BCLA CLEAR - Orthokeratology

      Abstract

      Orthokeratology (ortho-k) is the process of deliberately reshaping the anterior cornea by utilising specialty contact lenses to temporarily and reversibly reduce refractive error after lens removal. Modern ortho-k utilises reverse geometry lens designs, made with highly oxygen permeable rigid materials, worn overnight to reshape the anterior cornea and provide temporary correction of refractive error. More recently, ortho-k has been extensively used to slow the progression of myopia in children.
      This report reviews the practice of ortho-k, including its history, mechanisms of refractive and ocular changes, current use in the correction of myopia, astigmatism, hyperopia, and presbyopia, and standard of care. Suitable candidates for ortho-k are described, along with the fitting process, factors impacting success, and the potential options for using newer lens designs. Ocular changes associated with ortho-k, such as alterations in corneal thickness, development of microcysts, pigmented arcs, and fibrillary lines are reviewed. The safety of ortho-k is extensively reviewed, along with an overview of non-compliant behaviours and appropriate disinfection regimens. Finally, the role of ortho-k in myopia management for children is discussed in terms of efficacy, safety, and potential mechanisms of myopia control, including the impact of factors such as initial fitting age, baseline refractive error, the role of peripheral defocus, higher order aberrations, pupil size, and treatment zone size.

      Keywords

      Abbreviations

      CI
      confidence interval
      Dk
      oxygen permeability
      ECP(s)
      eyecare practitioner(s)
      FDA
      food and drug administration
      HOA(s)
      higher order aberration(s)
      ISO
      international organisation for standardization
      MPS
      multipurpose solutions
      Ortho-k
      orthokeratology
      QoL
      quality of life
      RMS
      root mean square error
      SER
      spherical equivalent refraction

      1. Introduction

      Orthokeratology (ortho-k) is the process of deliberately reshaping the anterior cornea by utilising specialty contact lenses to temporarily and reversibly reduce refractive error after lens removal [
      • Kerns R.L.
      Research in orthokeratology. Part I: introduction and background.
      ,
      • Mountford J.
      • Ruston D.
      • Dave T.
      Orthokeratology: principles and practice.
      ]. Ortho-k originated in the 1950’s when eyecare practitioners (ECPs) observed changes in corneal curvature and refractive error in some patients wearing flat-fitting rigid corneal contact lenses [
      • Morrison R.J.
      Contact lenses and the progression of myopia.
      ]. Today, modern ortho-k utilises reverse geometry lens designs, made with highly oxygen permeable rigid materials, worn overnight to reshape the anterior cornea and provide temporary correction of refractive error.
      This report reviews the practice of ortho-k, including its history, mechanisms of refractive and ocular changes, current use in the correction of myopia, astigmatism, hyperopia, and presbyopia, and standard of care. The role of ortho-k in myopia management for children is discussed in terms of efficacy, safety, and potential mechanisms of myopia control. Ultimately, the goal is to provide ECPs evidence-based guidance on ortho-k, to offer the best care for children with progressing myopia. To conclude, the potential future of ortho-k is considered.

      2. Historical overview

      At the International Society of Contact Lens Specialists meeting in 1962, Jessen described his technique of “ortho-focus” as a rigid polymethyl methacrylate (PMMA) contact lens moulding the cornea over months of daily wear so that the patient would not rely on corrective lenses to see clearly [
      • Jessen G.N.
      Orthofocus techniques.
      ]. Wesley suggested to change the name to “orthokeratology” and recommended scientific research in the application of this concept [
      • Nolan J.A.
      Flashback: the first ortho-k meeting.
      ]. Over the next two decades, academics researched the validity of daily wear ortho-k. Kerns, at the University of Houston, formalised a clinical study in 1976 [
      • Kerns R.L.
      Research in orthokeratology. Part II: experimental design, protocol and method.
      ], followed by Binder from the University of California in 1980 [
      • Binder P.S.
      • May C.H.
      • Grant S.C.
      An evaluation of orthokeratology.
      ], Coon from Pacific University in 1982 [
      • Coon L.J.
      Orthokeratology: part I historical perspective.
      ], and Polse with the Berkeley Orthokeratology Study in 1983 [
      • Polse K.A.
      • Brand R.J.
      • Schwalb J.S.
      The Berkeley orthokeratology study, part III: safety.
      ]. Their conclusions were in agreement: daily PMMA ortho-k lens wear was safe, but was of limited clinical benefit due to the slow onset and relatively small and temporary reduction of myopia [
      • Kerns R.L.
      Research in orthokeratology. Part III: results and observations.
      ,
      • Kerns R.L.
      Research in orthokeratology. Part VI: statistical and clinical analyses.
      ]. Following these four publications, minimal research was conducted over the next decade, possibly reflecting a waning interest in ortho-k and due to commonly encountered fitting challenges, such as lens decentration and induced astigmatism [
      • Kerns R.L.
      Research in orthokeratology. Part III: results and observations.
      ,
      • Kerns R.L.
      Research in orthokeratology. Part VI: statistical and clinical analyses.
      ].
      In the late 1980's, Wlodyga and Stoyan developed the first true reverse geometry rigid corneal contact lenses, with a back optic zone radius flatter than the adjacent peripheral curve [
      • Mountford J.
      • Ruston D.
      • Dave T.
      Orthokeratology: principles and practice.
      ,
      • Lui W.O.
      • Edwards M.H.
      • Cho P.
      Contact lenses in myopia reduction - from orthofocus to accelerated orthokeratology.
      ]. This novel ortho-k lens design was dubbed “accelerated ortho-k” due to its ability to rapidly reduce myopia [
      • Harris D.
      • Stoyan N.
      A new approach to orthokeratology.
      ,
      • Swarbrick H.A.
      Orthokeratology review and update.
      ]. With the advent of reverse geometry lens designs, approval for overnight wear in high oxygen permeability (Dk) rigid materials (for the correction of myopia), computerised numerical controlled lathes, and sophisticated topographers which accurately quantify corneal changes, ortho-k lenses are now worn overnight to provide clear, unaided vision during the day. Since the effect is temporary, the lenses need to be worn as a retainer, usually every night.
      For over a century, ECPs have considered various methods to slow the progression of myopia [
      • Morrison R.J.
      Contact lenses and the progression of myopia.
      ]. In an early retrospective analysis published in 1957, Morrison [
      • Morrison R.J.
      Contact lenses and the progression of myopia.
      ] reported no refractive progression in seven to 19-year-old children with previously steadily progressing myopia who wore flat-fitting rigid corneal lenses (∼2.00 D flatter than the flattest corneal meridian) for at least 18 h a day. Since the late 1990's, ortho-k has been perceived by ECPs to be one of the most effective methods of myopia control [
      • Cho P.
      • Cheung S.W.
      • Edwards M.H.
      Practice of orthokeratology by a group of contact lens practitioners in Hong Kong. Part 2: orthokeratology lenses.
      ,
      • Wolffsohn J.S.
      • Calossi A.
      • Cho P.
      • Gifford K.
      • Jones L.
      • Jones D.
      • et al.
      Global trends in myopia management attitudes and strategies in clinical practice - 2019 update.
      ,
      • Wolffsohn J.S.
      • Calossi A.
      • Cho P.
      • Gifford K.
      • Jones L.
      • Li M.
      • et al.
      Global trends in myopia management attitudes and strategies in clinical practice.
      ,
      • Douglass A.
      • Keller P.R.
      • He M.
      • Downie L.E.
      Knowledge, perspectives and clinical practices of Australian optometrists in relation to childhood myopia.
      ] (see Section 8). In 2005, half a century after Morrison’s clinical observations [
      • Morrison R.J.
      Contact lenses and the progression of myopia.
      ], a prospective single-arm intervention study suggested that ortho-k had the capacity to modulate myopia progression in children, relative to a historical control group of single-vision distance spectacle lens wearers [
      • Cho P.
      • Cheung S.W.
      • Edwards M.H.
      The longitudinal orthokeratology research in children (LORIC) in Hong Kong: a pilot study on refractive changes and myopic control.
      ]. This was followed by numerous peer-reviewed studies, including randomised and controlled clinical trials (Section 8.3 and Table 1), describing reductions in myopia progression in children and the myopia control effect of ortho-k for up to two years follow-up [
      • Chen C.C.
      • Cheung S.W.
      • Cho P.
      Myopia control using toric orthokeratology (TO-SEE study).
      ,
      • Cho P.
      • Cheung S.W.
      Retardation of myopia in orthokeratology (ROMIO) study: a 2-year randomized clinical trial.
      ,
      • Huang J.
      • Wen D.
      • Wang Q.
      • McAlinden C.
      • Flitcroft I.
      • Chen H.H.
      • et al.
      Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis.
      ,
      • Robboy M.W.
      • Hilmantel G.
      • Tarver M.E.
      • Eydelman M.B.
      Assessment of clinical trials for devices intended to control myopia progression in children.
      ].
      Table 1Characteristics and outcome of axial length elongation in representative orthokeratology myopia control studies in children.
      Author, YearAge (Years)Race

      (Duration (m))
      Myopia [SER] {A} (D)Method of assignmentIntervention (Control) (n)Baseline AL (mm)Change in AL (mean± SD; mm)MC (mm) (%)DropoutRemark
      Cho et al. 2005 [
      • Cho P.
      • Cheung S.W.
      • Edwards M.H.
      The longitudinal orthokeratology research in children (LORIC) in Hong Kong: a pilot study on refractive changes and myopic control.
      ]
      7 – 12Chinese (24)[0.25 to 4.50]Historical controlOK (n = 35)24.50 ± 0.710.29 ± 0.270.25#

