- Email: [email protected]
Corneal crosslinking for pellucid marginal degeneration
1
ARTICLE
Corneal crosslinking for pellucid marginal degeneration Niklas Pircher, MD, Jan Lammer, MD, Stephan Holzer, MD, Andreas Gschließer, MD, Gerald Schmidinger, MD
Purpose: To investigate the efficacy of corneal crosslinking (CXL) for pellucid marginal degeneration (PMD).
Setting: Medical University of Vienna. Design: Retrospective study. Methods: In eyes with a crab-claw pattern on corneal topography of a study cohort of 808 eyes, manual measurements of the cornea’s thinnest point on the inferior vertical Scheimpflug image (mCTi) and on the superior vertical Scheimpflug image (mCTs) were conducted. Eyes with paralimbal thinning were supposed as having PMD and included. A ratio between mCTi and mCTs was calculated. CXL was performed by irradiation of the inferior periphery of the cornea. During the follow-up, the mCTi, the mean keratometry (K) values in a central zone of 5.0 mm and in a 2.5 mm zone of the inferior cornea and the topographical corneal astigmatism were measured. The corrected distance visual
P
ellucid marginal degeneration (PMD) is a rare bilateral corneal ectatic disorder, characterized by a noninflammatory band of thinning in the inferior cornea, accompanied by steepening just superior to the thinned zone.1 The band of thinning is 1.0 to 2.0 mm wide and extends from the 4 to the 8 o’clock position, and could initially solely be visualized by slitlamp findings. Although some attempts to characterize PMD as well as to identify specific characteristics of PMD and keratoconus have been performed, differentiating between both ectatic disorders remains difficult.2,3 It is still under discussion whether PMD represents an independent corneal ectasia or a subform of keratoconus. The typical slitlamp findings and the significant different age of onset supports the theory that PMD is an individual entity. Today, Placidobased corneal topography, Scheimpflug photography, and anterior segment optical coherence tomography are commonly used to diagnose corneal disorders such as PMD and keratoconus.4–6 A crab-claw or butterfly corneal topography representing inferior steepening with a flatter
acuity (CDVA) was also evaluated. Patients were followed postoperatively for 12 months.
Results: Forty-eight eyes showed a crab-claw pattern in corneal topography. Twenty-two eyes matched the inclusion criteria for PMD and 16 eyes underwent CXL. The mCTi increased during the 12-month follow-up. The K value in the 2.5 mm zone of the inferior cornea decreased after 1 year, whereas the K value in the central zone of 5.0 mm remained stable. The corneal astigmatism continuously decreased, and the CDVA improved after 1 year. Conclusion: Manual pachymetric measurements in Scheimpflug images showed the potential for screening for PMD and the evaluation of the efficacy of CXL in eyes with PMD in the study cohort. A thickening of the mCTi and a flattening in the inferior part of the cornea was observed. J Cataract Refract Surg 2019; -:-–- Q 2019 ASCRS and ESCRS
vertical corneal meridian and an against-the-rule central astigmatism has been suggested to be characteristic of PMD.2,7–9 However, these patterns have also manifested in eyes with inferiorly decentered keratoconus and are therefore not sufficient for the diagnosis of PMD.10 Patients with PMD often show pronounced reduced visual acuity because of an irregular astigmatism resulting from a protrusion of the cornea superior to the thinned zone.2 Surgical management of PMD is challenging and includes intrastromal corneal rings or perforating keratoplasty; the latter includes a higher risk for postoperative astigmatism and a higher rejection rate because of its necessity of eccentric grafts.1,11 Even combined procedures, such as sliding keratoplasty and iontophoresis transepithelial corneal crosslinking (CXL) have been introduced more recently.12 In the past decade, CXL has proven to be a successful procedure in the treatment of keratoconus.13 A decrease in maximum keratometry (K) values, an increase in visual acuity, and a reduction in higher-order aberrations have been shown.14 To our knowledge, in addition to case
Submitted: September 5, 2018 | Final revision submitted: February 1, 2019 | Accepted: March 15, 2019 From the Department of Ophthalmology, Medical University of Vienna, Austria. Corresponding author: Gerald Schmidinger, MD, Department of Ophthalmology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Email: [email protected]. Q 2019 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2019.03.018
2
CXL FOR PMD
reports,15,16 only one study17 has investigated the effect of CXL on PMD to date. However, corneal topographies and the typical inferior thinning were not presented in that trial.17 The aim of the current study was to evaluate the efficacy of CXL in treating pachymetrically confirmed PMD. PATIENTS AND METHODS All investigations and measurements in this retrospective study were conducted in accordance with the Declaration of Helsinki, and Ethics Committee approval was obtained (EK Nr: 2070/ 2013). Patients were informed about the procedure and its potential risks, and their written informed consent was obtained before any surgical intervention in accordance with institutional and legal requirements. Pachymetric Measurements and Pellucid Marginal Degeneration Classification Consecutive patients with corneal ectatic diseases were registered in a patient file between 2008 and 2016 in the outpatient department at the Medical University of Vienna. All patients were examined with a Scheimpflug imaging device (Pentacam HR, OCULUS Optikger€ate GmbH) on their first visit to screen for findings considered as typical for corneal ectasia.6,18 In eyes showing a crab-claw pattern in corneal topography, the corneal thickness was measured manually paralimbal on the inferior (mCTi) and superior (mCTs) Scheimpflug image of the vertical meridian using a caliper tool (Figure 1). A ratio between the mCTi and mCTs measurements was calculated to evaluate its potential as a parameter for differential diagnosis between PMD and eccentric keratoconus. The mCTi was also compared with the automatically measured thinnest point of the corneal thickness produced by the Scheimpflug imaging device’s software. The inclusion criteria for PMD were a crab-claw pattern on corneal topography and a lower mCTi compared with the mCTs (Figure 1, A). Eyes with a crab-claw pattern on corneal topography without an inferior thinning on the Scheimpflug image were categorized as keratoconus and therefore excluded from data evaluation (Figure 1, B). Keratometric Measurements Changes in mean K values in a 5.0 mm diameter circular zone in the pupil center and in a 2.5 mm circular zone of the most inferior area of the cornea on the vertical meridian were detected using Scheimpflug tomography and the software tool “Corneal Power Distribution Display” given by the Pentacam. Furthermore,
changes in topographic corneal astigmatism were evaluated using corneal topography. Statistical Evaluation Continuous variables are given as the means G SD. To explore normal distribution, a Shapiro-Wilk analysis was performed. Statistically significant differences before surgical intervention and after 1 year were explored using a paired t test for nonindependent samples. Receiver operator characteristics curve analysis (area under the curve [AUC]) was used to evaluate the diagnostic significance in distinguishing between PMD and keratoconus using the ratio between mCTi and mCTs.
