trek for keratoconus

• Open access
• Published: 06 November 2023

New dawn for keratoconus treatment: potential strategies for corneal stromal regeneration

• Shengqian Dou 1 , 2 ,
• Xiaoxue Liu 1 , 3 , 4 ,
• Weiyun Shi 1 , 3 , 4 &
• Hua Gao   ORCID: orcid.org/0000-0002-1326-6946 1 , 3 , 4  

Stem Cell Research & Therapy volume  14 , Article number:  317 ( 2023 ) Cite this article

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Keratoconus is a progressive, ectatic and blinding disorder of the cornea, characterized by thinning of corneal stroma. As a highly prevalent among adolescents, keratoconus has been a leading indication for corneal transplantation worldwide. However, the severe shortage of donor corneas is a global issue, and the traditional corneal transplantation surgeries may superinduce multiple complications, necessitating efforts to develop more effective strategies for keratoconus treatment. In this review, we summarized several strategies to promote corneal stromal regeneration or improve corneal stromal thickness, including cell-based therapies, biosynthetic alternatives for inducing corneal regeneration, minimally invasive intrastromal implantation and bioengineered tissues for implantation. These strategies provided more accessible but safer alternatives from various perspectives for keratoconus treatment, paving the way for arresting the keratoconus progression in its earlier stage. For the treatments of corneal ectatic diseases beyond keratoconus, these approaches will provide important references and widen the therapy options in a donor tissue-independent manner.

Keratoconus is a progressive corneal ectatic disorder characterized by thinning of corneal stroma and asymmetrical conical protrusion of the cornea, which can lead to visual impairment or even blindness [ 1 , 2 , 3 ]. Keratoconus is one of the leading indications for corneal transplantation surgery worldwide [ 4 , 5 ], with an incidence of 1/2000 in the general population and even higher among young adults [ 2 , 6 ]. Keratoconus is the result of complex genetic and environmental interactions [ 7 , 8 , 9 ]. The most severe stage of keratoconus manifests with excessive ectasia, scarring and thinning stroma, which significantly impairs the vision, and the only option left for patients is corneal transplantation [ 1 ]. However, the severe shortage of the donor corneas available for transplant represents a global burden of blindness, with one cornea available for every 70 recipients in waiting [ 10 ]. Besides, traditional corneal transplantation surgeries can cause various complications, such as the severed corneal nerve plexus, dry eye, glaucoma and tissue rejection. Due to the immune rejection and chronic corneal allograft dysfunction, the poor long-term graft survival rate after keratoplasty usually brings a huge burden on patients. For these reasons, intense research effort has focused on corneal stromal regeneration to increase the corneal thickness of patients with keratoconus, and multiple therapy paradigms have been explored as alternative treatment modalities to preserve and improve the vision [ 11 , 12 , 13 , 14 ]. In this review, the strategies for corneal stromal regeneration are summarized, highlighting potential approaches for keratoconus treatment.

Strategies for corneal stromal regeneration

Cell therapy for keratoconus treatment.

Currently, corneal collagen cross-linking and corneal transplant remain the most preferred or even the only option for keratoconus treatment. However, neither of these approaches can fundamentally solve the underlying issue of the disease. Approximately 80–85% of the corneal thickness is composed of the corneal stroma, in which collagen fibrils and extracellular matrix are tightly arranged [ 15 , 16 ]. Keratocyte loss and excessive degradation of collagen fiber by matrix metalloproteinases are the culprit of keratoconus pathogenesis [ 17 , 18 ]. Hence, replacing or reviving the corneal stromal cells might be an ideal and direct approach; therefore, cell-based therapies for corneal stromal regeneration during keratoconus treatment have emerged and gained great concern.

To date, various ideas and choices for cell therapy of keratoconus were developed (Fig.  1 , Table 1 ). Keratocytes in the cornea are derived from neural crest cells. The number of keratocytes are limited in vivo, but they can be cultured in vitro and supplied as reliable cell source for intrastromal injection [ 19 , 20 ]. Besides, keratocyte progenitor cells, the committed stem cell populations that maintain capacity to self-renewal and differentiation, are thought to be a potential option for keratoconus treatment. The transplantation of healthy keratocyte progenitor cells into keratoconus corneas would provide a novel treatment modality that may slow the progression of keratoconus [ 21 ]. Moreover, the corneal stromal stem cells, a rare cell population resident in the peripheral cornea and limbus, can be isolated by specific surface markers from limbal stromal tissues [ 22 , 23 , 24 , 25 ]. Du et al. injected the human corneal stromal stem cells into mice corneas and did not observe elicit immune rejection over an extended period of time, suggesting an opportunity to develop cell-based therapies for corneal stromal diseases [ 26 ].

Cell sources used for keratoconus treatment. The figure was prepared by our group, and some of the elements in the diagram were provided by Figdraw ( http://www.figdraw.com )

However, several cell types mentioned above are still dependent on the corneal tissues, and the shortage of donor corneal tissues and the limited numbers of the particular cell populations is a significant challenge. The corneal stromal cells were found to have properties similar to other mesenchymal stem cells from various tissues [ 24 , 27 , 28 ], including adipose tissue [ 29 , 30 , 31 ], hematopoietic stem cells [ 32 ], dental pulp [ 33 , 34 ] and umbilical cord blood [ 35 ], which have been demonstrated to be used for keratoconus cell therapy [ 11 ]. For example, implantation of autologous adipose tissue-derived stem cells (ADSCs) into corneal stroma has been successfully tested for the treatment of keratoconus [ 30 , 31 , 36 , 37 ]. In addition, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) also provide sufficient cell sources that could be differentiated to keratocytes required for keratoconus therapy [ 38 ].

Biosynthetic alternatives for inducing corneal regeneration

Replacement of the damaged tissue with corneal transplants is widely accepted treatment for corneal blindness. Over ten years ago, Per Fagerholm et al. developed a kind of recombinant human collagen type III (RHCIII), which has undergone synthesized in yeast, chemically cross-linked, and molded into a biosynthetic cornea mimic [ 39 ]. They conducted a phase 1 clinical study in which the biosynthetic cornea mimics were implanted to replace the distorted corneas of 10 patients with keratoconus or central scar. Strikingly, corneal re-epithelialization occurred in all patients, and nerve regeneration and touch sensitivity were also restored, demonstrating the property of the biosynthetic mimics in facilitating endogenous tissue regeneration. After then, further optimization of the biosynthetic corneal implants was done [ 40 , 41 ]. More significantly, Christopher D. McTiernan et al. developed a regeneration-stimulating liquid corneal replacement in a syringe that gels in situ, LiQD cornea, that comprises short collagen-like peptides, polyethylene glycol and fibrinogen [ 42 ]. The self-assembling synthetic collagen analog, as a low-cost and immune-compatible alternative, offering a safe and effective option to help address the current donor cornea shortage. Detailed information of these approaches is listed in Table 1 .

Mechanical methods to improve corneal stomal thickness

• Minimally invasive intrastromal implantation

Beside the strategy of corneal stromal cell replacement, restoring the physical properties of the corneal stroma cannot be ignored during keratoconus treatment [ 14 ]. Substantial biomechanical imbalance and weakening of the cornea can distinctly deteriorate the ocular surface homeostasis [ 43 , 44 ]. As we know, eye-rubbing is one of the major risk factors for keratoconus progressive, which can induce distinct alterations in corneal biomechanics [ 45 , 46 , 47 ]. And mechanical stretch was a trigger for keratoconus development and biomechanics-enzymes axis played a pathogenic role in keratoconus, as identified in our study [ 48 ]. Therefore, strengthening the biomechanical properties of the cornea should be considered during keratoconus treatment.

In recent years, corneal collagen cross-linking therapy, as a primary operative correction for progressive keratoconus, are used routinely to increase the biomechanical stability of the cornea. However, for keratoconus that has progressed to the most severe stage, corneal transplantation is the only option [ 1 ] (Table 2 ). Penetrating keratoplasty (PK) is a transplant procedure with full-thickness resection of the cornea, followed by grafting it with a full-thickness donor cornea, which was the treatment of choice for keratoconus until the late twentieth century [ 49 , 50 , 51 ]. When indicated, refinements in surgical approaches, like the deep anterior lamellar keratoplasty (DALK) [ 49 , 50 , 51 ] and anterior lamellar keratoplasty (ALK) [ 52 ], that were surgical procedures for removing part of the cornea. For instance, DALK involves replacement of the pathological corneal stroma down to the Descemet’s membrane but with the functional corneal endothelium retained, offers an effective alternative procedure that may lessen the risks including graft rejection and irregular astigmatism in PK. Despite DALK's success in restoring keratoconus patients' vision, there is still room for improvement regarding the operational complexity, restoring the physical properties of corneal stroma, preservation of the anterior corneal structure and nerve plexus, and suture-related complications. Therefore, suture-free implementation with smaller access cuts may be a preferred surgical option to arrest the progress of keratoconus, such as epikeratophakia (EP) [ 53 , 54 ], Bowman layer (BL) transplantation [ 55 , 56 ] and allogenic lenticule implantation [ 57 , 58 , 59 , 60 ]. Besides, our group have introduced a new effective procedure for the treatment of advanced keratoconus, named “femtosecond laser-assisted minimally invasive lamellar keratoplasty” (FL-MILK), in which partial thickness corneal stroma (stromal button) was implanted to the allogeneic corneal stroma through a small incision created by femtosecond laser (intrastromal pocket) [ 61 ] (as illustrated schematically in Fig.  2 ). Our study also indicated that FL-MILK can stabilize progressive KC in mild-to-moderate cases and advanced cases at 24-month follow-up with sustainable flattening effect of the anterior cornea curvature [ 62 ]. Indeed, while improving the stromal thickness, this minimally invasive surgical methods can maximally maintain the structural integrity and physical properties of the cornea, providing a feasible option for keratoconus treatment that should be put on the agenda.

Minimally invasive surgical methods and bioengineered grafts for keratoconus treatment. An intrastromal pocket with a small incision were created by femtosecond laser, the human stromal button ( a ) or bioengineered BPCDX graft ( b ) were gently inserted into the intrastromal pocket to increase the corneal thickness. The figure was prepared by our group

Bioengineered corneal tissues for implantation

For the keratoplasty to treat keratoconus, several materials can be used as biomedical implants. The natural cornea has particular advantage in mechanical properties and structures, while the severe shortage of donor corneas presents a global concern. Hence, intense research efforts have focused on effective alternatives to conventional corneal grafts. May Grifith et al . successfully multilayered corneal equivalents constructed from immortalized cell lines [ 63 ]. Per Fagerholm et al . conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to induce corneal regeneration [ 39 ]. Our group have developed a protective decellularization strategy for the preparation of decellularized porcine cornea (DPC), which achieved equivalent levels in numerous properties compared with that of human cornea grafts [ 64 ]. All these studies offered prospects for visual rehabilitation of corneal blindness. Even more to the point, Mehrdad Rafat and colleagues have described a cell-free engineered corneal tissue, which was derived from purified type I porcine collagen with dual chemical and photochemical cross-linking applied, termed the bioengineered porcine construct, double cross-linked (BPCDX) [ 65 ] (Fig.  2 ). The authors extracted and purified collagen from a by-product of the food industry, the porcine skin, providing an abundant yet sustainable and cost-effective supply of raw materials for implants. At the same time, likewise, the authors insert the implant within the corneal stroma through a minimally invasive procedure. Notably, after 2 years of follow-up, no adverse event was reported, all participants' vision improved to the same degree as with a standard donor tissue transplant. The strategy proposed by this work in which accessible bioengineered corneal tissues and minimally invasive surgical methods were elaborately combined, would be an attractive option for treatment of advanced keratoconus, especially in resource-limited settings. Details of the approaches mentioned in this part are listed in Table 2 .

In this review, we summarized several approaches to promote corneal stromal regeneration or improve corneal stromal thickness, including cell-based therapies, biosynthetic alternatives for inducing corneal regeneration, minimally invasive intrastromal implantation and bioengineered tissues for implantation. Among these, a series of mechanical methods to improve corneal stomal thickness have been applied in clinical treatment of keratoconus. For instance, historically, PK has been the gold standard approach for the surgical treatment of advanced keratoconus with its good visual outcomes [ 50 , 51 ]. However, DALK is increasingly becoming the preferred primary surgical option in contemporary practice owing to its reduced rejection and astigmatism in PK complications. But the complexity of operation and risks of suture-related complications in DALK complications cannot be ignored, which prompted the occurrence of minimally invasive surgical methods [ 49 , 50 , 51 ]. For example, FL-MILK can maximally maintain the structural integrity and physical properties of the cornea while improving the stromal thickness, and its more precise and quick recovery might make it an effective alternative for the treatment of advanced keratoconus [ 61 ]. Besides, combined more accessible bioengineered corneal tissues and minimally invasive methods would be an attractive option for keratoconus treatment. Indeed, longer follow-up period and more cases are needed for several new improving approaches.

In addition, the severe shortage of donor tissue impeded the treatment of keratoconus through corneal transplant surgery, especially in resource-limited settings. Therefore, explorations in developing strategies to promote corneal stromal regeneration has never stopped. The ideal cell-based therapy is expected to replace or revive the diseased keratocyte cells by inducing regeneration or by exogenous transplantation of keratocyte-committed cells. Here we listed the cell sources, stage of research, advantages and limitations for various cell-based therapeutic methods. Among these, implantation of autologous ADSCs into corneal stroma has been successfully tested for the treatment of keratoconus in clinical trials [ 30 , 31 , 36 , 37 ], with its abundant and easily accessible cell source. Besides, biosynthetic alternatives for inducing corneal regeneration, including RHCIII [ 39 ] and LiQD cornea [ 42 ], providing low-cost and immune-compatible alternatives to help address the donor cornea shortage.

Conclusions

Collectively, this review highlighted the advances in therapeutic strategies that can promote corneal stromal regeneration or improve corneal stromal thickness for keratoconus treatment, providing important reference and foundations for developing potential interventions. These approaches have brought hopes for keratoconus therapy with more safe and accessible alternative options, reducing the surgical complication and burden of limited donor corneas globally. Generally, DALK has become an alternative to PK, while minimally invasive surgery will become a major trend in the future treatment of keratoconus. And keratocyte regeneration therapies will also usher in a new era, especially for the ADSCs-based treatment, though the potential of several novel therapies for achieving effective stromal regeneration need further explorations. Certainly, further studies should be conducted to confirm the optimal therapeutic methods and conditions for keratoconus intervention, and novel approaches would be developed to control and arrest the progression of keratoconus in its much earlier stage, which might hopefully postpone or prevent an invasive corneal surgery. For keratoconus treatment, the light is shining brighter on its way.

Availability of data and materials

All datasets used in this study are available from the corresponding author on reasonable request.

Abbreviations

Adipose tissue-derived stem cells

Embryonic stem cells

Induced pluripotent stem cells

Penetrating keratoplasty

Deep anterior lamellar keratoplasty

Anterior lamellar keratoplasty

Epikeratophakia

Bowman layer

Femtosecond laser-assisted minimally invasive lamellar keratoplasty

Bioengineered porcine construct, double cross-linked

Recombinant human collagen type III

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Acknowledgements

We thank Tong Liu for constructive suggestions on this review. Some of the elements in the diagram were provided by Figdraw ( http://www.figdraw.com )

This work was supported by the National Natural Science Foundation of China (82070923, 82101092, 82371032), Taishan Scholar Program (201812150, 202306390), Major Basic Research Project of Natural Science Foundation of Shandong Province (ZR2023ZD60) and the Academic Promotion Program and Innovation Project of Shandong First Medical University (2019RC009).

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Shengqian Dou, Xiaoxue Liu, Weiyun Shi & Hua Gao

Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China

Shengqian Dou

Eye Hospital of Shandong First Medical University, Jinan, China

Xiaoxue Liu, Weiyun Shi & Hua Gao

School of Ophthalmology, Shandong First Medical University, Jinan, China

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H.G. conceptualized, acquired funding and supervised this study. S.D. drafted the manuscript. X.L. performed literature search and collection. W.S. provided advice and discussed the manuscript.

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Correspondence to Hua Gao .

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Dou, S., Liu, X., Shi, W. et al. New dawn for keratoconus treatment: potential strategies for corneal stromal regeneration. Stem Cell Res Ther 14 , 317 (2023). https://doi.org/10.1186/s13287-023-03548-5

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Topography-guided corneal surface laser ablation combined with simultaneous accelerated corneal collagen cross-linking for treatment of keratoconus

• Yu Zhang 1 &
• Yueguo Chen 1  

BMC Ophthalmology volume  21 , Article number:  286 ( 2021 ) Cite this article

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to study the outcomes of topography-guided customized excimer laser subepithelial ablation combined with accelerated CXL for progressive keratoconus.

Thirty-one eyes of 30 patients with progressive keratoconus were included in this prospective study. Topography-guided excimer laser ablation without refractive correction was performed. Simultaneous accelerated collagen cross-linking with ultraviolet light of 30 mW/cm 2 for 4 min was followed. Uncorrected distance visual acuity (UCVA), manifest refraction, corrected distance visual acuity (CDVA), tomograghy were examined at postoperative 1, 6, and 12 months.

UDVA improved slightly after surgery ( P  > 0.05). BSCDVA improved significantly from 0.32 ± 0.20 logMAR to 0.15 ± 0.14 logMAR at postoperative 12 months ( P  < 0.05). During 12-month follow-ups, there were no significant differences in manifest refraction and corneal keratometry except for maximal keratometry value of the anterior surface (K apex ), which decreased significantly from 57.23 ± 5.09D to 53.13 ± 4.47D ( P  < 0.05). Even though the thinnest corneal thickness decreased from 465 ± 24 μm to 414 ± 35 μm ( P  < 0.05), curvature asymmetry index front (SIf), keratoconus vertex front (KVf) and Baiocchi Calossi Versaci index front (BCVf) decreased significantly till postoperative 12 months ( P  < 0.05). Corneal higher-order aberrations and coma also decreased significantly till 12 months after surgery ( P  < 0.05).

Conclusions

Topography-guided surface ablation without refractive correction combined with simultaneous accelerated collagen cross-linking provided good stability in refraction and corneal curvature, and also showed significant improvement in BSCDVA, corneal regularity and corneal optical quality.

Peer Review reports

Keratoconus is a progressive ectatic corneal disorder that results in corneal stroma impairment and biomechanical weakening. Corneal collagen cross-linking (CXL) is an effective treatment to halt the progression of keratoconus [ 1 ]. The classic Dresden CXL uses ultraviolet light of 3mW/cm 2 illumination and a single treatment process needs 60 min to reach a total energy of 5.4 J/cm 2  [ 2 ]. Recently, researchers have developed accelerated CXL protocols that speed up the procedure using higher-intensity radiation. Several accelerated protocols have been reported to provide comparable results to the classic Dresden CXL [ 3 , 4 ]. Furthermore, accelerated CXL has been proven to halt the progression of keratoconus in the majority of pediatric patients [ 5 ]. Despite reports of well prevention for keratoconus progression and slight improvements of keratometry following CXL, the benefits in terms of improvement in UDVA or CDVA are negligible [ 6 , 7 ]. In addition, approximately 15 % of keratoconus patients cannot tolerate contact lenses and some patients have difficulty in fitting the appropriate contact lenses. Thus, some attempts have been made to not only prevent the progression of keratoconus, but also improve visual quality in keratoconus patients.

