Intrastromal corneal ring segments for treating keratoconus

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effectiveness and safety of intrastromal corneal ring segments as a treatment for keratoconus.

Background

Description of the condition

Keratoconus is a relatively rare, degenerative disease of the cornea, the clear, front surface of the eye (Zadnik 1996). It is bilateral, asymmetric, and progressive. The cornea thins, steepens, and protrudes, and its outer surface becomes irregular, distorted, and sometimes even scarred, resulting in blurry vision, even with visual correction.

The best estimate of keratoconus incidence is 2 per 100,000 people per year; prevalence is 54.5 per 100,000 (Kennedy 1986). The onset of keratoconus generally occurs in the teenage years or 20s. It presents initially as blurred or distorted distance vision and can be difficult to distinguish from myopia or astigmatism, or both. With time, the corneal surface becomes irregular and its apex displaces inferiorly. Techniques that assess corneal shape and topography help with the diagnosis. It has been associated with many other conditions, both ocular and systemic, such as atopic diseases (hay fever, dermatitis), Down syndrome, and connective tissue disorders (Krachmer 1984).

Keratoconus is slowly progressive with gradual loss in visual acuity, especially low-contrast visual acuity, even with best visual correction in place (Davis 2006). Likewise, the corneal curvature worsens, gradually steepening, in association with decreasing best-corrected visual acuity (McMahon 2006). Younger age at onset is generally believed to be associated with faster progression and worse outcomes.

Although much research has been done, the cause of keratoconus remains unknown, but is probably a combination of genetics and environmental influences.

Description of the intervention

There are a variety of treatments for keratoconus, including spectacles, contact lenses, corneal collagen cross-linking, and corneal surgery. Spectacles are generally the first optical treatment and are used early in the disease course to correct myopia and astigmatism. When vision with spectacles is no longer adequate, rigid gas permeable contact lenses become the mainstay of optical treatment by correcting the cornea's irregular surface, but only while the contact lenses are worn (Zadnik 1996). Rigid gas permeable contact lenses are not prescribed for patients with keratoconus to attempt to flatten the cornea permanently. Corneal surgery, corneal collagen cross-linking, and intrastromal corneal rings attempt to treat the disease. Corneal surgery (either penetrating keratoplasty or deep anterior lamellar keratoplasty) actually removes the irregular, opaque cornea, either partially or completely. Corneal collagen cross-linking uses ultraviolet light and riboflavin eyedrops to strengthen the collagen fibers in the cornea (Wollensak 2003).

Intrastromal corneal ring segments (also referred to as INTACS, Ferrara rings, Kerarings, or corneal implants) were approved by the Food and Drug Administration in the United States through an Humanitarian Device Exemption in 2004 for use in patients with keratoconus whose corneas are not scarred, when spectacles and contact lenses no longer provide adequate visual correction. They are small, thin, arc-shaped pieces of plastic that are inserted in the stroma of the cornea during a brief outpatient procedure, under topical anesthesia (Rabinowitz 2013). The expectation is for modest corneal flattening (2 to 3 diopters) with a modest improvement in visual acuity (2 to 3 lines on a visual acuity chart) (Rabinowitz 2013).

How the intervention might work

The insertion of the corneal implants is thought to result in corneal flattening and reduction of the myopia (nearsightedness) and astigmatism that accompany keratoconus and adversely affect vision. A tunnel is created in the corneal stroma, either with a steel dissector or with a femtosecond laser, and the rings are inserted (an example is shown in Figure 1). In the case of INTACS, the clear optical zone between the two implants is larger than the pupil to prevent optical distortions postoperatively. The flattening is mechanical and does not affect the underlying biochemical abnormalities in keratoconus, so there are limits to how much flattening can be expected, how much the vision may improve, and how long the positive effects of the flattening may last. The rings can be removed, so the procedure is reversible in theory, but severe complications such as perforation of the cornea and severe corneal infection have been reported (Rabinowitz 2013).

Figure 1.

Example of intrastromal corneal rings implanted in the eye.