Surgical Intervention Only eyes with progressive PMD were scheduled for CXL. Progression was defined as follows: An increase of more than 1 diopter (D) of the K value in the 2.5 mm zone of the most inferior area of the cornea after at least 3 months. One surgeon (G.S.) performed all surgical procedures using the standard Dresden protocol for CXL, which has been previously described.19 After topical anesthesia with tetracaine 1% and oxybuprocaine 0.4%, 9.0 mm of corneal epithelium was debrided using a hockey knife. A riboflavin–dextran solution (Peschke D) was instilled every 3 minutes for 30 minutes for complete stromal penetration. Irradiation of ultraviolet-A (UVA) light was applied in about 9.0 mm radius with a UVA device (UVX-1000, IROC Innocross AG). The protocol was adapted by decentering the irradiation zone to the inferior part of the cornea to cover the area of thinning in the inferior periphery. A laser in situ keratomileusis sponge was used to protect the limbal structures during irradiation. After the surgery, the patients were provided with a therapeutic contact lens that was left in place until epithelial closure. The patients received antibiotic treatment for 1 week and antiinflammatory/lubricating eyedrops for 4 weeks. The patients were examined preoperatively and afterwards until reepithelialization was complete, and then at 1, 3, 6, and 12 months postoperatively. Corneal tomography data and corrected distance visual acuity (logarithm of the minimum angle of resolution) measurements were recorded at each examination.
RESULTS Between 2008 and 2016, 808 eyes (404 patients) with corneal ectasia were evaluated. Forty-eight eyes showed a crab-claw pattern in corneal topography. Twenty-two eyes were supposed as having PMD according to the inclusion criteria and 26 eyes as having keratoconus. The mean mCTi was 446 G 85 and 633 G 33 in eyes with PMD and in
Figure 1. A: A pellucid marginal degeneration case. A crab-claw pattern is shown in the corneal topography (left row). On the vertical Scheimpflug image (right row), a distinct inferior thinning was found, whereas the superior corneal thickness was found to be normal. B: A keratoconus case. A crab-claw pattern is shown in the corneal topography (left row). On the vertical Scheimpflug image (right row), no difference was found for the superior and inferior corneal thickness.
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CXL FOR PMD
eyes with keratoconus, respectively (P ! .01). The mean mCTs was 645 G 61 In eyes with PMD and 649 G 28 in eyes with keratoconus (P Z .98). The mean ratio between mCTi and mCTs was calculated as 0.69 G 0.13 in eyes included with PMD and 0.98 G 0.06 in eyes with keratoconus (P ! .01). The AUC value for ratio between mCTi and mCTs was 0.990; 95% confidence interval, 0.970-1.000. The Shapiro-Wilks test showed that the collected data were normally distributed (P O .05). Fourteen eyes with PMD had CXL up to 2018 because of progression in corneal topography. Two eyes had to be excluded from the data evaluation during the follow-up because reliable corneal topography measurements were not feasible with the Scheimpflug imaging device. No surgery-related events were observed. Epithelium healing was recorded after 5 days for all patients. Table 1 shows the changes in all collected parameters between the preoperative values and 12 months after CXL.