The combination of CXL and topography-guided photorefractive keratectomy (TG-PRK) was first proposed by Kanellopoulos AJ in 2007, which was known as Athens Protocol [ 8 , 9 ]. Previous studies, combining different protocols of CXL and photorefractive treatment performed at the same time or in two-steps, demonstrated a significant improvement of keratometry readings and visual function [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. In these previous studies, however, photorefractive ablation with partial refractive correction was used in all or part of the cases, aiming at reducing not only the lower but also the higher-order aberration and irregular corneal astigmatism [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. As we know, vertical asymmetry and higher-order aberrations are the main reasons for the poor visual function of keratoconus, and lower-order aberrations can be well corrected by spectacles, soft contact lens or implantable contact lens (ICL) implantation. So, photorefractive treatment should focus on correcting only higher-order aberrations, so as to minimize the loss of corneal stroma.

In this prospective study, we examined the evolution of the visual, refractive and tomographic changes during 1-year follow-up after simultaneous TG-PRK without refractive correction followed by accelerated CXL in patients with progressive keratoconus.

Subjects and methods

This prospective study comprised 31 eyes of 30 patients (both eyes of 1 patient), aged between 12 and 34 years (mean, 24.3 ± 6.3 years), diagnosed as progressive keratoconus and treated by TG-PRK combined with simultaneous accelerated CXL at Peking University Third Hospital from December, 2016 to March, 2018. KC1 or KC2 was graded on the basis of Amsler and Muckenhirn standard [ 21 ]. This study received approval from the ethics committee of Peking University Third Hospital and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from each participant or participant’s parents before our interventions.

The inclusion criteria were:(1)Corneal tomography and topography, clinical symptoms and signs demonstrated keratoconus, with a trend of progress in the past 12 months and met one of the following conditions: the maximum K reading increased by >1D; mean corneal refractive power increased by >1D; astigmatism increased by >1D;the spherical equivalent of manifest refraction increased by >1.0D with best spectacle corrected distance visual acuity (BSCDVA) lost more than one line; the thinnest corneal thickness decreased by >10%(2). Rigid gas permeable (RGP) contact lens intolerance or inadequate fitting(3)The thinnest thickness of cornea >450 μm and the predicted postoperative thickness of stromal bed >350 μm.

The exclusion criteria were:(1)Over mental tension or too young to well cooperate during surgery.(2)Active ocular infection or inflammation, the history of refractive surgery, herpes keratitis, and the ocular diseases other than keratoconus that seriously affected BSCDVA.(3)Prominent corneal scarring and BSCDVA >1.30 logMAR.(4)Definitively diagnosed and uncontrolled auto-immune diseases or connective tissue diseases.(5)The women in pregnant or lactating period.

Preoperative Examinations

All patients had a full ophthalmological examination, including uncorrected distance visual acuity (UDVA), cycloplegic and manifest refractions, BSCDVA, slit-lamp evaluation, Goldmann applanation tonometry, and fundoscopy examinations. With the Sirius combined topographer and tomographer (CSO, Italy), the following parameters were evaluated: maximal keratometry value of the anterior surface (K apex ), flat-axis keratometric value (K1), steep-axis keratometric value (K2), corneal astigmatism, minimum corneal thickness (ThkMin), curvature symmetry index front (SIf), keratoconus vertex front (KVf), Baiocchi Calossi Versaci index front (BCVf), root-mean-square of the total higher-order aberrations (HOA-RMS), coma (Coma-RMS), and spherical aberration (SA-RMS). Corneal topography data for topography-guided customized ablation were obtained from the placido-based topographer (Vario Topolyzer, Alcon, USA). Corneal endothelial cell density (ECD), hexagon cell percentage (HEX) and cell area variation coefficient (VC) were examined by specular microscopy (Topcon, Japan).

Surgical procedures

All treatments were performed by the same surgeon (YG Chen). Under topical anesthesia, fresh prepared 20 % alcohol was instilled into the epithelial trephine with a diameter of 9.0 mm, soaking for 20 s. Then the corneal epithelium was peeled and removed. TG-PRK was performed using the Topography-Guided (Topolyzer) software of WaveLight EX500 excimer laser system (Alcon, USA) with an optic zone of 5.0 ~ 6.0 mm. TG-PRK referred to the correction of neither refractive sphere nor cylinder, but 0 ~ -2.25D of compensated (“measured”) cylinder which was automatically calculated based on the Topolyzer topographic results. The ablation depth was calculated automatically by EX500, and controlled within 50 μm by reducing the optical zone to some extent. (Fig.  1 ) Mean maximum ablation depth was 42.16 ± 2.11 μm (28 ~ 50 μm). Before and during laser ablation, the static cyclotorsion and kappa angle of the eye were automatically compensated on the basis of the topographic examination. The ablation center was automatically set to the corneal vertex. Mitomycin C was not used. Irrigation with balanced salt solution was followed by corneal soaking with riboflavin (0.1 % riboflavin sodium phosphate ophthalmic solution VibeX Rapid; Avedro, Inc) for 10 min. The cornea was irradiated for 4 min by ultraviolet light (30mW/cm 2 , KXL ultraviolet instrument, Avedro, USA) with a total energy delivered of 7.2 J/cm 2 . A bandage soft contact lens was applied until complete epithelialization.

Postoperative treatment and follow up

Levofloxacin 0.5 % eye drops (Santian Pharmaceutical co., LTD, Japan) were applied 4 times a day until epithelial healing. Fluorometholone 0.1 % eye drops (Santian Pharmaceutical co., LTD, Japan) were applied 4 times a day in the first post-operative week and tapered weekly for 4 weeks. After contact lens removal, artificial tears or lubricants were used for at least 1 month according to the conditions of dry eye or delayed healing of epithelium.

The follow-up time points were 1 day, 5 days, 14 days, 1 month, 3 months, 6 months and 12 months after surgery. UDVA and slit lamp examination were performed at every time point. Corneal haze was evaluated according to the system reported by Fantes et al.[ 22 ] At 1-month, 6-month and 12-month follow-up, manifest refraction, BSCDVA, Sirius combined topographer and tomographer, Topolyzer topographer were examined. At 1-month follow-up, specular microscopy and anterior segment optical coherence tomography (AS-OCT) (Visante OCT; Carl Zeiss Meditec) were examined. Demarcation line depth was measured at corneal vertex using AS-OCT by an experienced technician.

Statistical analysis

SPSS 21.0 statistical software (SPSS, Inc., Chicago, IL) was used to analyze the data. Continuous data were expressed as mean values ± standard deviation. Visual acuity was converted to logMAR for statistical analysis. Repeated measurement variance analysis was used for the comparison of the overall difference of continuous parameters among preoperative and postoperative multiple time points. Dunnett-t test was used for comparing parameters between different two time points. Pearson Chi-Square test was used to compare BSCDVA change between different time points. P <0.05 was considered to be statistical significant.

Visual acuity

UDVA and BSCDVA detailed data are illustrated in Table  1 . There was no significant difference in UDVA between preoperative and postoperative time points ( P  > 0.05). BSCDVA improved significantly from baseline to postoperative 1-month and 6-month ( P  < 0.05), and remained relatively stable till postoperative 12 months ( P  > 0.05).

At postoperative 1-month, BSCDVA lost 2 lines in 5 eyes (16 %), 1 line in 1 eye (3 %), unchanged in 6 eyes (19 %) and increased over 2 lines in 16 eyes (52%). As time went by, BSCDVA improved gradually. At postoperative 12-month, only 1 eye lost 1 line of BSCDVA, and BSCDVA unchanged in 4 eyes (13 %), and increased over 2 lines in 21 eyes (68 %) ( P  < 0.05).(Fig.  2 )

Manifest Refraction

Table  2 shows the manifest refraction values during follow-ups. There were no significant overall differences in sphere, cylinder and spherical equivalent during the 12-month follow-up ( P  > 0.05). Only cylinder at postoperative 6 and 12 months decreased significantly, compared to the preoperative value ( P  < 0.05).

Corneal curvature

Table  3 shows corneal curvature parameters detected by Sirius combined topographer and tomographer during follow-ups. K apex decreased significantly at all visits compared to the previous value and the preoperative value ( P  < 0.05). At 12-month visit, mean K apex decreased to 53.13 ± 4.47D, compared to the preoperative mean K apex of 57.23 ± 5.09D ( P  < 0.05). Although the overall differences in K2 and mean K during follow-up were significant, only values at 6 and 12 months were significantly different from 1-month values ( P  < 0.05). There was no significant difference in corneal cylinder during 12-month follow-ups ( P  > 0.05). The corneal topography change of a typical case is shown in Fig.  3 .

Keratoconus parameters

Table  4 shows keratoconus parameters detected by Sirius combined topographer and tomographer during follow-ups. SIf decreased significantly at postoperative 1 month and remained stable until postoperative 12 months ( P  < 0.001). KVf began to decrease significantly at 6 months after operation and continued to decrease till 12 months after operation ( P  < 0.001). BCVf decreased significantly at postoperative 6 months and remained stable until postoperative 12 months ( P  < 0.001). ThkMin decreased significantly at postoperative 1 month, and increased continuously from postoperative 6 months to 12 months ( P  < 0.001).

Corneal aberration

Corneal HOA and coma decreased significantly at postoperative 1 month, and decreased continuously until 12 months after operation ( P  < 0.001). However, spherical aberration increased significantly at postoperative 1 month, and returned to the preoperative level at postoperative 6 and 12 months ( P  < 0.05). (Table  5 )

3.6 Corneal endothelial cell

There were no significant differences in ECD, HEX and cell area VC at postoperative 1 month, compared to the preoperative values ( P  > 0.05). (Table  6 )

Postoperative corneal changes and complications

At postoperative 1 month, the demarcation line was well defined in each case with a mean depth of 216 ± 25 µ m. Aseptic inflammatory sub-epithelial infiltration occurred in one eye (3.2 %). No extra specific treatment was used and the opacity was basically absorbed within 4 weeks. At postoperative 1 month, corneal haze started to appear and dissipated gradually from postoperative 3 months to 12 months. The number of eyes with haze of grade 0, 0.5, 1, and 2 at postoperative 12-month follow-up were 25 eyes (80.6 %), 4 eyes (13.0 %), 1 eye (3.2 %), and 1 eye (3.2 %), respectively.

The classic Dresden CXL using ultraviolet light of 3mw/cm 2 illumination is a time-consuming procedure, which can cause high percentage of haze [ 19 ] and the risk of progressive corneal flattening [ 20 ], especially in simultaneous combined treatments. The accelerated CXL uses ultraviolet light of high irradiation intensity. According to the Bunsen-Roscoe law of photochemical effect, the higher the illumination, the shorter the exposure time [ 23 ].The exposure time required is greatly shortened, which improves the treatment efficiency and increases patients’ compliance. Additionally, accelerated CXL was proved to be effective and have fewer complications [ 4 , 5 ]. So, recently, accelerated CXL has been widely used by most surgeons for CXL combined treatment [ 13 , 16 , 17 , 18 , 20 ]. In the current study, 30mW/cm 2 ultraviolet light intensity of illumination for 4 min was used for the first time.

Initially, epithelial removal prior to CXL was performed using manual debridement (with or without alcohol) [ 13 , 14 , 15 ]. Recently, transepithelial phototherapeutic keratectomy (PTK) has also been employed as a method for removing the epithelial [ 16 , 17 , 18 ]. Because of a doughnut-shaped model of the corneal epithelium in keratoconus [ 24 ], PTK removes some stromal tissue from the central cone, which flattens the cornea more than manual debridement [ 25 ], but consumes more corneal stromal tissue at the cone apex. The corneal surface following PTK is more consistent with the preoperative topography, which makes the subsequent TG-PRK become more accurate. PTK epithelial removal leaves some epithelium around the cone, which may reduce the ablation volume of the corneal stromal tissue during TG-PRK, but can cause under-correction. In the present study, manual debridement with alcohol was used, which could reduce the loss of corneal stroma at the cone apex to the greatest extent, and reduced the excessive friction stimulation of corneal stroma by mechanical scraping.

Topography-guided customized ablation attempts to maintain the aspheric shape of the cornea and neutralize corneal irregularities [ 26 ]. It has been shown to be effective in treating irregular astigmatism caused by iatrogenic corneal irregularities[ 27 ]. Since topography-guided ablation for normalizing the anterior cornea can bring in refractive change, especially astigmatism change [ 28 ], the clinical refraction should be adjusted to keep it neutral after refractive correction. Kanellopoulos found that topography-modified refraction (TMR) offered superior refractive and visual outcomes to standard clinical refraction in myopic topography-guided LASIK [ 29 ]. In the current study, we used TMR for reference to compensate for partial cylinder measured by topographer without refractive correction while topography-guided ablation of irregular corneas on the basis of ensuring the depth of corneal ablation.

In the current study, UDVA improved slightly after surgery, but there was no statistical significance. BSCDVA improved significantly from 0.32 ± 0.20 logMAR to 0.15 ± 0.14 logMAR at postoperative 12 months ( P  < 0.05). Manifest refraction, flat K, steep K and corneal cylinder all decreased slightly after surgery, but no statistical significance was found. However, K apex flattened significantly after surgery. Generally speaking, the improvement of UDVA, the decrease of refraction and corneal curvature were not obvious, which were different from most previous studies [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Because of partial correction of clinical refraction, there were improvements in UDVA [ 8 , 9 , 10 , 11 , 12 , 13 , 15 , 16 , 17 , 18 ], curvature readings [ 13 , 15 , 17 , 18 , 19 , 20 ] and manifest refraction [ 13 , 15 , 16 , 18 , 19 , 20 ] after surgery. The CXL plus TG-PRK in the present study aimed at halting the progression of keratoconus and reducing corneal HOA, so we did not carry out refractive correction, which was a main difference between the present study and previous studies [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Despite of the different TG-PRK protocol, the present study still showed improvements in BSCDVA and K apex similar to the previous studies [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], which increased the correction effect of frame glasses or ICL implantation when contact lenses were not tolerated or helped to regain a good contact lenses fitting.

The current study also showed that SIf, KVf and BCVf, which reflected the irregularity of the anterior corneal surface, reduced significantly after surgery and remained in a reduced state up to 12 months after surgery. Those indicated that the cornea became regular after surgery and resulted in the improvement of BSCDVA. Some previous studies showed similar results that index of surface variance (ISV) and index of height decentration (IHD) decreased significantly after surgery[ 17 ]. The current study also found that corneal aberrations including corneal HOA and coma decreased continuously within 12 months after surgery, which also indicated the improvement of corneal regularity due to TG ablation. Ahmet et al.[ 16 ] and Rechichi et al. [ 18 ] found that corneal HOA, coma and spherical aberration (SA) all significantly decreased at 24 months after surgery. The difference of the change of corneal SA might related to the different excimer laser system (Schwind Amaris, Germany) and different ablation mode (Transepithelial TG-PRK).

Like some previous studies [ 10 , 12 , 16 , 18 ], MMC was not used in the present study. Kymionis GD et al. found that CXL could destroy the regeneration of corneal anterior stromal cells by confocal microscopy, so it was not necessary to use MMC after PRK combined CXL [ 30 ]. The synergistic effect of CXL and MMC may cause more cell death and more corneal haze [ 19 ].Although haze was observed at each case in postoperative one month in the present study, it gradually faded away 3 to 12 months after operation. This slightly obvious haze may be related to alcohol deepithelialization and 4-week treatment of glucocorticoid eyedrops after surgery.

The limitations of this study are as follows. First, this study had a small sample and was lack of a control group. Second, we didn’t estimate the impact of corneal posterior surface when planning TG ablation. In future, software based on calculation of mean pupillary power or raytracing technology compensating anterior and posterior corneal surfaces refractive and aberrometric contributions are mandatory to optimize visual and refractive outcomes. Third, like most previous studies, we used uniform protocol in all cases. Pachymetry-based or topography-guided customized CXL might be more effective and safer [ 18 , 31 , 32 ]. Rechichi et al.[ 18 ]offset ablation center towards the location of cone apex, which might better reduce coma. These customized procedures provided a good reference for our surgical protocol in the future.

It has been reported that a small number of keratoconus (around 8 %) may still progress after CXL [ 33 ]. Thus regular and long-term follow-up of refraction and corneal topography/tomography at different time points after surgery is necessary, especially after the combined surgery with reduced corneal thickness. The research of long-term safety is warrant.

In conclusion, the current study showed the significant improvement in BSCDVA, K apex , corneal irregularity indices and RMS of HOA and coma, and also showed good stability in refraction and corneal curvature after simultaneous TG-PRK without refractive correction followed by accelerated CXL (30mW/cm 2 ) in patients with progressive mild-to-moderate keratoconus. The treatment protocol is convenient, time-saving, effective and safe. However, large-scale, comparative, long-term trials are required to determine the optimum parameters and evaluate the long-term safety and effectiveness of this combined surgery.

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request.

Abbreviations

• Corneal collagen cross-linking

Uncorrected distance visual acuity

Corrected distance visual acuity

Curvature symmetry index front

Keratoconus vertex front

Baiocchi Calossi Versaci index front

Topography-guided photorefractive keratectomy

Phototherapeutic keratectomy

Best spectacle corrected distance visual acuity

Maximal keratometry value of the anterior surface

Flat-axis keratometric value

Steep-axis keratometric value

Minimum corneal thickness

Root-mean-square of the total higher-order aberrations

Root-mean-square of coma

Root-mean-square of spherical aberration

Corneal endothelial cell density

Hexagon cell percentage

variation coefficient

Anterior segment optical coherence tomography

Implantable contact lens

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Key Clinical Innovation Program of Peking University third hospital, category A (BYSYZD2019002). 

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Zhang, Y., Chen, Y. Topography-guided corneal surface laser ablation combined with simultaneous accelerated corneal collagen cross-linking for treatment of keratoconus. BMC Ophthalmol 21 , 286 (2021). https://doi.org/10.1186/s12886-021-02042-x

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New treatments for keratoconus

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Keratoconus (KCN) is a bilateral asymmetric disorder which selectively affects corneal stroma causing progressive bulging, thinning, and biomechanical instability. The typical presentation is astigmatism with progression trend towards irregularity, high order aberrations (coma), and visual impairment with reduced quality of life [ 1 ]. Despite being considered a rare disease, KCN epidemiology appears to be changing rapidly. Prevalence and incidence data are variable among different countries and depend on diagnostic technologies employed, but according to a recent meta-analysis, the estimated prevalence of KCN in the world is 1.38/1000 [ 2 ]. KCN affects typically adolescence and progresses until the third or fourth decade of life so the impact of this disorder is to be taken into account for the involvement of the productive categories of the society; moreover, the economic burden of KCN represents a significant public health concern due to the rise in lifetime cost of affected patients [ 3 , 4 ].

