
      • Papas E.
      • Cole N.
      • Holden B.
      Corneal erosions in contact lens wear.
      ,
      • Dumbleton K.
      Adverse events with silicone hydrogel continuous wear.
      ,
      • Rae S.T.
      • Huff J.W.
      Studies on initiation of silicone elastomer lens adhesion in vitro: binding before the indentation ring.
      ].
      Indentation ring or corneal erosion may be presentIndentation ring
      Warpage/Refractive error/
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      metabolic
      Subtle to marked visual effectsPMMA and low Dk rigid corneal lenses can result in warpage; low Dk overnight wear is associated with small increase in myopia, while no change [
      • Dumbleton K.A.
      • Chalmers R.L.
      • Richter D.B.
      • Fonn D.
      Changes in myopic refractive error with nine months’ extended wear of hydrogel lenses with high and low oxygen permeability.
      ] or slight decrease found in high Dk [
      • Jalbert I.
      • Stretton S.
      • Naduvilath T.
      • Holden B.
      • Keay L.
      • Sweeney D.
      Changes in myopia with low-Dk hydrogel and high-Dk silicone hydrogel extended wear.
      ]
      Corneal topographical changesNone
      Superior epithelial arcuate lesionAsymptomatic mostly, irritation, photophobiaSteep corneas [
      • Young G.
      • Mirejovsky D.
      A hypothesis for the aetiology of soft contact lens-induced superior arcuate keratopathy.
      ]; poor CL wetting, tight fitting CLs [
      • O’Hare N.
      • Stapleton F.
      • Naduvilath T.
      • Jalbert I.
      • Sweeney D.F.
      • Holden B.A.
      Interaction between the contact lens and the ocular surface in the etiology of superior epithelial arcuate lesions.
      ]
      Full thickness corneal epithelial lesion, diffuse infiltratesSectorial hyperaemia
      Mucin ballsNoneLikely associated with lack of tear exchange; common with high Dk overnight wear, steep corneas [
      • Tan J.
      • Keay L.
      • Jalbert I.
      • Naduvilath T.J.
      • Sweeney D.F.
      • Holden B.A.
      Mucin balls with wear of conventional and silicone hydrogel contact lenses.
      ]
      Spherical translucent balls of mucin 20-200um, between lens and cornea; leave depression when removedNone
      Conjunctival epithelial flapsNoneLens edge and material shear forces on bulbar conjunctiva; increases with wear time [
      • Graham A.D.
      • Truong T.N.
      • Lin M.C.
      Conjunctival epithelial flap in continuous contact lens wear.
      ]
      NoneGoblet and epithelial cells detached from underlying conjunctiva, often superior and inferior
      PtosisCosmeticRigid:upper lid stretching, rubbing the lens while blinking, lid edema or blepharospasm [
      • van den Bosch W.A.
      • Lemij H.G.
      Blepharoptosis induced by prolonged hard contact lens wear.
      ]; Soft: inflammation or CL insertion and removal [
      • Bleyen I.
      • Hiemstra C.A.
      • Devogelaere T.
      • van den Bosch W.A.
      • Wubbels R.J.
      • Paridaens D.A.
      Not only hard contact lens wear but also soft contact lens wear may be associated with blepharoptosis.
      ]
      NoneNone
      Discomfort
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Inflammation
      Lens awareness, gritty, scratchyMultifactorial including: CL material, deposits, wettability, bioburden, CL movement, lens care solutions, inflammatory and other tear film components [
      • Nichols J.J.
      • Willcox M.D.
      • Bron A.J.
      • Belmonte C.
      • Ciolino J.B.
      • Craig J.P.
      • et al.
      The TFOS international workshop on contact lens discomfort: executive summary.
      ]
      Often noneHyperaemia
      Toxic and allergic disordersCL-related papillary conjunctivitis
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Mechanical/Hypersensitivity
      Increased discharge and greasing of CLs; itching on CL removal in early stages; later severe irritation; resolves within days of CL disuseMultifactorial: immunologic response to proteins deposited on CLs acting as an antigen [
      • Allansmith M.R.
      • Korb D.R.
      • GreinerJ V.
      • Henriquez A.S.
      • Simon M.A.
      • Finnemore V.M.
      Giant papillary conjunctivitis in contact lens wearers.
      ]; mechanical effect of CL edge [
      • Mondino B.J.
      • Brawman-Mintzer O.
      • Boothe W.A.
      Immunological complications of soft contact lenses.
      ,
      • Skotnitsky C.C.
      • Naduvilath T.J.
      • Sweeney D.F.
      • Sankaridurg P.R.
      Two presentations of contact lens-induced papillary conjunctivitis (CLPC) in hydrogel lens wear: local and general.
      ]
      NoneUpper tarsal hyperaemia; mucous and fine papillary response; 'giant' (compound) papillae in advanced disease
      Solution-induced corneal stainingStinging on insertion, dryness, redness at the end of wearing time, itching, mucous dischargeSolution toxicity &/or hypersensitivity; response to exposure to compounds adsorbed onto or absorbed by the CLDiffuse or midperipheral annular corneal punctate staining; can be associated with low grade inflammation [
      • Carnt N.
      • Jalbert I.
      • Stretton S.
      • Naduvilath T.
      • Papas E.
      Solution toxicity in soft contact lens daily wear is associated with corneal inflammation.
      ]
      Conjunctival hyperaemia
      Incomplete neutralisation of peroxideBurning and stingingFailure to neutralise low pHPunctate keratitisConjunctival injection
      Limbal Stem Cell Deficiency (LSCD)
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Mechanical
      Pain, decreased vision, foreign body sensation, CL intolerance and photophobia [
      • Bhatia R.P.
      • Srivastava R.
      • Ghosh A.
      Limbal stem cell study in contact lens wearers.
      ]
      Preservatives or enzymes may act as haptens causing a local delayed hypersensitivity response [
      • Wilson L.A.
      • McNatt J.
      • Reitschel R.
      Delayed hypersensitivity to thimerosal in soft contact lens wearers.
      ]; interactions between preservatives, lenses, and adsorbed surface mucoproteins may also contribute [
      • Plaut B.S.
      • Davies D.J.
      • Meakin B.J.
      • Richardson N.E.
      The mechanism of interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate).
      ,
      • Kaspar H.
      Binding characteristics and microbiological effectiveness of preservatives.
      ]. Mechanical irritation and inflammation of limbus as a result of CL friction [
      • Rossen J.
      • Amram A.
      • Milani B.
      • Park D.
      • Harthan J.
      • Joslin C.
      • et al.
      Contact lens-induced limbal stem cell deficiency.
      ]
      Progressive epitheliopathy with translucent epithelium, Vortex keratopathy, Loss of palisades of Vogt. [
      • Sejpal K.
      • Bakhtiari P.
      • Deng S.X.
      Presentation, diagnosis and management of limbal stem cell deficiency.
      ]