52.54 G 9.70 D at the 1-month visit. Thereafter, it dropped and remained below the preoperative values at 49.08 G 9.10 D (P Z .76) after 1 year. The mean simulated corneal astigmatism continuously decreased from the preoperative values of 13.6 G 3.72 D to 11.88 G 2.80 D (P Z .05). Visual Acuity
The corrected distance visual acuity showed a transient decrease at the 1-month follow-up visit but an increase thereafter (P Z .26). DISCUSSION In this study, we applied strict inclusion criteria concerning the definition of PMD. Accordingly, only eyes meeting the criteria defined by Krachmer1 were included in this trial. One key pathologic feature of PMD is the paralimbal inferior corneal thinning, which cannot be diagnosed by corneal topography. Even optical tomographic systems usually fail to detect the peripheral thinning because of segmentation errors in the periphery of the cornea. In contrast to our study, recent studies that evaluated the effect of CXL on PMD17,20,21 did not use strict inclusion criteria including pachymetric measurements. Using our PMD classification and inclusion criteria, we were able to find 22 PMD cases out of 48 ectatic eyes showing a crab-claw pattern in corneal topography. The difference in the ratio between the mCTi and mCTs was statistically significant in PMD and keratoconus cases, and showed the highest AUC value, indicating excellent power for distinguishing between both. Nevertheless, this parameter must be verified in further studies with new patient collectives. Eyes with progressive PMD were irradiated by decentering the irradiation zone inferiorly. The rationale behind this therapeutic approach was to strengthen the inferior cornea. In all treated eyes, the automatically measured thinnest corneal point was found in the center of the cornea and not in the inferior corneal periphery at baseline and during follow-up. As a
Pachymetry
The mean mCTi initially decreased from preoperative values of 456 G 74 mm to 447 G 77 mm at the 1-month follow-up. Thereafter, the mean mCTi increased to 459 G 74 mm at the 3-month follow-up, 471 G 79 mm at the 6-month follow-up, and to 495 G 70 mm after 1 year (P Z .03). Figure 2 shows examples of the increase in the mCTi after CXL. The mean preoperative automatically measured thinnest point of the corneal thickness was 487 G 55 mm and decreased to 451 G 58 mm (P Z .04). Scheimpflug Tomography
The mean preoperative K value in the central zone of 5.0 mm in the pupil center was 43.72 G 1.63 D. It did not change notably during the follow-ups, and it remained stable after 1 year (43.37 G 3.83 D, P Z .78). The preoperative mean K value in the 2.5 mm zone of the most inferior area of the cornea was 49.62 G 8.30 D and increased to
Table 1. Changes in the study cohort between the preoperative values at baseline and 12 months postoperatively. Kinf2.5 (D) Patient 1 2 3 4 5 6 7 8 9 10 11 12
mCTi (mm)*
aCT (mm)*
Corneal Astigmatism (D)*
CDVA (logMAR)
Preop
12 Mo
Preop
12 Mo
Preop
12 Mo
Preop
12 Mo
Preop
12 Mo
48.60 52.20 62.30 40.80 37.69 52.15 54.36 45.90 55.40 56.20 65.80 44.20
48.60 50.50 51.00 35.10 35.20 52.80 47.20 45.50 54.90 57.20 68.00 43.00
475 520 465 429 506 540 470 460 315 565 360 385
525 550 570 430 590 555 480 510 404 571 440 394
495 502 437 528 588 483 490 396 398 524 477 527
448 441 433 440 525 467 414 341 392 515 449 552
15.60 10.60 14.10 20.50 18.70 10.50 15.00 12.40 15.20 9.30 8.00 14.10
14.30 10.90 7.30 15.10 12.40 10.40 11.80 12.10 15.00 9.00 7.40 13.80
0.35 0.10 0.52 0.70 0.40 0.52 0.35 0.30 0.46 0.60 0.60 0.40
0.26 0.10 0.30 0.19 0.30 0.30 0.22 0.30 0.30 0.50 0.50 0.26
aCT Z automatically measured thinnest point of the corneal thickness; CDVA Z corrected distance visual acuity; Kinf2.5 Z mean keratometry value in a 2.5 mm circular zone in the most inferior area of the cornea; logMAR Z logarithm of the minimum angle of resolution; mCTi Z measurement of the cornea’s thinnest point on the inferior vertical Scheimpflug image *Statistically significant differences in the study cohort, P ! .05
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CXL FOR PMD
Figure 2. Differences in the manual measurement of the cornea’s thinnest point on the inferior vertical meridan of the Scheimpflug image using a caliper tool, preoperatively (upper row) and postoperatively (lower row) of Patient 1 and Patient 3, respectively. Compared with baseline, a significant thickening of the inferior thinnest area was observed.
result, the evaluation of pachymetric changes in the inferior periphery of the cornea was not possible when using automatically given pachymetric measurements. After an initial thinning in the early postoperative follow-up, the mCTi showed a remarkable increase during the rest of the followup period. This finding is comparable to the findings after standard CXL for keratoconus. After 1 year, the pachymetric values of the thinnest area of the cornea were higher than the preoperative values in all eyes. The thickness increase in the inferior area of corneal thinning in PMD because of CXL is a striking finding, indicating that an eccentric CXL procedure is of importance; this finding was previously published in a case report on Terrien marginal degeneration.22 Earlier studies have already suggested different theories regarding this effect of CXL. Corneal thickness might become augmented because CXL causes a pronounced increase in the resistance of corneal stroma to enzymatic digestion.22 CXL makes collagen types I and IV resistant to cleavage by matrix metallopeptidases.23 This might induce a downregulation of catalytic activity with a subsequent net increase in collagen production and resulting augmentation of corneal stroma.24,25 One might surmise that Scheimpflug thickness measurements might be affected by stromal changes after CXL such as haze; nevertheless, compared with ultrasound pachymetry, the Scheimpflug measurements demonstrated a highly significant correlation of corneal thickness measurements despite changes in the transparency of the cornea because of laser refractive surgery.26 The maximum K showed a distinct orientation change on corneal topography during all follow-up visits, and it was declared as not reliable. Hence, we circumvented incorrect data in corneal curvature by applying the “Corneal Power Distribution Display” analysis, by which the mean simulated K value of a specified zone can be estimated. Decentered radiation in the inferior part of the cornea might be assumed to lead to more pronounced changes at the inferior corneal curvature. Actually, after a slight increase after 1 month, a continuous decrease in the mean K value in the inferior part of the cornea (2.5 mm zone) was found, but no remarkable change in the mean K value in the center (5.0 mm zone) of the cornea was observed. An initial increase of corneal curvature is a Volume - Issue - - 2019
well-documented observation after CXL, albeit still not fully understood.27,28 It is most likely caused by a change in epithelial thickness during the first postoperative months because the epithelium has a strong masking effect in ectatic corneas.29 Patients with PMD often present with severe corneal astigmatism, which also decreased in all but 1 eye 1 year after CXL. To our knowledge, this paper is the first to evaluate the effect of CXL on PMD when using paralimbal thinning as a parameter to ensure the diagnosis. It seems to have a similar outcome as CXL on keratoconus. Patients with PMD benefit from a reduction in the inferior thinning of the cornea, a local flattening of the cornea, a decrease in corneal astigmatism, and an improvement in visual acuity. The use of manual pachymetric measurements of Scheimpflug images proved to be a more reliable method for evaluating changes in the thinnest area of the cornea after CXL in PMD in our study cohort. Nevertheless, newer optical coherence tomography-based corneal topography devices with better segmentation algorithm which ensure limbus-to-limbus tracing of the corneal anterior and posterior surfaces must be introduced because the possibility of manual tracing errors cannot be excluded when using Scheimpflug imaging.
