Outcomes of topography-guided PRK/CXL in keratoconus using the NIDEK CXIII system—”Bharat Protocol” (Pilot study)

Abstract

Purpose:

Outcome of topography-guided excimer laser ablation in conjunction with accelerated, high-fluence cross-linking in corneal ecstatic disease using the NIDEK CXIII equipped with CATz algorithm from the FinalFit software—”Bharat Protocol.”

Methods:

Retrospective case record review of 30 eyes of 17 patients of stage 1-3 keratoconus who underwent the procedure was performed. Data collected were for visual acuity, distortion-induced eye pain, and keratometry. Pachymetry, lower order and higher order aberrations, spherical aberrations, and topographic cylinder were documented from by Scheimpflug imaging (Pentacam 70700: Oculus, Wetzlar, Germany).

Results:

At a minimum follow-up of 6 months (range 6.2–13 months), there was significant improvement in UCVA (P < 0.00001), BCVA (P = 0.0061), decrease in Kmax (P = 0.0349), Ksteep (P < 0.0411), Kflat (P = 0.0099), and pachymetry (P = 0.0001). Significant improvement was also seen in distortion-induced eye pain (27/30 to 2/30; P < 0.00001). A more than two-line improvement in UCVA and BCVA was seen in 23/30 and 17/30 cases, respectively. Ectasia was stabilized in all cases at the last follow-up, and no complications were seen.

Conclusions:

The “Bharat” Protocol to arrest keratectasia progression and improve corneal regularity is a safe and efficacious alternative as a keratoconus management option. This is the first such study on Nidek Platform for the same.

The major vision limiting problem with keratoconus and other corneal ectatic disorders is moderate-to-high irregular astigmatism, which is difficult to treat with spectacles and/or soft contact lenses.[1] Excimer laser treatment of ectatic corneas, once considered inappropriate, is now on the rise owing to the improvements in laser technology in dealing with irregular astigmatism.[1] Topography-guided excimer laser ablation, introduced more than 10 years ago, aims to modify the highly aberrated and irregular cornea by primarily improving the central corneal symmetry and hence limiting the maximum degree of ablation. Furthermore, collagen cross-linking (CXL) has demonstrated the potential for retarding the progression of keratoconus.[2,3,4,5,6,7,8,9,10,11,12] Done simultaneously, a combination of the two procedures results in better visual outcomes in addition to stabilization of the disease process[13] in comparison with a collagen cross-linking that aims at stabilization of the disease process only. Kanellopoulos et al. termed this technique as Athens Protocol. Furthermore, studies were published by different groups to prove the same subsequently.[14,15,16,17,18,19,20,21] However, all these studies were performed using the “T-CAT” algorithm of the WaveLight Allegretto Wave Excimer Laser System (WaveLight Laser Technologie AG).

We present our technique of combined same-day topography-guided Photo-refractive keratectomy (PRK) using the Nidek CXIII excimer laser equipped with the customized aspheric treatment zone (CATz) algorithm followed by accelerated CXL (Avedro Inc., Waltham, USA) in patients with keratoconus. To our knowledge, this is the first such study using this platform. Taking a clue from the name Athens Protocol, of which this is a modification, we have named this as the “Bharat Protocol.”

Methods

Study Design and Subjects: A retrospective case record review of patients with Keratoconus in Stage 1-3 Amsler-Krumeich grading with minimum corneal thickness of 450 micron at presentation who underwent the procedure and were managed between April 2019 and May 2021 was performed. A cutoff of 450 micron was chosen because it is similar to the cut-off pachymetry in patients with Athens Protocol.[13] Any patient with corneal scarring, active corneal inflammation, ocular allergy, any prior corneal intervention like a collagen cross-linking or with any other anterior or posterior segment abnormality was excluded. The clinical and diagnostic data were retrieved from the medical records and tabulated.

Pre-operative Assessment: Data collected included 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. Refraction was documented in the form of spherical equivalent that was calculated taking appropriate sign into consideration. History included the assessment of brow pain. Corneal topography was performed using Scheimpflug imaging (Pentacam 70700: Oculus, Wetzlar Germany) and OPD Scan III (Nidek Inc., Tokyo, Japan). The reading of steep Keratometry (Ks), flat keratometry (Kf), maximum Keratometry (Kmax), thinnest pachymetry, and tomographic cylinder in the central 3 mm zone were noted from the Pentacam report. The data of spherical aberration, lower-order and higher-order aberration, and coma aberration both in the 0 and 90 axis was also collected from the Pentacam.