      Extending centripetally into cornea in a whorl shape. In late stages, superficial and deep vascularisation, scarring, conjunctivalisation, and calcification [
      • Sejpal K.
      • Bakhtiari P.
      • Deng S.X.
      Presentation, diagnosis and management of limbal stem cell deficiency.
      ]
      Chronic conjunctival redness
      Tear resurfacing disorders/Dry EyeContact lens induced dry eye (CLIDE)
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Inflammation
      Foreign body sensation, dryness, eye strain, blurred vision and discomfort [
      • Guillon M.
      • Maissa C.
      Dry eye symptomatology of soft contact lens wearers and nonwearers.
      ,
      • Kastelan S.
      • Lukenda A.
      • Salopek-Rabatic J.
      • Pavan J.
      • Gotovac M.
      Dry eye symptoms and signs in long-term contact lens wearers.
      ,
      • Li W.
      • Sun X.
      • Wang Z.
      • Zhang Y.
      A survey of contact lens-related complications in a tertiary hospital in China.
      ,
      • Nichols J.J.
      • Ziegler C.
      • Mitchell G.L.
      • Nichols K.K.
      Self-reported dry eye disease across refractive modalities.
      ]; asymptomatic on CL removal
      Partitioning of tear film leading to tear film thinning and instability [
      • Craig J.P.
      • Willcox M.D.
      • Argüeso P.
      • Maissa C.
      • Stahl U.
      • Tomlinson A.
      • et al.
      The TFOS International Workshop on Contact Lens discomfort: report of the contact lens interactions with the tear film subcommittee.
      ]
      Reduced tear break up time, reduced tear meniscus height, corneal stainingHyperaemia in severe cases
      Meibomian gland dysfunction
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Mechanical
      Symptoms of ocular irritation and intermittent blurred vision; may reduce comfortable wear timeChanges to morphological features of Meibomian glands, altered expressibility of glands, quality of meibum. Reduced tear break up time and lipid layer thickness. Mechanical trauma [
      • Ong B.L.
      • Larke J.R.
      Meibomian gland dysfunction: some clinical, biochemical and physical observations.
      ] and/or desquamated epithelial cell accumulation at gland orifices [
      • Korb D.R.
      • Henriquez A.S.
      Meibomian gland dysfunction and contact lens intolerance.
      ]
      Often noneStructural gland changes, altered expressibility, meibum quality, morphological changes to the lid margin occur
      Lid Wiper Epitheliopathy (LWE)
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Mechanical
      A sign of mechanical friction due to poor lubrication between lid margin and anterior CL [
      • Korb D.R.
      • Greiner J.V.
      • Herman J.P.
      • Hebert E.
      • Finnemore V.M.
      • Exford J.M.
      • et al.
      Lid-wiper epitheliopathy and dry-eye symptoms in contact lens wearers.
      ]
      Exhibits lissamine green/fluorescein staining of lid margin
      Lid parallel conjunctival folds (LIPCOF)
      Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.
      Mechanical
      Dry eye symptoms, discomfortGeneralised sign of dry ocular surface exacerbated by CL wear [
      • Ong B.L.
      • Larke J.R.
      Meibomian gland dysfunction: some clinical, biochemical and physical observations.
      ,
      • Korb D.R.
      • Henriquez A.S.
      Meibomian gland dysfunction and contact lens intolerance.
      ,
      • Pult H.
      • Purslow C.
      • Berry M.
      • Murphy P.J.
      Clinical tests for successful contact lens wear: relationship and predictive potential.
      ]
      NoneAppear nasal and temporal to inferior limbus
      Inferior closure stainInferior redness and discomfortIncomplete blinkingInferior/interpalpebral punctate stainInferior limbal hyperaemia
      3 and 9 o'clock stain (dellen in severe cases)lnterpalpebral redness; discomfort is rareDrying of corneal surface adjacent to rigid CL edgePunctate keratopathy in 3 and 9 o'clock positions with or without vascularized superficial stromal scarslnterpalpebral hyperaemia
      Dimple veilNone or blurred visionStatic air bubbles under lensFluorescein pooling in epithelial depressionNone
      Contact Lens DiscomfortContact lens discomfortReduced comfort while wearing CLs. Reduced comfortable wear timeOrigin not fully understood but aetiologies may include mechanical friction, inflammation, dry eye, MGDOften none, sometimes reduced TBUT, signs of LIPCOF, LWE, MGDOften none, occasionally mild hyperaemia
      * Denotes secondary aetiology; CL: contact lens; Dk: Oxygen permeability; PMMA: Polymethylmethacrylate.

      2. Contact lens-related corneal infection

      Corneal infection or MK is a rare but potentially severe complication of contact lens wear, which is associated with signficant morbidity including visual loss, societal cost and patient symptoms.

      2.1 Frequency

      Contact lens-related corneal infection accounts for around 35–65 % of new cases of hospital presenting MK in urban tertiary centres [
      • Dart J.K.G.
      • Stapleton F.
      • Minassian D.
      Contact lenses and other risk factors in microbial keratitis.
      ,
      • Green M.
      • Sara S.
      • Hughes I.
      • Apel A.
      • Stapleton F.
      Trends in contact lens microbial keratitis 1999 to 2015: a retrospective clinical review.
      ,
      • Jeng B.H.
      • Gritz D.C.
      • Kumar A.B.
      • Holsclaw D.S.
      • Porco T.C.
      • Smith S.D.
      • et al.
      Epidemiology of ulcerative keratitis in Northern California.
      ,
      • Jin H.
      • Parker W.T.
      • Law N.W.
      • Clarke C.L.
      • Gisseman J.D.
      • Pflugfelder S.C.
      • et al.
      Evolving risk factors and antibiotic sensitivity patterns for microbial keratitis at a large county hospital.
      ,
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Taylor H.R.
      • Snibson G.R.
      • Forde K.
      • et al.
      Microbial keratitis predisposing factors and morbidity.
      ]. In working age adults, contact lenses and trauma are the two main risk factors for corneal infection [
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Taylor H.R.
      • Snibson G.R.
      • Forde K.
      • et al.
      Microbial keratitis predisposing factors and morbidity.
      ], accounting for 2/3 of all urban cases.
      The annualised incidence of corneal infection varies with contact lens type and wear modality, and ranges from 1-2 per 10,000 wearers for daily use of soft and rigid corneal contact lenses to 20 per 10,000 for overnight wear with SiHy or hydrogel lenses [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ]. The risk of corneal infection increases with a greater number of days wear per week and with any overnight use, indicating a dose response effect [
      • Dart J.K.
      • Radford C.F.
      • Minassian D.
      • Verma S.
      • Stapleton F.
      Risk factors for microbial keratitis with contemporary contact lenses: a case-control study.
      ]. In overnight wear, there is greater risk in the first six months of wear, indicating possible adaptation with time and/or persistence of survivors in this lens wear modality [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ]. Daily disposable contact lens wear is associated with a lower risk of severe disease and vision loss [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ]. The incidence of contact lens-related MK has remained stable over time [
      • Stapleton F.
      • Keay L.
      • Jalbert I.
      • Cole N.
      The epidemiology of contact lens related infiltrates.
      ], however there have been no prospective studies of corneal infection since the mid-2000s, consequently no reliable incidence estimates with contemporary contact lenses, orthokeratology (See CLEAR Orthokeratology Report [
      • Vincent S.J.
      • Cho P.
      • Chan K.Y.
      • Fadel D.
      • Ghorbani-Mojarrad N.
      • González-Meijome J.M.
      • et al.
      CLEAR - orthokeratology.
      ]) and soft myopia control contact lenses.