WHAT WAS KNOWN Pellucid marginal degeneration (PMD) is a rare corneal ectatic disease and at present, it is unclear whether PMD represents a single entity or a subform of keratoconus. Moreover, distinguishing between both diseases is challenging. Corneal crosslinking (CXL) is a well-established method for the treatment of keratoconus; however, the efficacy of CXL in PMD has not been evaluated.
WHAT THIS PAPER ADDS CXL was successfully performed in eyes with PMD. When irradiating the characteristic corneal inferior thinning, a remarkable thickening of this area can be achieved. With CXL, patients with PMD benefit from a halt in the progression of the disease, a decrease in corneal astigmatism, and an improvement in visual acuity.
CXL FOR PMD
REFERENCES 1. Krachmer JH. Pellucid marginal corneal degeneration. Arch Ophthalmol 1978; 96:1217–1221 2. Karabatsas CH, Cook SD. Topographic analysis in pellucid marginal corneal degeneration and keratoglobus. Eye (Lond) 1996; 10:451–455 3. Tummanapalli SS, Maseedupally V, Rathi VM. Reply: Pellucid marginal degeneration and keratoconus; differential diagnosis by corneal topography. J Cataract Refract Surg 2013; 39:968–969 4. Klyce SD. Computer-assisted corneal topography. High-resolution graphic presentation and analysis of keratoscopy. Invest Ophthalmol Vis Sci 1984; 25:1426–1435 5. Rabinowitz YS, McDonnell PJ. Computer-assisted corneal topography in keratoconus. Refract Corneal Surg 1989; 5:400–408 6. Rabinowitz YS. Videokeratographic indices to aid in screening for keratoconus. J Refract Surg 1995; 11:371–379 7. Walker RN, Khachikian SS, Belin MW. Scheimpflug photographic diagnosis of pellucid marginal degeneration. Cornea 2008; 27:963–966 8. Maguire LJ, Klyce SD, McDonald MB, Kaufman HE. Corneal topography of pellucid marginal degeneration. Ophthalmology 1987; 94:519–524 9. Tummanapalli SS, Maseedupally V, Mandathara P, Rathi VM, Sangwan VS. Evaluation of corneal elevation and thickness indices in pellucid marginal degeneration and keratoconus. J Cataract Refract Surg 2013; 39:56–65 10. Lee BW, Jurkunas UV, Harissi-dagher M, Poothullil AM, Tobaigy FM, Azar DT. Ectatic disorders associated with a claw-shaped pattern on corneal topography. Am J Ophthalmol 2007; 144:154–156 11. Sridhar MS, Mahesh S, Bansal AK, Nutheti R, Rao GN. Pellucid marginal corneal degeneration. Ophthalmology 2004; 111:1102–1107 12. Spadea L, Maraone G, Cagini C. Sliding keratoplasty followed by transepithelial iontophoresis collagen cross-linking for pellucid marginal degeneration. J Refract Surg 2016; 32:47–50 13. Wittig-Silva C, Chan E, Islam FMA, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology 2014; 121:812–821 14. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen crosslinking in progressive keratoconus: preliminary results. J Refract Surg 2008; 24:S720–725 15. Spadea L. Corneal collagen cross-linking with riboflavin and UVA Irradiation in pellucid marginal degeneration. J Refract Surg 2010; 26:375–377 16. Hassan Z, Berta A, Nemeth G, Modis L, Szalai E. Collagen cross-linking in the treatment of pellucid marginal degeneration. Indian J Ophthalmol 2014; 62:367 17. Mamoosa B, Razmjoo H, Peyman A, Ashtari A, Ghafouri I, Moghaddam A. Short-term result of collagen crosslinking in pellucid marginal degeneration. Adv Biomed Res 2016; 5:194
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18. Kalin NS, Maeda N, Klyce SD, Hargrave S, Wilson SE. Automated topographic screening for keratoconus in refractive surgery candidates. CLAO J 1996; 22:164–167 19. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a–induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627 20. Kymionis GD, Karavitaki AE, Kounis GA, Portaliou DM, Yoo SH, Pallikaris IG. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. J Cataract Refract Surg 2009; 35:1298–1301 21. Kymionis GD, Grentzelos MA, Portaliou DM, Karavitaki AE, Krasia MS, Dranidis GK. Photorefractive keratectomy followed by same-day corneal collagen crosslinking after intrastromal corneal ring segment implantation for pellucid marginal degeneration. J Cataract Refract Surg 2010; 36:1783–1785 22. Hafezi F, Gatzioufas Z, Seiler TG, Seiler T. Corneal collagen cross-linking for terrien marginal degeneration. J Refract Surg 2014; 30:498–500 23. Zhang Y, Mao X, Schwend T, Littlechild S, Conrad GW. Resistance of corneal RFUVA–cross-linked collagens and small leucine-rich proteoglycans to degradation by matrix metalloproteinases. Invest Ophthalmol Vis Sci 2013; 54:1014–1025 24. Hayes S, Kamma-Lorger CS, Boote C, Young RD, Quantock AJ, Rost A, Khatib Y, Harris J, Yagi N, Terrill N, Meek KM. The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma. PLoS One 2013; 8:e52860 25. Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 2004; 29:35–40 26. Hashemi H, Mehravaran S. Central corneal thickness measurement with Pentacam, Orbscan II, and ultrasound devices before and after laser refractive surgery for myopia. J Cataract Refract Surg 2007; 33:1701–1707 27. Vinciguerra R, Romano MR, Camesasca FI, Azzolini C, Trazza S, Morenghi E, Vinciguerra P. Corneal cross-linking as a treatment for keratoconus : four-year morphologic and clinical outcomes with respect to patient age. Ophthalmology 2013; 120:908–916 28. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34:796–801 29. Haberman ID, Lang PZ, Broncano AF, Kim SW, Hafezi F, Randleman JB. Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time. J Cataract Refract Surg 2018; 44:306–312
Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned.