Surgical Planning: Data acquired from the OPD Scan III (Nidek Inc., Tokyo, Japan) were imported into the FinalFit software. Corneal aberrometry data were dissociated into a spherical, cylinder, and irregular ablation data using the CATz algorithm. [Fig. 1] The data were exported to an external hard drive and transported to the Nidek CXIII excimer laser system.

Figure 1.

Shows the pre-operative treatment planning sheet taken from the CATz algorithm of the FinalFit software of the prototype patient. The top half includes the actual topography of the patient pre-op showing a keratoconus eye (top-left) and the simulated target topography post-op showing a regularized cornea (top-middle). Top –right of the image shows the stages of management, ablation profile, refractive error if treated, and the zones of treatment. Inferior half of the image shows the dissociation of the total ablation profile into spherical, cylindrical and an irregular ablation

Surgical Procedure: After instilling a topical anesthetic solution (proparacaine 0.5%), phototherapeutic keratectomy (PTK) was performed for epithelial removal in a 8-mm diameter zone for all cases. Since epithelial mapping could not be performed, a fixed depth of 45 micron PTK was performed in all cases. The customized ablation was then performed with the surgical plan imported from the external hard drive. A standard optical zone of 6 mm was taken in all cases. An irregular ablation was targeted in all cases. In addition, mild refractive error upto a maximum of 1.5 D spherical equivalent was also treated in 7/30 patients if the pachymetry permitted. [Fig. 2] The maximum ablation performed was however limited upto 40 μm in all cases. After the laser ablation, the bed was washed and riboflavin (0.1% solution: 10 mg riboflavin in 10 ml HPMC) was applied every 2 minutes for the first 15 minutes. Subsequently, Ultraviolet A (UVA) (365 nm), 9 mW/cm² surface irradiation, was then performed for the next 10 minutes.[1] A thorough irrigation with balanced salt solution was performed, following which a bandage contact lens (BCL) was applied. BCL was kept in situ for 2 weeks. The patient was administered moxifloxacin 0.5% eye drops and carboxy-methyl-cellulose 0.5% eye drops every 2 hourly for the first 5 days. These were reduced to 4 times a day each after 5 days when topical dexamethasone 1% eye drops to be used 4 times a day were also added. Topical antibiotic was used for a total of 2 weeks and then stop without tapering. Topical steroids were used for 3 months in strict tapering schedule wherein steroid eye drops were used 6 times a day for the 1^st week and then were reduced to four times, thrice, twice, and once a day at every 2 weeks. Lubricant eye drops were used for 3-4 months at 6 times a day. All patients were advised to use UV protective goggles for upto 3 months after the procedure whenever outdoors. Patients were followed up on day 1, day 7, and then at 1, 3, and 6 months.

Figure 2.

Shows the stages of the ablation on the keratoconic cornea. Stage 1-myopic ablation (left) and 2-mutipoint ablation (right) are done in this patient as we also treated a -0.5 cyl of astigmatism. Similar ablation profile was done in 7/30 eyes wherein a myopic ablation of upto -1.5D was also done. The patient shall be subjected to only a multipoint ablation if no refractive error in incorporated for treatment as was done in other patients

Outcome assessment: This was performed at 6 months when UCVA, BCVA, steep keratometry (Ks), flat keratometry (Kf), maximum keratometry (Kmax), thinnest pachymetry, and tomographic astigmatism were noted from the Pentacam report. Spherical aberrations and lower-order and higher-order aberrations were also recorded from the Pentacam. The history of eye pain/brow pain was asked for specifically. Standard criteria to ascertain ectasia progression of a change 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 were taken.[1]

Statistical Analysis: All the parametric descriptive parameters were noted in the form of mean and standard deviation. A 2-tailed t test was applied to assess the difference in the outcome. P value of 0.05 was considered to be statistically significant.

Results

Patient Population: During the study period, a total of 76 keratoconus patients between grade 1-3 keratoconus were seen in the OPD. Of these, the protocol was performed on 53 eyes of 34 patients. Seventeen patients were lost to follow-up or had a missed follow-up at 6 months. Finally, the complete data of only 30 eyes of 17 patients were available and these were finally included in the study. Thirteen of the 17 patients had both eyes treated simultaneously. The mean age of the patients was 23.33 + 6.07 years (range: 15-39 years); M: F was 14:16. The minimum follow-up was 6 months (range 6.2-13 months).