      2.2 Pathophysiology, risk factors, presenting signs, differential diagnosis, management, outcomes

      The majority of contact lens-related infections are due to bacteria (around 80–95 %) [
      • Green M.
      • Sara S.
      • Hughes I.
      • Apel A.
      • Stapleton F.
      Trends in contact lens microbial keratitis 1999 to 2015: a retrospective clinical review.
      ,
      • Bennett L.
      • YH H.
      • Tai S.
      • Ernst B.
      • Schmidt E.J.
      • Parihar R.
      • et al.
      Contact lens versus non-contact lens-related corneal ulcers at an academic center.
      ], with the remainder caused by pathogens including Acanthamoeba spp. and filamentary fungi (such as Fusarium spp.). The most common bacterial pathogen in most centres is Pseudomonas aeruginosa (Fig. 1). The proportions of causative organisms vary depending on the climate for example in Australia, Pseudomonas aeruginosa is more common in tropical regions, compared to the temperate regions, where Staphylococcus aureus and Serratia spp. are more commonly recovered [
      • Stapleton F.
      • Keay L.J.
      • Sanfilippo P.G.
      • Katiyar S.
      • Edwards K.P.
      • Naduvilath T.
      Relationship between climate, disease severity, and causative organism for contact lens-associated microbial keratitis in Australia.
      ]. In addition, in daily disposable contact lens wear, keratitis is more likely to be caused by endogenous bacteria, such as Staphylococcus spp. compared to reusable soft lens wearers, in which environmental bacteria, such as Pseudomonas aeruginosa predominate [
      • Stapleton F.
      • Naduvilath T.
      • Keay L.
      • Radford C.
      • Dart J.
      • Edwards K.
      • et al.
      Risk factors and causative organisms in microbial keratitis in daily disposable contact lens wear.
      ]. Contact lens storage cases harbour environmental bacteria [
      • Wu Y.T.
      • Willcox M.
      • Zhu H.
      • Stapleton F.
      Contact lens hygiene compliance and lens case contamination: a review.
      ] and are thought to be the source of the pathogen in many reusable wearers with MK.
      Fig. 1
      Fig. 1Pseudomonas aeruginosa keratitis in a soft contact lens wearer. Image courtesy of Mr Stephen Tuft, Moorfields Eye Hospital. Image reproduced from Carnt et al., 2017 [
      • Carnt N.
      • Samarawickrama C.
      • White A.
      • Stapleton F.
      The diagnosis and management of contact lens-related microbial keratitis.
      ].
      Established risk factors, presenting signs, differential diagnosis, management and outcomes for different causative organisms are described in Table 2.
      Table 2Risk factors, presenting signs, differential diagnosis, management, and outcomes for each type of causative organism in contact lens-related microbial keratitis.
      Causative agent
      BacteriaAcanthamoebaFungi
      Risk factors
       ModifiablePoor hand and lens case hygiene [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ], overnight wear [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ], smoking [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ], showering in lenses [
      • Lim C.H.
      • Carnt N.A.
      • Farook M.
      • Lam J.
      • Tan D.T.
      • Mehta J.S.
      • et al.
      Risk factors for contact lens-related microbial keratitis in Singapore.
      ]
      Water exposure [
      • Carnt N.
      • Hoffman J.M.
      • Verma S.
      • Hau S.
      • Radford C.F.
      • Minassian D.C.
      • et al.
      Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.
      ], poor hand and lens hygiene[
      • Carnt N.
      • Hoffman J.M.
      • Verma S.
      • Hau S.
      • Radford C.F.
      • Minassian D.C.
      • et al.
      Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.
      ,
      • Brown A.C.
      • Ross J.
      • Jones D.B.
      • Collier S.A.
      • Ayers T.L.
      • Hoekstra R.M.
      • et al.
      Risk factors for Acanthamoeba keratitis-a multistate case-control study, 2008–2011.
      ], certain lens disinfecting solutions[
      • Carnt N.
      • Hoffman J.M.
      • Verma S.
      • Hau S.
      • Radford C.F.
      • Minassian D.C.
      • et al.
      Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.
      ,
      • Joslin C.E.
      • Tu E.Y.
      • Shoff M.E.
      • Booton G.C.
      • Fuerst P.A.
      • McMahon T.T.
      • et al.
      The association of contact lens solution use and Acanthamoeba keratitis.
      ]
      Certain lens disinfecting solutions [
      • Saw S.-M.
      • Ooi P.-L.
      • Tan D.T.H.
      • Khor W.-B.
      • Fong C.-W.
      • Lim J.
      • et al.
      Risk factors for contact lens-related fusarium keratitis: a case-control study in Singapore.
      ,
      • Chang D.C.
      • Grant G.B.
      • O’Donnell K.
      • Wannemuehler K.A.
      • Noble-Wang J.
      • Rao C.Y.
      • et al.
      Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution.
      ], non-scheduled lens replacement [
      • Saw S.-M.
      • Ooi P.-L.
      • Tan D.T.H.
      • Khor W.-B.
      • Fong C.-W.
      • Lim J.
      • et al.
      Risk factors for contact lens-related fusarium keratitis: a case-control study in Singapore.
      ]
       Non-modifiableMale sex [
      • Dart J.K.
      • Radford C.F.
      • Minassian D.
      • Verma S.
      • Stapleton F.
      Risk factors for microbial keratitis with contemporary contact lenses: a case-control study.
      ], young age [
      • Dart J.K.
      • Radford C.F.
      • Minassian D.
      • Verma S.
      • Stapleton F.
      Risk factors for microbial keratitis with contemporary contact lenses: a case-control study.
      ] high SES [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ]
      Caucasian race [
      • Carnt N.
      • Hoffman J.M.
      • Verma S.
      • Hau S.
      • Radford C.F.
      • Minassian D.C.
      • et al.
      Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.
      ], low SES [
      • Carnt N.
      • Hoffman J.M.
      • Verma S.
      • Hau S.
      • Radford C.F.
      • Minassian D.C.
      • et al.
      Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.
      ]
      Male sex [
      • Saw S.-M.
      • Ooi P.-L.
      • Tan D.T.H.
      • Khor W.-B.
      • Fong C.-W.
      • Lim J.
      • et al.
      Risk factors for contact lens-related fusarium keratitis: a case-control study in Singapore.
      ], high income [
      • Saw S.-M.
      • Ooi P.-L.
      • Tan D.T.H.
      • Khor W.-B.
      • Fong C.-W.
      • Lim J.
      • et al.
      Risk factors for contact lens-related fusarium keratitis: a case-control study in Singapore.
      ], Malay race [
      • Saw S.-M.
      • Ooi P.-L.
      • Tan D.T.H.
      • Khor W.-B.
      • Fong C.-W.
      • Lim J.
      • et al.
      Risk factors for contact lens-related fusarium keratitis: a case-control study in Singapore.
      ]
      Pathognomic signs & symptomsIrregular focal anterior-mid stromal lesion/s with overlying staining/ulcerEarly: Epithelial disruption, often in branched pattern, peri-neural infiltrates

      Late: scleritis, ring infiltrate
      Focal deep stromal lesion, fluffy edge, slough-like surface commonly with satellite infiltrates
      Common signsGeneralised conjunctival hyperaemia, pain and photophobia, bystander effects: anterior chamber reaction and lid oedema
      Differential DiagnosisFungal keratitis, sterile keratitis, marginal keratitis, peripheral ulcerative keratitisHerpes Simplex/Zoster keratitis, foreign body, healing abrasionBacterial keratitis, marginal keratitis
      Diagnostic tests (in addition to clinical judgement)Corneal scrape for culture
      Corneal scrape is positive in only around 50% of clinically diagnosed cases [83] SES: socioeconomic status; PCR: polymerase chain reaction; PHMB: polyhexamethylene biguanide.
      and smear, PCR
      Corneal epithelial biopsy, scrape and smear, PCR, in vivo confocal microscopyCorneal scrape and smear, in vivo confocal microscopy
      Management (typical)Intensive broad-spectrum topical antibiotics, typically fluoroquinolone (15 min loading dose for first 6 hours), hrly night and day, reduce frequency according to repithelialisation then qid; optional concurrent topical corticosteroids after 2 days*Biguanide (PHMB or chlorhexidine) monotherapy or with diamidine (brolene, hexamidine), hrly night and day 2-5 days; then qid; concurrent topical or oral corticosteroids if scleritis/ring infiltrate; Concurrent topical antibiotic if superinfectionTopical antifungal (eg natamycin), hrly for an extended period; highly invasive, so surgical intervention common
      Outcomes14% lose ≥ 2 lines VA [
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Taylor H.R.
      • Snibson G.R.
      • Forde K.
      • et al.
      Microbial keratitis predisposing factors and morbidity.
      ]
      43% lose ≥ 2 lines VA; 26% keratoplasty [
      • Carnt N.
      • Hoffman J.M.
      • Verma S.
      • Hau S.
      • Radford C.F.
      • Minassian D.C.
      • et al.
      Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.
      ]
      48% lose ≥ 2 lines VA; 17% keratoplasty [
      • Keay L.J.
      • Gower E.W.
      • Iovieno A.
      • Oechsler R.A.
      • Alfonso E.C.
      • Matoba A.
      • et al.
      Clinical and microbiological characteristics of fungal keratitis in the United States, 2001-2007: a multicenter study.
      ]
      Hrly = hourly, min = minutes, qid = four times per day.
      * Corneal scrape is positive in only around 50% of clinically diagnosed cases [
      • Allan B.D.
      • Dart J.K.
      Strategies for the management of microbial keratitis.
      ] SES: socioeconomic status; PCR: polymerase chain reaction; PHMB: polyhexamethylene biguanide.