Many treatments (both medical and surgical) have been developed in the last years to halt its progression and improve the outcome, but the management is still challenging. Many KCN patients need more than one treatment throughout their lives. The goal of KCN treatment changes according to the stage of the disease [ 5 ]. In the early stages, the refractive defect can be corrected with spectacles and contact lenses (CL): a wide variety of options are available on the market ranging from soft lenses and soft toric, to piggy-back and hybrid lenses. New technological advancements have led to the development of customized, aberration-controlling CL, such as customized soft and scleral lenses [ 6 , 7 ]. Nevertheless, with the progression of the disease, the correction with lenses becomes unsatisfactory or impossible due to the development of irregular astigmatism, CL intolerance, and corneal opacity.

In 1997, CXL (corneal crosslinking) was first introduced to the clinical management of KCN to halt the progression of the disease in the early stages [ 8 ]. CXL produces a stiffening of the cornea by means of a photochemical reaction that occurs after the stroma is soaked with riboflavin (B2 vitamin isomer) and then irradiated with UVA light, to result in a stabilization of the disease in the early stages [ 9 ]. Many procedures to perform CXL have been developed over time targeting to optimize its duration and phases in order to improve the topographic outcomes. The original long-lasting Dresden protocol has been overcome by accelerated high fluence protocol to limit phototoxicity [ 10 ]. Epithelium off technique seemed to be the most encouraging method to ensure a deep penetration of riboflavin into the stroma; on the other hand, this strategy involves epithelium removal and related complications. A solution has been proposed with “epithelium on” techniques, relying on different strategies to allow B2 vitamin penetration, like new riboflavin formulations with added corneal enhancing compounds (benzalkonium chloride, sodium ethylenediaminetetraacetic acid) or iontophoresis-assisted CXL [ 11 , 12 , 13 ]. However, clinical trials comparing standard and transepithelial CXL showed better outcomes with the standard technique, while the transepithelial approach yield also an increase in topographic parameters (Kmax) [ 14 , 15 ]. CXL in combination with other procedures (CXL PLUS) allows not only the stabilization of the disease but also a partial (in most cases) or total refractive correction to provide patients with better visual acuity: CXL and Photorefractive Keratectomy (PRK), CXL and Transepithelial Phototherapeutic Keratectomy (PTK), CXL and Intrastromal Corneal Ring Segment (ICRS) implantation, and CXL and phakic Intraocular Lens Implantation [ 16 ]. A 6-year follow-up study on simultaneous topography-guided PRK and CXL (SimLC) showed that corneal flattening amounts on average to 5.9 D with SimLC, while CXL alone (70% of eyes) flattens by 2.1 D. In addition, authors demonstrated that SimLC provided permanent stability at the end of follow-up. If on the one hand it is true that PRK reduces corneal strength by approximately 5–10%, on the other hand CXL strengthens the cornea by around 70%; so the synergy of the two procedures creates a reshaped and also stronger cornea, thus promising more stability [ 17 ].

With the progression of KCN, the astigmatism and the irregularity of the cornea increase and CXL is not the indicated treatment because the goal is no longer to stabilize the cornea, but to regularize it.

Intrastromal corneal ring segments (ICRS) are surgical inserts made of polymethyl methacrylate and implanted in the deep stroma. They are able to reduce corneal distortion by flattening the steep area of the cornea and reshaping it, to reduce coma and coma-like aberrations, and to increase CL tolerance and delay keratoplasty [ 18 , 19 ].

Intacs (Addition technology Inc.) and Ferrara (Ferrara Ophthalmics) rings are the most used types of ICRS for the management of keratoconus [ 20 , 21 ]. The intrastromal channel for ICRS implantation was initially sculpted mechanically, but currently FSL-assisted technique has become the most popular choice for its effectiveness and precision [ 22 ]. Nowadays, implantation nomograms, specific indications, and contraindications for ICRS implantation for each case are available to maximize the safety and efficacy of the treatment [ 19 ].

Combined therapeutic approach of CXL and ICRS leads to an increase in biomechanical corneal stiffness and stability which has proven useful in progressive keratoconus [ 23 ].

As the disease progresses, there are important changes affecting the corneal architecture and its transparency and partial or complete substitution of corneal tissue is needed.

When Descemet-endothelium complex (DEC) is compromised, a whole corneal transplantation (PKP) is indicated. When DEC is healthy, the DALK (deep anterior lamellar keratoplasty) technique is the preferred surgical option. However, the number of DALK performed is largely variable between different countries [ 24 ]. Surely one crucial aspect in DALK is that an optimal visual outcome depends on the absence of optical interface between deep stromal layers, obtained by the detection of the ideal cleavage between deep stroma and Descemet membrane (DM): Dua’s layer [ 25 ]. The big-bubble (BB) technique was developed to fulfill this need and shows earlier vision improvement compared to partial stromal removal leaving an uneven cleavage plane [ 26 ]. However, the technical difficulty, intra-operatory complications, such as DM perforation, limit DALK performance. Furthermore, its reproducibility depends on the level of experience of the surgeon. The use of femtosecond laser (FSL) can help standardize DALK procedure by reducing bias related to manual cuts [ 27 ].

FSL-integrated optical coherence tomography (iOCT) was recently used for direct visualization and calibration to perform precise anterior lamellar and side cuts for the removal of the anterior stroma [ 28 ].

FSL-assisted keratoplasty is performed with great accuracy and efficacy, many cutting patterns have been developed to increase host-graft apposition (top-hat, mushroom, zig-zag), minimizing post-operative astigmatism and improving visual outcome [ 29 , 30 ].

Moreover, FSL allows the creation of precise cuts into the corneal stroma to create pockets in which can be inserted devices to regularize corneal curvature like ICRS, or corneal stroma lenticules to restore thickness and mechanical stability by a tissue additive procedure (additive keratoplasty, AK). AK consists in the insertion of a corneal lamella, obtained from a human donor cornea (HDC) or from a lenticule extraction procedure, within the ectatic area to restore the lost thickness, and reduce the conic protrusion. This surgical technique takes advantage of FSL both for the creation of the lenticule (in HDC) and for the intrastromal pocket shaping [ 31 , 32 ]. The initial results show feasibility, safety, and clear lenticules. The main advantages of these techniques are their minimal invasiveness, low risk of immune rejection, no stitches, shorter surgery duration, and the use of topical anesthesia. However, stromal allograft rejection is still possible, so studies on the decellularization of the lenticules aim to reduce or halt the immune response without affecting the collagen architecture [ 33 ]. Furthermore, once restored corneal thickness and biomechanics, excimer refractive treatment is allowed, thus opening up new chances to improve visual outcome to KCN patients [ 19 , 34 ]. CXL can play a role also in advanced stages which already underwent lamellar or penetrating keratoplasty, by improving biomechanical and topographic indices in recurrent keratoconus (RKC) [ 35 ]. Some authors proposed AK combined with CXL to strengthen treatment of mild-to-moderate keratoconus [ 36 ] or CXL combined with excimer refractive treatment after AK to prevent secondary ectasia [ 19 , 34 ].

Among the emerging techniques for advanced stages, there are also Bowman layer transplantation (BLT) and gene therapy [ 37 ]. BLT is a mini-invasive technique that reinforces and flattens the cornea with secondary more comfortable CL wearing and stabilization of the ectasia slowing down disease progression and delaying the need for DALK or PKP [ 38 ].

Gene therapy is another innovative option to address KCN. Many studies have shown a genetic component in the etiology of the disease and genome-wide analyses have identified mutations and genomic loci likely to play a role in KCN development. Biophysical properties of the cornea (immune privilege, transparency, and stability) make this tissue an appropriate candidate for gene therapy. The basics of the technique are the same as for other tissues: the target gene sequence is modified by means of a viral vector which integrates into the cell DNA. The modified sequence provides translation of a healthy and functional protein so that the disease could be healed [ 39 , 40 ]. Despite recent advantages in vectors and in the ability to modulate corneal milieu to increase gene therapy acceptance, more studies are still needed.

The aim of the topical collection “New treatments for KCN” is to draw attention to the various treatments available, providing the reader with an overview on the options, their upsides, their limitations, and their possible future developments.

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Pedrotti, E., Chierego, C., Bonacci, E. et al. New treatments for keratoconus. Int Ophthalmol 40 , 1619–1623 (2020). https://doi.org/10.1007/s10792-020-01455-9

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• Review Article
• Published: 16 July 2020

A review of imaging modalities for detecting early keratoconus

• Xuemin Zhang 1 ,
• Saleha Z. Munir   ORCID: orcid.org/0000-0002-6010-9513 1 ,
• Syed A. Sami Karim 1 &
• Wuqaas M. Munir   ORCID: orcid.org/0000-0001-8070-6668 1  

Eye volume  35 ,  pages 173–187 ( 2021 ) Cite this article

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• Corneal diseases

Early identification of keratoconus is imperative for preventing iatrogenic corneal ectasia and allowing for early corneal collagen cross-linking treatments to potentially halt progression and decrease transplant burden. However, early diagnosis of keratoconus is currently a diagnostic challenge as there is no uniform screening criteria. We performed a review of the current literature to assess imaging modalities that can be used to help identify subclinical keratoconus.

A Pubmed database search was conducted. We included primary and empirical studies for evaluating different modalities of screening for subclinical keratoconus.

A combination of multiple imaging tools, including corneal topography, tomography, Scheimpflug imaging, anterior segment optical coherence tomography, and in vivo confocal microscopy will allow for enhanced determination of subclinical keratoconus. In patients who are diagnostically borderline using a single screening criteria, use of additional imaging techniques can assist in diagnosis. Modalities that show promise but need further research include polarization-sensitive optical coherence tomography, Brillouin microscopy, and atomic force microscopy.

Conclusions

Recognition of early keratoconus can reduce risk of post-refractive ectasia and reduce transplantation burden. Though there are no current uniform screening criterion, multiple imaging modalities have shown promise in assisting with the early detection of keratoconus.

目的: 早期发现圆锥角膜对预防医源性角膜扩张以及实施早期角膜胶原交联治疗避免其潜在进展和减少移植负担十分必要。然而, 由于没有统一的筛查标准, 当前圆锥角膜的早期诊断具有挑战性。我们对现有的文献进行了回顾分析, 以评估有助于识别亚临床圆锥角膜的影像学手段。方法: 我们检索了Pubmed数据库, 纳入评估亚临床圆锥角膜不同筛查方式的初步及试验研究。结果: 多摸式影像学检查手段: 角膜地形图、断层扫描、Scheimpflug成像、眼前节光学相干断层扫描和活体共焦显微镜等可提高亚临床圆锥角膜的检测率。对于在单一筛选标准临界值的患者中, 使用额外的成像技术有助于诊断。有临床应用前景但需要进一步研究的方法包括偏振敏感光学相干断层扫描、brillouin显微镜和原子力显微镜。结论: 识别早期圆锥角膜可以减少屈光后扩张的风险及移植负担。尽管目前没有统一的筛查标准, 但多种影像学手段已显示出圆锥角膜早期发现的前景。

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Introduction.

Keratoconus is a noninflammatory, asymmetric corneal disorder characterized by progressive corneal thinning and protrusion, with resulting compromise in quality of vision [ 1 ]. Keratoconus was first described by Dr. Benedict Duddell in 1736, and later more precisely explained in written descriptions by Dr. John Nottingham in 1854 [ 1 ]. Keratoconus can be associated with Down syndrome, connective tissue disorders, Leber’s congenital amaurosis, atopy, persistent eye rubbing, and hard contact lens wear [ 2 , 3 ]. Clinical manifestations, such as Vogt striae, Fleischer’s ring, conical corneal protrusion, and topographic changes, occur in later stages of the disease [ 2 ].

Keratoconus is a bilateral condition, but it may take years before the fellow eye of a patient with keratoconus manifests any clinical signs. “Forme fruste keratoconus” or subclinical keratoconus can be used to describe eyes in which there are only mild topographic changes, but no clinical findings, with manifest keratoconus in the fellow eye. Keratoconus suspect is used to describe patients with eyes suspicious for keratoconus on topography without clinical findings, but the fellow eye does not have keratoconus [ 1 ].

Accurate screening for keratoconus suspects is imperative when evaluating refractive surgery candidates given the risk for iatrogenic corneal ectasia [ 4 ]. Furthermore, early identification of keratoconus patients allows for early corneal collagen cross-linking treatments, which protects against further corneal deformation and has already been shown to reduce transplantation burden [ 5 ].

Unfortunately, the detection of early keratoconus is currently a diagnostic challenge as there are often no presenting clinical signs and no uniform screening criteria available [ 6 ]. Neither of the current keratoconus classification or staging systems, including the Keratoconus Severity Score from the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study nor the Amsler-Krumeich classification, provide guidelines for the detection of early keratoconus [ 7 ].

Gomes et al. used the Delphi method to attempt to generate a consensus with regards to definitions, diagnosis, and management of keratoconus [ 3 ]. The panel mentioned abnormal posterior corneal ectasia, epithelial thickness distribution, and clinical noninflammatory thinning as findings to diagnose keratoconus. They also mentioned steepening of the anterior surface, posterior surface, and the rate of corneal thinning as potential factors to monitor for documenting progression [ 3 ]. However, the Delphi panel spurred much debate as to the validity of using current posterior corneal measurement modalities [ 8 , 9 ]. As such, there is currently no accepted universal guideline to address diagnosis nor to document progression in keratoconus.

Given the importance of identifying forme fruste keratoconus and keratoconus suspects due to the lack of uniform criteria, this review will discuss current imaging modalities and advancements on the horizon that can be used to help detect early keratoconus.

A Pubmed database search was conducted. A total of 599 articles published from 1971 to 2019 were found in relation with keratoconus imaging, subclinical keratoconus, and forme fruste keratoconus. Of these, 100 articles were included in this analysis. We included primary and empirical studies. Exclusion criteria included case reports, non-English studies, and articles unrelated to the primary subject of this review.

Keratometry

The first keratometer, originally known as an ophthalmometer, was invented by Hermann Von Helmholtz in 1855 [ 10 ]. This was the first instrument described to measure the corneal radius in a living human eye. Later, a modified version of this device was introduced to the ophthalmic community by Javal and Schiotz, which made it easier to clinically measure corneal astigmatism and its axis [ 10 ]. The keratometer uses subjectively aligned mires to find minimum keratometry ( K ) and maximum K readings and their axes using four points that are focused on the 3.0–4.0 mm central corneal zone.

Distorted mires, steep corneas, and high astigmatism using a manual keratometer (Javal Schiotz or Bausch and Lomb) or automated keratometry may signify keratoconus. Although a keratometer is an inexpensive and easy to use tool in detecting corneal astigmatism, the measurements are limited to the central corneal curvature. Further, though it is accurate for regular spherocylindrical surfaces, it is not reliable when assessing irregular corneas. Qualitative visualization of the mires through manual keratometry is an excellent way to diagnose keratoconus, but it is more time intensive, decreasingly available, and less familiar to most providers who now rely on advancing qualitative technologies. When assessing repeatability of multiple devices, Hashemi et al. found that manual keratometry had comparable repeatability to other more advanced imaging modalities, though this is dependent on user experience. Similar to other devices, when the maximum K was >55.0 D, the manual keratometer had reduced measurement reliability [ 11 ]. More advanced technologies now rely on more quantitative data, which for better or for worse rely less on user experience.

Photo/video keratoscopy

Corneal topography refers to anterior corneal surface imaging. The most commonly used technology is Placido disc-based imaging, a noninvasive technique to analyse the anterior corneal surface quantitatively and qualitatively. It is currently the gold standard imaging modality in evaluating corneal ectasia [ 12 ]. The Placido disc is the oldest and most widely used topography method derived from the development of the Goode keratoscope by Antonio Placido da Costa in 1880 [ 13 ]. This device reflected concentric black and white rings off of the patient’s tear film, allowing analysis of the spaces between them to assess corneal curvature data. Similarly, hand-held keratoscopes are currently used at the slit lamp for a rapid qualitative assessment of topography using the reflection of seven concentric rings. The resulting mires are used to infer information, such as mires that are closer together represent steeper corneal curvature, whereas, widely spaced mires represent flatter curvature [ 13 ].

Current Placido disc-based corneal topographers, or photo/video keratoscopes, are devices that use photographs of Placido disc reflections off the anterior corneal surface and provide quantitative information by generating curvature maps using computational technology. The axial or sagittal curvature map measures the corneal curvature from the optical axis and assumes the corneal surface to be spherical, thus providing both a qualitative assessment through the use of differing colors and a global assessment of corneal curvature (Fig.  1 ). The tangential (or instantaneous) map measures the corneal surface based on the local curvature radii and more accurately reflects the peripheral cornea, thus providing higher data sensitivity [ 13 ].

Topography of a patient with a pattern diagnosis revealing a classic asymmetric bowtie pattern with skewed radial axis consistent with keratoconus.

Placido disc-based corneal topography can generate indices that quantify the amount of corneal surface irregularities [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Several indices have been evaluated and found to be sensitive in detecting keratoconus (Table  1a , b ). Maeda et al. used the average of simulated keratometry (SimK) values >45.7 to be 84% sensitive for clinical keratoconus, but misclassified 40% of the maps with mild keratoconus [ 16 ]. Though not specific, corneal wavefront aberrations such as vertical and total coma, corneal total higher-order aberrations, and higher-order astigmatism have also been shown to be significantly higher in subclinical keratoconus as compared with keratoconus [ 17 ].

Several multivariate keratoconus systems have also been evaluated with varying sensitivities and specificities (Table  2 ). The modified Rabinowitz–McDonnell test, characterized by K value >47.2 D and/or inferior–superior (I–S) value of >1.4 D, has been described in detecting keratoconus [ 23 ]. The modified Rabinowitz–McDonnell test has been found to be 96% sensitive and 85% specific in detecting keratoconus [ 16 ]. Maeda et al. developed the keratoconus prediction index (KPI), which is calculated through a discriminant analysis of eight topographic indices, including SimK1 (SimK value for the major axis), SimK2 (SimK value for the minor axis), surface asymmetry index, differential sector index, opposite sector index, center/surround index, and analysed area [ 19 ]. A KPI value of >0.23 is thought to be suggestive of keratoconus and was found to have a sensitivity of 89% and specificity of 99% for detecting keratoconus [ 19 ]. Neither of these tests were designed to identify keratoconus suspects. The keratoconus percentage index (KISA%) is an index derived from multiplying the K value, I–S value, keratometric astigmatism index (AST), and relative skewing of the steepest radial axes [ 20 , 22 ]. A KISA% index of >100% was noted to be sensitive and specific for diagnosis of keratoconus. Rabinowitz further suggested that a KISA% index of 60–100% can be used to diagnose suspects [ 22 ]. Smolek and Klyce trained a neural network using ten different topographic indices as network inputs to detect keratoconus suspects, with the keratoconus severity index (KSI) [ 18 , 24 ]. A KSI value of <15% is considered normal, whereas, values between 15 and 30% are considered as keratoconus suspects, and values >30% are subclinical keratoconus [ 18 ].