      (46%)
      19%
      (SVS) (n = 35)24.64 ± 0.580.54 ± 0.270%
      Walline et al. 2009 [
      • Walline J.J.
      • Jones L.A.
      • Sinnott L.T.
      Corneal reshaping and myopia progression.
      ]
      8 – 11Caucasian (24)0.75 to 4.00, {A > -1.00}Historical controlOK (n = 40)24.30 ± 0.730.250.32NR (56%)30%SCL: 2-week disposable from CLAMP study [
      • Walline J.J.
      • Jones L.A.
      • Mutti D.O.
      • Zadnik K.
      A randomized trial of the effects of rigid contact lenses on myopia progression.
      ]. Annual rate of axial elongation 0.16 mm greater in control group^
      (SCL) (n = 28)24.20 ± 0.690.57--
      Kakita et al. 2011 [
      • Kakita T.
      • Hiraoka T.
      • Oshika T.
      Influence of overnight orthokeratology on axial elongation in childhood myopia.
      ]
      8 – 16Japanese (24)[0.50 to 10.00]Self-selectionOK (n = 45)24.66 ± 1.110.39 ± 0.270.22^ (36%)7%
      (SVS) (n = 60)25.05 ± 1.060.61 ± 0.2417%
      Hiraoka et al. 2012 [
      • Hiraoka T.
      • Kakita T.
      • Okamoto F.
      • Takahashi H.
      • Oshika T.
      Long-term effect of overnight orthokeratology on axial length elongation in childhood myopia: a 5-year follow-up study.
      ]
      8 – 12Japanese (60)[0.50 to 5.00]Self-selectionOK (n = 29)24.09 ± 0.770.99 ± 0.470.42NR (30%)24%Significant axial elongation differences between groups in years 1 – 3 only*
      (SVS) (n = 30)24.22 ± 0.711.41 ± 0.6830%
      Santodomingo et al. 2012 [
      • Santodomingo-Rubido J.
      • Villa-Collar C.
      • Gilmartin B.
      • Gutiérrez-Ortega R.
      • Villa Collar C.
      • Gilmartin B.
      • et al.
      Myopia control with orthokeratology contact lenses in Spain: refractive and biometric changes.
      ]
      6 – 12European (24)[0.75 to 4.00], {A > -1.00}Self-selectionOK (n = 31)24.40 ± 0.810.47 ± 0.180.22NR (32%)6%Time by treatment group main effect for axial elongation*
      (SVS) (n = 30)24.22 ± 0.910.69 ± 0.3320%
      Cho & Cheung 2012 [
      • Cho P.
      • Cheung S.W.
      Retardation of myopia in orthokeratology (ROMIO) study: a 2-year randomized clinical trial.
      ]
      6 – 10Chinese (24)0.50 to 4.00, {A ≥ -1.25}RandomisedOK (n = 37)24.46 ± 0.750.36 ± 0.240.27^ (43%)27%
      (SVS) (n = 41)24.46 ± 0.790.63 ± 0.2620%
      Charm & Cho 2013 [
      • Charm J.
      • Cho P.
      High myopia-partial reduction ortho-k: a 2-year randomized study.
      ]
      8 – 11Chinese (24)[≥ 5.75], {A -1.25 to -3.50 WTR}RandomisedOK (n = 26)26.05 ± 0.800.19 ± 0.210.32# (63%)54%OK: Spherical or toric 4-zone lenses with 4.00D target. Residual refractive error corrected with spectacles
      (SVS) (n = 26)25.97 ± 0.530.51 ± 0.3238%
      Chen et al. 2013 [
      • Chen C.C.
      • Cheung S.W.
      • Cho P.
      Myopia control using toric orthokeratology (TO-SEE study).
      ]
      6 – 12Chinese (24)0.50 to 5.00, {A: -1.25 to -3.50 (Axis 180 ± 20)}Self-selectionOK (n = 43)24.37 ± 0.880.31 ± 0.270.33* (52%)19%Toric lenses
      (SVS) (n = 37)24.18 ± 1.000.64 ± 0.3138%
      Zhu et al. 2014 [
      • Zhu M.J.
      • Feng H.Y.
      • He X.G.
      • Zou H.D.
      • Zhu M.J.
      The control effect of orthokeratology on axial length elongation in Chinese children with myopia.
      ]
      7 – 14Chinese (24)[0.75 to ≥ 6.00], {A ≥ -1.50}RetrospectiveOK (n = 65)24.91 ± 0.830.34 ± 0.29 0.36^ (51%)--HM: significant difference in axial elongation between groups in year 1 only. OK: Euclid lenses with correction up to -6.00D. Residual myopia in HM group corrected with SVS.
      (SVS) (n = 63)24.85 ± 1.080.70 ± 0.35
      LM: [0.75 to 2.75]LM OK (n = 20)24.29 ± 0.730.37 ± 0.280.35^ (49%)
      LM SVS (n = 20)23.97 ± 0.870.72 ± 0.28
      MM: [3.00 to 5.75]MM OK (n = 23)24.78 ± 0.400.32 ± 0.310.47^ (59%)
      MM SVS (n = 21)24.74 ± 0.830.79 ± 0.39
      HM: [≥ 6.00]HM OK (n = 22)25.61 ± 0.730.33 ± 0.300.28# (46%)
      HM SVS (n = 22)25.77 ± 0.700.61 ± 0.36
      Swarbrick et al. 2015 [
      • Swarbrick H.A.
      • Alharbi A.
      • Watt K.
      • Lum E.
      • Kang P.
      Myopia control during orthokeratology lens wear in children using a novel study design.
      ]
      8 – 16Asian (12)1.00 to 4.00, {A > -1.50}Prospective, Randomised, 6 m crossoverOK (n = 32)24.72 ± 0.866 m: -0.02 ± 0.090.06^ (150%)19%OK (two designs); BE: 10.6 mm diameter, 2 RC and BE: 11 mm diameter, 1 RC.
      12 m: -0.05 ± 0.110.14^ (156%)25%
      Rigid (n = 26, same children)24.72 ± 0.886 m: 0.04 ± 0.08Contralateral eye study – participant given both OK lenses and rigid corneal lens treatment
      12 m: 0.09 ± 0.12
      Pauné et al. 2015 [
      • Pauné J.
      • Morales H.
      • Armengol J.
      • Quevedo L.
      • Faria-Ribeiro M.
      • González-Méijome J.M.
      Myopia control with a novel peripheral gradient soft lens and orthokeratology: a 2-year clinical trial.
      ]
      9 – 16Caucasian (24)0.75 to 7.00, {A > -1.25}Self-selectionOK (n = 29)24.77 ± 0.890.32 ± 0.200.20# (38%) 38%OK: Double RC Lens
      (SVS) (n = 41)24.36 ± 0.810.52 ± 0.2248%
      He et al. 2016 [
      • He M.
      • Du Y.
      • Liu Q.
      • Ren C.
      • Liu J.
      • Wang Q.
      • et al.
      Effects of orthokeratology on the progression of low to moderate myopia in Chinese children.
      ]
      7 – 11.5Chinese (12)[0.50 to 6.00], {A > -1.50}RetrospectiveOK (n = 141)24.71 ± 0.720.27 ± 0.170.11^ (29%)--Stratified patients into progressing speed groups, 38% of fast progressors were children < 9.4 years old
      (SVS) (n = 130)24.82 ± 0.770.38 ± 0.13
      [0.50 to 3.00], {A > -1.50}LM OK (n = 91)24.57 ± 0.720.28 ± 0.180.10* (26%)
      (LM SVS) (n = 68)24.46 ± 0.610.38 ± 0.15
      [3.25 to 6.00], {A > -1.50}MM OK (n = 50)24.97 ± 0.660.25 ± 0.160.13* (34%)
      (MM SVS) (n = 62)25.34 ± 0.680.38 ± 0.12
      Santodomingo et al. 2017 [
      • Santodomingo-Rubido J.
      • Villa-Collar C.
      • Gilmartin B.
      • Gutiérrez-Ortega R.
      • Sugimoto K.
      Long-term efficacy of orthokeratology contact lens wear in controlling the progression of childhood myopia.
      ]
      6 – 12European (84)0.75 to 4.00, {A > -1.00}ProspectiveOK (n = 14)24.39 ± 0.230.91 ± 1.80.44x (33%)54%Continuation of participants of Santodomingo, 2012 study [
      • Santodomingo-Rubido J.
      • Villa-Collar C.
      • Gilmartin B.
      • Gutiérrez-Ortega R.
      • Villa Collar C.
      • Gilmartin B.
      • et al.
      Myopia control with orthokeratology contact lenses in Spain: refractive and biometric changes.
      ]
      (SVS) (n = 16)24.08 ± 0.271.35 ± 1.746%
      A – refractive astigmatism; AL – axial length; BL – baseline; D – dioptres; LM – low myopia; MM – moderate myopia; HM – high myopia; MC – myopia control (difference in mean change in axial length between groups in mm and as percentage of change in control group); m – months; n – sample size; OK – orthokeratology; RC – reverse curve; SD – standard deviation; SCL – soft contact lenses; SER – spherical equivalent refraction; SVS – single-vision spectacles.
      Statistical comparison between the ortho-k and control groups at the final study time point (unless otherwise specified) for axial elongation over the entire study period (* p ≤ 0.05, # p ≤ 0.01, ^ p ≤ 0.001, X p > 0.05, NR not reported).
      Modern ortho-k lenses are typically approved by regulatory bodies for overnight wear for the temporary correction of refractive error of up to ∼6.00 D of myopia, and 1.75 D of astigmatism. Currently, no lenses have been approved for the correction of hyperopia or presbyopia, and only two ortho-k lens series (Bloom Night [Menicon] (up to 4.00 D myopia and ≤1.50 D with-the-rule astigmatism and ≤0.75 D against-the-rule astigmatism) and Paragon CRT [CooperVision] (up to 6.00 D myopia and 1.75 D astigmatism) have been granted marketing authorisation (CE approval) for myopia control in Europe. Therefore, the use of ortho-k for myopia control is considered “off-label” (prescribing a licensed product outside of the approved scope of treatment) for the vast majority of ortho-k lens designs in most countries. Eye care practitioners are encouraged to prescribe on-label products if available and appropriate and consider off-label alternatives if on-label approaches are not effective [
      • Jones L.
      • Drobe B.
      • Manuel González-Méijome J.
      • Gray L.
      • Kratzer T.
      • Newman S.
      • et al.
      IMI – industry guidelines and ethical considerations for myopia control report.
      ]. When prescribing or recommending off-label treatments such as ortho-k for myopia control, informed consent should be obtained [
      • Jones L.
      • Drobe B.
      • Manuel González-Méijome J.
      • Gray L.
      • Kratzer T.
      • Newman S.
      • et al.
      IMI – industry guidelines and ethical considerations for myopia control report.
      ,
      • Gifford K.L.
      • Richdale K.
      • Kang P.
      • Aller T.A.
      • Lam C.S.
      • Liu Y.M.
      • et al.
      IMI – clinical management guidelines report.
      ].

      3. Orthokeratology fitting and assessment

      3.1 Suitable candidates

      The characteristics of good potential candidates for ortho-k include [
      • Caroline P.J.
      Contemporary orthokeratology.
      ]; myopia up to approximately 4.50 D, corneal or refractive astigmatism up to ∼3.00 D, and a pupil diameter less than ∼6.00 mm in dim illumination to minimise symptoms associated with post-treatment elevated higher order aberrations (HOAs). Soft lens wearers who suffer from lens related discomfort or dryness [
      • Duong K.
      • Mcgwin G.
      • Franklin Q.X.
      • Cox J.
      • Pucker A.D.
      Treating uncomfortable contact lens wear with orthokeratology.
      ] may also benefit from ortho-k, and the typical requirements and contraindications for commencing contact lens wear apply (e.g. a healthy ocular surface, eyelids, tear film) (see CLEAR Evidence-based Practice Report) [
      • Wolffsohn J.S.
      • Dumbleton K.
      • Huntiens B.
      • Kandel H.
      • Koh S.
      • Kunnen C.
      • et al.
      CLEAR – evidence based contact lens practice.
      ]. Refractive correction of hyperopia and presbyopia is possible with ortho-k, but the outcomes are less predictable and highly variable compared to the correction of myopia (see Section 4.1.1.1).

      3.2 Spherical lens designs

      Ortho-k lens designs consist of four or five zones including [
      • Caroline P.J.
      Contemporary orthokeratology.
      ]; a central back optic zone radius, a reverse curve adjacent to and steeper than the back optic zone radius, one or two alignment curves that have the greatest influence on lens centration and movement, and a final peripheral curve that provides axial edge lift (Fig. 1) (for toric lens designs see Section 3.4).
      Fig. 1
      Fig. 1Spherical orthokeratology lens in situ. (A) optic zone, (B) reverse curve, (C) alignment curve/s, (D) peripheral curve. (Courtesy PolyU, HK and Jason Lau).
      For the correction of myopia, the back optic zone radius is fitted flatter than the flattest corneal meridian by the desired amount of refractive correction (and an additional refractive buffer of ∼0.75 D [the Jessen or compression factor] to account for daily regression in corneal flattening). Ortho-k lenses are fitted with apical clearance ∼≤10 μm for myopic corrections and do not bear on the central cornea. Fig. 2 demonstrates the post-lens tear layer thickness profile for ortho-k lens designs with different target refractive corrections. Conversely, for the correction of hyperopia and presbyopia, the central back optic zone radius is fitted steeper than the flat K.
      Fig. 2
      Fig. 2Top: Post-lens tear layer thickness profile for a four zone orthokeratology lens design for myopia. (A) optic zone, (B) reverse curve, (C) alignment curve, (D) peripheral curve. Bottom: Variation in post-lens tear layer thickness profile for orthokeratology lens designs targeting different refractive errors. Note: the width of the reverse and alignment curves vary between these lens designs for myopic and hyperopic corrections.