      2.3 Prevention

      Contact lenses, like all medical devices, carry a certain degree of risk. An evidence-based approach to decrease frequency and severity of contact lens-related infection includes attention to those risk factors associated with a greater impact on disease load as follows:

      3. Contact lens-related corneal inflammation

      For ECPs, the most important differential diagnosis for a contact lens wearer presenting with a painful red eye should focus on determining whether they have sight-threatening MK or a non-infectious or sterile keratitis, referred to as a corneal infiltrative event (CIE). Although accurately classifying ocular signs is important, understanding the incidence and risk factors for MK and CIEs helps the clinician with differential diagnosis. More importantly, knowledge of risk factors helps the clinician recommend contact lenses that will minimise risk of CIEs for patients who have non-modifiable risk factors that increase their risk.

      3.1 Signs associated with CIE

      Sweeney and co-workers developed a classification system for CIEs in the early 2000s that has been used in most of the larger studies of soft contact lens-related adverse events (see Section 2.3) [
      • Sweeney D.F.
      • Jalbert I.
      • Covey M.
      • Sankaridurg P.R.
      • Vajdic C.
      • Holden B.A.
      • et al.
      Clinical characterization of corneal infiltrative events observed with soft contact lens wear.
      ]. CIEs may or may not be accompanied by symptoms, but when they are symptomatic, the wearer typically presents with discomfort ranging from none to moderate pain, and a red and watery eye. Asymptomatic CIEs are almost exclusively reported in randomised clinical trials and present infrequently in population-based studies [
      • Carnt N.A.
      • Evans V.E.
      • Naduvilath T.J.
      • Willcox M.D.
      • Papas E.B.
      • Frick K.D.
      • et al.
      Contact lens-related adverse events and the silicone hydrogel lenses and daily wear care system used.
      ,
      • Diec J.
      • Tilia D.
      • Thomas V.
      Comparison of silicone hydrogel and hydrogel daily disposable contact lenses.
      ,
      • Szczotka-Flynn L.
      • Chalmers R.
      Incidence and epidemiologic associations of corneal infiltrates with silicone hydrogel contact lenses.
      ,
      • Szczotka-Flynn L.
      • Jiang Y.
      • Raghupathy S.
      • Bielefeld R.A.
      • Garvey M.T.
      • Jacobs M.R.
      • et al.
      Corneal inflammatory events with daily silicone hydrogel lens wear.
      ]. Tables 3 , 4a and 4b outline the incidence and risk factors for symptomatic CIEs.
      Table 3Incidence of CIEs in large observational contact lens studies.
      Study Design & Name (citation)Population FeaturesYears of WearCIE Incidence %/year (95% CI)
      Soft Contact Lenses
      ReCSS Retrospective Cohort Study of Pediatric Soft Contact Lens Wear [
      • Chalmers R.L.
      • McNally J.J.
      • Chamberlain P.
      • Keay L.
      Adverse event rates in the retrospective cohort study of safety of paediatric soft contact lens wear: the ReCSS study.
      ]
      N = 962, 782 patients in USA clinical practices and 181 subjects in 2 multi-national randomised controlled trials fit while 8 through 12 years old2,7130.74%/yr (0.48–1.14%)
      TEMPO Prospective Registry of Daily Disposable Wearers [
      • Chalmers R.L.
      • Hickson-Curran S.B.
      • Keay L.
      • Gleason W.J.
      • Albright R.
      Rates of adverse events with hydrogel and silicone hydrogel daily disposable lenses in a large postmarket surveillance registry: the TEMPO Registry.
      ]
      N = 1,171 registered patients newly fit with Daily Disposable soft contact lenses in 37 US clinical practices960.3Etafilcon A: 0.0% /yr (0–0.6%)

      Narafilcon B: 0.4%/yr (0.1–1.5%)
      CLAY Study Retrospective Chart Review [
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ]
      N = 3,549 patients wearing marketed soft contact lenses aged 8-32 years

      2,110 adults, 1,054 minors

      6 US optometry school clinics
      4,663All ages: 4.0%/yr (3.48– 4.61%)

      8-12 yrs: 0.97%/yr (0.31–2.35%)

      13-17 yrs 3.35%/yr (2.48–4.43%)

      18–25 yrs 5.71%/yr (4.65–7.0%)

      > 26 yrs: 3.40%/yr (2.57–4.53%)
      FDA Mandated Prospective Post-Market Surveillance Registry [
      • Chalmers R.L.
      • McNally J.J.
      • Schein O.D.
      • Katz J.
      • Tielsch J.M.
      • Alfonso E.
      • et al.
      Risk factors for corneal infiltrates with continuous wear of contact lenses.
      ]
      N = 6,245 registered patients newly fit with lotrafilcon A for 30 night overnight wear in 31 US clinical practices5,561Annual incidence:

      2.54%/yr (2.18–2.97%)
      UK Hospital Prospective Case Control Study [
      • Efron N.
      • Morgan P.B.
      • Hill E.A.
      • Raynor M.K.
      • Tullo A.B.
      Incidence and morbidity of hospital-presenting corneal infiltrative events associated with contact lens wear.
      ]
      N = 181 hospital presenting patients, hospital, and community controlsN/ADaily Disposable Hydrogel: 0.14%/yr

      Daily Wear Hydrogel: 0.20%/yr

      Daily Wear SiHy 0.56%/yr
      Rigid Lenses for Orthokeratology
      Observational

      FDA Mandated Retrospective Post-Market Surveillance [
      • Bullimore M.A.
      • Sinnott L.T.
      • Jones-Jordan L.A.
      The risk of microbial keratitis with overnight corneal reshaping lenses.
      ]
      N = 1317 Orthokeratology patients

      640 adults, 677 minors

      86 US clinical practices
      2,599Adults: 0.17%/yr (0.02–0.62%)

      Minors: 0.42%/yr: (0.15–0.91%)
      Table 4aModifiable risk factors for CIs from recent soft contact lens studies.
      Risk factor Study CitationOvernight WearReusable lens useMPS disinfectionSilicone HydrogelsLens case ageRinse with Tap waterSmoking
      ReferentDaily WearDaily DisposableHydrogen PeroxideHydrogelN/ANo Tap Water RinseNo
      CLRS Case Control [
      • Richdale K.
      • Lam D.Y.
      • Wagner H.
      • Zimmerman A.B.
      • Kinoshita B.T.
      • Chalmers R.
      • et al.
      Case-control pilot study of soft contact lens wearers with corneal infiltrative events and healthy controls.
      ]
      aOR = 5.5

      Upper 95%

      CI: 21.5
      aOR = 9.5

      Upper 95%

      CI: 92.2
      aOR = 17.3

      Upper 95%

      CI: 107.7
      --> 6 months

      aOR = 7.7

      Upper 95%

      CI: 31.6
      aOR = 2.85

      Upper 95%

      CI: 8.2
      --
      CIEs in University Students [
      • Zimmerman A.B.
      • Emch A.J.
      • Geldis J.
      • Nixon G.J.
      • Mitchell G.L.
      Contact Lens corneal inflammatory events in a university population.
      ]
      If using PHMB

      OR = 10.0

      (2.0–51.2)
      --Polyquad, DW

      OR = 18.4

      (1.9–173.9)

      PHMB, overnight wear

      OR = 10.0

      (2.0–51.2)
      NSNS----
      SiHy Daily Wear [
      • Szczotka-Flynn L.
      • Jiang Y.
      • Raghupathy S.
      • Bielefeld R.A.
      • Garvey M.T.
      • Jacobs M.R.
      • et al.
      Corneal inflammatory events with daily silicone hydrogel lens wear.
      ]
      ----NS------NS
      Private Practice Case Control [
      • Chalmers R.L.
      • Keay L.
      • McNally J.
      • Kern J.
      Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates.
      ]
      OR = 4.0

      (2.3–6.8)
      DW Only

      OR = 12.5

      (1.5–100.6)
      NSDW Only

      OR = 2.0

      (1.1–3.8)
      ----NS
      CLAY Retrospective Chart Review [
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ]
      aOR = 3.25