Of note, the use of Placido-based corneal topography generates both intrinsic errors derived from the device itself and extrinsic errors derived from unmeasured patient factors, such as inadequate eyelid opening, poor patient focus, and poor tear film quality. Since Placido-based systems rely on curvature maps, they do not represent true elevation. This can lead to false assumptions about the simulated elevation of the cornea [ 13 ]. Corneal irregularity may lead to inaccurate topographic maps, thus making it difficult to differentiate keratoconus from contact lens-induced warpage [ 25 ], poor tear film quality, or lid artefact using topography alone [ 19 ]. More importantly, there is concern that topography does not detect all patients with subclinical keratoconus or those at risk for post-refractive ectasia. Randleman et al. reported that the preoperative topography was normal in 27% of 93 patients who developed post-refractive surgery corneal ectasia [ 9 ].

Corneal tomography (visible light-based)

Dynamic skiascopy.

The NIDEK OPD-scan wavefront analyzer (NIDEK Co Ltd, Gamagori, Japan) provides an axial curvature map, keratometry data, and a Placido disc image (Fig.  2 ). It combines placido-disc-based corneal topography with a ray tracing aberrometer, based on the principle of dynamic retinoscopy, to provide information on the anterior cornea along with refractive error, keratometry, and the patient’s quality of vision [ 13 ]. The OPD scan also provides optical path difference (OPD) maps which detects total refractive error in the eye as well as the refractive error contributed by the internal structures of the eye [ 26 ]. The NIDEK OPD scan has been used to evaluate the quality of vision in patients with keratoconus after corneal transplants [ 27 ], after intracorneal ring segment implantation [ 28 ], and after accelerated corneal cross-linking [ 29 ]. Asgari et al. evaluated mild and moderate keratoconus eyes after accelerated cross-linking and found that the OPD scan III had higher aberrometric repeatability in mild compared with moderate cases [ 30 ]. Further studies are needed to use NIDEK OPD scan in patients with forme fruste keratoconus.

The optical path difference (OPD) map, a representation of total refractive error of the eye, reveals inferior steepening (top left image). The axial curvature map is a placido-derived interpolation of the anterior corneal surface, displaying inferior steepening consistent with keratoconus (top middle image). The internal OPD map, which displays only the refractive error contributed by internal structures of the eye, suggesting an internal ocular contribution to the appearance of the OPD map (top right image). The mesopic map displays the corneal light reflex in comparison to angle alpha and angle kappa, the difference of which can be elevated in keratoconus (bottom left image). Higher-order astigmatism and increased corneal wavefront aberrations are also noted in keratoconus (bottom middle image). The Placido disc reveals concentric mires with noted steepening and irregularity inferiorly consistent with keratoconus (bottom right image).

Slit-scanning topography

The Orbscan (Bausch and Lomb, Rochester, NY, USA) uses slit-scanning technology to provided anterior and posterior elevation, keratometry maps, and wide-field pachymetry. Orbscan II is a later version that also added Placido-based topography analysis [ 1 ]. The Orbscan system has been found to provide useful information in detecting subtle changes in early keratoconus [ 31 ]. The Orbscan system incorporates anterior corneal curvature indices, pachymetry, and assessment of focal elevations and depressions from computer-generated best-fit sphere [ 32 ]. An I–S value of greater than or equal to 1.2 D, average central keratometry of greater than or equal to 47.2, posterior float of greater than or equal to 42 μm, and thinnest point pachymetry of less than or equal to 463 μm have been considered as abnormal and concerning for subclinical keratoconus [ 32 ].

Rao et al. has combined videokeratography screening with Orbscan II to detect eyes at high risk of post-refractive surgery ectasia. They chose a value of posterior elevation greater than 40 μm, or two standard deviations from the mean posterior elevation in normal eyes, as a sign of forme fruste keratoconus [ 33 ]. Slit-scanning technology had fallen out of favor due to low resolution and prolonged image acquisition time leading to artefact. However, Orbscan 3 was recently introduced, with studies ongoing as to its comparability to other modern instruments [ 34 ].

Scheimpflug imaging

The Pentacam Scheimpflug system (Oculus, Wetzlar, Germany) has a 180° rotating Scheimpflug camera, which allows creation of a pachymetric map, characterization of the anterior chamber angle, and measurement of both the anterior and posterior surfaces of the cornea [ 1 ] (Fig.  3 ).

Axial power and tangential maps are displayed in the left column, pachymetry and relative pachymetry map in the middle, and elevation of the anterior and posterior cornea relative to reference surfaces in the right column, with similar inferocentral “hot spot” regions across various maps indicative of keratoconus.

Elevation maps are derived from comparing the reconstruction of the anterior and posterior surface to a best fitted surface, such as a sphere, toroid, revolution ellipsoid or non-revolution ellipsoid with a typical reference of 8 mm, thus providing anterior and posterior elevation of corneal apex, as well as elevation of the minimum thickness point. The pachymetric map is also reconstructed based on the anterior and posterior corneal surfaces [ 21 ].

The Pentacam measures both the anterior and posterior surface elevation and fits a best-possible sphere, toric ellipsoid, or ellipse to both surfaces. Apical protrusion can steepen the best-fit surface, thus decreasing the difference between the best-fit surface and cone apex. The Belin/Ambrỏsio Enhanced Ectasia Display of the Scheimpflug system circumvents this problem by generating an enhanced best-fit sphere that excludes a 3.0–4.00 m area of thinnest pachymetry when calculating the reference image [ 35 ]. The “Belin ABCD” keratoconus grading system has also been incorporated in the OCULUS Pentacam software version 6.08r16 [ 36 ]. It uses the anterior (“A”) and posterior (“B” for back surface) radius of curvature taken from a 3 mm zone over the thinnest corneal area and corneal thickness (“C”) at the thinnest point, as well as distance best corrected visual acuity (“D”) to assess keratoconus stage, and is graded from stages 0 to 4 [ 37 ]. The 3.0 mm zone corresponds to the Belin/Ambrosio Enhanced Ectasia Display exclusion zone, and contains the most ectatic area on the cornea [ 38 ]. It also adds a modifier of “−” for no scarring, “+” for scarring that does not obstruct iris details, and “++” for scarring that does obstruct iris details. The anterior corneal curvature in stages 1–4 have been found to correlate with the Amsler-Krumeich classification. It allows for the posterior corneal surface to be assessed, unlike the traditional Amsler-Krumeich classification system or the CLEK classification system [ 36 ]. The Belin ABCD keratoconus grading system grades the anterior and posterior corneal surfaces and thus may better depict further structural and functional changes in the cornea, however further research is needed to define parameters to assess subclinical keratoconus. Sedaghat et al. found that there was significant change in the anterior and posterior radii of curvature of the 3.0 mm zone, as well as significant improvement in corrected distance visual acuity, but no change in corneal thickness, after Keraring implantation in keratoconus patients [ 39 ].

In comparing subclinical keratoconus eyes to eyes with myopic astigmatism, Cui et al. found that the difference between central corneal thickness and minimum corneal thickness of more than 5.5 μm seemed to have the best predictive accuracy for subclinical keratoconus [ 40 ]. Corneal densitometry, or corneal backscatter, which has been implicated in ocular surface disease, has been shown to be elevated in the anterior layer and correlated with severity of corneal keratometry in keratoconus [ 41 ]. De Sanctis et al. found that posterior corneal elevation of greater than 29 μm could be used as a relatively specific (90.8%), but nonsensitive (68%) measure of detecting subclinical keratoconus [ 42 ]. They suggested that though posterior corneal elevation derived from the Pentacam cannot be used alone to diagnose subclinical keratoconus, that it can be adjunct to other factors [ 42 ]. Similarly Mihaltz et al. found that posterior elevation, with a cutoff value of 15.5 μm, was the most effective parameter to use in diagnosing keratoconus with 95.1% sensitivity and 94.3% specificity [ 43 ]. Muftuoglu et al. found that back difference elevation, or relative change in elevation from baseline elevation in a 4.0 mm exclusion zone over the thinnest point of the cornea, with a cutoff of 13.2 μm was able to detect forme fruste keratoconus with higher sensitivity (74%) and specificity (65%) than posterior elevation [ 44 ].

The Pentacam HR is a newer model that uses a high-resolution rotating Scheimpflug camera to further capture images of the anterior segment and obtain total corneal refractive power and distribution, anterior chamber angle and depth measurements, corneal and crystalline lens optical opacities [ 45 ]. The Pentacam AXL is the newest model which also integrates an axial length measurement [ 46 ].

The Sirius Corneal tomographer (Costruzione Strumenti Oftalmici, Firenze, Italy) has a single Scheimpflug rotating camera and Placido disc, but it only has a single 25 scan setting with 1 Placido image, as compared with the Pentacam which has 25 or 50 three-dimensional scans [ 47 ]. It is also able to derive anterior and posterior cornea, anterior lens, and iris profiles from the Scheimpflug images. Zhang et al. retrospectively analysed 1632 eyes using the Sirius imaging system, specifically evaluating the corneal anterior surface, posterior surface, and minimum thickness data in suspects and found statistically significant differences for those values in patients with subclinical keratoconus as compared with normal [ 47 ]. Arbelaez et al. applied a support vector machine, a machine learning classifier, to the corneal measurements provided by Sirius and were able to accurately classify eyes as normal, keratoconus, subclinical keratoconus, or abnormal [ 48 ]. They found posterior corneal curvature and pachymetric data to be important in the detection of subclinical keratoconus [ 48 ].

Dual Scheimpflug imaging

The Galilei camera (Ziemer Ophthalmic Systems AG, Port, Switzerland) is a relatively new device that is similar to the Pentacam in that it combines Placido disc-based corneal topography with elevation data from Scheimpflug technology, but has simultaneously recording dual rotating Scheimpflug cameras spaced 180° apart [ 49 ]. This has the benefit of tracking eye movements and decentration, thus reducing motion error especially with scans at oblique angles [ 50 ].

The indices that have been deemed diagnostically significant in assessing for forme fruste keratoconus include an irregular astigmatism index of >0.450, a standard deviation of corneal power >1.065, and a surface regularity index of >0.735 [ 50 ]. Feizi et al. analysed parameters measured using Galilei in 23 subclinical eyes when compared with normal and eyes with keratconus, and found that though surface indices and elevation data had a 100% predictive ability to distinguish keratoconus, none of the variables could independently detect subclinical keratoconus. They suggest that a 3-factor model with keratometric values, elevation data, and surface indices had the highest predictive value for detecting subclinical keratoconus [ 51 ]. Jafarinasab et al. evaluated the maximum anterior and posterior corneal elevation in the central 3.0, 5.0, and 7.0 mm zones using the Galilei camera. They found that the posterior elevation in the 3.0 mm zone best distinguished keratoconus from normal, but that the 7.0 mm zone with optimal cutoff for posterior elevation of 50.5 μm best distinguished subclinical keratoconus eyes with 79.9% sensitivity and 94% specificity [ 52 ].

Shetty et al. assessed the repeatability of several parameters using Pentacam, Galilei, and Sirius in 55 eyes of 55 patients with keratoconus. They found that the devices showed repeatability in mean keratometry, thinnest corneal thickness, anterior chamber depth, and mean posterior keratometry. However, it was noted that there were significant differences between the devices and thus cannot be used interchangeably for anterior segment imaging [ 53 ]. Similarly, in the assessment of repeatability using the Orbscan II, the Galilei, and the Pentacam HR by Meyer et al. keratometric and pachymetric measurements were disparate in keratoconus eyes, especially with the Orbscan. The Pentacam HR had the highest repeatability for keratometry measurements and the Galilei showed highest repeatability for pachymetry meaurements [ 54 ].

Anterior segment optical coherence tomography

While visible light-based tomography systems are very widely used and incorporate both anterior and posterior corneal indices and corneal thickness measurements to aid with the assessment [ 3 ], they are sensitive to poor ocular surface, have relatively long image acquisition time, and are unable to provide corneal anatomic detail [ 55 ]. Optical coherence tomography (OCT) may be able to overcome these limitations with higher resolution images and faster acquisition times, thus limiting motion artifact [ 56 ].

OCT is an imaging technique based on low-coherence interferometry using near-infrared light and is able to provide high-resolution information on tissue morphology, including thickness maps of the individual corneal layers [ 56 ] (Fig.  4 ). Spectral domain and swept-source OCT devices allow anterior and posterior topography, in addition to cross-sectional corneal imaging, with faster acquisition time while maintaining detail [ 57 ].

Focal corneal thinning is noted in this anterior segment optical coherence tomography which is consistent with keratoconus.

Time-domain optical coherence tomography (TD-OCT)

The Visante-OCT system (Carl Zeiss Meditec Inc, Dublin, CA, USA) has a scan speed of 2048 A-scans/s with eight radial scans that are centered on the cornea [ 58 ], and is currently the fastest available commercial TD-OCT system [ 59 ]. In this system, a combination of reflected light from the sample arm (i.e., the eye) and a reference arm (typically a mirror) gives rise to an interference pattern. When scanning the reference arm, a reflectivity profile or axial depth scan (A scan) is obtained. A cross-sectional tomography (B scan) can then be obtained by combining a series of A scans [ 59 ]. Li et al. [ 60 ] described an OCT pachymetry-based method using the Visante anterior segment OCT System (Carl Zeiss Meditec Inc.) to assess for focal corneal thinning in the central 5 mm zone, as well as asymmetric thinning in a 2–5 mm diameter zone in subclinical keratoconus. This was found to be comparable to a topography-based KISA% method for the diagnosis of keratoconus [ 60 ]. Qin et al. used five pachymetric variables and found that this further improved to diagnostic power, with the best single pachymetric variable being the minimum corneal thickness [ 61 ]. However, the clinical utility of these metrics remains limited, as ascertaining these measures requires manual intervention given no analytical software is included on this platform. Further, the acquisition time of these systems is limited due to the required cycle time of the reference mirror.

Spectral-domain OCT (SD-OCT)

Instead of a reference arm moving as in time-domain OCT, a stationary mirror allows for higher speeds and thus improved resolution in SD-OCT. The sample and reference reflections produce interference that is detected as spectrum, and subsequent fourier transformation of the subsequent spectral interferogram produces the A scan [ 59 ]. Available instruments include RTVue-OCT (Model RT100, Optovue Inc, Fremont, CA, USA), 3D OCT-1000 (version 3.01, Mark II; Topcon Corporation, Tokyo, Japan), Cirrus OCT (version 3.0, Model 4000; Carl Zeiss Meditec, Inc., Dublin, CA), and Spectralis OCT (Heidelberg Engineering, Germany).

The RTVue-OCT with corneal module has a scan speed of 26,000 A-scans/s, with a scan beam wavelength of 8409 nm, axial resolution of 5 μm, and transverse resolution of 8 μm. The low magnification cornea anterior module (CAM-L) is a lens adapter to allow for assessment of the cornea when used with the RTVue-OCT [ 59 ]. The RTVue-OCT is one of the few instruments that includes analytical software that can generate keratoconus analysis tables using the thinnest corneal pachymetry. It was found to correlate with the time-domain OCT system, but generated higher thinnest corneal thickness readings for normal eyes compared with the time-domain OCT [ 58 ]. Li et al. found that with RTVue-OCT, corneas with subclinical keratoconus had significantly higher corneal epithelial, stromal, and pachymetric pattern standard deviation scores. They found the epithelial pattern standard deviation of >0.041 to be 96% sensitive and 100% specific for detecting subclinical keratoconus. Li et al. also assessed corneas with Cirrus HD-OCT, and determined five pachymetric diagnostic parameters to assess focal and asymmetric thinning in keratoconus based on an OCT pachymetric map focused on the central 5 mm zone [ 60 ].

Swept-source optical coherence tomography (SS-OCT)

Swept-source anterior segment optical coherence tomography (SS-OCT) devices use low-coherence interferometry using a long wavelength scanning-laser source and balanced photodetectors to analyse the anterior and posterior cornea [ 62 , 63 ]. Both SS-OCT and SD-OCT use Fourier domain detection, however SS-OCT instruments use a tunable swept laser with a wavelength of around 1050 nm and a single photodiode detector as compared with SD-OCT which uses a broadband near-infrared superluminescent diode as a light source with a wavelength of around 840 nm. SS-OCT has an even faster scanning speed and uses a longer laser wavelength and higher laser power, which allows for improved signals detection of deeper layers [ 64 ].

Steinberg et al. found that when using SS-OCT (Casia SS1000; Tomey Corp, Inc, Nagoya, Japan) with a combination of automated and newly-calculated parameters, it is capable of a high specificity (93%) but low sensitivity (51%) in detecting subclinical keratoconus [ 62 ]. The Casia analysis program is able to calculate keratometric, anterior, posterior, pachymetric, and Fourier indices based on anterior and posterior corneal surface data. The automated parameters with highest accuracy for detecting subclinical keratoconus include Fourier indices based on higher-order irregular astigmatism and asymmetry. The newly generated variables were based on asymmetry between upper and lower corneal hemispheres, and based on changes that occur surrounding the thinnest corneal thickness or point of maximum keratometry progression [ 62 ]. They found that while posterior corneal elevation effectively distinguished keratoconus eyes from normal eyes, that it should not be used as a stand-alone parameter for diagnosing subclinical eyes [ 62 ]. Gutierrez-Bonet et al. found that choroidal vascularity, choroidal, stromal, and vascular areas were thicker in keratoconus patients using SS-OCT, though the reason behind the changes is not yet known [ 65 ].

SS-OCT has been noted to have good agreement with a Scheimpflug system on most values of the anterior and posterior corneal keratometry indices [ 66 ] and was found to have better repeatability of measuring corneal thickness and posterior corneal elevation [ 63 ]. Jhanji et al. found that SS-OCT demonstrated better reproducibility coefficients and intraclass correlation coefficients as compared to slit-scanning tomography [ 67 ].

Epithelial mapping

The corneal epithelium can change and rebuild itself in response to changes in the stroma and thus can prevent early diagnosis of keratoconus using topography. Thus, evaluating epithelial thickness can be a useful tool in assessing early stages of keratoconus. High-resolution OCT, very-high frequency digital ultrasound, or confocal imaging can all be used to evaluate this, however OCT benefits from being noncontact and an extremely low acquisition time thus reducing motion artefact. With epithelial mapping, Temstet et al. found that a thin epithelial thickness in the thinnest corneal zone with a cut-off point of 52 μm differentiated forme fruste keratoconus from normal eyes with a 88.9% sensitivity and a 59.5% specificity [ 68 ]. Ostadian et al. found that patients with subclinical keratoconus had lower minimum epithelial thickness as well as compensatory thickening in the inferior and one eighth of the temporal aspect of the SD-OCT corneal epithelial map [ 69 ]. Li et al. found that keratoconus eyes had larger pattern and map standard deviation, more negative minimum–maximum, greater superior–inferior, and lower inferior and minimum corneal epithelial thickness values [ 70 ]. Similarly, Rocha et al. found apical epithelial thickness to be significantly thinner in keratoconus eyes, with increased variability [ 71 ].