      3.3 Assessing the lens fit and treatment

      The development of computer systems has allowed topographers to analyse thousands of points on the corneal surface, reconstruct the corneal shape, and chart them as color-coded maps to aid ECP interpretation [
      • Mountford J.
      • Ruston D.
      • Dave T.
      Orthokeratology: principles and practice.
      ,
      • Maeda N.
      Evaluation of optical quality of corneas using corneal topographers.
      ]. Advances in corneal topography have contributed to the resurgence of modern ortho-k. Eyecare practitioners are not only able to visualise the initial corneal shape, but also assess patient suitability for ortho-k, and design lenses. Topographers can accurately quantify changes in corneal shape, which allows the ECP to monitor lens centration, assess and troubleshoot the lens fit, as well as manage patient treatment [
      • Mountford J.
      An analysis of the changes in corneal shape and refractive error induced by accelerated orthokeratology.
      ,
      • Chui W.S.
      • Cho P.
      A comparative study of the performance of different corneal topographers on children with respect to orthokeratology practice.
      ,
      • Faria-Ribeiro M.
      • Belsue R.N.
      • López-Gil N.
      • González-Méijome J.M.
      Morphology, topography, and optics of the orthokeratology cornea.
      ].
      An ortho-k lens can be fitted using a suite of diagnostic lenses and assessing the lens in situ. For an optimum fitting lens, the optic zone is centred on the pupil with sodium fluorescein pooling within the reverse curve, and approximately 1 mm of movement upon blinking [
      • Caroline P.J.
      Contemporary orthokeratology.
      ]. However, reliable assessment of the cornea-to-lens fitting relationship of reverse geometry lenses is difficult, even for experienced ECPs [
      • Mountford J.
      • Cho P.
      • Chui W.S.
      Is fluorescein pattern analysis a valid method of assessing the accuracy of reverse geometry lenses for orthokeratology?.
      ], since sodium fluorescein does not fluoresce for tear layers less than approximately 20 μm thick [
      • Carney L.G.
      Luminance of fluorescein solutions.
      ], and for myopic ortho-k lens designs the central post-lens tear layer is less than this. The fit of the lens in an open eye condition may also not necessarily inform how the lens fits when worn in closed eye conditions. Consequently, in modern ortho-k practice, corneal topography (corneal height, curvature, and eccentricity data) guides initial lens selection and informs lens modifications. Therefore, obtaining reliable pre-treatment corneal topography maps that are not affected by misalignment, poor tear film quality, or eyelid artefacts are essential.
      The initially selected or ordered lens is worn for an overnight trial, and the patient is reviewed the following morning, within two hours of waking, as signs of corneal oedema will likely resolve after two hours of eyelid opening. Following lens removal, ocular health is assessed (with particular attention to signs of corneal hypoxic stress and central corneal staining due to lens bearing), along with visual acuity, refractive error, and corneal topography. If this lens is considered satisfactory, it is dispensed to the patient. Corneal topography difference maps (post-lens wear minus pre-lens wear) are used to assess the location of the treatment zone (the central region of desired corneal flattening for the correction of myopia) and the magnitude of change in corneal power. Common corneal topography difference maps are displayed in Fig. 3.
      Fig. 3
      Fig. 3Common tangential power difference maps (post-orthokeratology lens wear minus pre-lens wear). (A) early bullseye, (B) central island, (C) frowny face, (D) smiley face with false central island. (Courtesy PolyU, HK).
      For the correction of myopia, the desired outcome is a ‘bulls-eye’ pattern over the pupil, which indicates the lens was well centred overnight and resulted in central corneal flattening and mid-peripheral corneal steepening [
      • Caroline P.J.
      Contemporary orthokeratology.
      ]. A laterally decentred bulls-eye pattern (nasal or temporal lens decentration) may be due to an overall lens diameter that is too small, an alignment curve that is too flat, or corneal astigmatism (which may require a toric or quadrant specific back surface lens design) (see Section 3.4). A ‘smiley face’ pattern arises due to a high-riding lens, when the sagittal height of the lens is less than that of the cornea (alignment curve too flat or total diameter too small), and the sagittal height of the lens needs to be increased to ensure there is central apical clearance during overnight wear. Conversely, a ‘frowny face’ pattern is caused by a lens that decentres inferiorly due to the alignment curve being too steep, or the overall diameter too small, requiring a decrease in the sagittal height of the lens. Any lens, and therefore treatment zone, decentration can induce astigmatism and coma which adversely affect visual performance [
      • Joslin C.E.
      • Wu S.M.
      • McMahon T.T.
      • Shahidi M.
      Higher-order wavefront aberrations in corneal refractive therapy.
      ].
      A ‘central island’ pattern (the opposite of a bulls-eye pattern) indicates a region of central corneal steepening surrounded by an annulus of corneal flattening (this is the intended outcome in hyperopic/presbyopic ortho-k). In ortho-k for myopia, this arises due to reverse and alignment curves that are too steep or a total diameter that is too large, and requires refitting with a lens with less apical clearance, readily diagnosed using corneal topography [
      • Maldonado-Codina C.
      • Efron S.
      • Morgan P.
      • Hough T.
      • Efron N.
      Empirical versus trial set fitting systems for accelerated orthokeratology.
      ]. An incomplete bulls-eye pattern (i.e. an incomplete central circular region of flattening) can be confused for a central island at the initial aftercare visit. However, the apical power of the post-lens wear topography map will not be steeper than the pre-treatment map, and the bulls-eye pattern will become complete following continued lens wear without modification. Based on the corneal topography difference maps at aftercare visits, overnight lens wear can either continue or the lens may need to be modified to improve the lens fit with reassessment after another overnight trial. A recommended review schedule is outlined in Section 6 and Table 2.
      Table 2Elements of good clinical practice in orthokeratology.
      Details
      Practice standardOffice equipment
      • Corneal topographer
      • Slit lamp with 40x magnification
      • Non-contact optical biometer for axial length measurement (for myopia control therapy) [
        • Gifford K.L.
        • Richdale K.
        • Kang P.
        • Aller T.A.
        • Lam C.S.
        • Liu Y.M.
        • et al.
        IMI – clinical management guidelines report.
        ,
        • Wolffsohn J.S.
        • Kollbaum P.S.
        • Berntsen D.A.
        • Atchison D.A.
        • Benavente A.
        • Bradley A.
        • et al.
        IMI – clinical myopia control trials and instrumentation report.
        ]
      Eyecare practitioner and staff [
      • Cho P.
      • Cheung S.W.
      • Mountford J.
      • White P.
      Good clinical practice in orthokeratology.
      ]
      • Eye care practitioners should have undergone proper ortho-k training and have a thorough understanding of ortho-k
      • Support staff should be well trained on handling emergency calls, lens handling procedures and be able to provide accurate ortho-k information
      • All staff should behave professionally when communicating with patients/adult caregivers and ensure they fully understand the information listed on the information and consent sheet
      Before commencing ortho-kInformation sheet
      • Explain ortho-k benefits, potential risks, limitations, on- and off-label treatments with respect to myopia control
      • Fee schedule and refund policy
      • Importance of compliance of lens use and aftercare
      • Role and responsibilities of adult caregivers to help monitor lens use and care
      • Aftercare schedule
      Consent [
      • Jones L.
      • Drobe B.
      • Manuel González-Méijome J.
      • Gray L.
      • Kratzer T.
      • Newman S.
      • et al.
      IMI – industry guidelines and ethical considerations for myopia control report.
      ]
      • Adult caregivers must provide written informed consent
      • Children must provide assent to wear the lenses
      • Both adult caregivers and children should be briefed before signing the consent/assent forms
      • They should be given the opportunity to discuss details, time to think about other options, and ask questions
      Education materials
      • Oral and written instructions of proper lens application and removal (including the use of lubricant)
      • Oral and written instructions of lens and accessories care and maintenance
      Emergency contact and instruction
      • Contact number for after office hours in case of emergency
      • Contact person and number of the designated practitioner when the eyecare practitioner is on leave
      • Oral and written instructions on how to loosen a bound lens upon waking in the morning
      Preliminary evaluation
      • High quality pre-fit corneal topography maps must be obtained
      • Careful evaluation of ocular health (including lid eversion and evaluation of the corneal endothelium) by slit lamp biomicroscopy
      After commencing ortho-kDelivery
      • Ensure both patient and adult caregiver can handle and disinfect the lenses properly
      • Revisit hand hygiene procedure before dispensing
      Aftercare schedule [
      • Cho P.
      • Cheung S.W.
      • Mountford J.
      • White P.
      Good clinical practice in orthokeratology.
      ]
      • 1st aftercare (after delivery of every lens): early the next morning after an overnight wear, within 2 h after waking, to assess binding, and ocular health, including corneal oedema
      • Subsequent aftercare (7 days, 14 days (optional), 1 month, 3 months, and 3 or 6 monthly after commencement of lens wear thereafter): any time of the day
      • Early morning aftercare every 6 months recommended (to assess ocular health, including corneal oedema)
      • Unscheduled aftercare: in case of unexpected symptoms
      Aftercare procedures [
      • Gifford K.L.
      • Richdale K.
      • Kang P.
      • Aller T.A.
      • Lam C.S.
      • Liu Y.M.
      • et al.
      IMI – clinical management guidelines report.
      ,
      • Cho P.
      • Cheung S.W.
      • Mountford J.
      • White P.
      Good clinical practice in orthokeratology.
      ]
      • Careful review of lens wear and care procedures (identify non-compliant behaviours); remind and re-educate where necessary
      • Regular aftercare procedures include measurements of:
        • Unaided visual acuity
        • Refraction/Over-refraction
        • Ocular health
        • Corneal topography
        • Lens condition
        • Axial length (to monitor effectiveness of myopia control therapy) (if available)
      • Particular attention to lens binding, corneal oedema, and corneal epithelial integrity at the 1st aftercare
      Accessories

      3.4 Toric orthokeratology lens designs

      Ortho-k lenses with a spherical back optic zone radius applied to a toric cornea (typically with greater than 1.50 D corneal toricity) can result in lens decentration, often infero-temporally) [
      • Maseedupally V.K.
      • Gifford P.
      • Lum E.
      • Naidu R.
      • Sidawi D.
      • Wang B.
      • et al.
      Treatment zone decentration during orthokeratology on eyes with corneal toricity.
      ,
      • Li Z.
      • Cui D.
      • Long W.
      • Hu Y.
      • He L.
      • Yang X.
      Predictive role of paracentral corneal toricity using elevation data for treatment zone decentration during orthokeratology.
      ,
      • Chen Z.
      • Xue F.
      • Zhou J.
      • Qu X.
      • Zhou X.
      Prediction of orthokeratology lens decentration with corneal elevation.
      ]. This can lead to a decentred treatment zone and poor visual outcomes due to induced astigmatism, increased comatic HOAs, and glare [
      • Maseedupally V.K.
      • Gifford P.
      • Lum E.
      • Naidu R.
      • Sidawi D.
      • Wang B.
      • et al.
      Treatment zone decentration during orthokeratology on eyes with corneal toricity.
      ,
      • Hiraoka T.
      • Mihashi T.
      • Okamoto C.
      • Okamoto F.
      • Hirohara Y.
      • Oshika T.
      Influence of induced decentered orthokeratology lens on ocular higher-order wavefront aberrations and contrast sensitivity function.
      ]. Therefore, patients with corneal astigmatism of approximately 1.75 D or greater were considered unsuitable for ortho-k [
      • Caroline P.J.
      Contemporary orthokeratology.
      ] until the development of back surface toric reverse geometry lenses in the mid to late 2000’s. Currently, the majority of toric ortho-k lenses available cater for with-the-rule astigmatism up to ∼1.75 D (with FDA approval up to 1.50 D for some lenses), and only a few lenses that correct for greater magnitudes of astigmatism (e.g. DRL [Precilens] 4.00 D at any axis, and Z-Night [Menicon] 2.50 D with-the-rule).
      Toric back surface ortho-k lens designs may have a spherical [
      • Chan B.
      • Cho P.
      • De Vecht A.
      Toric orthokeratology.
      ] or toric optic zone [
      • Pauné J.
      • Cardona G.
      • Quevedo L.
      Toric double tear reservoir contact lens in orthokeratology for astigmatism.
      ], along with different sagittal heights and tangent angles along orthogonal meridians of the reverse, alignment, or peripheral lens curves to improve lens stabilisation and treatment zone centration. Back surface toric designs produce an elliptical shaped treatment zone which decreases in size with increasing corneal toricity [
      • Tomiyama E.S.
      • Logan A.-K.
      • Richdale K.
      Corneal elevation, power, and astigmatism to assess toric orthokeratology lenses in moderate-to-high astigmats.
      ]. Eyes with greater corneal toricity typically display greater differences in corneal height (along the principal corneal meridians) [
      • Tomiyama E.S.
      • Logan A.-K.
      • Richdale K.
      Corneal elevation, power, and astigmatism to assess toric orthokeratology lenses in moderate-to-high astigmats.
      ,
      • Batres L.
      • Piñero D.
      • Carracedo G.
      Correlation between anterior corneal elevation differences in main meridians and corneal astigmatism.
      ]. For an 8 mm chord diameter, the relationship between the anterior corneal height profile and corneal toricity are linear and highly correlated (approximately 1.00 D of corneal astigmatism per 25 μm difference in corneal height) (Fig. 4). Thresholds for corneal toricity or corneal height difference to consider a toric lens design vary between manufacturers and lens designs. However, corneal toricity greater than ∼1.50 D or a corneal height difference along the principal meridians of ∼30 μm over an 8 mm chord may benefit from a back surface toric design with respect to centration [
      • Li Z.
      • Cui D.
      • Long W.
      • Hu Y.
      • He L.
      • Yang X.
      Predictive role of paracentral corneal toricity using elevation data for treatment zone decentration during orthokeratology.
      ].
      Fig. 4
      Fig. 4Relationship between anterior corneal height difference (along principal meridians) and anterior corneal toricity for an 8 mm chord. Lines of best fit extracted from data of 305 healthy participants using Pentacam (red) and Sirius instruments (green) [
      • Batres L.
      • Piñero D.
      • Carracedo G.
      Correlation between anterior corneal elevation differences in main meridians and corneal astigmatism.
      ], and 25 healthy participants using the Pentacam instrument (blue) [
      • Tomiyama E.S.
      • Logan A.-K.
      • Richdale K.
      Corneal elevation, power, and astigmatism to assess toric orthokeratology lenses in moderate-to-high astigmats.
      ]. The black line displays the fitting approach described by Li et al. [
      • Li Z.
      • Cui D.
      • Long W.
      • Hu Y.
      • He L.
      • Yang X.
      Predictive role of paracentral corneal toricity using elevation data for treatment zone decentration during orthokeratology.
      ] between the anterior corneal height difference along principal meridians and back surface toricity incorporated into the lens design (also for an 8 mm chord).
      The first prospective study of toric ortho-k [
      • Chen C.C.
      • Cheung S.W.
      • Cho P.
      Myopia control using toric orthokeratology (TO-SEE study).
      ,
      • Chen C.C.
      • Cheung S.W.
      • Cho P.
      Toric orthokeratology for highly astigmatic children.
      ] included 43 children aged six to 12 years with myopia up to 5.00 D and with-the-rule refractive astigmatism between 1.25 and 3.50 D. A fenestrated peripheral toric back surface (toric alignment curve with spherical back optic zone radius) ortho-k lens design was used and after one month of lens wear, on average refractive astigmatism had reduced by 79% (1.91 ± 0.64 to 0.40 ± 0.39 D) and corneal toricity had reduced by 44% (2.30 ± 0.51 to 1.28 ± 0.53 D). Myopia also reduced by 81% after one month (2.53 ± 1.31 to 0.41 ± 0.43 D), and since many myopic children are also astigmatic, the myopia control efficacy of this toric ortho-k lens design has also been investigated (see Section 8.3.2).

      4. Ocular changes associated with orthokeratology

      4.1 Corneal changes

      During ortho-k, the cornea undergoes changes at the cellular level that are clinically observed as changes in thickness and topography. Unless otherwise specified, the changes reported in this section are associated with ortho-k for myopia.