      (1.4–7.5)
      Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio.
      2 weekly

      aOR = 3.0

      (1.2–7.5)

      Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio.
      Monthly

      aOR = 3.4

      (1.4–8.6)

      Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio.
      Other intervals

      aOR = 5.1

      (1.8–14.2)
      aOR = 2.85 (1.3–6.3)aOR = 1.85 (1.3–2.7)------
      SiHy Continuous Wear [
      • Szczotka-Flynn L.
      • Lass J.H.
      • Sethi A.
      • Debanne S.
      • Benetz B.A.
      • Albright M.
      • et al.
      Risk factors for corneal infiltrative events during continuous wear of silicone hydrogel contact lenses.
      ]
      ------------HR+ 4.1 (1.7–9.9)
      Retrospective Chart Review [
      • Chalmers R.L.
      • Keay L.
      • Long B.
      • Bergenske P.
      • Giles T.
      • Bullimore M.A.
      Risk factors for contact lens complications in US clinical practices.
      ]
      --NSNSIRR = 1.3 (1.01–1.7)------
      Prospective Case Control [
      • Radford C.F.
      • Minassian D.
      • Dart J.K.
      • Stapleton F.
      • Verma S.
      Risk factors for nonulcerative contact lens complications in an ophthalmic accident and emergency department: a case-control study.
      ]
      OR = 1.3 (1.0–1.7)Dailies (CIBA Vision)--SiH OR = 1.9 (1.5–2.6)----
      OR = 2.2 (1.5–3.2)
      Abbreviations; CLRS: Contact lens risk survey, CIEs: Corneal infiltrative events, Conj: Conjunctiva, OR: Odds ratio, aOR: Adjusted odds ratio IRR: Incidence rate ratio, CI: Confidence interval, SiHy: Silicone hydrogel, CLAY: Contact lens assessment in youth; PHMB: polyhexamethylene biguanide.
      * Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio.
      Table 4bNon-modifiable risk factors for CIEs from recent soft contact lens studies.
      Risk Factor

      Study Citation
      AgeBacterial BioburdenPrevious Red EyeHigh Rx >5.0DRecent Use of EyedropsRecent Cold or FluNew to Lens Wear
      ReferentN/ANo BurdenNo Previous Red Eye< 5.0DNo Recent Drop UseNo Recent Cold or Flu> 1 Year of Lens Wear
      CLRS Case Control [
      • Richdale K.
      • Lam D.Y.
      • Wagner H.
      • Zimmerman A.B.
      • Kinoshita B.T.
      • Chalmers R.
      • et al.
      Case-control pilot study of soft contact lens wearers with corneal infiltrative events and healthy controls.
      ]
      NSLid Margin

      OR = 8.1

      Bulbar Conj.

      OR = 16.7

      Contact Lens

      OR = 35.3

      Lens Case

      OR = 3.6
      aOR = 4.2

      Upper 95% CI 13.5
      --aOR = 7.7

      Upper 95% CI 24.8
      aOR = 3.4

      Upper 95% CI 9.7
      --
      CIEs in University Students [
      • Zimmerman A.B.
      • Emch A.J.
      • Geldis J.
      • Nixon G.J.
      • Mitchell G.L.
      Contact Lens corneal inflammatory events in a university population.
      ]
      20% lower/yr from 18 to 36------------
      SiHy Daily Wear Prospective [
      • Szczotka-Flynn L.
      • Jiang Y.
      • Raghupathy S.
      • Bielefeld R.A.
      • Garvey M.T.
      • Jacobs M.R.
      • et al.
      Corneal inflammatory events with daily silicone hydrogel lens wear.
      ]
      NSLid Bioburden

      OR = 4.3 (1.1–16.7)
      ----------
      Case Control [
      • Chalmers R.L.
      • Keay L.
      • McNally J.
      • Kern J.
      Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates.
      ]
      5% less per year after 18 years----Mean Rx

      Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio, Mos: months, yr: year, IRR: Incidence rate ratio, Rx: prescription.
      OR = 1.09 (1.02–1.16)
      ------
      CLAY Retrospective Chart Review [
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ]
      Non-Linear Highest risk: 15 to 25 yrs----NS----Approximately 1/3 risk in 1st year of wear
      SiHy 30 Night Wear Prospective [
      • Szczotka-Flynn L.
      • Lass J.H.
      • Sethi A.
      • Debanne S.
      • Benetz B.A.
      • Albright M.
      • et al.
      Risk factors for corneal infiltrative events during continuous wear of silicone hydrogel contact lenses.
      ]
      NSLens Bioburden at 4 Mos

      HR+ = 8.7(2.9–26.0) at 12 Mos

      HR+ = 4.8 (2.3–9.9)
      ----------
      Retrospective Chart Review [
      • Chalmers R.L.
      • Keay L.
      • Long B.
      • Bergenske P.
      • Giles T.
      • Bullimore M.A.
      Risk factors for contact lens complications in US clinical practices.
      ]
      Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio, Mos: months, yr: year, IRR: Incidence rate ratio, Rx: prescription.
      < 25 yr

      IRR = 1.35 (1.1–1.7)
      ----IRR = 1.5 (1.2–1.9)----IRR = 0.07 (0.01–0.46)
      Prospective Case Control [
      • Radford C.F.
      • Minassian D.
      • Dart J.K.
      • Stapleton F.
      • Verma S.
      Risk factors for nonulcerative contact lens complications in an ophthalmic accident and emergency department: a case-control study.
      ]
      -------------->3 yr OR = 2.4 (1.7–3.4)
      Abbreviations; CLRS: Contact lens risk survey, CIEs: Corneal infiltrative events, Conj: Conjunctiva, OR: Odds ratio, aOR: Adjusted odds ratio, IRR: Incidence rate ratio, CI: Confidence interval, SiHy: Silicone hydrogel, CLAY: Contact lens assessment in youth.
      * Univariate model only, -- Data not captured in study or unable to test due to homogeneity in sample, NS Not Significant, + Hazard Ratio, Mos: months, yr: year, IRR: Incidence rate ratio, Rx: prescription.
      The number of infiltrates, their size, location and presence of overlying staining help determine the differential diagnoses for the sub-categories of CIEs. In patients with CIEs, signs and symptoms typically begin to resolve as soon as lens wear is temporarily ceased. An important differential between CIEs and MK is that the discomfort/pain is not relieved by contact lens removal in MK, but the pain progressively increases [
      • Carnt N.
      • Samarawickrama C.
      • White A.
      • Stapleton F.
      The diagnosis and management of contact lens-related microbial keratitis.
      ].
      Contact lens peripheral ulcers (CLPU) occur in the periphery or mid-periphery of the cornea, have overlying fluorescein staining and are <1 mm in diameter with regular edges (Fig. 2). CLPU events will resolve to a small scar over time. Although they are not infectious, management of CLPUs usually involves coverage by a combination antibiotic-steroid combination in countries where ECPs have access to prescribing them.
      Fig. 2
      Fig. 2Left: CLPU. Right: Infiltrative Keratitis; Images courtesy of CORE.
      Infiltrates seen with contact lens acute red eye (CLARE) can be diffuse, or multiple focal, much smaller and often do not have overlying staining. They are accompanied by eye redness, watering and pain on waking and are highly associated with overnight wear of lenses. These will resolve with cessation of lens wear, although coverage with antibiotic-steroid is sometimes used to manage the condition.
      Infiltrative keratitis presents as single or multiple anterior focal infiltrates that sometimes show overlying fluorescein staining (Fig. 2). It presents with mild to moderate irritation, some redness and occasional discharge. Management of infiltrative keratitis depends on the degree of redness, discomfort and presence of overlying staining. It is managed similarly, with prophylactic coverage with antibiotics or combination agents.
      The differential diagnosis of CIEs is equivocal [
      • Efron N.
      • Morgan P.
      Rethinking contact lens associated keratitis.
      ]. Using data from the Manchester Keratitis Study, the authors propose that the various classification schemes at the time were most likely describing an infiltrative response that is actually a continuum of disease rather than distinct conditions. Most importantly for the practicing clinician, they also conclude that if a contact lens wearing patient presents with an increasingly uncomfortable red eye with an infiltrate that contact lens wear should be ceased and intensive antimicrobial treatment commenced immediately.