Volume - Issue - - 2019
ARTICLE
Corneal crosslinking for pellucid marginal degeneration Niklas Pircher, MD, Jan Lammer, MD, Stephan Holzer, MD, Andreas Gschließer, MD, Gerald Schmidinger, MD
Purpose: To investigate the efficacy of corneal crosslinking (CXL) for pellucid marginal degeneration (PMD).
Setting: Medical University of Vienna. Design: Retrospective study. Methods: In eyes with a crab-claw pattern on corneal topography of a study cohort of 808 eyes, manual measurements of the cornea’s thinnest point on the inferior vertical Scheimpflug image (mCTi) and on the superior vertical Scheimpflug image (mCTs) were conducted. Eyes with paralimbal thinning were supposed as having PMD and included. A ratio between mCTi and mCTs was calculated. CXL was performed by irradiation of the inferior periphery of the cornea. During the follow-up, the mCTi, the mean keratometry (K) values in a central zone of 5.0 mm and in a 2.5 mm zone of the inferior cornea and the topographical corneal astigmatism were measured. The corrected distance visual
P
ellucid marginal degeneration (PMD) is a rare bilateral corneal ectatic disorder, characterized by a noninflammatory band of thinning in the inferior cornea, accompanied by steepening just superior to the thinned zone.1 The band of thinning is 1.0 to 2.0 mm wide and extends from the 4 to the 8 o’clock position, and could initially solely be visualized by slitlamp findings. Although some attempts to characterize PMD as well as to identify specific characteristics of PMD and keratoconus have been performed, differentiating between both ectatic disorders remains difficult.2,3 It is still under discussion whether PMD represents an independent corneal ectasia or a subform of keratoconus. The typical slitlamp findings and the significant different age of onset supports the theory that PMD is an individual entity. Today, Placidobased corneal topography, Scheimpflug photography, and anterior segment optical coherence tomography are commonly used to diagnose corneal disorders such as PMD and keratoconus.4–6 A crab-claw or butterfly corneal topography representing inferior steepening with a flatter
acuity (CDVA) was also evaluated. Patients were followed postoperatively for 12 months.
Results: Forty-eight eyes showed a crab-claw pattern in corneal topography. Twenty-two eyes matched the inclusion criteria for PMD and 16 eyes underwent CXL. The mCTi increased during the 12-month follow-up. The K value in the 2.5 mm zone of the inferior cornea decreased after 1 year, whereas the K value in the central zone of 5.0 mm remained stable. The corneal astigmatism continuously decreased, and the CDVA improved after 1 year. Conclusion: Manual pachymetric measurements in Scheimpflug images showed the potential for screening for PMD and the evaluation of the efficacy of CXL in eyes with PMD in the study cohort. A thickening of the mCTi and a flattening in the inferior part of the cornea was observed. J Cataract Refract Surg 2019; -:-–- Q 2019 ASCRS and ESCRS
vertical corneal meridian and an against-the-rule central astigmatism has been suggested to be characteristic of PMD.2,7–9 However, these patterns have also manifested in eyes with inferiorly decentered keratoconus and are therefore not sufficient for the diagnosis of PMD.10 Patients with PMD often show pronounced reduced visual acuity because of an irregular astigmatism resulting from a protrusion of the cornea superior to the thinned zone.2 Surgical management of PMD is challenging and includes intrastromal corneal rings or perforating keratoplasty; the latter includes a higher risk for postoperative astigmatism and a higher rejection rate because of its necessity of eccentric grafts.1,11 Even combined procedures, such as sliding keratoplasty and iontophoresis transepithelial corneal crosslinking (CXL) have been introduced more recently.12 In the past decade, CXL has proven to be a successful procedure in the treatment of keratoconus.13 A decrease in maximum keratometry (K) values, an increase in visual acuity, and a reduction in higher-order aberrations have been shown.14 To our knowledge, in addition to case
Submitted: September 5, 2018 | Final revision submitted: February 1, 2019 | Accepted: March 15, 2019 From the Department of Ophthalmology, Medical University of Vienna, Austria. Corresponding author: Gerald Schmidinger, MD, Department of Ophthalmology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Email: [email protected]. Q 2019 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2019.03.018
2
CXL FOR PMD
reports,15,16 only one study17 has investigated the effect of CXL on PMD to date. However, corneal topographies and the typical inferior thinning were not presented in that trial.17 The aim of the current study was to evaluate the efficacy of CXL in treating pachymetrically confirmed PMD. PATIENTS AND METHODS All investigations and measurements in this retrospective study were conducted in accordance with the Declaration of Helsinki, and Ethics Committee approval was obtained (EK Nr: 2070/ 2013). Patients were informed about the procedure and its potential risks, and their written informed consent was obtained before any surgical intervention in accordance with institutional and legal requirements. Pachymetric Measurements and Pellucid Marginal Degeneration Classification Consecutive patients with corneal ectatic diseases were registered in a patient file between 2008 and 2016 