      4.1.1 Changes in corneal topography

      Corneal topographical changes observed in modern ortho-k are believed to be due to hydraulic forces in the post-lens tear film that cause tangential stresses across the corneal epithelial surface, resulting in changes to anterior corneal shape and thickness [
      • Mountford J.
      A model of forces acting in orthokeratology.
      ].

      4.1.1.1 Orthokeratology for hyperopia or presbyopia

      Compared to ortho-k for the correction of myopia, research regarding ortho-k for hyperopia is limited. Ortho-k for hyperopia or presbyopia induces central corneal steepening surrounded by an annulus of mid-peripheral corneal flattening [
      • Gifford P.
      • Swarbrick H.A.
      Time course of corneal topographic changes in the first week of overnight hyperopic orthokeratology.
      ,
      • Lu F.
      • Sorbara L.
      • Simpson T.
      • Fonn D.
      Corneal shape and optical performance after one night of corneal refractive therapy for hyperopia.
      ,
      • Gifford P.
      • Au V.
      • Hon B.
      • Siu A.
      • Xu P.
      • Swarbrick H.A.
      Mechanism for corneal reshaping in hyperopic orthokeratology.
      ], with the greatest change in corneal topography observed after the first night of lens wear and plateauing over time [
      • Gifford P.
      • Swarbrick H.A.
      Time course of corneal topographic changes in the first week of overnight hyperopic orthokeratology.
      ] (Fig. 5). The goal of steepening the central cornea is to increase central corneal refractive power to correct hyperopia or presbyopia (typically using a monovision approach). The time course of refractive change for mild hyperopia (+1.50 D) is similar to myopic ortho-k, with the largest refractive change taking place after the first night of lens wear and reaching the full target correction by the seventh day [
      • Gifford P.
      • Swarbrick H.A.
      Time course of corneal topographic changes in the first week of overnight hyperopic orthokeratology.
      ,
      • Gifford P.
      • Alharbi A.
      • Swarbrick H.A.
      Corneal thickness changes in hyperopic orthokeratology measured by optical pachometry.
      ]. However, the region of central steepening is typically smaller than the region of central flattening for an equivalent myopic correction and duration of lens wear [
      • Gifford P.
      • Swarbrick H.A.
      The effect of treatment zone diameter in hyperopic orthokeratology.
      ]. Variable results have been reported for higher refractive errors (e.g. for a +3.50 D target correction, after seven nights of lens wear participants were on average 1.50 D to 2.00 D under-corrected) [
      • Gifford P.
      • Swarbrick H.A.
      Time course of corneal topographic changes in the first week of overnight hyperopic orthokeratology.
      ]. Further, refractive regression of the hyperopic correction has been observed throughout the day, with greater retention after seven days of lens wear [
      • Gifford P.
      • Swarbrick H.A.
      Time course of corneal topographic changes in the first week of overnight hyperopic orthokeratology.
      ] (Fig. 5).
      Fig. 5
      Fig. 5The mean change in best vision sphere (BVS) on day one and seven of overnight orthokeratology lens wear for; (A) the treatment of presbyopia in emmetropes (dashed line denotes target spherical equivalent refraction change of 2 D) [
      • Gifford P.
      • Swarbrick H.A.
      Refractive changes from hyperopic orthokeratology monovision in presbyopes.
      ] and (B) the treatment of hyperopia (dashed lines denote target spherical equivalent refraction changes of 1.5 and 3.5 D) [
      • Gifford P.
      • Swarbrick H.A.
      Time course of corneal topographic changes in the first week of overnight hyperopic orthokeratology.
      ]. Error bars represent the standard deviation. (AM – measurements are within 1 h of waking; PM – measurements are 8 h after lens removal).
      It is hypothesised that the changes in corneal topography induced by hyperopic ortho-k are a result of para-central corneal compressive forces and a central suction force within the post-lens tear film. However, since lens fenestrations do not appear to affect the corneal response in hyperopic ortho-k, the observed corneal changes may be due to a moulding effect, where the cornea conforms to the posterior lens surface, rather than hydraulic forces [
      • Gifford P.
      • Au V.
      • Hon B.
      • Siu A.
      • Xu P.
      • Swarbrick H.A.
      Mechanism for corneal reshaping in hyperopic orthokeratology.
      ]. Changes in corneal curvature are limited to the anterior cornea in hyperopic ortho-k without any noticeable effect on the posterior cornea [
      • Gifford P.
      • Alharbi A.
      • Swarbrick H.A.
      Corneal thickness changes in hyperopic orthokeratology measured by optical pachometry.
      ]. Further investigation is required to understand the exact mechanism by which hyperopic ortho-k induces corneal changes.
      The correction of presbyopia using ortho-k is possible through a monovision or multifocal correction. In monovision, the dominant eye is corrected for distance viewing and the non-dominant eye is corrected for near viewing. After fitting a hyperopic ortho-k lens with a target correction of +2.00 D in one eye of 13 emmetropic presbyopes, monovision provided functional near vision that did not compromise distance vision (although only a modest 1.00 D refractive change after one week of lens wear was achieved) [
      • Gifford P.
      • Swarbrick H.A.
      Refractive changes from hyperopic orthokeratology monovision in presbyopes.
      ] (Fig. 5).
      Ortho-k lenses can also provide both distance and near refractive correction by reducing the treatment zone size and creating a multifocal effect. In hyperopic ortho-k, the area of central corneal steepening is surrounded by an annulus of corneal flattening creating a centre-near optical effect that increases negative spherical aberration and the depth of field [
      • Calossi A.
      Corneal asphericity and spherical aberration.
      ]. For myopic ortho-k, the opposite occurs where central corneal flattening and mid-peripheral corneal steepening creates a centre-distance optical effect [
      • Charman W.N.
      Developments in the correction of presbyopia I: spectacle and contact lenses.
      ]. Further research to better understand and evaluate the clinical performance of ortho-k for the correction of presbyopia is required.

      4.1.1.2 Orthokeratology for myopia

      In contrast, ortho-k for the correction of myopia induces central corneal flattening surrounded by an annulus of mid-peripheral corneal steepening. This mid-peripheral steepening creates significant changes in relative peripheral refraction in the horizontal, vertical, and oblique meridians [
      • Kang P.
      • Swarbrick H.A.
      New perspective on myopia control with orthokeratology.
      ,
      • Queirós A.
      • Amorim-de-Sousa A.
      • Lopes-Ferreira D.
      • Villa-Collar C.
      • Gutiérrez ÁR.
      • González-Méijome J.M.
      Relative peripheral refraction across 4 meridians after orthokeratology and LASIK surgery.
      ]. While the exact mechanism by which ortho-k lenses work to slow myopia progression is not understood, it has been hypothesised that the myopic relative peripheral refraction shift contributes to this effect [
      • Maeda N.
      Evaluation of optical quality of corneas using corneal topographers.
      ,
      • Mountford J.
      An analysis of the changes in corneal shape and refractive error induced by accelerated orthokeratology.
      ,
      • Chui W.S.
      • Cho P.
      A comparative study of the performance of different corneal topographers on children with respect to orthokeratology practice.
      ] (see Section 9).
      The reduction in central corneal refractive power within the treatment zone accounts for most of the reduction in myopic refractive error [
      • Mountford J.
      An analysis of the changes in corneal shape and refractive error induced by accelerated orthokeratology.
      ,
      • Mountford J.
      • Noack D.
      A mathematical model for corneal shape changes associated with ortho-k.
      ], with one study reporting that the change in apical corneal power was on average 0.34 ± 0.57 D less than the change in refractive error [
      • Chan B.
      • Cho P.
      • Mountford J.
      Relationship between corneal topographical changes and subjective myopic reduction in overnight orthokeratology: a retrospective study.
      ]. The greatest change in corneal topography occurs after the first night of ortho-k lens wear and typically stabilises by seven to 14 days [
      • Kang P.
      • Swarbrick H.A.
      Time course of the effects of orthokeratology on peripheral refraction and corneal topography.
      ,
      • Kang S.Y.
      • Kim B.K.
      • Byun Y.J.
      Sustainability of orthokeratology as demonstrated by corneal topography.
      ,
      • Sridharan R.
      • Swarbrick H.A.
      Corneal response to short-term orthokeratology lens wear.
      ], dependent upon the target refractive correction (i.e. time to stabilisation increases with increasing ametropia [
      • Owens H.
      • Garner L.F.
      • Craig J.P.
      • Gamble G.
      Posterior corneal changes with orthokeratology.
      ,
      • Fan L.
      • Jun J.
      • Jia Q.
      • Wangqing J.
      • Xinjie M.
      • Yi S.
      Clinical study of orthokeratology in young myopic adolescents.
      ]) (Fig. 6). These changes are temporary and regress by about 0.25 – 0.75 D throughout the day [
      • Mountford J.
      Retention and regression of orthokeratology with time.
      ,
      • Nichols J.J.
      • Marsich M.M.
      • Nguyen M.
      • Barr J.T.
      • Bullimore M.A.
      Overnight orthokeratology.
      ,
      • 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.
      ] (Fig. 6). The treatment zone diameter decreases slightly throughout the day due to the regression in anterior corneal surface changes [
      • Guo H.C.
      • Jin W.Q.
      • Pan A.P.
      • Wang Q.M.
      • Qu J.
      • Yu A.Y.
      Changes and diurnal variation of visual quality after orthokeratology in myopic children.
      ]. Smaller magnitude corneal changes have also been reported in older (19 - 57 years) compared to younger (six to 12 years) participants, suggesting a more rapid corneal response in younger eyes [
      • Jayakumar J.
      • Swarbrick H.A.
      The effect of age on short-term orthokeratology.
      ].
      Fig. 6
      Fig. 6(A) The mean change in apical corneal power immediately after ortho-k lens removal (AM) and 8.5 h later (PM) during the first 90 days of lens wear, for an early three zone ortho-k lens design (Contex) [
      • Mountford J.
      Retention and regression of orthokeratology with time.
      ]. (B) Change in spherical equivalent refraction (SER) for lower (mean initial SER -1.5 ± 0.3 D) and higher levels of myopia (mean initial SER -3.2 ± 0.5 D) during the first month of ortho-k lens wear, along with the change in vertical treatment zone diameter (lower and higher myopia groups combined) [
      • Owens H.
      • Garner L.F.
      • Craig J.P.
      • Gamble G.
      Posterior corneal changes with orthokeratology.
      ]. Dashed lines indicate the mean target refractive change, and the error bars denote the standard deviation.
      Sectorial differences in both central and mid-peripheral corneal topography changes following ortho-k have been reported [
      • Kang P.
      • Swarbrick H.A.
      Time course of the effects of orthokeratology on peripheral refraction and corneal topography.
      ,
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ]. Greater flattening has been observed in the temporal compared to the nasal sector within the central treatment zone, along with greater steepening in the temporal mid-periphery compared to the nasal mid-periphery [
      • Maseedupally V.
      • Gifford P.
      • Lum E.
      • Swarbrick H.A.
      Central and paracentral corneal curvature changes during orthokeratology.
      ]. The treatment zone diameter and shape (circle or oval) is dependent on multiple variables, such as the back optic zone diameter, baseline corneal curvature and toricity, and target refractive error [
      • Swarbrick H.A.
      Orthokeratology review and update.
      ,
      • Gifford P.
      • Tran M.
      • Priestley C.
      • Maseedupally V.
      • Kang P.
      Reducing treatment zone diameter in orthokeratology and its effect on peripheral ocular refraction.
      ].
      Based on Munnerlyn’s formula [
      • Munnerlyn C.R.
      • Koons S.J.
      • Marshall J.
      Photorefractive keratectomy: a technique for laser refractive surgery.
      ], adapted from corneal ablation calculations in refractive surgery to epithelial thinning in ortho-k for the correction of myopia, the treatment zone diameter (TZD) is inversely related to the target refractive change (Fig. 7). Munnerlyn’s formula (below), using an assumed corneal refractive index of 1.337, provides good predictions of refractive outcomes for myopia up to 4.00 D after three months of lens wear [
      • Alharbi A.
      • Swarbrick H.A.
      The effects of overnight orthokeratology lens wear on corneal thickness.
      ]:
      TZDmm=2.7xcentralepithelialthinning(μm)Targetrefractivechange(D)