      3.2 Incidence of CIEs

      The incidence of CIEs varies widely depending on the proportion of the study population with risk factors for CIEs, the contact lens wearing schedule (daily versus overnight wear), contact lens replacement schedule (daily disposable versus reusable), contact lens material (hydrogel versus SiHy), history of prior CIEs and the age of the wearer (Table 3 and Fig. 3). It is clear that studies that included large proportions of wearers using daily disposable soft contact lens have rates that are approximately ten times lower than with reusable contact lenses, with incidence ranging from 0.0 % to 0.4 %/yr depending on daily disposable contact lens material [
      • Chalmers R.L.
      • Hickson-Curran S.B.
      • Keay L.
      • Gleason W.J.
      • Albright R.
      Rates of adverse events with hydrogel and silicone hydrogel daily disposable lenses in a large postmarket surveillance registry: the TEMPO Registry.
      ,
      • Efron N.
      • Morgan P.B.
      • Hill E.A.
      • Raynor M.K.
      • Tullo A.B.
      Incidence and morbidity of hospital-presenting corneal infiltrative events associated with contact lens wear.
      ].The incidence of CIEs in overnight wear reusable soft contact lens studies ranges between 2.5–7.0% per year in observational cohort studies [
      • Stapleton F.
      • Keay L.
      • Jalbert I.
      • Cole N.
      The epidemiology of contact lens related infiltrates.
      ] and these rates have been fairly robust over time [
      • Steele K.R.
      • Szczotka-Flynn L.
      Epidemiology of contact lens-induced infiltrates: an updated review.
      ].
      Fig. 3
      Fig. 3Incidence of CIEs per 100 wearers per year. Error bars show 95% confidence intervals. (Modified from Chalmers et al., 2021, [
      • Chalmers R.L.
      • McNally J.J.
      • Chamberlain P.
      • Keay L.
      Adverse event rates in the retrospective cohort study of safety of paediatric soft contact lens wear: the ReCSS study.
      ]).

      3.3 Risk factors for CIEs

      CIE incidence varies depending on the presence of risk factors in the population that is being studied (Fig. 3). The most consistent risk factors, divided into those that are modifiable by different choice of wear schedule, lens replacement schedule, frequency of case replacement, disinfection system, compliance with lens care or lens material and other factors are not modifiable, such as the age of the wearer, sex, their refractive error, or general or eye health history (Table 4a, Table 4b; note that some studies did not analye all of the factors listed).
      Among the modifiable risk factors, overnight wear increases risk significantly [
      • Radford C.F.
      • Minassian D.
      • Dart J.K.
      • Stapleton F.
      • Verma S.
      Risk factors for nonulcerative contact lens complications in an ophthalmic accident and emergency department: a case-control study.
      ,
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ,
      • Richdale K.
      • Lam D.Y.
      • Wagner H.
      • Zimmerman A.B.
      • Kinoshita B.T.
      • Chalmers R.
      • et al.
      Case-control pilot study of soft contact lens wearers with corneal infiltrative events and healthy controls.
      ,
      • Zimmerman A.B.
      • Emch A.J.
      • Geldis J.
      • Nixon G.J.
      • Mitchell G.L.
      Contact Lens corneal inflammatory events in a university population.
      ,
      • Chalmers R.L.
      • Keay L.
      • McNally J.
      • Kern J.
      Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates.
      ]. In these studies the increased risk ranged from 2.5–10 times higher depending on the subgroup being studied. Use of reusable contact lenses was consistently identified, with increased risk from 3.0–12.5 times the risk compared to daily disposable use [
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ,
      • Richdale K.
      • Lam D.Y.
      • Wagner H.
      • Zimmerman A.B.
      • Kinoshita B.T.
      • Chalmers R.
      • et al.
      Case-control pilot study of soft contact lens wearers with corneal infiltrative events and healthy controls.
      ,
      • Chalmers R.L.
      • Keay L.
      • McNally J.
      • Kern J.
      Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates.
      ], however one study showed differences in risk between types of daily disposable contact lenses [
      • Radford C.F.
      • Minassian D.
      • Dart J.K.
      • Stapleton F.
      • Verma S.
      Risk factors for nonulcerative contact lens complications in an ophthalmic accident and emergency department: a case-control study.
      ]. Compared to use of hydrogen peroxide disinfection, the use of multi-purpose systems was associated with a higher risk [
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ,
      • Richdale K.
      • Lam D.Y.
      • Wagner H.
      • Zimmerman A.B.
      • Kinoshita B.T.
      • Chalmers R.
      • et al.
      Case-control pilot study of soft contact lens wearers with corneal infiltrative events and healthy controls.
      ,
      • Zimmerman A.B.
      • Emch A.J.
      • Geldis J.
      • Nixon G.J.
      • Mitchell G.L.
      Contact Lens corneal inflammatory events in a university population.
      ] and SiHy contact lens wear showed increased risk in a number of studies [
      • Radford C.F.
      • Minassian D.
      • Dart J.K.
      • Stapleton F.
      • Verma S.
      Risk factors for nonulcerative contact lens complications in an ophthalmic accident and emergency department: a case-control study.
      ,
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ,
      • Chalmers R.L.
      • Keay L.
      • McNally J.
      • Kern J.
      Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates.
      ].
      Non-modifiable risk factors that put a wearer at increased risk are shown in Table 4b. Older teens and young adults carry increased risk of CIEs [
      • Chalmers R.L.
      • Wagner H.
      • Mitchell G.L.
      • Lam D.Y.
      • Kinoshita B.T.
      • Jansen M.E.
      • et al.
      Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
      ,
      • Zimmerman A.B.
      • Emch A.J.
      • Geldis J.
      • Nixon G.J.
      • Mitchell G.L.
      Contact Lens corneal inflammatory events in a university population.
      ,
      • Chalmers R.L.
      • Keay L.
      • McNally J.
      • Kern J.
      Multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates.
      ,
      • Chalmers R.L.
      • Keay L.
      • Long B.
      • Bergenske P.
      • Giles T.
      • Bullimore M.A.
      Risk factors for contact lens complications in US clinical practices.
      ] and the presence of bacterial bioburden on the eyes, contact lenses and contact lens cases also add to risk [
      • Szczotka-Flynn L.
      • Jiang Y.
      • Raghupathy S.
      • Bielefeld R.A.
      • Garvey M.T.
      • Jacobs M.R.
      • et al.
      Corneal inflammatory events with daily silicone hydrogel lens wear.
      ,
      • Richdale K.
      • Lam D.Y.
      • Wagner H.
      • Zimmerman A.B.
      • Kinoshita B.T.
      • Chalmers R.
      • et al.
      Case-control pilot study of soft contact lens wearers with corneal infiltrative events and healthy controls.
      ,
      • Szczotka-Flynn L.
      • Lass J.H.
      • Sethi A.
      • Debanne S.
      • Benetz B.A.
      • Albright M.
      • et al.
      Risk factors for corneal infiltrative events during continuous wear of silicone hydrogel contact lenses.
      ].

      3.4 Prevention and advice to wearers

      The clinician should consider the risk factors for each contact lens wearer to arrive at the best contact lens option for that patient. In general, use of daily disposable contact lenses and avoiding overnight wear bring lower risk for CIEs, as does use of hydrogen peroxide disinfection for wearers of reusable contact lenses. For example, a 23 year old with a history of previous CIEs or with blepharitis should be encouraged to wear daily disposable contact lenses in order to mitigate the added risk that their age and history contribute. Similarly, patients with high refractive errors or a history of a previous red eye should be steered toward daily disposable contact lenses as the safest choice for them. All daily disposable contact lenses wearers should be advised at all follow-up visits to never sleep in their contact lenses and to discard contact lenses every day.