in the outpatient department at the Medical University of Vienna. All patients were examined with a Scheimpflug imaging device (Pentacam HR, OCULUS Optikger€ate GmbH) on their first visit to screen for findings considered as typical for corneal ectasia.6,18 In eyes showing a crab-claw pattern in corneal topography, the corneal thickness was measured manually paralimbal on the inferior (mCTi) and superior (mCTs) Scheimpflug image of the vertical meridian using a caliper tool (Figure 1). A ratio between the mCTi and mCTs measurements was calculated to evaluate its potential as a parameter for differential diagnosis between PMD and eccentric keratoconus. The mCTi was also compared with the automatically measured thinnest point of the corneal thickness produced by the Scheimpflug imaging device’s software. The inclusion criteria for PMD were a crab-claw pattern on corneal topography and a lower mCTi compared with the mCTs (Figure 1, A). Eyes with a crab-claw pattern on corneal topography without an inferior thinning on the Scheimpflug image were categorized as keratoconus and therefore excluded from data evaluation (Figure 1, B). Keratometric Measurements Changes in mean K values in a 5.0 mm diameter circular zone in the pupil center and in a 2.5 mm circular zone of the most inferior area of the cornea on the vertical meridian were detected using Scheimpflug tomography and the software tool “Corneal Power Distribution Display” given by the Pentacam. Furthermore,
changes in topographic corneal astigmatism were evaluated using corneal topography. Statistical Evaluation Continuous variables are given as the means G SD. To explore normal distribution, a Shapiro-Wilk analysis was performed. Statistically significant differences before surgical intervention and after 1 year were explored using a paired t test for nonindependent samples. Receiver operator characteristics curve analysis (area under the curve [AUC]) was used to evaluate the diagnostic significance in distinguishing between PMD and keratoconus using the ratio between mCTi and mCTs.
Surgical Intervention Only eyes with progressive PMD were scheduled for CXL. Progression was defined as follows: An increase of more than 1 diopter (D) of the K value in the 2.5 mm zone of the most inferior area of the cornea after at least 3 months. One surgeon (G.S.) performed all surgical procedures using the standard Dresden protocol for CXL, which has been previously described.19 After topical anesthesia with tetracaine 1% and oxybuprocaine 0.4%, 9.0 mm of corneal epithelium was debrided using a hockey knife. A riboflavin–dextran solution (Peschke D) was instilled every 3 minutes for 30 minutes for complete stromal penetration. Irradiation of ultraviolet-A (UVA) light was applied in about 9.0 mm radius with a UVA device (UVX-1000, IROC Innocross AG). The protocol was adapted by decentering the irradiation zone to the inferior part of the cornea to cover the area of thinning in the inferior periphery. A laser in situ keratomileusis sponge was used to protect the limbal structures during irradiation. After the surgery, the patients were provided with a therapeutic contact lens that was left in place until epithelial closure. The patients received antibiotic treatment for 1 week and antiinflammatory/lubricating eyedrops for 4 weeks. The patients were examined preoperatively and afterwards until reepithelialization was complete, and then at 1, 3, 6, and 12 months postoperatively. Corneal tomography data and corrected distance visual acuity (logarithm of the minimum angle of resolution) measurements were recorded at each examination.
RESULTS Between 2008 and 2016, 808 eyes (404 patients) with corneal ectasia were evaluated. Forty-eight eyes showed a crab-claw pattern in corneal topography. Twenty-two eyes were supposed as having PMD according to the inclusion criteria and 26 eyes as having keratoconus. The mean mCTi was 446 G 85 and 633 G 33 in eyes with PMD and in
Figure 1. A: A pellucid marginal degeneration case. A crab-claw pattern is shown in the corneal topography (left row). On the vertical Scheimpflug image (right row), a distinct inferior thinning was found, whereas the superior corneal thickness was found to be normal. B: A keratoconus case. A crab-claw pattern is shown in the corneal topography (left row). On the vertical Scheimpflug image (right row), no difference was found for the superior and inferior corneal thickness.
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eyes with keratoconus, respectively (P ! .01). The mean mCTs was 645 G 61 In eyes with PMD and 649 G 28 in eyes with keratoconus (P Z .98). The mean ratio between mCTi and mCTs was calculated as 0.69 G 0.13 in eyes included with PMD and 0.98 G 0.06 in eyes with keratoconus (P ! .01). The AUC value for ratio between mCTi and mCTs was 0.990; 95% confidence interval, 0.970-1.000. The Shapiro-Wilks test showed that the collected data were normally distributed (P O .05). Fourteen eyes with PMD had CXL up to 2018 because of progression in corneal topography. Two eyes had to be excluded from the data evaluation during the follow-up because reliable corneal topography measurements were not feasible with the Scheimpflug imaging device. No surgery-related events were observed. Epithelium healing was recorded after 5 days for all patients. Table 1 shows the changes in all collected parameters between the preoperative values and 12 months after CXL.