Polarization-sensitive optical coherence tomography (PS-OCT)

PS-OCT measures birefringence of tissue and is used to study the microscopic structure of fibrous tissues [ 72 ]. It is able to provide information on distribution of birefringence, unlike conventional OCT. A superluminescent diode emits a vertically polarized low-coherence beam, which is then split into sample and reference beams [ 72 ]. After the beams rotated and processed through tissue, the beams combine and are then split again by a polarizing beam splitter to be recorded by photodetectors [ 72 ]. Corneal tissue is optically birefringent, with stroma composed of 200 lamellae of parallel collagen fibrils. The fibrils in different lamella are typically oriented orthogonally to each other, with birefringent properties that thus cancel each other out [ 73 ].

In keratoconus corneas, the typical parallel collagen fibril arrangement is disrupted and thus results in a change in birefringence [ 72 , 74 ], resulting in a change in net retardation and optic axis orientation [ 72 , 73 , 75 ]. Fukuda et al. found that some cases of keratoconus suspects had increased birefringence and no alterations in posterior elevation, suggesting that collagen fiber changes may actually develop before posterior corneal elevation changes [ 76 ]. PS-OCT may be able to detect disruptions in fibril arrangement in subclinical keratoconus and could potentially be applied to clinical use in the future.

In vivo confocal microscopy

Slit confocal microscopy.

While other imaging modalities assess corneal curvature and elevation, confocal microscopy assesses the corneal architecture at the cellular level. Ozgurhan et al. suggests that anterior and posterior stromal keratocyte density are lower in subclinical keratoconus, and even lower in keratoconus as compared with controls [ 77 ]. On the other hand, Weed et al. found that anterior and posterior stromal keratocyte density increased in moderate and advanced keratoconus [ 78 ]. Erie et al. suggests that there is no difference in keratocyte density between keratoconus patients and controls, but that keratoconus patients who were also contact lens wearers did have 10% lower keratocyte density [ 79 ].

Ucakhan et al. reports that elongated superficial epithelial cells, stromal folds, thickened subbasal nerves, and increased pleomorphism and polymegathism of endothelial cells are suggestive of keratoconus [ 80 ]. Ozgurhan et al. also suggests that mean subbasal nerve density and mean stromal nerve diameter are higher in patients with subclinical keratoconus as compared with normal eyes [ 77 ]. Given limited studies and conflicting findings, confocal microscopy currently remains of limited diagnostic value for subclinical keratoconus, but may eventually serve as a good adjunctive method for diagnosis.

Noncontact tonometry

It is thought that biomechanical alternations of the cornea are related to the onset of keratoconus [ 74 , 81 ] and can also be useful in monitoring efficacy of cross-linking [ 5 ]. Other imaging modalities using videokeratography or OCT can detect alterations in shape of cornea, but they are unable to measure biomechanical structural changes in corneal morphology [ 82 ].

Two such examples of this technology are the Ocular Response Analyzer (ORA, Reichert, Inc., Depew, NY) and the CorVis ST (CST; Oculus, Wetzlar, Germany). The ORA uses a rapid air pulse to indent the cornea and uses an electro-optical system to record pressure measurements. The pressure when the cornea is indented is recorded and the pressure when the cornea moves back outward is recorded as well, thus allowing for dynamic bidirectional applanation [ 83 ]. Corneal hysteresis is the difference between these measurements and reflects corneal viscosity. Corneal resistance factor can also be calculated from these values and represents the overall resistance of the cornea [ 83 ]. Although outside the scope of this imaging review, Schweitzer et al. suggest that corneal hysteresis and corneal resistance factor provided by ORA can provide information in screening for subclinical keratoconus, but have been to be insufficient alone in identifying subclinical keratoconus [ 84 , 85 , 86 ].

The CorVis ST is another commercially available device that uses a single air puff to cause deformation of the cornea, and uses a Scheimpflug camera to record the response of the cornea [ 87 , 88 ]. The Corvis records A½ length, A½ velocity, highest concavity deformation amplitude, radius of curvature, peak distance, central corneal thickness, and intraocular pressure [ 89 ].

Wu et al. noted that two indices, the radius value of the central concave curvature at highest concavity and the central corneal thickness, were increased in subclinical keratoconus patients using the CorVis ST [ 90 ]. Vinciguerra et al. found that the Corvis Biomechanical Index (CBI), which encompasses multiple corneal deformation characteristics, to be 100% specific and 94.1% sensitivity with a cutoff value of 0.5 in correctly classifying keratoconus eyes from healthy eyes [ 88 ]. Another parameter, the tomographic and biomechanical index (TBI) with a cutoff value of 0.76 provided 100% sensitivity and 100% specificity for detecting clinical ectasia [ 42 ]. In a case series of 12 patients with normal topography and tomography, Vinciguerra et al. further demonstrated an early evidence of biomechanical abnormalities in subclinical keratoconus eyes using CBI [ 82 ]. In a comparison between corneal tomography, Pentacam HR, and Corvis ST, Kataria et al. demonstrated that the TBI with a 0.63 cutoff actually showed the highest diagnostic accuracy for detecting eyes with mild ectasia [ 91 ]. Though further studies are needed, biomechanical analysis may be able to complement other modalities in diagnosing subclinical keratoconus.

Brillouin light-scattering microscopy

Brillouin microscopy is a noninvasive way to assess corneal mechanical changes. Brillouin spectroscopy measures the interaction between laser light (photons) and thermally generated acoustic vibrations (phonons). Thermal motion of atoms in the cornea generates acoustic vibrations, which lead to scattering of light. The frequency of scattered light is different from incident light, and is referred to as a Brillouin frequency shift. In a cornea, the Brillouin frequency shift allows for measurement of the bulk elastic modulus of the cornea [ 92 ]. The Brillouin system is comprised of a light source or laser on the cornea, and a high-contrast analyser to measure the frequency shift of the scattered light.

In corneas with keratoconus, it has been proposed that the degeneration of the cornea occurs in a focal fashion, rather than a generalized weakening, which then causes a cycle of strain and subsequent thinning of the cornea [ 81 ]. Brillouin light-scattering microscopy seems to validate this point. In early stage keratoconus, Brillouin light-scattering microscopy showed that cone regions had lower Brillouin shifts as compared with outside-cone regions [ 92 , 93 ]. The Brillouin frequency shift increases with age at ~4 MHz per decade in normal corneas, whereas the central aspect of keratoconus corneas have a significantly smaller Brillouin frequency shift both in vivo and ex vivo [ 94 ]. Furthermore, the Brillouin frequency shift has been found to correlate with geometric keratoconus indices at the point of maximum posterior elevation [ 92 ]. Unfortunately, Seiler et al. all found that a single measurement of Brillouin frequency shift to not be sensitive nor specific enough to detect early keratoconus [ 94 ]. Webb et al. were able to use Brillouin microscopy to assess for any localized stiffening in the cornea, and found that there was no change after cross-linking [ 95 ].

Atomic force microscopy (AFM)

While this modality is not yet in clinical use, atomic force microscopy can be used to assess both topographic and biomechanical properties of tissue [ 96 ]. AFM uses a laser beam reflected from the back of the cantilever which is scanned across the eye and detected by a position-sensitive photodiode. In addition, the cantilever tip can also indent tissue to assess stiffness of tissue. Dias et al. used atomic force microscopy to assess 24 human cadaver eyes and found that the stiffness of the anterior corneal stroma increased significantly after cross-linking [ 97 ]. Further studies are needed to assess how it may apply to clinical diagnostic criteria.

Optical coherence elastography (OCE)

OCE is able to assess localized mechanical stress on the cornea via a noncontact based system such as an air puff or a contact-based system such as anaesthetic drops, coupled with the use of OCT to track the corneal deformation [ 98 , 99 ]. Singh et al. describes the ability to separate phase velocities of the elastic wave in different layers of the cornea, and found that this method was able to detect a change in elasticity in porcine corneas after cross-linking [ 100 ]. Though studies are currently limited, this may serve to be an alternate technique to noninvasively and accurately assess local biomechanical corneal distortions.

The detection of subclinical keratoconus is challenging as there are no uniform diagnostic criteria. As shown by the response to the attempt by Gomes et al. to establish a global consensus, such a conclusion remains elusive [ 3 ]. Despite the availability of multiple imaging modalities, there is still controversy with regards to detecting subclinical keratoconus. When assessing patients prior to refractive surgery, being conscious of multiple modalities for diagnosing subclinical keratoconus can aid in improved diagnosis and reducing risk of post-refractive ectasia (Table  3 ). Furthermore, accurate early identification of keratoconus can allow for earlier cross-linking treatments and thus decrease future disease burden. Further studies are needed to better identify a universal set of criteria to identify subclinical keratoconus. Technologies such as polarization sensitivity OCT, atomic force microscopy, Brillouin light-scattering microscopy, and optical coherence elastography may be promising new modalities that can be adapted into clinical practice.

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Zhang, X., Munir, S.Z., Sami Karim, S.A. et al. A review of imaging modalities for detecting early keratoconus. Eye 35 , 173–187 (2021). https://doi.org/10.1038/s41433-020-1039-1

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How to use topography-guided laser procedures to treat keratoconus

Topography-guided PRK, with or without the addition of corneal crosslinking, can improve visual acuity and quality in patients with keratoconus.

There are many conditions that can cause irregular corneal surfaces, one of which is keratoconus. Surgeons looking for new approaches to treat keratoconus and improve patients’ vision should consider topography-guided treatment in combination with crosslinking. This is especially, but not exclusively, effective in the early stages of the condition, where crosslinking might be used to halt its progression before the corneal refractive procedure is applied.

Key considerations

It should be noted that treating patients with keratoconus using laser-vision correction is an off-label procedure that should be approached with caution and only after taking into consideration many factors, discussed as follows.

Patient age

If a patient is older than 40 years, I do not primarily offer crosslinking because nature itself performs crosslinking once a person reaches a certain age. 1,2 Such patients can undergo photorefractive keratectomy (PRK) or topography-guided PRK without crosslinking to achieve stable results without any progression of keratoconus if they are followed up for 12 months with stable topography. 1

The refraction will not be fully altered down to zero because the regularity must come before the refraction. In keratoconus patients the refraction is not usually the main problem.

Corneal thickness

If the cornea is too thin or too steep, for example with a reading of 65 K, topography-guided treatment for the keratoconus procedure is not effective. To be a suitable candidate, a patient must have a calculated corneal thickness of at least 400 µm at the thinnest point after the topography-guided treatment.

For example, if a patient has a corneal thickness of 470 µm and receives the treatment for 70 µm, that leaves another 400µm of residual tissue following the laser treatment. I then feel comfortable with the procedure, safe in the knowledge the patient will be okay postoperatively.

Stage of keratoconus

Typically, the early stages of keratoconus are in younger patients and the condition is progressive until the age of 30. 2 For patients aged between 25 and 30 years, I do a combination topography-guided session, which means I perform a topography-guided treatment followed by crosslinking immediately afterwards.

Patients aged over 40 years can start to experience a decrease in vision because they no longer tolerate contact lenses. In these patients, I am happy to perform topography-guided treatment without crosslinking. However, all these patients must show up for regular follow-up every 6 months and I would perform crosslinking in cases of progression.

Other considerations

A high number of patients with keratoconus also suffer from atopic disease and do not tolerate rigid gas-permeable contact lenses.

Laser vision correction is not an ideal approach for treating keratoconus but might provide an alternative to corneal transplantation. Vision in patients with corneal transplants is limited to irregular astigmatism and they have a lifetime risk for corneal graft rejection in cases of penetrating transplantations.

Screening patients

The main reason I screen patients for topography-guided treatment to treat keratoconus is because they are unhappy with their glasses or do not tolerate their contact lenses. First, I consider the patient’s age. If the patient is young and does not achieve good vision with glasses, I recommend topography-guided treatment in combination with crosslinking.

If the patient is 40 years or older, then I consider corneal thickness, corneal steepening and how happy or unhappy the patient is with his or her visual acuity. If the visual acuity is better than 20/30, I do nothing.

If the visual acuity is less than 20/40, then I move forward with the procedure. The K reading must be 60 D or less and the corneal thickness must be at least 450 µm.

An adult refugee from Iran presented to me with keratoconus. He was referred to me by chance because I am of Iranian origin and can speak Farsi.

He had undergone crosslinking to stop the progression of keratoconus, in Iran, at the age of 32. His preoperative visual acuity was only 20/100 (Figure 1). His vision could not be increased with refraction and he was unable to tolerate contact lenses.

He shared that he could not read and was having trouble learning the German language because the courses he was undertaking were in German and he was unable to see anything. He was the first patient I treated with topography-guided PRK because he had been crosslinked 4 years earlier.

Three months postoperatively, his vision had increased from 20/100 to 20/25 unaided. The difference map on the Pentacam (Oculus) was identical to the calculated ablation pattern (Figure 1). Four months later, I performed the same procedure on his second eye.

Surgical pearls

For surgeons who are new to topography-guided treatment, I recommend starting with the ‘topo smooth’ software of the CRS-Master (Carl Zeiss Meditec). This has the advantage that you do not need to perform any calculations. It is just ‘one click’.

If the patient is highly myopic, one can just reduce the sphere by 1 to 2 D but should not add astigmatism to the refraction because this can result in a refractive surprise. The optical zone should not be too big because the laser increases the treatment zone up to 9 mm including the transition zone. The optical zone should be 6 to no more than 6.5 mm, depending on how much tissue ablation is needed.

I also use a treatment-planning device (OCT Zeiss Cirrus 5000, Carl Zeiss Meditec) for epithelial mapping to assess how thick the corneal epithelium is. I can receive a calculation for the ablation and add the tissue.

This means if the patient has an epithelial thickness of 45 µm, I can add 45 µm in the calculation. Then I can perform a trans topography-guided PRK with the Mel 90 Excimer laser in one step, which makes it all easier.

All topography-guided PRKs in patients with keratoconus must be performed as transepithelial procedures. One should also never forget to apply 0.02% mitomycin to the treated area for 60–80 seconds to inhibit the development of corneal haze.

Topography-guided PRK can be a reasonable procedure, with or without the addition of corneal crosslinking, to increase visual acuity and quality. The procedure is easy to calculate and to perform.

Navid Ardjomand, MD E: [email protected] Prof. Navid Ardjomand is a consultant ophthalmic surgeon specialising in cornea, cataract and refractive surgery, and an associate professor at the Medical University Graz. He is a consultant for Carl Zeiss Meditec.

• Khakshoor H, Razavi F, Eslampour A, Omdtabrizi A. Photorefractive keratectomy in mild to moderate keratoconus: outcomes in over 40-year-old patients. Indian J Ophthalmol. 2015;63:157-161.
• Fujimoto H, Maeda N, Shintani A, et al. Quantitative evaluation of the natural progression of keratoconus using three-dimensional optical coherence tomography. Invest Ophthalmol Vis Sci . 2016;57: OCT169-OCT175.

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• Diseases & Conditions
• Keratoconus

To diagnose keratoconus, your eye doctor will review your medical and family history and conduct an eye exam. Other tests also may be done to find out more about the shape of your cornea. Tests to diagnose keratoconus include:

• Eye refraction. This test uses special equipment that measures your eyes. You may be asked to look through a device that contains wheels of different lenses, called a phoropter. This device helps judge which combination gives you the sharpest vision. Some doctors may use a hand-held instrument called a retinoscope to evaluate the eyes.
• Slit-lamp examination. This test involves directing a vertical beam of light on the surface of the eye and using a low-powered microscope to view the eye. The eye doctor evaluates the shape of your cornea and looks for other potential problems in the eye.
• Keratometry. This exam involves focusing a circle of light on the cornea and measures the reflection. This determines the basic shape of the cornea.
• Computerized corneal mapping. Special photographic tests, such as corneal tomography and corneal topography, record images to create a detailed shape map of the cornea. Corneal tomography also can measure the thickness of the cornea. This type of testing can often detect early signs of keratoconus before the disease is visible by slit-lamp examination.
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Our caring team of Mayo Clinic experts can help you with your keratoconus-related health concerns Start Here

Treatment for keratoconus depends on the severity of your condition and how quickly the condition is progressing. Generally, there are two approaches to treating keratoconus: slowing the progression of the disease and improving vision.

If keratoconus is progressing, corneal collagen cross-linking may be indicated to slow it or stop it from getting worse. This treatment aims to stabilize the structure of the cornea. It may decrease the bulging of the cornea and help achieve better vision with glasses or contact lenses. This treatment also has the potential to prevent you from needing a cornea transplant in the future.

Improving vision depends on the severity of keratoconus. Mild to moderate keratoconus can be treated with eyeglasses or contact lenses. This will likely be a long-term treatment, especially if the cornea becomes stable with time or from cross-linking.

In some people with keratoconus, the cornea becomes scarred with advanced disease. For others, wearing contact lenses becomes difficult. In these people, cornea transplant surgery might be necessary.

• Eyeglasses or soft contact lenses. Glasses or soft contact lenses can correct blurry or distorted vision in early keratoconus. But people frequently need to change their prescription for eyeglasses or contacts as the shape of their corneas change.
• Hard contact lenses. Hard contact lenses are often the next step in treating more-advanced keratoconus. Hard lenses include rigid, gas permeable types. Hard lenses may feel uncomfortable at first, but many people adjust to wearing them and they can provide excellent vision. This type of lens can be made to fit your corneas.
• Piggyback lenses. If rigid lenses are uncomfortable, your eye doctor may recommend "piggybacking" a hard contact lens on top of a soft one.
• Hybrid lenses. These contact lenses have a rigid center with a softer ring around the outside for increased comfort. People who can't tolerate hard contact lenses may prefer hybrid lenses.
• Scleral lenses. These lenses are useful for very irregular shape changes in your cornea in advanced keratoconus. Instead of resting on the cornea like traditional contact lenses do, scleral lenses sit on the white part of the eye, called the sclera, and vault over the cornea without touching it.

If you're using rigid or scleral contact lenses, make sure to have them fitted by an eye doctor with experience in treating keratoconus. You'll also need to have regular checkups to determine whether the lenses still fit well. An ill-fitting lens can damage your cornea.

Video: Keratoconus

Scleral contact lenses cover the white part of the eye and arch over the cornea. A protective layer of saline lies between the eye and contact lens. These lenses are a good alternative to surgery for many patients with keratoconus.

• Corneal cross-linking. In this procedure, the cornea is saturated with riboflavin eye drops and treated with ultraviolet light. This causes cross-linking of the cornea, which stiffens the cornea to prevent further shape changes. Corneal cross-linking may help to reduce the risk of progressive vision loss by stabilizing the cornea early in the disease.