      Fig. 7
      Fig. 7Relationship between target refractive change, central epithelial thinning, and treatment zone diameter in orthokeratology for myopia, based on Munnerlyn’s formula, assuming a total corneal refractive index of 1.377 [
      • Swarbrick H.A.
      • Wong G.
      • O’Leary D.J.
      Corneal response to orthokeratology.
      ] (solid lines) and epithelial refractive index of 1.400 [
      • Patel S.
      • Tutchenko L.
      The refractive index of the human cornea: a review.
      ] (dashed lines).
      Reducing the back optic zone diameter of an ortho-k lens can reduce the treatment zone area, resulting in an annulus of greater mid-peripheral corneal refractive power and inducing a positive shift in spherical aberration [
      • Gifford P.
      • Tran M.
      • Priestley C.
      • Maseedupally V.
      • Kang P.
      Reducing treatment zone diameter in orthokeratology and its effect on peripheral ocular refraction.
      ,
      • Carracedo G.
      • Espinosa-Vidal T.M.
      • Martínez-Alberquilla I.
      • Batres L.
      The topographical effect of optical zone diameter in orthokeratology contact lenses in high myopes.
      ]. Further studies are needed to determine if treatment zone size influences the myopia control efficacy of ortho-k (see Section 9.4.2).
      In general, the time taken for ortho-k induced ocular changes in corneal topography and SER to regress to pre-treatment levels following the cessation of lens wear increases with increasing treatment duration and baseline level of myopia. However, large individual variations have been observed [
      • Lee T.T.
      • Cho P.
      Discontinuation of orthokeratology and myopic progression.
      ,
      • Kang P.
      • Swarbrick H.
      Discontinuation of long term orthokeratology lens wear and subsequent refractive surgery outcome.
      ]. In children who wore ortho-k lenses to correct up to 4.00 D of myopia for either one [
      • Lau J.K.
      • Wan K.
      • Cheung S.W.
      • Vincent S.J.
      • Cho P.
      Weekly changes in axial length and choroidal thickness in children during and following orthokeratology treatment with different compression factors.
      ] or 24 months [
      • Santodomingo-Rubido J.
      • Villa-Collar C.
      • Gilmartin B.
      • Gutiérrez-Ortega R.
      Short-term changes in ocular biometry and refraction after discontinuation of long-term orthokeratology.
      ], on average, corneal flattening and the change in SER had regressed by ∼80 to 100% compared to pre-treatment values one week after ceasing lens wear. It should be noted that variations from the pre-treatment SER may be related to myopia progression in studies of six months or more in duration. Following longer-term lens wear in children (mean four years), residual corneal flattening was still apparent along the flatter corneal meridian (mean 0.07 mm) two weeks after ceasing lens wear, which was greater for children with more myopia prior to treatment [
      • Wu R.
      • Stapleton F.
      • Swarbrick H.A.
      Residual corneal flattening after discontinuation of long-term orthokeratology lens wear in Asian children.
      ]. In adults, following 12 months of ortho-k lens wear, on average, changes in SER and contrast sensitivity were not statistically different from pre-treatment values after one [
      • Hiraoka T.
      • Okamoto C.
      • Ishii Y.
      • Okamoto F.
      • Oshika T.
      Recovery of corneal irregular astigmatism, ocular higher-order aberrations, and contrast sensitivity after discontinuation of overnight orthokeratology.
      ] or four weeks [
      • Kobayashi Y.
      • Yanai R.
      • Chikamoto N.
      • Chikama T.
      • Ueda K.
      • Nishida T.
      Reversibility of effects of orthokeratology on visual acuity, refractive error, corneal topography, and contrast sensitivity.
      ] of ceasing lens wear. However, changes in some HOAs (e.g. primary spherical aberration) may remain elevated one month after ceasing lens wear for larger pupil diameters (5 mm or greater) [
      • Lorente-Velázquez A.
      • Madrid-Costa D.
      • Nieto-Bona A.
      • González-Mesa A.
      • Carballo J.
      Recovery evaluation of induced changes in higher order aberrations from the anterior surface of the cornea for different pupil sizes after cessation of corneal refractive therapy.
      ]. Based on recovery data obtained within the first 72 h after ceasing lens wear, the regression to baseline SER appears to take longer for higher levels of baseline myopia [
      • Barr J.T.
      • Rah M.J.
      • Meyers W.
      • Legerton J.
      Recovery of refractive error after corneal refractive therapy.
      ].

      4.1.2 Corneal thickness

      Total corneal thickness changes following overnight ortho-k for myopia and hyperopia are displayed in Fig. 8.
      Fig. 8
      Fig. 8Average total thickness changes across the central cornea (0 mm denotes corneal apex) on the morning of day 4 of orthokeratology treatment for myopia (red) [
      • Alharbi A.
      • Swarbrick H.A.
      The effects of overnight orthokeratology lens wear on corneal thickness.
      ] and hyperopia (green) [
      • Gifford P.
      • Alharbi A.
      • Swarbrick H.A.
      Corneal thickness changes in hyperopic orthokeratology measured by optical pachometry.
      ]. The error bars are one standard deviation.

      4.1.2.1 Orthokeratology for hyperopia or presbyopia

      In early studies of hyperopic ortho-k, the corneal epithelium was reported to thicken, more so centrally than in the mid-periphery, in both animals [
      • Choo J.D.
      • Caroline P.J.
      • Harlin D.D.
      • Papas E.B.
      • Holden B.A.
      Morphologic changes in cat epithelium following continuous wear of orthokeratology lenses: a pilot study.
      ] and humans [
      • Haque S.
      • Fonn D.
      • Simpson T.
      • Jones L.
      Epithelial thickness changes from the induction of myopia with CRTH RGP contact lenses.
      ]. More recent work using optical pachymetry revealed central stomal thickening following overnight hyperopic ortho-k, which resolved over the course of the day, and mid-peripheral epithelial thinning that persisted throughout the day, which likely contributes to the refractive correction [
      • Gifford P.
      • Alharbi A.
      • Swarbrick H.A.
      Corneal thickness changes in hyperopic orthokeratology measured by optical pachometry.
      ].

      4.1.2.2 Orthokeratology for myopia

      The epithelial and total corneal thickness across the horizontal corneal meridian have been measured using a modified optical pachymeter before and after ortho-k for the correction of myopia [
      • Alharbi A.
      • Swarbrick H.A.
      The effects of overnight orthokeratology lens wear on corneal thickness.
      ]. Central corneal thickness decreased due to epithelial thinning, while the mid-peripheral cornea became thicker due to epithelial and stromal changes. Later, these results were confirmed with optical coherence tomography [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ,
      • Haque S.
      • Fonn D.
      • Simpson T.
      • Jones L.
      Corneal and epithelial thickness changes after 4 weeks of overnight corneal refractive therapy lens wear, measured with optical coherence tomography.
      ,
      • Wang J.
      • Fonn D.
      • Simpson T.L.
      • Sorbara L.
      • Kort R.
      • Jones L.
      Topographical thickness of the epithelium and total cornea after overnight wear of reverse-geometry rigid contact lenses for myopia reduction.
      ,
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      • Nieto Bona A.
      • et al.
      Short-term effects of overnight orthokeratology on corneal cell morphology and corneal thickness.
      ,
      • Kim W.K.
      • Kim B.J.
      • Ryu I.H.
      • Kim B.J.
      • Kim S.W.
      Corneal epithelial and stromal thickness changes in myopic orthokeratology and their relationship with refractive change.
      ] and confocal microscopy [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ,
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      • Nieto Bona A.
      • et al.
      Short-term effects of overnight orthokeratology on corneal cell morphology and corneal thickness.
      ]. Stromal oedema may be partly responsible for the mid-peripheral corneal thickening related to the oxygen transmissibility of the contact lens material [
      • Haque S.
      • Fonn D.
      • Simpson T.
      • Jones L.
      Corneal refractive therapy with different lens materials. Part 1: corneal, stromal, and epithelial thickness changes.
      ]. These thickness changes underpin the topographic changes detailed in Section 4.1.1. Using Munnerlyn’s formula [
      • Munnerlyn C.R.
      • Koons S.J.
      • Marshall J.
      Photorefractive keratectomy: a technique for laser refractive surgery.
      ], studies have demonstrated that changes in corneal epithelial thickness can account for refractive changes induced by ortho-k [
      • Alharbi A.
      • Swarbrick H.A.
      The effects of overnight orthokeratology lens wear on corneal thickness.
      ,
      • Kim W.K.
      • Kim B.J.
      • Ryu I.H.
      • Kim B.J.
      • Kim S.W.
      Corneal epithelial and stromal thickness changes in myopic orthokeratology and their relationship with refractive change.
      ]. These analyses provide evidence that redistribution of the anterior corneal tissue, rather than an overall bending of the cornea, is responsible for the refractive effects of ortho-k. Epithelial thinning of 15 to 17 μm has been observed for a target treatment of 2.50 to 2.75 D of myopia [
      • Alharbi A.
      • Swarbrick H.A.
      The effects of overnight orthokeratology lens wear on corneal thickness.
      ,
      • Haque S.
      • Fonn D.
      • Simpson T.
      • Jones L.
      Corneal and epithelial thickness changes after 4 weeks of overnight corneal refractive therapy lens wear, measured with optical coherence tomography.
      ]. Small meridional variations in mid-peripheral epithelial tissue changes have also been reported for toric corneas fitted with spherical ortho-k lens designs [
      • Zhou J.
      • Xue F.
      • Zhou X.
      • Naidu R.K.
      • Qian Y.
      Thickness profiles of the corneal epithelium along the steep and flat meridians of astigmatic corneas after orthokeratology.
      ].

      4.1.3 Corneal cellular changes

      To better understand the cellular mechanism underlying corneal thickness changes with ortho-k, studies have investigated changes in corneal morphology. Using confocal microscopy, an increase in endothelial cell polymegethism has been reported after one year of ortho-k lens wear in 15 young adults, which reduced after one month of cessation of ortho-k, but did not return to the baseline level [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ]. Additionally, endothelial cell density does not change significantly in children or young adults after one to two years of ortho-k [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ,
      • Hiraoka T.
      • Furuya A.
      • Matsumoto Y.
      • Okamoto F.
      • Kakita T.
      • Oshika T.
      Influence of overnight orthokeratology on corneal endothelium.
      ,
      • Cheung S.W.
      • Cho P.
      Does a two-year period of orthokeratology lead to changes in the endothelial morphology of children?.
      ]. Similarly, the middle and posterior stromal keratocyte densities do not change significantly after one year of ortho-k. However, a decrease in anterior stromal keratocyte density has been reported, along with an increase in activated keratocytes (those with highly reflective nuclei) [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ]. Studies have also reported a decrease in epithelial basal cell density after longer-term lens wear (up to five years) [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      Long-term changes in corneal morphology induced by overnight orthokeratology.
      ,
      • Zhong X.
      • Chen X.
      • Xie R.Z.
      • Yang J.
      • Li S.
      • Yang X.
      • et al.
      Differences between overnight and long-term wear of orthokeratology contact lenses in corneal contour, thickness, and cell density.
      ]. This is likely due to compression of epithelial cellular layers during ortho-k, which may render them less visible during imaging [
      • Nieto-Bona A.
      • González-Mesa A.
      • Nieto-Bona M.P.
      • Villa-Collar C.
      • Lorente-Velázquez A.
      • Nieto Bona A.
      • et al.
      Short-term effects of overnight orthokeratology on corneal cell morphology and corneal thickness.
      ].