Why it is important to do this review

Although rare, keratoconus has a marked negative effect on patients' quality of life. One report equates the vision-specific quality of life in keratoconus with that of much older patients with age-related macular degeneration (Kymes 2004). Patients with keratoconus experience blurry vision, dependence on uncomfortable contact lenses, and even the prospect of legal blindness and invasive corneal procedures, from a relatively young age. The systematic evaluation of a possibly viable, minimally invasive, therapeutic alternative that could be better than contact lenses would be valuable to patients afflicted with this potentially visually-disabling disease.

Objectives

To evaluate the effectiveness and safety of intrastromal corneal ring segments as a treatment for keratoconus.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs). If outcomes from RCTs are not available, we will discuss findings from other study designs, such as cohort studies and case series.

Types of participants

We will include participants with keratoconus and will exclude any participants with non-keratoconic ectasia (e.g., post-LASIK [laser-assisted in situ keratomileusis]). We will consider keratoconus as defined by the included studies, and document whether corneal topography data and slit lamp data were used for diagnosis.

Types of interventions

We will include studies that compared intrastromal corneal ring segments with spectacles or contact lenses. We will include intrastromal corneal ring segments with or without photorefractive keratectomy (although its use in keratoconus is controversial and decidedly non-standard), and with or without corneal collagen cross-linking. We will include any type of ring studied (e.g., INTACS versus Ferrara).

Types of outcome measures

Outcome measures will assess variables associated with keratoconus disease progression.

Primary outcomes

Our primary outcome for comparison of treatments will be:

  1. uncorrected distance visual acuity (UCVA) in the study eye at 12 months after intervention.

This will be considered as:

  • the proportion with UCVA 20/40 or better in the study eye; and

  • the mean change in UCVA from baseline in the study eye, measured on the Early Treatment in Diabetic Retinopathy Study (ETDRS) chart or equivalent.

Secondary outcomes

Secondary outcomes of interest, assessed at three, six, 12, and 24 months, will include:

  1. UCVA in the study eye at three, six, and 24 months, measured as: i) the proportion with UCVA 20/40 or better; and ii) the mean change in UCVA from baseline;

  2. best-corrected distance visual acuity (BCVA) in the study eye, measured as: i) the proportion with BCVA of 20/40 or better; and ii) the mean change in BCVA from baseline;

  3. corneal curvature in the study eye (mean change in diopters);

  4. corneal thickness in the study eye (mean change in mm);

  5. refractive error in the study eye (mean change of spherical equivalent in diopters);

  6. contact lens tolerance (yes/no, or scale – as reported by study, categorized by type of contact lens worn); and

  7. surgeons' experience with intrasomal corneal rings.

We will document and report adverse events reported by the included studies. Specific adverse events of interest include:

  1. penetration of the ring(s) into the anterior chamber;

  2. corneal infection;

  3. migration or extrusion of the ring(s);

  4. other corneal complications, e.g., corneal abrasion, corneal scarring; and

  5. loss of one or more lines of BCVA.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (latest issue), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to present), EMBASE (January 1980 to present), PubMed (1966 to present), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to present), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic search for trials.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), PubMed (Appendix 4), LILACS (Appendix 5), mRCT (Appendix 6), ClinicalTrials.gov (Appendix 7) and the ICTRP (Appendix 8).

Searching other resources

We will search the reference lists of included studies and use the Science Citation Index to identify potentially relevant studies that cited included studies. We will not search conference proceedings specifically for the purposes of this review, as RCTs presented at these meetings are searched by the Cochrane Eyes and Vision Group and included in CENTRAL.

Data collection and analysis

Selection of studies

Two authors independently will assess the eligibility of all records identified by the searches, beginning with titles and abstracts. Each author will classify each record as (1) definitely relevant, (2) possibly relevant, or (3) definitely not relevant according to the 'Criteria for considering studies for this review'. We will obtain full-text copies of each record classified as either (1) definitely relevant, or (2) possibly relevant.

Two authors independently will assess the full-text report(s) of studies and classify each study as (a) include, (b) unclear, or (c) exclude. We will resolve discrepancies at each stage by consensus. We will document all studies excluded after assessment of the full-text report and the reasons for exclusion. We will contact study investigators for studies classified as unclear for additional information to determine eligibility. If no response is received after four weeks, we will classify the reference based on the information available. For articles written in languages not read by the review authors, we will request assistance by colleagues to assess the studies for eligibility, and to translate the study information when needed.