You may need surgery if you have corneal scarring, extreme thinning of your cornea, poor vision with the strongest prescription lenses or an inability to wear any type of contact lenses. Depending on the location of the bulging cone and the severity of your condition, surgical options include:

• Intrastromal corneal ring segments (ICRS). For mild to moderate keratoconus, your eye doctor may recommend inserting small synthetic rings in your cornea. This treatment can help flatten the cornea, which can help improve vision and make contact lenses fit better. Sometimes, this procedure is done in combination with corneal cross-linking.
• Cornea transplant. If you have corneal scarring or extreme thinning, you'll likely need a cornea transplant. Depending on your situation, your eye doctor may recommend replacing all or part of your cornea with healthy donor tissue. A cornea transplant is known as a keratoplasty.

Cornea transplant for keratoconus generally is very successful. Possible complications include graft rejection, poor vision, infection and astigmatism. Astigmatism is often managed by wearing hard contact lenses again, which is usually more comfortable after a cornea transplant.

More Information

Keratoconus care at Mayo Clinic

• Cornea transplant

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Preparing for your appointment

If you're having difficulty with your vision, you'll likely start by seeing an eye doctor, called an ophthalmologist or optometrist. If your eye doctor determines that you might have keratoconus, you may be referred to an ophthalmologist who has had special training in corneal disease and surgery. A trained ophthalmologist can interpret corneal imaging studies and determine if you need cross-linking or a cornea transplant.

Here's some information to help you get ready for your appointment.

What you can do

Before your appointment make a list of:

• Symptoms you've been having and for how long.
• Recent major stresses or life changes.
• All medications, eye drops, vitamins and supplements you take, including the doses.
• Questions to ask your doctor.

For keratoconus some basic questions to ask include:

• What's the most likely cause of my symptoms?
• What are other possible causes?
• Do I need any tests?
• Is this condition temporary?
• What treatments are available, and which do you recommend?
• What are the alternatives to the primary approach you're suggesting?
• I have other health conditions. How can I best manage them together?
• Do you have any brochures or other printed material I can take with me? What websites do you recommend?

What to expect from your doctor

Your eye doctor is likely to ask you a number of questions, such as:

• What types of symptoms have you been having?
• When did you begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• Does anything seem to improve your symptoms?
• Do you rub your eyes?
• What, if anything, appears to worsen your symptoms?
• Does anyone in your family have keratoconus?
• Santodomingo-Rubido J, et al. Keratoconus: An updated review. Contact Lens and Anterior Eye. 2022; doi:10.1016/j.clae.2021.101559.
• Izquierdo L. Keratoconus. 1st ed. Elsevier; 2023. https://www.clinicalkey.com. Accessed Jan. 20, 2023.
• Stein HA, et al., eds. Cornea. In: The Ophthalmic Assistant. 11th ed. Elsevier; 2023. https://www.clinicalkey.com. Accessed Jan. 20, 2023.
• What is keratoconus? American Academy of Ophthalmology. https://www.aao.org/eye-health/diseases/what-is-keratoconus. Accessed Jan. 25, 2023.
• Salmon JF. Common eye disorders. In: Kanski's Clinical Ophthalmology: A Systematic Approach. 9th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Jan. 25, 2023.
• Keratoconus. American Optometric Association. https://www.aoa.org/healthy-eyes/eye-and-vision-conditions/keratoconus?sso=y. Accessed Feb. 6, 2023.
• Ami TR. Allscripts EPSi. Mayo Clinic. Nov. 23, 2022.
• Chodnicki KD (expert opinion). Mayo Clinic. Feb. 13, 2023.

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Keratoconus Treatment Toolbox: An Update

Submitted: 09 July 2020 Reviewed: 30 October 2020 Published: 29 November 2020

DOI: 10.5772/intechopen.94854

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Keratoconus is a bilateral, asymmetric, progressive disease of the cornea which can lead to visual impairment and blindness as irregular astigmatism increases and corneal scar occurs. Currently, many methods are available for a treatment of keratoconus. The treatment can help enhance visual rehabilitation and prevent progression in keratoconus patients. The treatment options included non-surgical and surgical managements. This review offers a summary of the current and emerging treatment options for keratoconus- eyeglasses, contact lens, corneal collagen cross-linking (CXL), CXL Plus, intrastromal corneal ring segment (ICRS), Corneal Allogenic Intrastromal Ring Segments (CAIRS), Penetrating Keratoplasty (PK), Deep Anterior Lamellar Keratoplasty (DALK), Bowman layer transplantation (BL transplantation) and gene therapy.

• corneal collagen cross-linking
• intrastromal corneal ring segment
• Bowman layer transplantation

Author Information

Vatookarn roongpoovapatr *.

• Department of Ophthalmology, Mettapracharak (Wat Rai Khing) Hospital, Thailand
• Miller School of Medicine, Bascom Palmer Eye Institute, University of Miami, USA

Mohamed Abou Shousha

Puwat charukamnoetkanok.

*Address all correspondence to: [email protected]

1. Introduction

Keratoconus is a bilateral, asymmetric, progressive ectatic disease of the cornea characterized by progressive corneal thinning which can lead to visual impairment and blindness as corneal protrusion progresses, irregular astigmatism increases and corneal scar occurs [ 1 ]. Keratoconus is often under the radar because of decreased awareness, underdiagnosis and undertreatment. The exact pathological mechanism remains unknown, but both genetic and environmental factors may contribute to development and progression of this disease [ 2 ]. The reported evidences of pathogenesis of keratoconus include histochemistry, biomechanics, enzymology, proteomics, and molecular genetics [ 2 ]. The disease process starts with fragmentation of the epithelial basement membrane, fibrillation of Bowman’s membrane and anterior stroma [ 3 ]. Bowman’s membrane breakage occurs later together with epithelial abnormality resulting in proteolytic enzymes release that weakens corneal stromal collagen and stromal thinning [ 3 ]. The reported prevalence of keratoconus varies between countries and ethnicities, in which Asian is higher than Caucasian about 4.4 to 7.5 times [ 4 , 5 ]. The prevalence is ranged from 0.3 in 100, 000 to 2300 in 100,000 in Russia and India respectively [ 6 ]. However, the prevalence may be higher in tertiary eye care center or refractive surgery center [ 7 ]. Keratoconus is more common in men than women, although both gender are affected [ 5 ]. The onset of symptoms usually presents during adolescent and may progress until the 30s. Keratoconus is associated with eye rubbing such as in allergic conjunctivitis, floppy eyelid syndrome, obstructive sleep apnea, Down’s syndrome and Leber congenital amaurosis [ 1 , 8 , 9 , 10 ]. Genetic predisposition accounts for an increased risk of keratoconus in patient that has a positive family history about 15 to 67 times [ 11 ].

2. Terminology and staging

Nowadays, there remain many controversies regarding disease definition, diagnosis, and management of keratoconus. Keratoconus is usually a bilateral disease in which the normal contralateral eye is believed to be in the preclinical stage of keratoconus with different terms such as subclinical keratoconus, keratoconus suspect, forme fruste keratoconus [ 12 ]. Despite the advancement of the investigations for the diagnosis of keratoconus and subclinical keratoconus, there are no definitive criteria for discriminating subclinical keratoconus from normal cornea currently [ 13 ]. The detection of keratoconus and subclinical keratoconus is crucial to prevent ectasia after refractive surgery. Moreover, some treatment modalities such as corneal collagen crosslinking can prevent vision loss in keratoconus if implement in the early stage of the disease [ 14 ]. The early stage symptoms may manifest as reduced vision, fluctuation of vision, progressive myopia and astigmatism, increasing higher order aberrations [ 4 , 15 ]. When the disease progresses into an advance stage, there is a severe visual loss from high myopia, irregular astigmatism and corneal scarring.

The following criteria are mandatory to diagnose keratoconus- abnormal posterior elevation, abnormal corneal thickness distribution and clinical noninflammatory corneal thinning [ 10 ]. However, there is no clinically adequate classification system for keratoconus currently. One of the most popular grading systems is Amsler-Krumeich classification system which classified severity of diseases based on the amount of myopia and astigmatism, corneal thickness or scarring and central keratometry readings [ 16 , 17 ]. However, Amsler-Krumeich classification system is considered as outdated because it relies on “old” indices (corneal steepness, refractive change, the presence of scarring), and fails to address disease impact [ 18 ]. Nowadays, other alternate classification systems are growing in number such as Shabayek-Alio system which is based on corneal higher aberrations and the keratoconus severity score (KSS) which considers average corneal power and root mean square (RMS) [ 19 , 20 ]. The “ABCD grading system” that incorporates anterior and posterior corneal curvature, thinnest pachymetric values based on the thinnest point and distant visual acuity may better reflects the anatomical change than some previous classification that uses pachymetric value based on apical measurement [ 21 ]. In routine clinical practice, the term “advanced keratoconus” usually apply to any case with unacceptably poor spectacle distance vision and contact lens intolerance [ 18 ].

3. Diagnosis

The keratoconus diagnosis is bases on the history and clinical examination. However, the investigations are very useful to augment the clinical examination and detect the early stage of disease. Moreover, the accurate diagnosis and early detection of keratoconus in essential in this era which laser refractive surgery has increased markedly. Failure to detect keratoconus and subclinical keratoconus can lead to ectasia after refractive surgery [ 22 ]. Corneal topography is the primary diagnostic tool for keratoconus detection. However, corneal topography is not a faultless method and therefore other diagnostic tools such as corneal pachymetry to characterize the corneal thinning and aberrometry to characterize degradation of the corneal optics should be used as complimentary techniques [ 22 ]. Corneal tomography which based on rotating Scheimpflug camera, such as Pentacam, Galilei, or Sirius systems, provide the topographic, pachymetric, and aberrometric information simultaneously as their use is adequate enough for the keratoconus detection [ 12 , 22 ]. Currently, OCT technology is being used to differentiate between eye with keratoconus and normal eye because it can provide accurate pachymetric characterization, define epithelial thickness irregularity and asymmetry that present in keratoconus [ 7 , 23 ]. By analyzing the biomechanical properties of the cornea that may precede the anatomical change, the Ocular Response Analyzer and Corvis systems can provide good diagnostic accuracy [ 22 ]. Analysis of the Corneal Microstructure change in keratoconic eye from confocal microscopy such as reducing corneal nerve fiber density and nerve fiber length, reducing keratocyte density, increasing corneal stromal nerve thickness, may be useful in detecting structural changes occurring before manifestation of topographic signs [ 22 , 24 ]. A combination of multiple imaging modalities, including corneal topography, corneal tomography, Scheimpflug imaging, anterior segment optical coherence tomography, and in vivo confocal microscopy will enhance early keratoconus detection. Modalities during investigations but show promise include polarization-sensitive optical coherence tomography, Brillouin microscopy, and atomic force microscopy [ 25 ].

4. Disease progression

Steepening of the anterior corneal surface.

Steepening of the posterior corneal surface.

Thinning and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point” [ 10 ].

An increase in maximum corneal refractive power (K max ) by more than 1 diopter (D) within 1 year

An increase in (corneal) myopia by more than 3 D or astigmatism by more than 1.5 D within 12 months

An increase in mean corneal refractive power by more than 1.5 D within 12 months

A reduction in minimal corneal thickness of more than 5% within 12 months.

The regular topographic/tomographic check-ups can identify keratoconus progression. Regarding the examination intervals, the individual risk profiles need to be taken into consideration. The risk factors that should be considered include eye rubbing, ocular allergies, young age, steep corneal curvature gradient, high astigmatism, marked visual loss, documented progression in the fellow eye, atopic dermatitis or Down’s syndrome [ 28 ]. In children, keratoconus tends to be more severe and progress faster requiring closer follow-up intervals [ 26 ]. The patient with low risks can be monitored less frequently than the one with high risks. Keratoconus progression is often associated with a decrease in best spectacle-corrected visual acuity (BSCVA), however, a change in both uncorrected visual acuity and BSCVA is not required to document progression [ 10 ].

5. Treatment

The important goals of keratoconus management are stopping disease progression and visual rehabilitation [ 10 ]. In cases of ocular allergies, patients should be treated with topical antiallergy and lubricants and should be instructed to avoid eye rubbing to halt disease progression. Corneal collagen crosslinking is a promising procedure to stop disease progression with minimal side effects [ 29 ]. For the visual rehabilitation, several treatment options corresponding to keratoconus grading have been established. Keratoconus can be treated by both nonsurgical and surgical approaches depend on severity and progression of the disease [ 15 ]. The keratoconus treatment toolbox is listed as in Table 1 .

5.1 Nonsurgical treatment

A nonsurgical treatment of keratoconus is spectacles and contact lens. For early stage of disease, those who achieve visual acuity 20/40 or better, spectacles can provide acceptable vision [ 15 ]. A toric soft contact lens also provides satisfactory vision for correcting myopia and regular astigmatism in early keratoconus. However, as the diseases progress, spectacles or soft contact lens may not provide acceptable vision because of the higher- order aberrations, in particular vertical coma was increased [ 30 ]. Therefore, other special lens such as rigid gas permeable (RGP) contact lens, hybrid lenses, piggy back, miniscleral lens, semiscleral lens or scleral lenses are needed to provide satisfactory vision [ 31 ]. The ultimate goal of fitting contact lens in keratoconus is to improve visual acuity without compromise ocular health. However, contact lens use does not slow or stop progression of the disease. In keratoconus, the cone is steeper but the cornea beyond the cone is flatter. In mild keratoconus, traditional RGP lens can provide an ideal fit. However, as the disease progress into advanced stages, it becomes difficult to achieve an ideal fit but compromised fit which is not damage to the ocular surface is acceptable. High oxygen transmissibility lens should be selected to prevent hypoxic-related corneal changes [ 31 ].

nipple cone: small, paracentral, steeper located inferiorly or inferonasally

oval cone: inferiorly or inferotemporally steeper cornea

globus cone: overall steeper cornea, involves more than three forth of the cornea up to limbus

Power: Low minus for mild keratoconus, high minus for severe keratoconus

Base curve: Flatter base curve for mild keratoconus, steeper base curve for severe keratoconus

Diameter: Based on the cone location, its size and steepness, nipple has a small diameter, usually start with a small diameter such as 8.7 mm, oval cone needs larger diameter lens, globus cone or severe apical displacement need large diameter contact lens.

A contact lens type is selected based on the manifest refraction and the degree of keratoconus. The contact lens of choice for keratoconus patients is RGP lens. However, if the patients develop intolerance or discomfort, customized soft toric contact lens, PBCL, hybrid lens or scleral lens can be considered. The indications, advantages and disadvantages of each contact lens type are summarized as in Table 2 [ 30 , 31 , 34 ]. Fitting contact lens in keratoconus can improve vision and delay the need for keratoplasty. Moreover, contact lens in keratoconus patient also have a role in correcting residual refractive error after Corneal collagen cross-linking (CXL), after Intrastromal corneal ring segments (ICRS) or post-keratoplasty [ 31 ].

The keratoconus treatment toolbox.

RGP = Rigid gas permeable contact lens, IOL = intraocular lenses, PBCL = Piggyback lens, TG-PRK = Topo guided- Photo Refractive Keratectomy.

Contact lens in keratoconus (KC).

RGP = Rigid gas permeable, Hybrid lens = rigid lens in the center and a soft skirt in the periphery, PBCL = Piggy back lens (RGP lens sitting on top of a soft contact lens) KC = keratoconus, GPC = giant papillary conjunctivitis, VA = visual acuity.

5.2 Surgical treatment

Even though the specialized imaging device can provide grading scheme of keratoconus, for practical purposes, the term “advanced keratoconus” may apply to any cases that have unacceptably poor spectacle distance vision and contact lens intolerance. As the diseases progress, spectacles or contact lens cannot provide acceptable vision. This group of patients requires a surgical management such as Corneal collagen cross-linking (CXL), Intrastromal corneal ring segments (ICRS), and Corneal transplantation to restore vision and/or stabilize progression of diseases.

The special considerations in surgical management of keratoconus are listed in Table 3 .

5.2.1 Corneal collagen cross-linking (CXL)

Keratoconus typically progresses until the fourth decade, when most but not all, slows or stabilizes [ 36 ]. Corneal crosslinking (CXL) has been proposed as a new treatment modality to stop progression of keratoconus since the late 1990s [ 27 ]. Currently, CXL is the gold standard and only minimally invasive surgical procedure that halt the progression of keratoconus [ 27 ]. The indications for CXL are progressive keratoconus in adults and postoperative ectasia, central corneal thickness more than 400 μm, K max 58 D or less [ 36 , 38 ]. However, the procedure is not approved for stable keratoconus currently. CXL is the promising treatment that can prevent progressive visual loss due to disease evolution and delay invasive surgical procedures such as corneal transplantation. The mechanism of cornea strengthening is a photochemical reaction of corneal collagen by the Riboflavin as a photosensitizer in the photopolymerization process and ultraviolet A irradiation (UVA). The interaction between Riboflavin and UVA can increases the formation of intrafibrillar and interfibrillar carbonyl-based collagen covalent bonds [ 37 ].

The standard Dresden protocol was proposed as a treatment option for keratoconus by Wollensak et al. in 2003 [ 38 ]. This standard technique is conducted under topical anesthesia. The central corneal epithelium is removed followed by application of 0.1% riboflavin solution (0.1% riboflavin in 2o% dextran solution) as a photosensitizer every 5 minutes for 30 minutes. Then the cornea is exposed to 370 nm UVA with an irradiance of 3 mW/cm 2 or 5.4 J/cm 2 , during which time riboflavin solution is re-applied every 5 minutes. After the treatment, topical antibiotics eye drops are applied and bandage contact lens placed upon the eye [ 38 ]. Although this standard protocol has been proven to be an effective procedure to halt keratoconus progression [ 39 ], it is a time-consuming procedure, may create patient discomfort and has post-operative complications related to corneal abrasion. The reported complications in association with CXL include corneal haze, corneal infection, corneal edema, and corneal melting. Adverse effects are common but mostly transient and of low clinical significance [ 40 ]. However, anterior corneal stromal haze is a typical postoperative finding that often occurs in the first month after treatment and typically resolves after 12 to 20 weeks [ 41 ]. The posterior aspect of this haze is an indistinct hyperreflective demarcation line seen in the mid stroma that represents the depth of CXL [ 37 ]. Two trends have emerged to modify the standard Dresden protocol. The first is a tendency to shorten treatment times [ 42 ]. Alternative treatment protocols with different formulations of riboflavin solution and delivery methods by altered UV exposures have been proposed. These newer techniques can shorten duration times, reduce patient discomfort, and minimize postoperative complications. The second trend is “epi-on” approach, such that the epithelium remains intact during CXL. These modifications were described in the following sections.