52.54 G 9.70 D at the 1-month visit. Thereafter, it dropped and remained below the preoperative values at 49.08 G 9.10 D (P Z .76) after 1 year. The mean simulated corneal astigmatism continuously decreased from the preoperative values of 13.6 G 3.72 D to 11.88 G 2.80 D (P Z .05). Visual Acuity
The corrected distance visual acuity showed a transient decrease at the 1-month follow-up visit but an increase thereafter (P Z .26). DISCUSSION In this study, we applied strict inclusion criteria concerning the definition of PMD. Accordingly, only eyes meeting the criteria defined by Krachmer1 were included in this trial. One key pathologic feature of PMD is the paralimbal inferior corneal thinning, which cannot be diagnosed by corneal topography. Even optical tomographic systems usually fail to detect the peripheral thinning because of segmentation errors in the periphery of the cornea. In contrast to our study, recent studies that evaluated the effect of CXL on PMD17,20,21 did not use strict inclusion criteria including pachymetric measurements. Using our PMD classification and inclusion criteria, we were able to find 22 PMD cases out of 48 ectatic eyes showing a crab-claw pattern in corneal topography. The difference in the ratio between the mCTi and mCTs was statistically significant in PMD and keratoconus cases, and showed the highest AUC value, indicating excellent power for distinguishing between both. Nevertheless, this parameter must be verified in further studies with new patient collectives. Eyes with progressive PMD were irradiated by decentering the irradiation zone inferiorly. The rationale behind this therapeutic approach was to strengthen the inferior cornea. In all treated eyes, the automatically measured thinnest corneal point was found in the center of the cornea and not in the inferior corneal periphery at baseline and during follow-up. As a
Pachymetry
The mean mCTi initially decreased from preoperative values of 456 G 74 mm to 447 G 77 mm at the 1-month follow-up. Thereafter, the mean mCTi increased to 459 G 74 mm at the 3-month follow-up, 471 G 79 mm at the 6-month follow-up, and to 495 G 70 mm after 1 year (P Z .03). Figure 2 shows examples of the increase in the mCTi after CXL. The mean preoperative automatically measured thinnest point of the corneal thickness was 487 G 55 mm and decreased to 451 G 58 mm (P Z .04). Scheimpflug Tomography
The mean preoperative K value in the central zone of 5.0 mm in the pupil center was 43.72 G 1.63 D. It did not change notably during the follow-ups, and it remained stable after 1 year (43.37 G 3.83 D, P Z .78). The preoperative mean K value in the 2.5 mm zone of the most inferior area of the cornea was 49.62 G 8.30 D and increased to
Table 1. Changes in the study cohort between the preoperative values at baseline and 12 months postoperatively. Kinf2.5 (D) Patient 1 2 3 4 5 6 7 8 9 10 11 12
mCTi (mm)*
aCT (mm)*
Corneal Astigmatism (D)*
CDVA (logMAR)
Preop
12 Mo
Preop
12 Mo
Preop
12 Mo
Preop
12 Mo
Preop
12 Mo
48.60 52.20 62.30 40.80 37.69 52.15 54.36 45.90 55.40 56.20 65.80 44.20
48.60 50.50 51.00 35.10 35.20 52.80 47.20 45.50 54.90 57.20 68.00 43.00
475 520 465 429 506 540 470 460 315 565 360 385
525 550 570 430 590 555 480 510 404 571 440 394
495 502 437 528 588 483 490 396 398 524 477 527
448 441 433 440 525 467 414 341 392 515 449 552
15.60 10.60 14.10 20.50 18.70 10.50 15.00 12.40 15.20 9.30 8.00 14.10
14.30 10.90 7.30 15.10 12.40 10.40 11.80 12.10 15.00 9.00 7.40 13.80
0.35 0.10 0.52 0.70 0.40 0.52 0.35 0.30 0.46 0.60 0.60 0.40
0.26 0.10 0.30 0.19 0.30 0.30 0.22 0.30 0.30 0.50 0.50 0.26
aCT Z automatically measured thinnest point of the corneal thickness; CDVA Z corrected distance visual acuity; Kinf2.5 Z mean keratometry value in a 2.5 mm circular zone in the most inferior area of the cornea; logMAR Z logarithm of the minimum angle of resolution; mCTi Z measurement of the cornea’s thinnest point on the inferior vertical Scheimpflug image *Statistically significant differences in the study cohort, P ! .05
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Figure 2. Differences in the manual measurement of the cornea’s thinnest point on the inferior vertical meridan of the Scheimpflug image using a caliper tool, preoperatively (upper row) and postoperatively (lower row) of Patient 1 and Patient 3, respectively. Compared with baseline, a significant thickening of the inferior thinnest area was observed.