Data extraction and management

Two authors independently will extract data using data extraction forms developed by the Cochrane Eyes and Vision Group, and modified for the specific purposes of this review. We will extract the following study characteristics for each included study: methods, participants, interventions, outcomes, and funding sources. One review author will enter the data into Review Manager 5.2 (RevMan 2012), and a second review author will verify the data entered. We will resolve discrepancies by discussion. We will contact study investigators to request missing data. If no response is received after four weeks, we will document that data were not reported and report the information available.

Assessment of risk of bias in included studies

Two review authors independently will assess the risks of bias in studies according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Discrepancies between authors will be resolved through discussion.

We will consider the following parameters when assessing risk of bias in randomized trials: (a) selection bias (random sequence generation, adequacy of allocation concealment); (b) performance bias (masking of participants and study personnel); (c) detection bias (masking of outcome assessors); (d) attrition bias (completeness of follow-up, reasons for missing data); (e) reporting bias (selective outcome reporting); and (f) other potential sources of bias (such as funding source).

We will assess each included study for each parameter as having a "low risk of bias", a "high risk of bias", or an "unclear risk of bias" (insufficient information to permit judgment of low or high risk, or impact on risk of bias unclear). We will contact the study investigators when study methods are unclear or when additional information would facilitate making an assessment. If no response is received after four weeks, we will assess the risk of bias based on the information available.

Measures of treatment effect

The primary outcome for this review, UCVA at three months, will be assessed as both a dichotomous outcome and a continuous outcome. We will assess primary and secondary dichotomous outcomes as risk ratios with 95% confidence intervals. We also will report adverse events as risk ratios with 95% confidence intervals, when data are available.

We will report continuous outcomes as mean differences (with 95% confidence intervals) in the mean changes from baseline between groups, or comparing pre-intrasomal corneal rings results to post-intrasomal corneal rings results. When mean changes from baseline are not available, we will calculate the mean differences (with 95% confidence intervals) based on mean values at a follow-up time point, assuming baseline values between groups were distributed uniformly. When distributions are skewed, we will report the median and interquartile ranges, whenever sufficient data are available.

Unit of analysis issues

The unit of analysis will be the participant (i.e., one eye per participant). For studies in which both eyes of a single participant were included and analyzed separately, we will report whether appropriate adjustments for within person correlation of outcomes were performed.

Dealing with missing data

When data are missing or incomplete, we will contact study authors for additional information. If no response is received after four weeks, we will use the information available and document missing data. We will not employ imputation methods for missing data for the purposes of this review.

Assessment of heterogeneity

We will assess clinical, methodological, and statistical heterogeneity among included studies. We will assess clinical heterogeneity based on the characteristics of the participants, interventions, and outcomes of the included studies. We will consider study methods and risk of bias when assessing methodological heterogeneity. We will use the I2 statistic to examine statistical heterogeneity. We will consider an I2 value greater than 60% to indicate substantial statistical heterogeneity. When substantial clinical, methodological, or statistical heterogeneity is present, we will not conduct meta-analyses and instead, we will report the study results independently.

Assessment of reporting biases

We will examine reporting biases at the individual study level (selective outcome reporting) and review level (publication bias). We will assess selective outcome reporting for each included study by comparing study outcomes prespecified in study protocols, or clinical trial registrations, with those that were reported. We will examine publication bias based on the symmetry of funnel plots when ten or more studies are included in a meta-analysis.

Data synthesis

When no substantial heterogeneity is detected, we will combine results in a meta-analysis. We will use a random effects model for meta-analyses including three or more studies. We will use a fixed-effect model when there are fewer than three studies. We will calculate the summary risk ratio with 95% confidence interval for dichotomous outcomes, and the summary mean difference between groups with 95% confidence interval for continuous outcomes. We will document study results that are not included in a meta-analysis as narrative summaries.