5.2.1.1 Accelerated CXL (ACXL)

According to Bunsen- Roscoe law of photochemical reciprocity, which states that “the same photochemical effect can be achieved with a reduced irradiation interval provided the total energy level is kept constant through a corresponding increase in irradiation intensity” [ 37 ]. ACXL is a modified CXL technique that increase the intensity of ultraviolet A (UV-A) irradiation and shortening the exposure time without altering the total energy delivered. Currently commercial devices now offer ultrafast settings such as 43 mW/cm 2 for 2 minutes [ 42 ]. Using this setting, would achieve the standard Dresden protocol energy dose of 3.4 J or a radiant exposure of 5.4 J/cm 2 within 2 minutes [ 42 ]. However, it ignores the requirement of oxygen in the CXL reaction, the time needed for oxygen replenishment, and potential physical damage due to higher irradiance [ 36 ]. The reduced efficacy of ACXL is believed to be due to depletion of oxygen in these high-fluence treatments [ 43 ]. The efficacy, safety, and treatment protocols of accelerated CXL are still being investigated and in evolution.

5.2.1.2 Epi-on CXL/transepithelial CXL

Due to the epithelial debridement is a major contributor to the postoperative complications of CXL, such as infective keratitis and an abnormal wound-healing response [ 37 ]. This issue has perpetuated interest in epithelium-on technique. Epi-on CXL has less discomfort to the patient and reduces postoperative complications [ 43 ]. This CXL technique has low complication rate, 0% to 3.9% of the patients has only transient haze [ 37 ]. According to the hydrophilic property of riboflavin solution, the penetration through the intact hydrophobic corneal epithelium is difficult. The standard formulations show minimal penetration through intact epithelium. The modifications by adding various additives, such as benzalkonium chloride, topical anesthetic, tris(hydroxymethyl) aminomethane (trometamol), sodium ethylenediaminetetraacetic acid, have been proposed to improve epithelial permeability to riboflavin [ 36 ]. Riboflavin penetration can be improved by increased riboflavin concentration and iontophoresis [ 36 ]. Since even the low amount of riboflavin surface films will markedly block UV-A transmission, transepithelial formulations are often rinsed from epithelial surface before irradiation [ 36 ]. The iontophoretic delivery system uses of mild electrical current for delivering riboflavin through the epithelium [ 36 ]. It allows greater and deeper riboflavin penetration in the corneal stroma than the conventional epithelium-on technique. Overall, the effectiveness of transepithelial techniques has been disappointing [ 27 ]. Epi-on CXL has limited keratocyte apoptosis, shallower demarcation line and less biomechanical rigidity than standard epi-off CXL [ 37 ]. In general, better outcomes can be achieved by standard epithelium off technique and epi-on CXL have resulted in progression of the disease after treatment [ 36 , 44 ]. However, recent research with innovative transepithelial CXL system achieved 4-fold higher corneal stromal concentrations of riboflavin than commercially available epi-on CXL system, and this level is theoretically adequate for effective CXL [ 44 ].

5.2.1.3 Pulsed-light accelerated CXL (PLA-CXL)

Due to the presence of oxygen is required for CXL, but high-exposure doses of UVA light cause a decrease in the oxygen concentration rapidly [ 45 ]. The recent technique has focused on pulsing the UVA light with “on” and “off” periods to increase the efficacy of CXL treatment by replenishing the consumed oxygen [ 46 ]. This technique is an effective treatment modality to stop progression in progressive keratoconus but regresses some of the cases [ 46 ].

5.2.1.4 CXL plus

Despite the fact that CXL can halt the progression of keratoconus and provide corneal stability, functional visual acuity remains a problem [ 47 ]. Recent data from the systematic review disclosed that conventional epi-off CXL can flattening cornea 2 D approximately and improving visual acuity 2 lines or 10 letters on average [ 48 ]. CXL normalizes the corneal shape by changing the physical properties of the cornea, resulting in reduction of all corneal aberrations, high order and low order. The improvement in uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) are related to improvement in the total corneal aberrations and only high-order aberrations respectively [ 49 ].

CXL + Topo guided PRK

CXL + ICRS

CXL + Topo guided PRK + phakic IOLS

CXL + ICRS+ + phakic IOLS

Three steps treatment of keratoconus by ICRS implantation, CXL and phakic IOLS significantly improve UDVA, CDVA, higher order aberrations and corneal shape in moderate to severe keratoconus [ 57 ]. Moreover, keratometry (K steep , K flat , K max ) and refraction (sphere, SE, but not cylinder) were also improved [ 58 ]. The time interval between ICRS implantation and CXL was 4–6 weeks and ICL implantation was performed 6–8 months after CXL [ 57 , 58 ].

5.2.1.5 CXL in thin cornea

The 0.1% riboflavin in 20% dextran solution is used in original Dresden protocol. Only the anterior 300 μm of stroma can be treated [ 38 , 59 ]. This standard technique requires corneal pachymetry more than 400 μm after de-epithelization to decrease complications such as corneal stromal scar and corneal endothelial cytotoxicity [ 47 , 60 ]. In order to combat this issue, there are various modifications to the conventional CXL protocol for CXL in thin cornea. These modifications include hypoosmolar riboflavin, transepithelial CXL, iontophoresis-assisted CXL, Customized epithelial debridement technique, Lenticule-assisted CXL, contact-lens- assisted CXL (CACXL) and individualized corneal CXL [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].

Hypoosmolar riboflavin has lower colloidal pressure (310 mOsmol/L vs. 402.7 mOsmol/L in isotonic riboflavin) that causes stromal swelling to double its thickness where stromal bed is less than 400 μm [ 60 ]. However, the efficacy of CXL using hypoosmolar riboflavin was lower than traditional CXL with isotonic riboflavin. The possible theory to explain is that in hydrated corneas (using hypoosmolar riboflavin) concentration of collagen fibrils is decreased, hence fewer collagen fibrils are available for CXL [ 60 , 61 ]. By changing the osmolarity of the riboflavin solution, while maintaining the concentration at 0.1%, probably does not alter the final riboflavin concentration in the cornea. On the contrary, modifying other parameters to obtain a more shallow depth of treatment; ie, the intensity of the UVA light, the duration of treatment, or the intensity of riboflavin concentration will alter the final riboflavin concentration in the cornea and require new dose–response assays [ 61 ]. Unfortunately, these modified techniques have not yet distinguished themselves as more effective than any other in terms of topographic or visual outcomes.

Despite the fact that CXL has a promising clinical outcomes, risk factors for ongoing ectasia include the application of isotonic riboflavin solution to thicken a thin cornea prior to treatment, corneas steeper than 58 D and age > 35 years [ 18 , 68 ]. The most frequent definition of treatment failure is the continual progression of keratoconus with an enhancement of K max reading of 1.0 D 0r 1.5 D over the preoperative value [ 40 , 47 ]. The outcomes of different CXL techniques are listed as in Table 4 .

Special considerations in surgical management of keratoconus.

currently little to recommend UV-CXL in corneas thinner than 400 μm [ 18 ] .

CCT = central corneal thicknesses, Epi-on CXL = Epithelium-0n Corneal collagen cross-linking, ICRS = Intrastromal corneal ring segments, DALK = Deep Anterior Lamellar Keratoplasty, PK = Penetrating keratoplasty, D = diopter, KC = keratoconus, K max  = Maximal corneal steepness, BCVA = best corrected visual acuity.

Adapted from Surv Ophthalmol. 2015 Sep;60(5):459–80. [ 18 ] J Cataract Refract Surg. 2015 Apr;41(4):842–72 [ 37 ].

Outcomes of surgical treatment of keratoconus.

CXL = Corneal collagen cross-linking, PRK = Photorefractive keratectomy, IOL = intraocular lenses, UDVA = Uncorrected Distance visual acuity, CDVA = Corrected Distance visual acuity, BCVA = Best Corrected Visual Acuity, BSCVA = Best Spectacles Corrected visual acuity, D = Diopter, SE = spherical equivalent.

Other than standard CXL, formulation of riboflavin solutions, riboflavin concentration, total UVA energy that was used for each study may be different.

5.2.2 Intrastromal corneal ring segments (ICRS)

Intrastromal corneal ring segments (ICRS) were FDA-approved in 1999 for the treatment of low myopia. ICRS implantation causes displacement of the collagen fibers resulting in flattening of the central cornea and tissue adjacent to the ring is displaced forward [ 37 ]. ICRS are segments of polymethylmethacrylate (PMMA) plastic available in numerous arc-lengths, thicknesses, and designs. Five types of ICRS are available for keratoconus: 1) Intacs (Addition technology Inc.) 2) Intacs SK (Addition technology Inc.), 3) Ferrara Rings (Ferrara ophthalmics) and 4) Keraring (Mediphacos).5). MyoRing (Dioptex, GmbH, Linz, Austria). The devices are inserted into stromal tunnels that may be created manually using a corkscrew blade or femtosecond laser with no difference in results (except that channels tend to be slightly shallower when created manually and more often decentered when created by laser) [ 37 ]. The objective of ICRS implantation is to improve visual and topographic outcomes and restoration of contact lens tolerance [ 15 , 18 , 37 ]. Maximal flattening effect occurs with segments at 60–79% corneal thickness. Shallower than 60%, the effect may be lessened and can induced ocular surface complications. On the contrary, deeper than 80%, there may have no topographic effect [ 88 ]. The outcome achieved is directly proportional to the thickness of the ICRS and inversely proportional to its diameter [ 37 ]. ICRS can be used alone or used in combination with other treatment options such as CXL for stabilizing disease progression [ 15 ]. The outcomes of ICRS are listed as in Table 4 .

Although, ICRS has good visual and topographic results, some complications have been reported. Intraoperative complications rate are low, but can occur and usually relate to corneal tunnel creation such as insufficient tunnel depth, asymmetry or decentration, or Bowman’s layer perforation [ 15 ]. The post-operative complications have been reported such as corneal neovascularization, keratitis, deposits around ring segment, corneal haze, halos, pain, corneal melting or edema, segment extrusion, visual fluctuation, and photophobia [ 15 ]. This procedure is reversible and not preclude from further surgeries such as CXL and/or corneal transplantation. Due to complications such as stromal necrosis, segment extrusion of synthetic ICRS material, corneal allogenic ICRS (CAIRS) combined with CXL has been reported. Instead of using PMMA to create segment, CAIRS is trephined from donor cornea. CAIRS were implanted into mid-depth corneal tunnel that was created by femtosecond laser, followed by ACXL [ 89 ]. This procedure has a promising result in term of improvement of UDVA by 2.79 lines, CDVA by 1.29 lines. Moreover, this procedure demonstrated improvement of SE, K max, K steep and topographic astigmatism and halt progression in all cases during follow period [ 89 ].

5.2.3 Corneal transplantation

Treatment options for advanced keratoconus that has corneal thickness less than 400 μm, K max more than 58 D may be limited to corneal transplantation that can stabilize the cone and enable continued contact lens wear [ 86 ]. The keratoplasty techniques may be penetrating keratoplasty (PK), Deep Anterior Lamellar Keratoplasty (DALK) or Bowman layer transplantation.

5.2.3.1 Penetrating keratoplasty (PK)

Penetrating or lamellar keratoplasty techniques are used depending on the extent of corneal scarring [ 15 ]. PK provides long term good vision but has slow visual rehabilitation from residual astigmatism and anisometropia [ 15 ]. Both PK and DALK tend to worsen any existing ocular surface problems, as both involve surface incisions, injury of corneal nerves, placement of long-lasting sutures, and requiring post-operative topical corticosteroids [ 18 ]. Despite the facts that long term graft survival following PK for keratoconus is good, averaging 97% at 5 years, 90% at 10 years and 80% at 20–25 years, most of the patients with advanced KC are transplanted early in life, therefore it is more likely that more than one graft may be required over their lifetime ultimately [ 18 ].

5.2.3.2 Deep anterior lamellar keratoplasty (DALK)

The visual outcomes of BCVA, UDVA for DALK remains debated. The recent data from systematic review and meta-analysis demonstrated that the visual outcomes were worse [ 90 ] or better [ 81 ] than those for PK. The outcomes of DALK for keratoconus are better than PK [ 81 ] or equivalent [ 81 ] in terms of refractive error, astigmatism and rejection rate. Fifty percent of eyes may encounter Descemet membrane perforation which is the most significant intra-operative complications [ 18 ]. Other complications such as a double anterior chamber and persistent corneal edema have been reported. DALK may be less prone to secondary ocular hypertension because of their lower steroid requirement (owing to the smaller risk of rejection) [ 18 ]. Another advantage DALK is the lack of endothelial rejection because there is no endothelial defense reaction [ 15 ]. The reported rates of postoperative complications such as graft rejection, secondary glaucoma, complicated cataracts, and constant endothelial cell loss are lower with DALK than PK [ 15 ].

5.2.3.3 Bowman layer transplantation

The PK or DALK may be disrupted by complications such as suture-related problems, graft rejection, epithelial wound-healing abnormalities, corneal curvature changes due to progression of KC in the peripheral host cornea resulting in disappointing visual results [ 86 ]. In KC corneas, pathological changes include the reduction of number of keratocytes, organization of the stromal lamellae, fragmentation or absent of Bowman’s layer (BL) [ 91 ] It has been suggested that the BL may be the strongest biomechanical element of the human cornea followed by the anterior third of the cornea [ 92 ]. Therefore, the BL may play a structural role in maintaining the shape/tectonic stability in KC corneas [ 87 ]. This procedure was first described in 2014, Bowman’s layer graft was positioned inside the recipient corneal stroma in a sandwich technique, without corneal incision or sutures, to pull the anterior corneal surface flatter and create homogeneous corneal topography [ 86 ]. BL transplantation can be performed under local anesthesia and low dose topical steroid can stop within 1 year post-operative, minimizing the risk of glaucoma development or cataract formation [ 86 , 87 , 93 ]. The reported complications are low such as intraoperative microperforation of the Descemet’s membrane [ 87 , 93 ]. Because of the transplanted tissue is acellular, no episodes of allograft rejection have been observed [ 86 , 87 ]. This procedure may postpone penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) and potentially allowed long term contact lens wear [ 86 ]. Although graft preparation and surgical technique can be challenging, assisted technologies, such as femtosecond laser and intraoperative anterior segment optical coherence tomography (OCT), may help conquer these barriers [ 94 , 95 ]. “Bowman layer onlay,” a recently developed surgical technique in which an isolated Bowman’s layer graft, is positioned onto the patient’s anatomical Bowman’s layer or anterior stroma, has demonstrated the rapid re-epithelization and integration of the tissue and comparable clinical outcomes to intrastromal transplantation [ 96 ]. The outcomes of each keratoplasty techniques are listed in Table 4 .

There are a variety of nomograms for the treatment of keratoconus which are mainly focused on the keratoconus grading, risk factors, the progressive nature of the disease, and contact lens tolerance [ 15 ]. The management algorithm in various stages of keratoconus is shown in Table 5 .

Management algorithm in various stages of keratoconus.

Adapted from JAMA Ophthalmol. 2014 Apr 1;132(4):495–501.

The classification of keratoconus was based on Krumeich JH et al.A. Live-epikeratophakia for keratoconus. J Cataract Refract Surg. 1998 Apr;24(4):456–63. [ 17 ]

Stage 1 K max  < 48 D, thickness > 500 μm, absence of scarring.

Stage 2 K max 48–53 D, thickness 400–500 μm, absence of scarring.

Stage 3 K max 54–55 D, thickness 200–400 μm, absence of scarring.

Stage 4 K max > 55 D, thickness < 200 μm, central corneal scarring.

6. Future directions

Treatment for advanced KC has trended away from invasive procedures such as PK and even DALK toward minimally invasive procedures such as CXL, ICRS or BL transplantation. Although keratoconus is a multifactorial disease, the pathogenesis of the disease is very much affected by genetic factors and positive family history [ 2 , 8 , 97 ]. By identifying pathogenic genes and changing the structure of cell proteins, gene therapy may be a very promising and effective treatment modality to change the course of the disease [ 15 ].

7. Conclusion

The two most important goals of management of keratoconus are stopping disease progression and visual rehabilitation. An ocular allergy should be treated. Care providers should instruct the patients to avoid eye rubbing to halt disease progression. A careful follow up is needed to document disease progression and provide prompt treatment. A nonsurgical treatment of keratoconus includes spectacles or contact lens. Contact lens use does not slow or halt progression but can provide satisfactory vision in early stages of keratoconus. A contact lens type is selected based on the manifest refraction and the degree of keratoconus.

The five operations (CXL, ICRS, PK, DALK and BL transplantation) currently represent the available surgical treatment options for advanced KC. Treatment for advanced KC has trended away from invasive procedures such as PK and even DALK toward minimally invasive procedures such as CXL, ICRS or BL transplantation. CXL and ICRS were once regarded only for mild to moderate keratoconus, their roles are now expanding in advanced diseases as well.

PK and DALK provide long term good vision but has slow visual rehabilitation and may be disrupted by complications such as suture-related problems and graft rejection. BL transplantation was introduced for advanced KC with extreme thinning/steepening. This novel procedure may postpone penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) and potentially allow long term contact lens wear. Since genetic factors play significant roles in KC, advances in gene therapy may soon yield innovative treatments of this disease.

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• 64. Cagil N, Sarac O, Can GD, Akcay E, Can ME. Outcomes of corneal collagen crosslinking using a customized epithelial debridement technique in keratoconic eyes with thin corneas. Int Ophthalmol. 2017;37:103-9
• 65. Sachdev MS, Gupta D, Sachdev G, Sachdev R. Tailored stromal expansion with a refractive lenticule for crosslinking the ultrathin cornea. J Cataract Refract Surg. 2015;41:918-23
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• 67. Lombardo M, Giannini D, Lombardo G, Serrao S. Randomized Controlled Trial Comparing Transepithelial Corneal Cross-linking Using Iontophoresis with the Dresden Protocol in Progressive Keratoconus. Ophthalmology. 2017;124:804-12
• 68. Sloot F, Soeters N, van der Valk R, Tahzib NG. Effective corneal collagen crosslinking in advanced cases of progressive keratoconus: J Cataract Refract Surg. 2013;39:1141-5
• 69. Soeters N, Wisse RPL, Godefrooij DA, Imhof SM, Tahzib NG. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol. 2015;159:821-828.e3
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• 72. Toprak I, Yildirim C. Effects of corneal collagen crosslinking on corneal topographic indices in patients with keratoconus. Eye Contact Lens. 2013;39:385-7
• 73. Al Fayez MF, Alfayez S, Alfayez Y. Transepithelial Versus Epithelium-Off Corneal Collagen Cross-Linking for Progressive Keratoconus: A Prospective Randomized Controlled Trial. Cornea. 2015;34 Suppl 10:S53-56
• 74. Craig JA, Mahon J, Yellowlees A, Barata T, Glanville J, Arber M, et al. Epithelium-off photochemical corneal collagen cross-linkage using riboflavin and ultraviolet a for keratoconus and keratectasia: a systematic review and meta-analysis. Ocul Surf. 2014;12:202-14
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• 80. Torquetti L, Ferrara G, Almeida F, Cunha L, Araujo LPN, Machado AP, et al. Intrastromal corneal ring segments implantation in patients with keratoconus: 10-year follow-up. J Refract Surg Thorofare NJ 1995. 2014;30:22-6
• 81. Liu H, Chen Y, Wang P, Li B, Wang W, Su Y, et al. Efficacy and safety of deep anterior lamellar keratoplasty vs. penetrating keratoplasty for keratoconus: a meta-analysis. PloS One. 2015;10:e0113332
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Bullous keratopathy, fuchs' dystrophy, keratoconus, refractive error, cornea transplants, endothelial keratoplasty (dsek & dmek), anterior lamellar keratoplasty (alk), penetrating keratoplasty (pk), artificial cornea, traveling to indianapolis for your transplant, descemet's stripping only (dso), other treatment options, artificial iris, cataract surgery with advanced lens options, corneal crosslinking, dry eye treatments, glaucoma surgery, lasik/refractive surgery, lens exchange, how the eye works, what is the cornea, how to care for your eyes, financial assistance/help, covid-19 and your transplant, read our latest annual report.