result, the evaluation of pachymetric changes in the inferior periphery of the cornea was not possible when using automatically given pachymetric measurements. After an initial thinning in the early postoperative follow-up, the mCTi showed a remarkable increase during the rest of the followup period. This finding is comparable to the findings after standard CXL for keratoconus. After 1 year, the pachymetric values of the thinnest area of the cornea were higher than the preoperative values in all eyes. The thickness increase in the inferior area of corneal thinning in PMD because of CXL is a striking finding, indicating that an eccentric CXL procedure is of importance; this finding was previously published in a case report on Terrien marginal degeneration.22 Earlier studies have already suggested different theories regarding this effect of CXL. Corneal thickness might become augmented because CXL causes a pronounced increase in the resistance of corneal stroma to enzymatic digestion.22 CXL makes collagen types I and IV resistant to cleavage by matrix metallopeptidases.23 This might induce a downregulation of catalytic activity with a subsequent net increase in collagen production and resulting augmentation of corneal stroma.24,25 One might surmise that Scheimpflug thickness measurements might be affected by stromal changes after CXL such as haze; nevertheless, compared with ultrasound pachymetry, the Scheimpflug measurements demonstrated a highly significant correlation of corneal thickness measurements despite changes in the transparency of the cornea because of laser refractive surgery.26 The maximum K showed a distinct orientation change on corneal topography during all follow-up visits, and it was declared as not reliable. Hence, we circumvented incorrect data in corneal curvature by applying the “Corneal Power Distribution Display” analysis, by which the mean simulated K value of a specified zone can be estimated. Decentered radiation in the inferior part of the cornea might be assumed to lead to more pronounced changes at the inferior corneal curvature. Actually, after a slight increase after 1 month, a continuous decrease in the mean K value in the inferior part of the cornea (2.5 mm zone) was found, but no remarkable change in the mean K value in the center (5.0 mm zone) of the cornea was observed. An initial increase of corneal curvature is a Volume - Issue - - 2019
well-documented observation after CXL, albeit still not fully understood.27,28 It is most likely caused by a change in epithelial thickness during the first postoperative months because the epithelium has a strong masking effect in ectatic corneas.29 Patients with PMD often present with severe corneal astigmatism, which also decreased in all but 1 eye 1 year after CXL. To our knowledge, this paper is the first to evaluate the effect of CXL on PMD when using paralimbal thinning as a parameter to ensure the diagnosis. It seems to have a similar outcome as CXL on keratoconus. Patients with PMD benefit from a reduction in the inferior thinning of the cornea, a local flattening of the cornea, a decrease in corneal astigmatism, and an improvement in visual acuity. The use of manual pachymetric measurements of Scheimpflug images proved to be a more reliable method for evaluating changes in the thinnest area of the cornea after CXL in PMD in our study cohort. Nevertheless, newer optical coherence tomography-based corneal topography devices with better segmentation algorithm which ensure limbus-to-limbus tracing of the corneal anterior and posterior surfaces must be introduced because the possibility of manual tracing errors cannot be excluded when using Scheimpflug imaging.
WHAT WAS KNOWN Pellucid marginal degeneration (PMD) is a rare corneal ectatic disease and at present, it is unclear whether PMD represents a single entity or a subform of keratoconus. Moreover, distinguishing between both diseases is challenging. Corneal crosslinking (CXL) is a well-established method for the treatment of keratoconus; however, the efficacy of CXL in PMD has not been evaluated.
WHAT THIS PAPER ADDS CXL was successfully performed in eyes with PMD. When irradiating the characteristic corneal inferior thinning, a remarkable thickening of this area can be achieved. With CXL, patients with PMD benefit from a halt in the progression of the disease, a decrease in corneal astigmatism, and an improvement in visual acuity.
CXL FOR PMD
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18. Kalin NS, Maeda N, Klyce SD, Hargrave S, Wilson SE. Automated topographic screening for keratoconus in refractive surgery candidates. CLAO J 1996; 22:164–167 19. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a–induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627 20. Kymionis GD, Karavitaki AE, Kounis GA, Portaliou DM, Yoo SH, Pallikaris IG. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. J Cataract Refract Surg 2009; 35:1298–1301 21. Kymionis GD, Grentzelos MA, Portaliou DM, Karavitaki AE, Krasia MS, Dranidis GK. Photorefractive keratectomy followed by same-day corneal collagen crosslinking after intrastromal corneal ring segment implantation for pellucid marginal degeneration. J Cataract Refract Surg 2010; 36:1783–1785 22. Hafezi F, Gatzioufas Z, Seiler TG, Seiler T. Corneal collagen cross-linking for terrien marginal degeneration. J Refract Surg 2014; 30:498–500 23. Zhang Y, Mao X, Schwend T, Littlechild S, Conrad GW. Resistance of corneal RFUVA–cross-linked collagens and small leucine-rich proteoglycans to degradation by matrix metalloproteinases. Invest Ophthalmol Vis Sci 2013; 54:1014–1025 24. Hayes S, Kamma-Lorger CS, Boote C, Young RD, Quantock AJ, Rost A, Khatib Y, Harris J, Yagi N, Terrill N, Meek KM. The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma. PLoS One 2013; 8:e52860 25. Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 2004; 29:35–40 26. Hashemi H, Mehravaran S. Central corneal thickness measurement with Pentacam, Orbscan II, and ultrasound devices before and after laser refractive surgery for myopia. J Cataract Refract Surg 2007; 33:1701–1707 27. Vinciguerra R, Romano MR, Camesasca FI, Azzolini C, Trazza S, Morenghi E, Vinciguerra P. Corneal cross-linking as a treatment for keratoconus : four-year morphologic and clinical outcomes with respect to patient age. Ophthalmology 2013; 120:908–916 28. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34:796–801 29. Haberman ID, Lang PZ, Broncano AF, Kim SW, Hafezi F, Randleman JB. Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time. J Cataract Refract Surg 2018; 44:306–312
Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned.
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