Subgroup analysis and investigation of heterogeneity

When sufficient data are available, we will conduct subgroup analyses based on receipt of additional therapy (e.g., participants who received intrastromal corneal ring segments only and participants who received intrastromal corneal ring segments plus photorefractive keratectomy).

Sensitivity analysis

When sufficient data are available, we will conduct sensitivity analyses to examine the impact of excluding unpublished studies, industry-funded studies, and studies assessed as having a high risk of bias, for any risk of bias parameter.

Acknowledgements

We acknowledge the Cochrane Eyes and Vision Group (CEVG) Trials Search Co-ordinator, Lori Rosman, for developing the search strategy for this review. We thank Joseph Barr, Barbara Hawkins, and CEVG editors for comments to the protocol.

Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research (NIHR) to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the Department of Health.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Keratoconus] explode all trees
#2 keratocon*
#3 #1 or #2
#4 (cornea* near/2 implant*)
#5 (cornea* near/2 ring*)
#6 (Intrastromal near/2 ring*)
#7 (Intracorneal near/2 ring*)
#8 (Intacs or Keraring* or "Kera ring" or Ferrara*)
#9 (Stromal near/2 implant*)
#10 #4 or #5 or #6 or #7 or #8 or #9
#11 #3 and #10

Appendix 2. MEDLINE (OvidSP) search strategy

1. exp Keratoconus/
2. keratocon*.tw.
3. or/1-2
4. (cornea* adj2 implant*).tw.
5. (cornea* adj2 ring*).tw.
6. (Intrastromal adj2 ring*).tw.
7. (Intracorneal adj2 ring*).tw.
8. (Intacs or Keraring* or "Kera ring" or Ferrara*).tw.
9. (Stromal adj2 implant*).tw.
10. or/4-9
11. 3 and 10

Appendix 3. EMBASE.com search strategy

#1 'keratoconus'/exp
#2 keratocon*:ab,ti
#3 #1 OR #2
#4 'intrastromal corneal ring segment'/exp
#5 (cornea* NEAR/2 implant*):ab,ti
#6 (cornea* NEAR/2 ring*):ab,ti
#7 (intrastromal NEAR/2 ring*):ab,ti
#8 (intracorneal NEAR/2 ring*):ab,ti
#9 intacs:ab,ti OR keraring*:ab,ti OR 'kera ring':ab,ti OR ferrara*:ab,ti
#10 (stromal NEAR/2 implant*):ab,ti
#11 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10
#12 #3 AND #11

Appendix 4. PubMed search strategy

#1 keratocon*[tiab] NOT Medline[sb]
#2 (cornea*[tiab] AND implant*[tiab]) NOT Medline[sb]
#3 (cornea*[tiab] AND ring*[tiab]) NOT Medline[sb]
#4 (Intrastromal[tiab] AND ring*[tiab]) NOT Medline[sb]
#5 (Intracorneal[tiab] AND ring*[tiab]) NOT Medline[sb]
#6 (Intacs[tiab] OR Keraring*[tiab] OR "Kera ring"[tiab] OR Ferrara*[tiab]) NOT Medline[sb]
#7 (Stromal[tiab] AND implant*[tiab]) NOT Medline[sb]

Appendix 5. LILACS search strategy

(keratocon$ OR Queratocono OR Ceratocone OR MH:C11.204.627$) AND (implant$ OR ring$ OR Intacs OR Keraring$ OR "Kera ring" OR Ferrara$)

Appendix 6. metaRegister of Controlled Trials search strategy

Keratocon* AND (ring OR implant OR Intacs OR Keraring OR "Kera ring" OR Ferrara)

Appendix 7. ClinicalTrials.gov search strategy

Keratoconus AND (ring OR implant OR Intacs)

Appendix 8. ICTRP search strategy

Keratoconus AND ring OR Keratoconus AND implant OR Keratoconus AND Intacs OR Keratoconus AND Keraring OR Keratoconus AND Ferrara

Contributions of authors

Karla Zadnik (KZ) designed and wrote the protocol. Kristina Lindsley (KL) assisted with writing the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Grant 1 U01 EY020522, National Eye Institute, National Institutes of Health, USA.

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