      4.1.4 Pigmented arcs

      Pigmented corneal arcs or rings are increasingly reported in ortho-k lens wearers [
      • Cho P.
      • Chui W.S.
      • Cheung S.W.
      Reversibility of corneal pigmented arc associated with orthokeratology.
      ,
      • Liang J.B.
      • Chou P.I.
      • Wu R.
      • Lee Y.M.
      Corneal iron ring associated with orthokeratology.
      ,
      • Hiraoka T.
      • Furuya A.
      • Matsumoto Y.
      • Okamoto F.
      • Kakita T.
      • Oshika T.
      Corneal iron ring formation associated with overnight orthokeratology.
      ,
      • Cho P.
      • Cheung S.W.
      • Mountford J.
      • Chui W.S.
      Incidence of corneal pigmented arc and factors associated with its appearance in orthokeratology.
      ,
      • González-Méijome J.M.
      • González-Pérez J.
      • Garcia-Porta N.
      • Diaz-Rey A.
      • Parafita-Mato M.A.
      Pigmented corneal ring associated with orthokeratology in Caucasians: case reports.
      ,
      • Huang P.W.
      • Yeung L.
      • Sun C.C.
      • Chen H.M.
      • Peng S.Y.
      • Chen Y.T.
      • et al.
      Correlation of corneal pigmented arc with wide epithelial thickness map in orthokeratology-treated children using optical coherence tomography measurements.
      ,
      • Liu C.F.
      • Lee J.S.
      • Sun C.C.
      • Lin K.K.
      • Hou C.H.
      • Yeung L.
      • et al.
      Correlation between pigmented arc and epithelial thickness (COPE) study in orthokeratology-treated patients using OCT measurements.
      ,
      • Mountford J.
      Design variables and fitting philosophies of reverse geometry lenses.
      ,
      • Rah M.J.
      • Barr J.T.
      • Bailey M.D.
      Corneal pigmentation in overnight orthokeratology: a case series.
      ,
      • Barr J.T.
      • Rah M.J.
      • Jackson J.M.
      • Jones L.A.
      Orthokeratology and corneal refractive therapy: a review and recent findings.
      ]. Although the composition of the pigmentation has not been confirmed, due to similarities in clinical appearance with other corneal iron depositions, it is presumed that the pigmented arc or ring is comprised of iron [
      • Hiraoka T.
      • Furuya A.
      • Matsumoto Y.
      • Okamoto F.
      • Kakita T.
      • Oshika T.
      Corneal iron ring formation associated with overnight orthokeratology.
      ,
      • Huang P.W.
      • Yeung L.
      • Sun C.C.
      • Chen H.M.
      • Peng S.Y.
      • Chen Y.T.
      • et al.
      Correlation of corneal pigmented arc with wide epithelial thickness map in orthokeratology-treated children using optical coherence tomography measurements.
      ,
      • Liu C.F.
      • Lee J.S.
      • Sun C.C.
      • Lin K.K.
      • Hou C.H.
      • Yeung L.
      • et al.
      Correlation between pigmented arc and epithelial thickness (COPE) study in orthokeratology-treated patients using OCT measurements.
      ,
      • Cho P.
      • Chui W.S.
      • Mountford J.
      • Cheung S.W.
      Corneal iron ring associated with orthokeratology lens wear.
      ]. The pigmented arc typically originates in the inferior cornea, presumably in the epithelial layer, and has been observed as early as two weeks after commencing ortho-k [
      • Cho P.
      • Chui W.S.
      • Mountford J.
      • Cheung S.W.
      Corneal iron ring associated with orthokeratology lens wear.
      ]. Over time, the pigmented arc can expand into a complete ring (e.g. after one month of lens wear [
      • Cho P.
      • Chui W.S.
      • Mountford J.
      • Cheung S.W.
      Corneal iron ring associated with orthokeratology lens wear.
      ]). It surrounds the treatment zone corresponding to the location of the reverse curve of the ortho-k lens (Fig. 9), and this clinically benign observation has been shown to be reversible after ceasing lens wear for approximately two months [
      • Cho P.
      • Chui W.S.
      • Cheung S.W.
      Reversibility of corneal pigmented arc associated with orthokeratology.
      ], but likely varies with the duration of lens wear and target refraction. The incidence and intensity of corneal pigmented arcs or rings increase with longer duration of lens wear [
      • Cho P.
      • Cheung S.W.
      • Mountford J.
      • Chui W.S.
      Incidence of corneal pigmented arc and factors associated with its appearance in orthokeratology.
      ] and incidence rates of over 90% have been reported in retrospective case series of Taiwanese children wearing ortho-k lenses for an average period of almost two years [
      • Huang P.W.
      • Yeung L.
      • Sun C.C.
      • Chen H.M.
      • Peng S.Y.
      • Chen Y.T.
      • et al.
      Correlation of corneal pigmented arc with wide epithelial thickness map in orthokeratology-treated children using optical coherence tomography measurements.
      ,
      • Liu C.F.
      • Lee J.S.
      • Sun C.C.
      • Lin K.K.
      • Hou C.H.
      • Yeung L.
      • et al.
      Correlation between pigmented arc and epithelial thickness (COPE) study in orthokeratology-treated patients using OCT measurements.
      ].
      Fig. 9
      Fig. 9Slit lamp image of a pigmented ring in an orthokeratology lens wearer corresponding to the location of the reverse curve after one year of lens wear. The right image provided without colour to enhance visualisation of the ring. (Courtesy PolyU, HK).

      4.1.5 Fibrillary lines

      In the normal cornea, fibrillary lines appear as vertically or slightly curved greyish-white fibrils located within the corneal epithelium and sub-epithelial layer [
      • Bron A.J.
      Superficial fibrillary lines. A feature of the normal cornea.
      ], in comparison to stromal nerve fibres and Vogt striae in keratoconus, which are typically located in the posterior cornea [
      • Hollingsworth J.G.
      • Efron N.
      Observations of banding patterns (Vogt striae) in keratoconus: a confocal microscopy study.
      ]. Retro-illumination can be used to differentiate fibrillary lines from superficial corneal dystrophies, since corneal dystrophies are readily visualised using this technique, while fibrillary lines are not [
      • Brown N.A.
      • Bron A.J.
      Superficial lines and associated disorders of the cornea.
      ].
      Marked fibrillary lines in ortho-k lens wearers are believed to represent the sub-basal and epithelial nerve plexus [
      • Bron A.J.
      Superficial fibrillary lines. A feature of the normal cornea.
      ] and have only been reported in detail in two ortho-k lens wearers [
      • Cheung S.W.
      • Cho P.
      • Bron A.J.
      • Chui W.S.
      • Chan B.
      Case report: the occurrence of fibrillary lines in overnight orthokeratology.
      ,
      • Lum E.
      • Swarbrick H.A.
      Fibrillary lines in overnight orthokeratology.
      ] (Fig. 10). It is now believed that they represent an altered sub-basal nerve plexus, probably due to epithelial neural reorganisation, an altered epithelial migratory pattern or corneal biomechanical stress induced by ortho-k lenses [
      • Cheung S.W.
      • Cho P.
      • Bron A.J.
      • Chui W.S.
      • Chan B.
      Case report: the occurrence of fibrillary lines in overnight orthokeratology.
      ,
      • Lum E.
      • Swarbrick H.A.
      Fibrillary lines in overnight orthokeratology.
      ].
      Fig. 10
      Fig. 10Fibrillary lines associated with orthokeratology lens wear under low (left) and high (right) magnification. (Courtesy PolyU, HK).
      Such changes have also been reported using corneal confocal microscopy, with a redistribution of the sub-basal nerve plexus away from the treatment zone centre (Fig. 11), and a reduction in nerve density [
      • Lum E.
      • Golebiowski B.
      • Swarbrick H.A.
      Mapping the corneal sub-basal nerve plexus in orthokeratology lens wear using in vivo laser scanning confocal microscopy.
      ,
      • Nombela-Palomo M.
      • Felipe-Marquez G.
      • Hernandez-Verdejo J.L.
      • Nieto-Bona A.
      Short-term effects of overnight orthokeratology on corneal sub-basal nerve plexus morphology and corneal sensitivity.
      ]. These changes were also associated with a decrease in corneal sensitivity in the area of reduced nerve density [
      • Nombela-Palomo M.
      • Felipe-Marquez G.
      • Hernandez-Verdejo J.L.
      • Nieto-Bona A.
      Short-term effects of overnight orthokeratology on corneal sub-basal nerve plexus morphology and corneal sensitivity.
      ,
      • Lum E.
      • Golebiowski B.
      • Swarbrick H.A.
      Reduced corneal sensitivity and sub-basal nerve density in long-term orthokeratology lens wear.
      ]. The causal nature of this relationship cannot be confirmed from these studies, but these changes appear to have no significant visual or ocular health consequence and are reversible upon cessation of lens wear [
      • Cheung S.W.
      • Cho P.
      • Bron A.J.
      • Chui W.S.
      • Chan B.
      Case report: the occurrence of fibrillary lines in overnight orthokeratology.
      ,
      • Lum E.
      • Swarbrick H.A.
      Fibrillary lines in overnight orthokeratology.
      ].
      Fig. 11
      Fig. 11The sub-basal corneal nerve plexus (black lines) superimposed upon a tangential power corneal topography map of a short-term (one year) (A) and long-term (B) (9 years) orthokeratology lens wearer from Lum et al. [
      • Lum E.
      • Golebiowski B.
      • Swarbrick H.A.
      Mapping the corneal sub-basal nerve plexus in orthokeratology lens wear using in vivo laser scanning confocal microscopy.
      ]. Reproduced with permission from the Association for Research and Vision in Ophthalmology.
      In summary, corneal changes induced by ortho-k are often reversible after ceasing lens wear, which is compatible with the recovery of the topographic and refractive effects induced by the treatment. While corneal thickness recovery occurs within days or weeks of lens discontinuation, the reversal of other effects, such as the redistribution of the sub-basal plexus, nerve may take longer, likely dependent upon the duration of treatment and target refraction.

      4.2 Corneal biomechanics

      In altering the corneal shape, ortho-k may also affect corneal biomechanics, which in turn, could affect the ability of the cornea to be reshaped by an ortho-k lens. Corneal biomechanics characterise the tissue’s response to external forces. Some devices measure corneal biomechanics through corneal applanation with controlled pressure, while other devices use corneal indentation. The clinical meaning of these metrics remains relatively unknown. Corneal biomechanics may be used to predict the corneal response to the forces imposed by ortho-k lens wear and may change during the course of the treatment. Thus measuring such changes may help to better understand the corneal reshaping process.
      The Ocular Response Analyzer (Reichert Inc., USA) and CorVis ST (Oculus Optikgeräte GmbH, Wetzlar, Germany) are two instruments currently available to characterise corneal biomechanical properties. The former is more commonly used and measures corneal biomechanics through applanation pressure to reflect viscoelastic properties and resistance of the cornea known as corneal hysteresis and corneal resistance factor, respectively. Earlier studies reported a mild reduction in corneal hysteresis and corneal resistance factor by approximately 1 mmHg or less on average, after ortho-k [
      • Chen R.
      • Mao X.
      • Jiang J.
      • Shen M.
      • Lian Y.
      • Zhang B.
      • et al.
      The relationship between corneal biomechanics and anterior segment parameters in the early stage of orthokeratology: a pilot study.
      ,
      • Chen D.
      • Lam A.K.C.
      • Cho P.
      A pilot study on the corneal biomechanical changes in short-term orthokeratology.
      ,
      • Yeh T.N.
      • Green H.M.
      • Zhou Y.
      • Pitts J.
      • Kitamata Wong B.
      • Lee S.
      • et al.
      Short-term effects of overnight orthokeratology on corneal epithelial permeability and biomechanical properties.
      ]. Using corneal indentation, the measured corneal tangent modulus in short-term ortho-k lens wear is not significantly different to daily rigid corneal lens wear in the contralateral eye [
      • Lam A.K.C.
      • Leung S.Y.Y.
      • Hon Y.
      • Shu-Ho L.
      • Wong K.Y.
      • Tiu P.K.
      • et al.
      Influence of short-term orthokeratology to corneal tangent modulus: a randomized study.
      ]. Although there was a reduction in corneal hysteresis and corneal resistance factor, this observation may be associated with the variability of the Ocular Response Analyzer, rather than actual changes in the intrinsic properties of the cornea.
      A short-term pilot study showed that the onset of changes in corneal topography might be related to corneal hysteresis [
      • González-Méijome J.M.
      • Villa-Collar C.
      • Queirós A.
      • Jorge J.
      • Parafita M.A.
      Pilot study on the influence of corneal biomechanical properties over the short term in response to corneal refractive therapy for myopia.
      ], with a slower onset and recovery in topographical and thickness changes observed for corneas with higher baseline corneal hysteresis values. A lower corneal hysteresis and a higher tangent modulus has also been associated with greater corneal flattening along the flattest meridian in ortho-k-treated eyes [
      • Lam A.K.C.
      • Leung S.Y.Y.
      • Hon Y.
      • Shu-Ho L.
      • Wong K.Y.
      • Tiu P.K.
      • et al.
      Influence of short-term orthokeratology to corneal tangent modulus: a randomized study.
      ]. In a 6-month study, individuals who dropped out of the study due to significant residual refractive error (mean residual sphere -1.90 D) or were “non-responsive” to the treatment had flatter baseline corneal curvatures and a significantly lower tangent modulus compared to those who completed the study [
      • Lam A.K.C.
      • Hon Y.
      • Leung S.Y.Y.
      • Shu-Ho L.
      • Chong J.
      • Lam D.C.C.
      Association between long-term orthokeratology responses and corneal biomechanics.
      ]. Among the successfully treated ortho-k participants, those with higher values of corneal stiffness had a greater reduction in myopia [
      • Lam A.K.C.
      • Hon Y.
      • Leung S.Y.Y.
      • Shu-Ho L.
      • Chong J.
      • Lam D.C.C.
      Association between long-term orthokeratology responses and corneal biomechanics.
      ]. While the geometric properties of the cornea change following ortho-k, the magnitude of change does not correlate with metrics of corneal biomechanics. A recent study [
      • Wan K.
      • Cheung S.W.
      • Wolffsohn J.S.
      • Orr J.B.
      • Cho P.
      Role of corneal biomechanical properties in predicting of speed of myopic progression in children wearing orthokeratology lenses or single-vision spectacles.
      ] reported a significant difference in corneal hysteresis in spectacle-wearing children showing slow and fast axial elongation and hence, it may be beneficial to recommend ortho-k as early as possible for myopic children with low corneal hysteresis.
      At present, it is not clear, with the methodologies available, if corneal biomechanical properties are able to predict the corneal response to ortho-k treatment, if long term ortho-k wear leads to modification of natural corneal biomechanics, or if there are diurnal changes in these properties.