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Approximately 50 to 200 of every 100,000 people are afflicted with keratoconus. In the USA, a study found a prevalence of 54.5 per 100,000 people ( Kennedy et al, Am J Ophthalmol 1986; 100:267-73 ). Keratoconus occurs in all races and usually affects both eyes.  Sensitive techniques, such as corneal topography, often detect keratoconus in both eyes in cases thought to be only in one eye based on physical examination and refraction.  Keratoconus often starts in puberty and slowly progresses over decades and then stabilizes. In progressive cases, severe irregular astigmatism and scarring may require a corneal transplant in order to restore useful vision to the eye.

Heredity of keratoconus has not been clearly established.  While there are families in which multiple persons are affected, factors such as allergic conditions and contact lens use make analysis difficult.  As a general rule, chances of a blood relative developing clinical keratoconus are less than 10%.  

Conditions associated with keratoconus include atopic disease (atopic or allergic dermatitis, allergic rhinitis, asthma), Down’s syndrome (5-8 % of Down’s patients), and connective tissue disorders (Ehlers-Danlos syndrome and osteogenesis imperfecta). Chronic eye rubbing is associated with keratoconus and may accelerate progression. Eye rubbing may be the common link between keratoconus and allergies, atopic disease and Down’s syndrome.   

Findings in keratoconus include protrusion of the cornea, striae or wrinkles of the posterior cornea (Vogt’s striae), superficial scarring of the anterior cornea, and staining of the corneal surface epithelium with iron (Fleischer ring). Corneal hydrops, or marked swelling of the cornea in keratoconus, may occur when severe bulging of the cornea results in a tear in the deepest layer of the cornea (Descemet’s membrane), allowing fluid from the inside of the eye to permeate the cornea. Severe haziness, often accompanied by blister like lesions of the superficial cornea, results in impairment of vision and discomfort.

Keratoconus Treatments

Cross-linking is the only FDA-approved treatment for halting the progression of keratoconus. Once the condition progresses, Intacs or a cornea transplant are more advanced treatment options.

Crosslinking for Keratoconus

The Cornea Research Foundation of America contributed to the recent US Food and Drug Administration (FDA) approval of cross-linking for halting or slowing the progression of keratoconus and corneal extasia after prior refractive surgery. These studies were designed to assess the safety and effectiveness of CXL for halting or slowing the progression of these conditions.  We are providing patients with continued access to cross-linking through an ongoing investigational study. View this informational brochure to learn about the procedure.

Treating visual focusing problems associated with keratoconus

Intacs for keratoconus.

If keratoconus progresses to the point where a contact lens cannot be fit or does not adequately correct vision, surgery may be indicated. Small plastic ring segments placed in the cornea can produce a more regular corneal surface in about 2 out of 3 keratoconus patients.

Cornea Transplants for Keratoconus

Historically, in about 1 out of 5 patients, keratoconus progresses to the point where a cornea transplant is needed to restore a more normal shape to the cornea.  Data from the Cornea Transplant Database  of corneal transplant shows that transplants performed for keratoconus are in the highest category for successful outcomes.  In most cases, Dr. Price recommends the newer targeted transplant technique known as deep anterior lamellar keratoplasty (DALK) to help minimize the risk of graft rejection. Keratoconus Support Group

Historically, Keratoconus Group was established in 2007 and is the largest support community for patients with keratoconus with more than 15,000 members on their forums and discussion boards. Visit their website to connect with others experiencing keratoconus.

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• v.61(8); 2013 Aug

Topography-guided custom ablation treatment for treatment of keratoconus

Rohit shetty.

Department of Cornea and Refractive Surgery, Narayana Nethralaya Superspeciality Eye Hospital and Postgraduate Institute, Bangalore, Karnataka, India

Sharon D’Souza

Samaresh srivastava.

1 Department of Cornea and Refractive Surgery, Raghudeep Eye Clinic, Ahmedabad, Gujarat, India

Keratoconus is a progressive ectatic disorder of the cornea which often presents with fluctuating refraction and high irregular astigmatism. Correcting the vision of these patients is often a challenge because glasses are unable to correct the irregular astigmatism and regular contact lenses may not fit them very well. Topography-guided custom ablation treatment (T-CAT) is a procedure of limited ablation of the cornea using excimer laser with the aim of regularizing the cornea, improving the quality of vision and possibly contact lens fit. The aim of the procedure is not to give a complete refractive correction. It has been tried with a lot of success by various groups of refractive surgeons around the world but a meticulous and methodical planning of the procedure is essential to ensure optimum results. In this paper, we attempt to elucidate the planning for a T-CAT procedure for various types of cones and asphericities.

The major problem with keratoconus and other corneal ectatic disorders is progressive, asymmetrical corneal steepening associated with an increase in myopic and astigmatic refractive errors, combined with midperipheral and/or peripheral corneal thinning. High irregular astigmatism is typically seen with keratoconus, which is difficult to treat with spectacles and/or contact lenses. In the past, treatment of corneas with keratoconus using excimer laser was difficult as well as considered inappropriate, as the laser treatment results in further thinning of the cornea, and possible destabilization of the corneal structure. This could lead to progressive deterioration of the corneal shape and worsening of ectasia. Further, options for correcting irregular astigmatism induced by these ectatic disorders were few in the past, with limited and unpredictable anatomical and functional outcomes.[ 1 ] Recently, however, improvements in laser technology have led to several options for dealing with irregular astigmatism.[ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]

There are two customized approaches for treatment of irregular astigmatism: Wavefront-guided[ 3 , 4 , 5 , 6 , 7 , 8 , 9 ] and corneal topography-guided treatments.[ 10 , 11 , 12 , 13 , 14 ] Wavefront-guided treatment was used in the past for aberrated corneas, but the difficulty remained in capturing satisfactory and repeatable images especially in highly irregular corneas, thereby, not allowing for satisfactory treatment in severely aberrated eyes.

Topography-guided excimer laser ablation was introduced more than 10 years ago, primarily for the treatment of highly aberrated and irregular corneas. The concept of topography-guided laser ablation is to modify the cornea by treating anatomical rather than physiological changes, and consequently is less influenced by intraocular factors than wavefront-guided laser ablation. The topography-guided custom ablation treatment (T-CAT) is designed to improve the central corneal symmetry, without attempting to correct other spherical, or regular astigmatic, optical defects. By not attempting to correct the whole optical defect of the eye, the T-CAT treatment can be kept to a small degree of ablation with the maximum depth of tissue loss typically being less than 50 μm. Since the procedure is done after removing the epithelium, similar to a photorefractive keratectomy (PRK) the terminology of topography-guided-PRK (TPRK) can be used interchangeably with T-CAT. However, while a topography-guided correction can improve the topography and corrected distance visual acuity (CDVA), the refraction is not always predictable. The custom topographical neutralization technique (TNT) was developed[ 15 ] to provide a neutralizing refractive effect to compensate for refractive changes in a single treatment. Although the article elaborately explains the technique for zone enlargement and neutralization of irregular cornea, the effectiveness of the procedure in keratoconus eyes has not been as clearly elucidated by the authors.

The use of topical riboflavin combined with ultraviolet A (UVA) irradiation in collagen cross-linking (CXL) has demonstrated the potential for retarding the progression of keratoconus. Kanellopoulos et al .,[ 16 ] first reported CXL to stabilize keratoconus progression followed by customized PRK to normalize the corneal surface by reducing irregular astigmatism and potentially reducing the refractive error as well as providing improved visual outcomes in addition to stabilizing the disease process.[ 17 , 18 ]

We present our technique in patients with keratoconus who underwent combined same-day T-CAT followed by accelerated CXL (Avedro Inc., Waltham, USA) to achieve stabilization of corneal ectasia and enhance visual rehabilitation.

Materials and Methods

Our protocol to define progression of keratoconus is an increase of 0.5 diopter (D) or more in two or more keratometry values in the steep meridian between two sagittal curve maps or a decrease in corneal thickness of 10% or more at the thinnest point between two pachymetry maps on Pentacam (Oculus, Wetzlar, Germany) in the last 6 months. Pre-operative thinnest pachymetry of 450 μm or a predicted post-operative thinnest pachymetry of at least 400 μm after T-CAT is a prerequisite.

Pre-operative assessment

Each patient undergoes assessment of uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) on the Snellen's chart, which was converted into decimal values for reporting and analysis. Corneal topography was performed using Pentacam (Oculus) and Topolyzer, (WaveLight Laser Technologie AG, Erlangen, Germany). Corneal thickness was measured using the Pentacam. Five readings, one central and four from each of the four quadrants acquired from the Pentacam were used for the T-CAT treatment planning. Corneal asphericity (Q) was measured using the Topolyser.

Inclusion criteria

• Mild-to-moderate grade Keratoconus
• Thinnest pachmetry >450 μm
• Poor contact lens fit/unhappy with glasses or contact lenses
• No active allergic eye disease.
• No active ocular inflammation
• No central scarring of the cornea

Surgical procedure

After instilling a topical anesthetic solution (proparacaine 0.5%), an 8-mm diameter zone of corneal epithelium is mechanically removed and the customized ablation performed. T-CAT is performed by linking the Topolyzer with the WaveLightAllegretto Wave™ Excimer Laser System (WaveLight Laser Technologie AG). The software uses data from eight topographies and averages the data. “No tilt” option is chosen in all cases. In order to remove the minimum possible tissue, the optical zone diameter is kept between 5.5 and 6.5 mm in all cases. The maximum ablation we perform is 40 μm in the thinnest region of the cornea. Zernike optimization is done in all patients to match defocus (C4) and spherical aberration (C12) keeping the refractive correction as zero. The aim of the procedure is to topographically neutralize the cornea, making it more regular, and is not necessarily a reduction in the spherical equivalent of the eye. Therefore, the procedure is targeted to make the cornea more aspheric, improve contact lens fitting post-operatively and assure better BCVA to the patient by reducing the corneal aberrations and is therefore not a ‘refractive correction’ such as LASIK or photorefractive keratectomy (PRK) Figs. ​ Figs.1 1 and ​ and2 2 .

Simulated visual acuity in a keratoconus patient before treatment showing blurred vision with aberrations on the iTrace Visual Function Analyzer

Simulated improved visual acuity post-TCAT treatment showing reduced aberrations and clearer ‘E’ on the iTrace Visual Function Analyzer

The bed is washed after ablation and riboflavin (0.1% solution: 10 mg riboflavin in 10 ml dextran-T-500 20% solution) is applied every 2 minutes for the first 20 minutes. Ultraviolet A (UVA) (365 nm), 30 mW/cm 2 surface irradiation is then performed for the next 4 minutes. A thorough irrigation with balanced salt solution is done, following which a bandage contact lens (BCL) is applied for 3 days or until complete healing of the epithelium. The patient was put on a tapering dose of prednisolone acetate 1% eye drops, topical antibiotic, and a lubricating eye drop.

Patients are followed up on day 1, day 7, and then at 1, 3, and 6 months. UCVA, BCVA, corneal biomechanics using CorvisST (Oculus Inc) and corneal topography on Pentacam and Topolyzer are evaluated at each visit.

Concept of T-PRK (Our Protocol)

Corneal asphericity (Q) depends on the location of the cone in keratoconus. Topographic neutralization will induce a change in the Q value and refractive error. While planning a T-CAT, we can choose to manipulate the Q or the refractive correction to achieve the desired post-operative corneal asphericity.

A cornea with a central cone (in which > 50% of the cone is within the 3-mm zone on pentacam posterior elevation map) will have a high negative Q value and a high myopic refractive error. In such eyes, if no refractive correction is performed, then the ablation for topography-guided ablation will induce a small change in refraction and Q but will not achieve the desired outcome.

In this case, we have an option of reducing the Q to a less negative value or applying a partial refractive correction, both of which will achieve a more neutral cornea. The decision to plan a partial refractive treatment is based on the spherical equivalent and the pachymetry. Corneas with spherical equivalent <6D and with thinnest pachymetry of >475 μm can be planned for partial refractive treatment, but in corneas with thinnest pachymetry between 450 and 475 μms and higher spherical equivalent, refractive treatment is not done in order to avoid excessive tissue ablation. The refractive correction results in some reduction of myopia and a reduction of Q induced by the ablation.

If refraction is not touched, the Q value alone can be reduced by 20-30% pre-operatively to preserve the asphericity of the cornea post-operatively.

Similarly, a cornea with a decentered cone (in which > 50% of the cone is outside the central 3 mm on the pentacam posterior elevation map) has a less negative Q or even a positive Q value and lower corneal myopia. In these cases, the topography-guided ablation will attempt to regularize the cornea and in effect cause a more negative Q post-operatively and a myopic shift of the refraction. We need to anticipate this change and adjust the Q and refractive correction pre-operatively to compensate for the post-operative change. If no refractive correction is performed, Q can be changed to zero pre-operatively, to prevent too much overshoot of Q post-operatively. If refractive correction is performed, then Q can be left unchanged. Refractive correction was performed for up to 50% of patient's refractive error, simultaneously manipulating to keep the maximum ablation on thinnest point <40 μms.

Based on this concept, we would like to present two case examples:

Case examples

A 22-year-old male patient presented to us with keratoconus both eyes, intolerant to contact lens. His right eye UCVA was 6/18 and BCVA was 6/9 with a spectacle correction of −1.0 DS/−3.5DC@70°. His pre-operative pentacam map is shown in Fig. 3 which shows an early keratoconus with a partially inferiorly decentred cone. The pre-operative Q measured by Topolyser was −0.67 which also suggests a mild decentration of the cone and it was retained unchanged.

Case 1 pre-operative pentacam 4 map showing a slightly decentred cone in keratoconus

He underwent T-CAT with CXL for his right eye. T-CAT was performed with a refractive correction-1.25DS/-2DC@70° after Zernike optimization, maintaining the maximum central ablation to be less than 40 microns.

Post-operatively his UCVA was 6/12, BCVA was 6/6 with a spectacle correction of +1.00DS/−1.50DC@20°. His pentacam post-operatively [ Fig. 4 ] revealed regularization of the cornea with flattening of the K-values at various points on the sagittal curvature map.

Case 1 post-TCAT pentacam 4 map showing better centration of the cone with flattening in the sagittal curvature

A 28 year-old male patient with keratoconus presented with UCVA of 6/60 and BCVA of 6/9 with a spectacle correction −5.5DC@30°. His pre-operative pentacam [ Fig. 5 ] revealed grade 2 keratoconus. His pre-operative Q as measured by Topolyzer was −0.54 which suggests a more decentred cone. The Q value was retained unchanged during the planning for T-CAT. The refractive power treated was +0.75DS/−3DC@6° after Zernike optimization.

Case 2 pre-operative pentacam showing a steep cornea in keratoconus

Post-operatively his UCVA improved to 6/24p and BCVA TO 6/6p with a spectacle correction of −1DS/−2.25DC@30°. His pentacam revealed good centration of the cone post-operatively, with relative flattening of the cornea [ Fig. 6 ].

Case 2 post-TCAT pentacam showing flattening of the cone with better centration of the cone

The treatment of progressive keratoconus involves multiple approaches, taking into account several factors, the primary ones being corneal biomechanical stability and irregular astigmatism leading to visual deterioration.[ 19 ] Simultaneous TPRK with CXL offers the unique advantage of tackling both parameters at one sitting.[ 20 ]

TPRK flattens some of the cone apex (in a fashion similar to an eccentric partial myopic PRK but simultaneously flattens an arcuate, broader area of the cornea away from the cone, usually in the superior nasal periphery; this ablation pattern resembles part of a hyperopic treatment and thus will cause some amount of steepening or elevation adjacent to the cone, effectively normalizing the cornea. This treatment offers an effective tissue sparing ablation pattern in highly irregular corneas such as ectasia in keratoconus.

Kymionis et al ., recently reported a series of 31 keratoconus eyes treated with simultaneous T-CAT and C3R.[ 20 ] Their study showed a decrease in mean SE of only 1.22D (95% C.I., 2.5-0.1). In terms of visual acuity, there was a loss of 1 Snellen's line in 10% of the patients while 48% showed a gain of 1 line or more.[ 20 ] In another study comparing sequential and same-day TPRK and C3R for treatment of keratoconus, Kanellopoulos noted a SE reduction of 3.20 ± 1.4 D in the simultaneous group.[ 21 ] Kanellopoulos aimed to achieve a maximum ablation of 50 μ while we had aimed to achieve about 40 μ of ablation.

The decrease in the steep keratometry (K) readings on topography has been variable across studies; 2.35 D (95% C.I., 0.2-4.75) (Kymionis et al ., 2011), 3.07 D (95% C.I., 0.99-5.21) (Kymionis et al ., 2009), and 3.50 ± 1.3 D (Kanellopoulos).[ 19 , 20 , 21 ] Krueger et al ., described two case reports of simultaneous TPRK and C3R in which the steep K reading reduced by 3.3 D at the end of 36 months in one eye in the first case but increased by 0.9 D in the fellow eye at the end of 3 years.[ 22 ] The second case showed a decrease of 4.1 D in one eye at the end of 3 years while the fellow eye demonstrated no change in the steep K reading at 30 months. The same authors also reported an improvement in UCVA at 3 months, which remained stable up to 30 months post-operatively in their second case report.[ 22 ]

The combination of T-CAT and CXL has been described in the recent past as a two-step procedure with CXL being done first, followed by PRK after a 1 year interval,[ 18 ] as well as a simultaneous procedure.[ 19 , 20 , 21 , 22 ] The simultaneous method has a number of advantages over the sequential technique, such as less post-operative haze,[ 21 , 23 , 24 ] more predictable refractive results and visual outcome due to ablation of normal non-crosslinked tissue, and less post-surgical recovery period.[ 22 ]

Conclusions

Various studies have evaluated the efficacy of T-CAT with CXL in keratoconus[ 19 , 20 , 21 , 22 ] and the procedure appears to be alternative efficient modality of treatment. Future studies can be aimed at evaluating the biomechanical and topographical stability of the procedure. This is necessary to determine the safety of this treatment and standardize its efficacy in keratoconus management.

Source of Support: Nil

Conflict of Interest: None declared.