      4. Metabolic complications

      Contact lens wear results in metabolic stress to the cornea, which is influenced by both the oxygen transmissibility of the contact lens as well as the degree to which tear exchange is impeded by the contact lens (See CLEAR Material Impact Report [
      • Morgan P.
      • Murphy P.J.
      • Gifford K.
      • Gifford P.
      • Golebiowski B.
      • Johnson L.
      • et al.
      CLEAR - Effect of contact lens materials and designs on the anatomy and physiology of the eye.
      ]).
      Although the development of recent lens materials has led to a decrease in the frequency and severity of disorders resulting from hypoxia, these complications still exist because high Dk lenses are not universally prescribed [
      • Morgan P.
      • Woods C.
      • Tranoudis I.G.
      • Efron E.
      • Jones L.
      • merchan N.L.
      • et al.
      International lens prescribing in 2019.
      ], oxygen transmissibility is limited by lens thickness in specific designs and lens powers [
      • Holden B.A.
      • Mertz G.W.
      • McNally J.J.
      Corneal swelling response to contact lenses worn under extended wear conditions.
      ,
      • Vincent S.J.
      • Alonso-Caneiro D.
      • Collins M.J.
      The time course and nature of corneal oedema during sealed miniscleral contact lens wear.
      ], and individual responses to hypoxia vary. Moreover, closed eye wear by intention (e.g. orthokeratology) or by neglect (non-compliance) further limits oxygen to the eye. Metabolic complications from hypoxia manifest as distinct clinical entities (Table 5).
      Table 5Contact lens complications attributed to hypoxia.
      ConditionPresenting signsTemporal patternLens type
      Limbal rednessDilation of limbal blood vesselsShort-term, reversibleHydrogel [
      • Dumbleton K.A.
      • Chalmers R.L.
      • Richter D.B.
      • Fonn D.
      Vascular response to extended wear of hydrogel lenses with high and low oxygen permeability.
      ,
      • Diec J.
      • Tilia D.
      • Thomas V.
      Comparison of silicone hydrogel and hydrogel daily disposable dontact lenses.
      ,
      • Fonn D.
      • MacDonald K.E.
      • Richter D.
      • Pritchard N.
      The ocular response to extended wear of a high Dk silicone hydrogel contact lens.
      ,
      • Papas E.
      On the relationship between soft contact lens oxygen transmissibility and induced limbal hyperaemia.
      ,
      • Holden B.A.
      • Sweeney D.F.
      • Swarbrick H.A.
      • Vannas A.
      • Nilsson K.T.
      • Efron N.
      The vascular response to long-term extended contact lens wear.
      ,
      • McMonnies C.W.
      • Chapman-Davies A.
      • Holden B.A.
      The vascular response to contact lens wear.
      ], Scleral [
      • Fadel D.
      Scleral lens issues and complications related to a non-optimal fitting relationship between the ens and ocular surface.
      ]
      Epithelial stainingDiffuse, punctate, coalesced staining with sodium fluoresceinShort-term, reversibleHydrogel [
      • Hamano H.
      • Watanabe K.
      • Hamano T.
      • Mitsunaga S.
      • Kotani S.
      • Okada A.
      A study of the complications induced by conventional and disposable contact lenses.
      ,
      • Nichols Jj
      • Sinnott Lt.
      Tear film, contact lens, and patient factors associated with corneal staining.
      ], PMMA [
      • Hamano H.
      • Watanabe K.
      • Hamano T.
      • Mitsunaga S.
      • Kotani S.
      • Okada A.
      A study of the complications induced by conventional and disposable contact lenses.
      ], rigid corneal [
      • Hamano H.
      • Watanabe K.
      • Hamano T.
      • Mitsunaga S.
      • Kotani S.
      • Okada A.
      A study of the complications induced by conventional and disposable contact lenses.
      ]
      Epithelial oedemaCircumscribed oedemaShort-term, reversiblePMMA [
      • Dallos J.
      Sattler’s Veil.
      ], Hybrid [
      • Fernandez-Velazquez F.J.
      Severe epithelial edema in Clearkone SynergEyes contact lens wear for keratoconus.
      ]
      Epithelial vacuolesRound, distinct borders, unreversed illuminationLong-term, reversible but recalcitrantHydrogel [
      • Zantos S.G.
      Cystic formations in the corneal epithelium during extended wear of contact lenses.
      ]
      Epithelial bullaeOval, blurred borders, unreversed illuminationLong-term, reversibleHydrogel [
      • Zantos S.G.
      Cystic formations in the corneal epithelium during extended wear of contact lenses.
      ], Scleral [
      • Nixon A.D.
      • Barr J.T.
      • VanNasdale D.A.
      Corneal epithelial bullae after short-term wear of small diameter scleral lenses.
      ]
      Epithelial microcystsSmall, irregular shaped vesicles, reversed illuminationLong-term, reversible but recalcitrantHydrogel [
      • Zantos S.G.
      Cystic formations in the corneal epithelium during extended wear of contact lenses.
      ,
      • Ruben M.
      • Brown N.
      • Lobascher D.
      • Chaston J.
      • Morris J.
      Clinical manifestations secondary to soft contact lens wear.
      ], rigid corneal [
      • Rah M.J.
      • Jackson J.M.
      • Jones L.A.
      • Marsden H.J.
      • Bailey M.D.
      • Barr J.T.
      Overnight orthokeratology: preliminary results of the Lenses and Overnight Orthokeratology (LOOK) study.
      ,
      • Fonn D.
      • Holden B.A.
      Rigid gas-permeable vs. Hydrogel contact lenses for extended wear.
      ]
      Corneal warpageChange in corneal contour with topography or keratometryShort-term, variable resolutionHydrogel [
      • Ruiz-Montenegro J.
      • Mafra C.H.
      • Wilson S.E.
      • Jumper J.M.
      • Klyce S.D.
      • Mendelson E.N.
      Corneal topographic alterations in normal contact lens wearers.
      ,
      • Wilson S.E.
      • Lin D.T.
      • Klyce S.D.
      • Reidy J.J.
      • Insler M.S.
      Topographic changes in contact lens-induced corneal warpage.
      ], PMMA [
      • Ruiz-Montenegro J.
      • Mafra C.H.
      • Wilson S.E.
      • Jumper J.M.
      • Klyce S.D.
      • Mendelson E.N.
      Corneal topographic alterations in normal contact lens wearers.
      ,
      • Wilson S.E.
      • Lin D.T.
      • Klyce S.D.
      • Reidy J.J.
      • Insler M.S.
      Topographic changes in contact lens-induced corneal warpage.
      ,
      • Hartstein J.
      Corneal warping due to wearing of corneal contact lenses. A report of 12 cases.
      ], rigid corneal [
      • Ruiz-Montenegro J.
      • Mafra C.H.
      • Wilson S.E.
      • Jumper J.M.
      • Klyce S.D.
      • Mendelson E.N.
      Corneal topographic alterations in normal contact lens wearers.
      ,
      • Wilson S.E.
      • Lin D.T.
      • Klyce S.D.
      • Reidy J.J.
      • Insler M.S.
      Topographic changes in contact lens-induced corneal warpage.
      ,
      • Hartstein J.
      Corneal warping due to wearing of corneal contact lenses. A report of 12 cases.
      ], Scleral [
      • Severinsky B.
      • Fadel D.
      • Davelman J.
      • Moulton E.
      Effect of scleral lenses on corneal topography in keratoconus.
      ]
      Changes in refractive errorVariable refraction, myopic shift with low Dk materialsShort-term, variable resolutionPMMA [
      • Hartstein J.
      Corneal warping due to wearing of corneal contact lenses. A report of 12 cases.
      ], Hydrogel [
      • Dumbleton K.A.
      • Chalmers R.L.
      • Richter D.B.
      • Fonn D.
      Changes in myopic refractive error with nine months’ extended wear of hydrogel lenses with high and low oxygen permeability.
      ,
      • Jalbert I.
      • Stretton S.
      • Naduvilath T.
      • Holden B.
      • Keay L.
      • Sweeney D.
      Changes in myopia with low-Dk hydrogel and high-Dk silicone hydrogel extended wear.
      ,
      • Harris M.G.
      • Sarver M.D.
      • Polse K.A.
      Corneal curvature and refractive error changes associated with wearing hydrogel contact lenses.
      ], SiHy [
      • Jalbert I.
      • Stretton S.
      • Naduvilath T.
      • Holden B.
      • Keay L.
      • Sweeney D.
      Changes in myopia with low-Dk hydrogel and high-Dk silicone hydrogel extended wear.
      ]
      VascularisationExtension of blood vessels into the previously avascular corneaLong-term, ghost vessels remainHydrogel [
      • Dumbleton K.A.
      • Chalmers R.L.
      • Richter D.B.
      • Fonn D.
      Vascular response to extended wear of hydrogel lenses with high and low oxygen permeability.
      ,
      • Holden B.A.
      • Sweeney D.F.
      • Swarbrick H.A.
      • Vannas A.
      • Nilsson K.T.
      • Efron N.
      The vascular response to long-term extended contact lens wear.
      ,
      • Keech P.M.
      • Ichikawa L.
      • Barlow W.
      A prospective study of contact lens complications in a managed care setting.
      ]