      4.3 Intraocular pressure

      Most tonometers apply a force to the corneal tissue to derive the internal pressure of the eye, either with direct contact or using non-contact methods. This measurement is influenced by the properties of the tissue, particularly corneal thickness. Eyes with thinner corneas tend to underestimate the actual intraocular pressure while those with thicker corneas tend to overestimate the actual intraocular pressure [
      • Feltgen N.
      • Leifert D.
      • Funk J.
      Correlation between central corneal thickness, applanation tonometry, and direct intracameral iop readings.
      ]. Besides thickness, the rigidity of corneal tissue may also affect applanation tonometry, such that stiffer corneas result in a relative overestimation of intraocular pressure, while more flexible corneas result in an underestimation [
      • Drance S.M.
      The coefficient of scleral rigidity in normal and glaucomatous eyes.
      ].
      Studies that have attempted to investigate the influence of ortho-k on intraocular pressure measurements have shown small and clinically insignificant variations (under 1 mmHg, on average) using different methods of tonometry [
      • Chang C.J.
      • Yang H.H.
      • Chang C.A.
      • Wu R.
      • Tsai H.Y.
      The influence of orthokeratology on intraocular pressure measurements.
      ], that remain stable throughout treatment [
      • Ishida Y.
      • Yanai R.
      • Sagara T.
      • Nishida T.
      • Toshida H.
      • Murakami A.
      Decrease in intraocular pressure following orthokeratology measured with a noncontact tonometer.
      ]. Data from these reports also suggest that ortho-k does not affect the reliability of the tonometric measurements. Since there is no evidence of any physiological changes associated with aqueous humour production or outflow during ortho-k treatment which might explain the changes in intraocular pressure reported, it is likely that such variations in intraocular pressure are artefacts related to measurements obtained from the reshaped cornea, rather than actual changes in the true intraocular pressure.

      5. Safety of orthokeratology

      The safety of ortho-k has been a topic of interest due to its popular use as a myopia control intervention for children, involving overnight wear and hence, potential increased risk of serious corneal infection. In the early 2000′s, several independent case reports of microbial keratitis (MK) in ortho-k lens wearers were published [
      • Lau L.I.
      • Wu C.C.
      • Lee S.M.
      • Hsu W.M.
      Pseudomonas corneal ulcer related to overnight orthokeratology.
      ,
      • Hsiao C.H.
      • Lin H.C.
      • Chen Y.F.
      • Ma D.H.K.
      • Yeh L.K.
      • Tan H.Y.
      • et al.
      Infectious keratitis related to overnight orthokeratology.
      ,
      • Tseng C.H.
      • Fong C.F.
      • Chen W.L.
      • Hou Y.C.
      • Wang I.J.
      • Hu F.R.
      Overnight orthokeratology-associated microbial keratitis.
      ,
      • Wilhelmus K.R.
      Acanthamoeba keratitis during orthokeratology.
      ] (see Section 5.1.4). Inappropriate lens care and non-compliance, along with continuing lens wear despite significant discomfort, were identified as risk factors for MK, with another report [
      • Cope J.R.
      • Collier S.A.
      • Schein O.D.
      • Brown A.C.
      • Verani J.R.
      • Gallen R.
      • et al.
      Acanthamoeba keratitis among rigid gas permeable contact lens wearers in the United States, 2005 through 2011.
      ] specifying that topping up care solutions and use of tap water were examples of non-compliant behaviours increasing risk. These reports demonstrate that ortho-k can lead to sight-threatening MK, however, the less common use of ortho-k, compared to other contact lens modalities (for vision correction), renders it hard to identify cases even in larger meta-analyses and studies [
      • Li S.M.
      • Kang M.T.
      • Wu S.S.
      • Liu L.R.
      • Li H.
      • Chen Z.
      • et al.
      Efficacy, safety and acceptability of orthokeratology on slowing axial elongation in myopic children by meta-analysis.
      ,
      • Van Meter W.S.
      • Musch D.C.
      • Jacobs D.S.
      • Kaufman S.C.
      • Reinhart W.J.
      • Udell I.J.
      Safety of overnight orthokeratology for myopia: a report by the American Academy of Ophthalmology.
      ,
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.G.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ]. The estimated incidence of MK related to ortho-k is 13.9 per 10 000 patient years in children (95% confidence interval [CI] 1.7 - 50.4) and 0 per 10 000 patient years in adults (95% CI 0 - 31.7), based on at least three months of lens wear [
      • Bullimore M.A.
      • Sinnott L.T.
      • Jones-Jordan L.A.
      The risk of microbial keratitis with overnight corneal reshaping lenses.
      ] (see Section 5.1.4).
      Importantly, the vast majority of complications that arise during ortho-k lens wear are not serious adverse events. Over a 10-year follow-up period, 11.1% of Japanese children aged eight to 16 years wearing ortho-k lenses experienced an adverse event (95% CI 8.2 - 14.6%), the most common being conjunctivitis and superficial corneal staining [
      • Hiraoka T.
      • Sekine Y.
      • Okamoto F.
      • Mihashi T.
      • Oshika T.
      Safety and efficacy following 10-years of overnight orthokeratology for myopia control.
      ]. The incidence of adverse events was comparable to a soft lens control group. Another study of European children aged six to 12 years wearing ortho-k lenses for one year [
      • Santodomingo-Rubido J.
      • Villa-Collar C.
      • Gilmartin B.
      • Gutiérrez-Ortega R.
      Orthokeratology vs. spectacles: adverse events and discontinuations.
      ] estimated the incidence of all adverse events as 13.3% of eyes (95% CI 8.4 - 20.6%) per annum, the majority being non-significant adverse events (i.e. an adverse event of no immediate clinical concern not warranting discontinuation from lens wear) (9.2% of eyes [95% CI 5.2 - 15.7%] per annum).

      5.1 Complications

      5.1.1 Corneal staining

      Superficial trace corneal staining is the most common complication observed in ortho-k lens wearers [
      • Liu Y.M.
      • Xie P.
      The safety of orthokeratology - a systematic review.
      ,
      • Chan B.
      • Cho P.
      • Cheung S.W.
      Orthokeratology practice in children in a university clinic in Hong Kong.
      ]. It is typically observed in the central cornea and peaks during the first few weeks or months of lens wear [
      • Santodomingo-Rubido J.
      • Villa-Collar C.
      • Gilmartin B.
      • Gutiérrez-Ortega R.
      Orthokeratology vs. spectacles: adverse events and discontinuations.
      ,
      • Cho P.
      • Chan B.
      • Cheung S.W.
      • Mountford J.
      Do fenestrations affect the performance of orthokeratology lenses?.
      ]. A positive correlation has been reported between corneal staining and higher baseline myopia prior to ortho-k treatment [
      • Liu Y.M.
      • Xie P.
      The safety of orthokeratology - a systematic review.
      ] which may be related to the greater corneal flattening required for the correction of higher degrees of myopia. Close observation is required during overnight lens wear due to the risk of potential complications associated with corneal staining. Persistent central corneal staining is associated with lens binding [
      • Liu Y.M.
      • Xie P.
      The safety of orthokeratology - a systematic review.
      ] and may require the cessation of overnight wear until the staining resolves.

      5.1.2 Lens binding and imprinting

      Lens binding is a relatively common phenomenon (incidence of ∼30 to 60% [
      • Dave T.
      Overnight and extended wear of RGP lenses.
      ]) observed on eye opening after overnight ortho-k lens wear, and is associated with a corneal indentation ring and central corneal staining [
      • Rah M.J.
      • Barr J.T.
      • Bailey M.D.
      Corneal pigmentation in overnight orthokeratology: a case series.
      ,
      • Barr J.T.
      • Rah M.J.
      • Jackson J.M.
      • Jones L.A.
      Orthokeratology and corneal refractive therapy: a review and recent findings.
      ,
      • Liu Y.M.
      • Xie P.
      The safety of orthokeratology - a systematic review.
      ]. Corneal epithelial trauma induced by the adherent lens edge causes localised corneal distortion and the indentation ring typically displays fluorescein pooling rather than staining [
      • Swarbrick H.A.
      • Holden B.A.
      Rigid gas permeable lens binding significance and contributing factors.
      ]. The negative ‘suction’ pressure under the centre of the lens and positive pressure at the edge of the lens was originally hypothesised to cause conventional (not reverse geometry) lens binding, however steeper fitting lenses result in less frequent binding than flat fitting lenses [
      • Swarbrick H.A.
      • Holden B.A.
      Effects of lens parameter variation on rigid gas-permeable lens adherence.
      ]. Pressure exerted by the eyelids during overnight lens wear and a consequent thinning and increased viscosity of the post-lens tear film due to the expulsion of the aqueous tear layer may play a role [
      • Swarbrick H.A.
      • Holden B.A.
      Rigid gas permeable lens binding significance and contributing factors.
      ,
      • Chui W.S.
      • Cho P.
      Recurrent lens binding and central island formations in a fast-responding orthokeratology lens wearer.
      ]. It has been claimed that modifying the ortho-k lens fit to increase post-lens tear exchange may reduce the recurrence of ortho-k lens binding and subsequent corneal indentation ring [
      • Liu Y.M.
      • Xie P.
      The safety of orthokeratology - a systematic review.
      ]. However, others suggest that modifications to the fit may not resolve lens binding in some ortho-k lens wearers [
      • Ruston D.
      • Dave T.
      • Mountford J.
      Lens delivery, aftercare routine and problem-solving.
      ]. Early work [
      • Swarbrick H.A.
      • Holden B.A.
      Effects of lens parameter variation on rigid gas-permeable lens adherence.
      ] examining lens adherence following overnight rigid corneal lens wear indicated that flat fitting lenses with apical bearing are more likely to result in lens binding upon waking, that persists for a longer duration than steep fitting lenses. Therefore, slightly increasing the central post-lens tear layer thickness may potentially be of benefit, but could also alter the refractive outcome. Lens fenestrations reduce the incidence of lens binding in children wearing ortho-k lenses by ∼20%, but does result in dimple veiling during the first week of lens wear [
      • Cho P.
      • Chan B.
      • Cheung S.W.
      • Mountford J.
      Do fenestrations affect the performance of orthokeratology lenses?.
      ]. Importantly, patients must be aware of the potential for lens binding and taught how to use lubricating drops upon waking and apply gentle pressure using the eyelid adjacent to the inferior and superior limbus to mobilise a bound lens prior to attempting lens removal.

      5.1.3 Microcysts

      Corneal microcysts are a clinical sign of hypoxia [
      • Jones L.W.
      • Jones D.A.
      Non-inflammatory corneal complications of contact lens wear.
      ]. Due to the use of high Dk rigid lens materials, microcysts have been observed only occasionally in ortho-k lens wearers and have not warranted clinical management due to the small numbers detected [
      • 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.
      ,
      • Barr J.T.
      • Rah M.J.
      • Jackson J.M.
      • Jones L.A.
      Orthokeratology and corneal refractive therapy: a review and recent findings.
      ]. Anecdotal reports indicate that microcysts are more commonly seen in children who require higher myopia correction and in those who wear ortho-k lenses for longer periods overnight [

      Guo B, Cho P, Efron N, A case of microcystic corneal oedema associated with over-wear of decentered orthokeratology lenses during COVID 19 lockdown. Clin Exp Optom; in press.

      ], which may be due to reduced oxygen availability to the cornea.

      5.1.4 Microbial keratitis

      MK is the most significant and potentially vision-threatening complication associated with ortho-k lens wear. No studies to date have investigated and quantified the risk factors associated with the development of MK with ortho-k, however, most initial cases of MK reported were from Asia and involved female lens wearers [
      • Kam K.W.
      • Yung W.
      • Li G.K.H.
      • Chen L.J.
      • Young A.L.
      Infectious keratitis and orthokeratology lens use: a systematic review.
      ,
      • Watt K.G.
      • Swarbrick H.A.
      Trends in microbial keratitis associated with orthokeratology.
      ]. A review of the first 16 peer-reviewed articles between 2001 and 2005, which included the first 50 reports of MK in ortho-k, was performed to characterise microbes causing MK, and identify risk factors [
      • Watt K.
      • Swarbrick H.A.
      Microbial keratitis in overnight orthokeratology: review of the first 50 cases.
      ]. Most cases were from East Asia (80%) and in patients between nine to 15 years of age (61%), likely reflecting the demographic of ortho-k lens wearers and their use for myopia control. MK was associated with Pseudomonas aeruginosa as the primary infective organism in 52% of cases, with Acanthamoeba the second most common, at 30% of cases. The most common complication of MK was the development of corneal scars, which significantly affected the visual outcome after the resolution of the infection [
      • Kam K.W.
      • Yung W.
      • Li G.K.H.
      • Chen L.J.
      • Young A.L.
      Infectious keratitis and orthokeratology lens use: a systematic review.
      ]. A follow-up review [
      • Watt K.G.
      • Swarbrick H.A.
      Trends in microbial keratitis associated with orthokeratology.
      ] of published reports of MK in ortho-k spanning 2001 to 2007, including the first 50 cases outlined above and an additional 73 cases, reiterated that the majority of patients affected were East Asian females aged between eight and 15 years. The infectious organism was Pseudomonas aeruginosa in 38% of cases and Acanthamoeba in 33% of cases.
      A more recent systematic review [
      • Kam K.W.
      • Yung W.
      • Li G.K.H.
      • Chen L.J.
      • Young A.L.
      Infectious keratitis and orthokeratology lens use: a systematic review.
      ] involving 173 eyes of 166 patients (cases published in the literature between 2002 and 2014) also confirmed that most of the patients with MK were young females (mean age at diagnosis: 15 years) using ortho-k for myopia control. Positive cultures were obtained in 70% of patients (from either the cornea, contact lens, or case) and Pseudomonas aeruginosa (36%) and Acanthamoeba (32%) were the most frequently identified microorganisms. The high prevalence of cases of Acanthamoeba keratitis associated with ortho-k in these reviews emphasises the importance of eliminating the use of tap water in care regimens for overnight ortho-k [
      • Robertson D.M.
      • McCulley J.P.
      • Cavanagh H.D.
      Severe Acanthamoeba keratitis after overnight orthokeratology.
      ,
      • Li W.
      • Wang Z.
      • Qu J.
      • Zhang Y.
      • Sun X.
      Acanthamoeba keratitis related to contact lens use in a tertiary hospital in China.
      ].
      In a retrospective post-marketing surveillance study [
      • Bullimore M.A.
      • Sinnott L.T.
      • Jones-Jordan L.A.
      The risk of microbial keratitis with overnight corneal reshaping lenses.
      ], the incidence of MK associated with overnight ortho-k was estimated in children and adults using de-identified data from 1317 patients, including 640 adults (49% and 1164 patient-years of lens wear) and 677 children (51%, 1435 patient-years of lens wear), provided by randomly selected ECPs, stratified by lens order volume and lens company. Eight incidents of corneal infiltrates associated with a painful red eye were identified (six in children and two in adults). Two were classified as MK (based on an expert panel consensus) and occurred in children, but neither resulted in a loss of visual acuity. The overall estimated incidence of MK was 7.7 per 10 000 patient years in all patients (95% CI 0.9 - 27.8), 13.9 per 10 000 patient years in children (95% CI 1.7 - 50.4), and 0 per 10 000 patient years in adults (95% CI 0 - 31.7), based on at least 3 months of lens wear. The estimated incidence of MK in overnight ortho-k wear is greater than estimates for daily wear of soft lenses (annualised incidence per 10 000 wearers of 1.2 [95% CI 1.1 - 1.5] for soft lenses worn on a daily wear basis, and 2.0 [95% CI 1.7 - 2.4] for daily disposable lenses) [
      • Stapleton F.
      • Keay L.
      • Edwards K.
      • Naduvilath T.
      • Dart J.K.G.
      • Brian G.
      • et al.
      The incidence of contact lens-related microbial keratitis in Australia.
      ]. For some patients, a viable myopia correction or myopia control strategy may be available in these soft lens modalities, which should be a consideration when discussing the potential management options. Further prospective studies are still required to estimate the true incidence of MK associated with overnight ortho-k lens wear and identify potential risk factors.