      Scleral [
      • Tan D.T.
      • Pullum K.W.
      • Buckley R.J.
      Medical applications of scleral contact lenses: 2. Gas-permeable scleral contact lenses.
      ]
      Stromal oedemaStriae 5–6 % oedemaShort-term, reversibleHydrogel [
      • Polse K.A.
      • Mandell R.B.
      Etiology of corneal striae accompanying hydrogel lens wear.
      ,
      • Kame R.T.
      Clinical management of hydrogel-induced edema.
      ]
      Folds 10 % oedema
      Endothelial blebsCircumscribed black zones, separation of cellsShort-term, reversibleHydrogel [
      • Zantos S.G.
      • Holden B.A.
      Transient endothelial changes soon after wearing soft contact lenses.
      ,
      • Szczotka-Flynn L.B.
      • Debanne S.
      • Benetz B.A.
      • Wilson T.
      • Brennan N.
      Daily wear contact lenses manufactured in etafilcon a are noninferior to two silicone hydrogel lens types with respect to hypoxic stress.
      ], rigid corneal [
      • Inagaki Y.
      • Akahori A.
      • Sugimoto K.
      • Kozai A.
      • Mitsunaga S.
      • Hamano H.
      Comparison of corneal endothelial bleb formation and disappearance processes between rigid gas-permeable and soft contact lenses in three classes of dk/l.
      ], Scleral [
      • Giasson C.J.
      • Rancourt J.
      • Robillard J.
      • Melillo M.
      • Michaud L.
      Corneal endothelial blebs induced in scleral lens wearers.
      ], SiHy [
      • Szczotka-Flynn L.B.
      • Debanne S.
      • Benetz B.A.
      • Wilson T.
      • Brennan N.
      Daily wear contact lenses manufactured in etafilcon a are noninferior to two silicone hydrogel lens types with respect to hypoxic stress.
      ]
      Endothelial polymegethism and pleomorphismVariation in endothelial cell size or shapeLong-term, not completely reversiblePMMA [
      • Schoessler J.P.
      • Woloschak M.J.
      Corneal endothelium in veteran PMMA contact lens wearers.
      ,
      • Mac Rae S.M.
      • Matsuda M.
      • Phillips D.S.
      The long-term effects of polymethylmethacrylate contact lens wear on the corneal endothelium.
      ] Hydrogel [
      • Mac Rae S.M.
      • Matsuda M.
      • Shellans S.
      • Rich L.F.
      The effects of hard and soft contact lenses on the corneal endothelium.
      ]

      Rigid corneal [
      • Orsborn G.N.
      • Schoessler J.P.
      Corneal endothelial polymegathism after the extended wear of rigid gas-permeable contact lenses.
      ]
      Corneal exhaustion syndromeCorneal oedema accompanied by decreased tolerance to contact lens wearLong-term, reversible but recalcitrantPMMA [
      • Sweeney D.F.
      Corneal exhaustion syndrome with long-term wear of contact lenses.
      ], Hydrogel [
      • Sweeney D.F.
      Corneal exhaustion syndrome with long-term wear of contact lenses.
      ]
      PMMA: Polymethylmethacrylate; SiHy: silicone hydrogel.

      4.1 Limbal redness

      Reducing oxygen to the cornea promotes limbal blood flow and the manifestation of circumlimbal flush. Limbal redness is routinely observed with reusable and daily disposable hydrogel contact lenses, though it has been largely eliminated with SiHy contact lenses in both daily and overnight wear [
      • Diec J.
      • Tilia D.
      • Thomas V.
      Comparison of silicone hydrogel and hydrogel daily disposable contact lenses.
      ,
      • Dumbleton K.A.
      • Chalmers R.L.
      • Richter D.B.
      • Fonn D.
      Vascular response to extended wear of hydrogel lenses with high and low oxygen permeability.
      ,
      • Fonn D.
      • MacDonald K.E.
      • Richter D.
      • Pritchard N.
      The ocular response to extended wear of a high Dk silicone hydrogel contact lens.
      ,
      • Holden B.A.
      • Sweeney D.F.
      • Swarbrick H.A.
      • Vannas A.
      • Nilsson K.T.
      • Efron N.
      The vascular response to long-term extended contact lens wear.
      ,
      • McMonnies C.W.
      • Chapman-Davies A.
      • Holden B.A.
      The vascular response to contact lens wear.
      ]. Redness varies inversely with oxygen transmissibility of the soft contact lens material [
      • Papas E.
      On the relationship between soft contact lens oxygen transmissibility and induced limbal hyperaemia.
      ]. Similarly, limbal redness has been reported as a strong indicator of hypoxic stress in other modalities, including scleral lens wear [
      • Fadel D.
      Scleral lens issues and complications related to a non-optimal fitting relationship between the lens and ocular surface.
      ].

      4.2 Epithelial staining

      Corneal staining in contact lens wear has been proposed as a potential response to epithelial hypoxia and has been reported with polymethylmethacrylate (PMMA), rigid corneal, and conventional hydrogel contact lens wear [
      • Hamano H.
      • Watanabe K.
      • Hamano T.
      • Mitsunaga S.
      • Kotani S.
      • Okada A.
      A study of the complications induced by conventional and disposable contact lenses.
      ]. Consistent with earlier reports in high Dk contact lenses [
      • Ladage P.M.
      • Jester J.V.
      • Petroll W.M.
      • Bergmanson J.P.
      • Cavanagh H.D.
      Role of oxygen in corneal epithelial homeostasis during extended contact lens wear.
      ,
      • Ladage P.M.
      • Yamamoto K.
      • Li L.
      • Ren D.H.
      • Petroll W.M.
      • Jester J.V.
      • et al.
      Corneal epithelial homeostasis following daily and overnight contact lens wear.
      ,
      • Stapleton F.
      • Kasses S.
      • Bolis S.
      • Keay L.
      Short term wear of high Dk soft contact lenses does not alter corneal epithelial cell size or viability.
      ] epithelial staining is also associated with contemporary SiHy contact lenses [
      • Nichols Jj
      • Sinnott Lt.
      Tear film, contact lens, and patient factors associated with corneal staining.
      ].

      4.3 Epithelial oedema

      Epithelial oedema is a complication associated primarily with PMMA corneal lens wear. However, it has also been reported with contemporary hybrid contact lenses [
      • Fernandez-Velazquez F.J.
      Severe epithelial edema in Clearkone SynergEyes contact lens wear for keratoconus.
      ]. Historically, central corneal clouding was described as a visual disturbance characterised by glare and haloes surrounding lights [
      • Dallos J.
      Sattler’s Veil.
      ]. This phenomenon was attributed to a disruption in the corneal epithelium that produced stromal light scattering [
      • Lambert S.R.
      • Klyce S.D.
      The origins of Sattler’s veil.
      ]. Hypotonic reflex tearing is also believed to inhibit the fluid barrier and osmotically induce epithelial oedema [
      • Cox I.G.
      • Holden B.A.
      Can vision loss be used as a quantitative assessment of corneal edema?.