      5.2 Non-compliance

      Non-compliance related to hygiene procedures and care procedures remains a serious concern and is a major causative factor of serious ocular complications for all contact lens modalities [
      • Wu Y.T.Y.
      • Willcox M.
      • Zhu H.
      • Stapleton F.
      Contact lens hygiene compliance and lens case contamination: a review.
      ,
      • Fonn D.
      • Jones L.
      Hand hygiene is linked to microbial keratitis and corneal inflammatory events.
      ,
      • Carnt N.
      • Samarawickrama C.
      • White A.
      • Stapleton F.
      The diagnosis and management of contact lens-related microbial keratitis.
      ,
      • Stellwagen A.
      • MacGregor C.
      • Kung R.
      • Konstantopoulos A.
      • Hossain P.
      Personal hygiene risk factors for contact lens-related microbial keratitis.
      ]. Over time, contact lens patients may become lax in lens care and handling techniques [
      • Claydon B.E.
      • Efron N.
      Non-compliance in contact lens wear.
      ], and in adhering to the recommended aftercare schedule [
      • Jun J.
      • Zhiwen B.
      • Feifu W.
      • Lili L.
      • Fan L.
      Level of compliance in orthokeratology.
      ]. In China, poor lens care and inadequate hand washing were the two most common non-compliant behaviours in ortho-k lens wearers [
      • Jun J.
      • Zhiwen B.
      • Feifu W.
      • Lili L.
      • Fan L.
      Level of compliance in orthokeratology.
      ]. The lens case has also been identified as the most contaminated item in new ortho-k lens wearers [
      • Boost M.V.
      • Cho P.
      Microbial flora of tears of orthokeratology patients, and microbial contamination of contact lenses and contact lens accessories.
      ]. A later study investigating microbial contamination of lenses and accessories in a group of existing ortho-k lens wearers reported the highest contamination rate for the suction holder, followed by the lens case and lenses. The authors recommended using fingers for ortho-k lens removal and avoiding the use of a suction holder to minimise the risk of potential infection [
      • Cho P.
      • Boost M.V.
      • Cheng R.
      Non-compliance and microbial contamination in orthokeratology.
      ]. Both studies identified high contamination rates in lens accessories, due to failure to clean and/or disinfect and replace regularly, which were frequently overlooked by patients/adult caregivers and ECPs. The presence of Gram-negative rods in contact lenses and accessories also indicated poor drying of hands after washing in ortho-k lens wearers [
      • Cheung S.W.
      • Boost M.V.
      • Sen Shi G.
      • Cho P.
      Microbial contamination of periorbital tissues and accessories of children.
      ]. These studies emphasise two critical areas that require attention from ECPs and patients: proper hand hygiene and lens and accessories care. A list of reported common non-compliant behaviours in ortho-k lens wearers is presented in Table 3.
      Table 3List of common non-compliant behaviours in orthokeratology wearers.
      Common non-compliant behaviours in ortho-k
      • Storing of lens accessories in the bathroom [
        • Boost M.V.
        • Cho P.
        Microbial flora of tears of orthokeratology patients, and microbial contamination of contact lenses and contact lens accessories.
        ,
        • Cho P.
        • Boost M.V.
        • Cheng R.
        Non-compliance and microbial contamination in orthokeratology.
        ]
      • Failure to disinfect the lens accessories weekly [
        • Cho P.
        • Boost M.V.
        • Cheng R.
        Non-compliance and microbial contamination in orthokeratology.
        ]
      Good compliance is essential in ortho-k because of the involvement of overnight lens wear in children. Reinforcement and warnings on the importance of ortho-k care procedures at regular aftercare visits could help to improve compliance [
      • Cho P.
      • Boost M.V.
      • Cheng R.
      Non-compliance and microbial contamination in orthokeratology.
      ]. However, patients/adult caregivers may begin to miss aftercare consultations as early as three months after commencing lens wear, with excuses of being too busy, and considering aftercare visits unnecessary in the absence of discomfort [
      • Jun J.
      • Zhiwen B.
      • Feifu W.
      • Lili L.
      • Fan L.
      Level of compliance in orthokeratology.
      ]. Eyecare practitioners should therefore educate adult caregivers properly before commencement of the therapy and continue to be vigilant about aftercare visits. To help increase the safe wear of ortho-k lenses, it is essential for adult caregivers to work with ECPs and ensure that their children return for aftercare consultations as scheduled. Eyecare practitioners are also advised to be proactive to ensure their ortho-k patients return (e.g. calling adult caregivers at least three times) [
      • Cho P.
      • Cheung S.W.
      • Mountford J.
      • White P.
      Good clinical practice in orthokeratology.
      ]. To encourage adult caregivers to bring their children in for regular aftercare consultations, ECPs should consider charging management fees which encompass the necessary number of aftercare visits (package fee), even for annual replacement lenses, rather than requiring payment at each consultation.

      5.3 Orthokeratology lens care regimens

      As ortho-k lenses come under the umbrella of rigid corneal lenses, the care systems and solutions used are similar, along with advice regarding hand hygiene. Given the numerous reported cases of Acanthamoeba keratitis in ortho-k lens wearers [
      • Kam K.W.
      • Yung W.
      • Li G.K.H.
      • Chen L.J.
      • Young A.L.
      Infectious keratitis and orthokeratology lens use: a systematic review.
      ,
      • Watt K.G.
      • Swarbrick H.A.
      Trends in microbial keratitis associated with orthokeratology.
      ,
      • Watt K.
      • Swarbrick H.A.
      Microbial keratitis in overnight orthokeratology: review of the first 50 cases.
      ,
      • Li W.
      • Wang Z.
      • Qu J.
      • Zhang Y.
      • Sun X.
      Acanthamoeba keratitis related to contact lens use in a tertiary hospital in China.
      ], emphasising the importance of not using tap water for any rinsing, cleaning, or storage process is particularly important.
      New care systems have gradually been introduced, with multipurpose solutions (MPS) becoming more commonplace (see CLEAR Maintenance Report) [
      • Willcox M.
      • Keir N.
      • Maseedupally V.
      • Masoudi S.
      • McDermott A.
      • Mobeen R.
      • et al.
      CLEAR – contact lenses wettability, cleaning, disinfection and interactions with tears.
      ]. Solutions using 1-step hydrogen peroxide systems provide broad overall microbial disinfection rates across different microorganisms [
      • Nichols J.J.
      • Chalmers R.L.
      • Dumbleton K.
      • Jones L.
      • Lievens C.W.
      • Merchea M.M.
      • et al.
      The case for using hydrogen peroxide contact lens care solutions: a review.
      ]. However, these are not as widely used by rigid corneal lens wearers, likely due to the perceived convenience that MPS provide [
      • Nichols J.J.
      • Chalmers R.L.
      • Dumbleton K.
      • Jones L.
      • Lievens C.W.
      • Merchea M.M.
      • et al.
      The case for using hydrogen peroxide contact lens care solutions: a review.
      ,
      • Nichols J.J.
      Contact lenses 2016. A status quo remains for much of the contact lens industry.
      ]. This may also be influenced by ECP prescribing habits, despite the greater efficacy of peroxide systems [
      • Nichols J.J.
      • Chalmers R.L.
      • Dumbleton K.
      • Jones L.
      • Lievens C.W.
      • Merchea M.M.
      • et al.
      The case for using hydrogen peroxide contact lens care solutions: a review.
      ], which is important as most rigid corneal lenses (including ortho-k lenses) are used for 12 months or more.

      5.3.1 Multipurpose solutions

      Multi-purpose formulations usually include a variety of surfactants, chelating agents, and chemical polymeric disinfectants to clean and disinfect lenses when not being worn [
      • Kuc C.J.
      • Lebow K.A.
      Contact lens solutions and contact lens discomfort: Examining the correlations between solution components, keratitis, and contact lens discomfort.
      ]. The MPS used with rigid corneal lenses are usually similar to soft contact lens MPS, but contain a higher concentration of antimicrobial agents [
      • Boost M.V.
      • Cho P.
      • Lai S.
      Efficacy of multipurpose solutions for rigid gas permeable lenses.
      ,
      • Choy C.K.M.
      • Cho P.
      • Boost M.V.
      Cytotoxicity of rigid gas-permeable lens care solutions.
      ]. The varying chemicals in MPS work to provide different essential steps in successful rigid corneal lens wear, and the contents of these care systems continue to be regularly updated and improved by manufacturers to provide convenience and efficient disinfection, leading to a wide range of formulations available for contact lens wearers. It is advised that patients receive thorough training in contact lens care, with emphasis on the importance of daily rubbing and rinsing to remove stubborn lens deposits [
      • Cho P.
      • Poon H.Y.
      • Chen C.C.
      • Yuon L.T.
      To rub or not to rub? - effective rigid contact lens cleaning.
      ]. They should also be cautioned about the cytotoxicity of some MPS constituents, such as chlorohexidine gluconate, which may not be advisable to apply directly to the cornea [
      • Choy C.K.M.
      • Cho P.
      • Boost M.V.
      Cytotoxicity of rigid gas-permeable lens care solutions.
      ]. Solutions containing an identical type and concentration of preservative (PHMB) can still vary in antimicrobial efficacy and cytotoxicity, which highlights that MPS performance is dependent upon the solution formulation rather than the biocide alone [
      • Santodomingo-Rubido J.
      • Mori O.
      • Kawaminami S.
      Cytotoxicity and antimicrobial activity of six multipurpose soft contact lens disinfecting solutions.
      ].
      A study [
      • Boost M.V.
      • Cho P.
      • Lai S.
      Efficacy of multipurpose solutions for rigid gas permeable lenses.
      ] investigated the efficacy of rigid lens solutions in different storage conditions over a 12-week period. Most MPS gradually lost their antimicrobial efficacy over time, but still met FDA requirements throughout the study, although some MPS demonstrated reduced effectiveness in colder conditions [
      • Boost M.V.
      • Cho P.
      • Lai S.
      Efficacy of multipurpose solutions for rigid gas permeable lenses.
      ]. When investigating MPS in combating non-Food and Drug Administration (FDA)/International Organisation for Standardization (ISO) microbes, a study found all MPS tested to be effective against bacterial strains, but less successful against fungi [
      • Boost M.V.
      • Lai S.
      • Ma C.
      • Cho P.
      Do multipurpose contact lens disinfecting solutions work effectively against non-FDA/ISO recommended strains of bacteria and fungi?.
      ]. Other studies have also reported similar results [
      • Miller M.J.
      • Callahan D.E.
      • McGrath D.
      • Manchester R.
      • Norton S.E.
      Disinfection efficacy of contact lens care solutions against ocular pathogens.
      ,
      • Lowe R.
      • Vallas V.
      • Brennan N.A.
      Comparative efficacy of contact lens disinfection solutions.
      ,
      • Hildebrandt C.
      • Wagner D.
      • Kohlmann T.
      • Kramer A.
      In-vitro analysis of the microbicidal activity of 6 contact lens care solutions.
      ].
      As contact lens cases have been identified as a primary source of infection [
      • Cho P.
      • Boost M.V.
      • Cheng R.
      Non-compliance and microbial contamination in orthokeratology.