Outcome assessment: The pre-op and post-op data are compiled in in Table 1. There were statistically significant improvement in prep-and post-op UCVA (P < 0.00001) and BCVA (P = 0.0061). Although there were minimal, nonsignificant changes in the refractive spherical equivalent (P = 0.348) or the topographic cylinder (P = 0.1402), a more than 2 line improvement in UCVA and BCVA was seen in 23/30 and 17/30 cases, respectively. A loss of UCVA by 1 line was seen in 4/30 patients. However, no patient had a loss of BCVA in the present study. Pentacam revealed a decrease in Kmax (P = 0.0349), Ksteep (P < 0.0411), Kflat (P = 0.0099), and pachymetry (P = 0.0001). Aberrometry data revealed a statistical significant change in RMS lower-order aberrations (P = 0.0119), koma 90° (P = 0.0267), and spherical aberrations (P = 0.0089), whereas the changes in RMS higher-order aberrations (P = 0.1598) and koma 0° (P = 0.7735) were insignificant. Figs. 3 and 4: show the pre-op and post-op comparative sagittal curvature maps of the prototype patient. Although the anterior maps show the ablation pattern [Fig. 3], the posterior maps show that there was no progression in the keratoconus [Fig. 4].

Table 1.

Pre-op and post-op comparative uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), steep keratometry (Ks), flat keratometry (Kf), maximum keratometry (Kmax), and thinnest pachymetry data. Also noted is the spherical equivalent from the manifest refraction. Scheimpflug imaging data include topographic cylinder, spherical aberration, and lower-order and higher-order aberration. Special mention is also of the coma aberration both in the 0 and 90°

	Pre-op		Post-op		Paired t-test
	Mean	SD	Mean	SD
UCVA	0.302	0.224	0.616	0.273	P<0.0001
BCVA	0.601	0.292	0.794	0.23	P=0.0061
Sph Eq	-2.325	1.87	-1.717	2.35	P=0.3487
Topo Cyl	2.76	1.09	3.316	1.72	P=0.1402
Kf	46.94	4.5	43.89	4.36	P=0.0099
Ks	49.75	4.5	47.21	4.91	P=0.0411
Kmax	55.99	8	51.76	7.14	P=0.0349
Pachy	464.93	29.905	413.866	36.24	P=0.0001
RMS LOA	11.3953	6.68	7.14	6	P=0.0119
RMS HOA	2.776	1.53	2.261	1.27	P=0.1598
Koma 0	0.112	1.05	0.04	0.87	P=0.7735
Koma 90	-1.79	0.92	-1.223	1.01	P=0.0267
SA	-0.704	1.174	0.033	0.919	P=0.0089

Figure 3.

Shows the pre-op and post-op comparative anterior sagittal curvature maps of the prototype patient. The difference map (right) shows the ablation area on the cornea. The post-op map (left) shows a regularized cornea as compared to a typical keratoconic cornea pre-op (middle). Note that the ablation profile is corresponding to the cone in the Keratoconus

Figure 4.

Shows the pre-op and post-op comparative posterior sagittal curvature maps of the prototype patient. The map shows that there has been no progression of the disease

Ectasia was stabilized in all cases at the last follow-up. No complications, either due to laser ablation or due to collagen cross-linking, were observed.

Discussion

The main reason of a decreased visual acuity, decreased BCVA, and distortion-induced poor quality of vision and eye pain is the abnormality in the corneal topography and a resulting irregular astigmatism on the corneal surface. This leads to a poor vision not correctable with glasses. The essence of any keratoconus treatment hence ideally must involve correcting such corneal irregularity.[1] Herein lies the concept of topographic regularization using a customized algorithm based ablation on the cornea selectively targeting the irregular astigmatism and making the cornea regular.

Kanellopoulos and Binder, in 2007, are credited with first such attempt of a two-step sequential approach of conventional Dresden Protocol CXL followed by topo-guided PRK after 1 year. This procedure had limitations of a variable ablation rate in a cross-linked than a virgin cornea leading to unpredictable refractive results and possible limited effectiveness of PRK, higher risk of post-PRK haze formation post-CXL and the fact that a second-step PRK removed part of the cross-linked corneal tissue, thereby potentially decreasing the efficacy of CXL.[14] To overcome these limitations, simultaneous topo-guided PRK followed by CXL was first performed by Kymionis et al.[15] in 1 contact-lens intolerant patient of pellucid marginal degeneration and then by Kymionis et al. in patients with progressive keratoconus.[16] Significant improvement was seen in all evaluated parameters including spherical equivalent (SE), defocus, uncorrected and corrected distance visual acuity (UDVA and CDVA), and keratometric values. Their simultaneous approach was reported to be superior on account of patients’ comfort, minimization of the potential stromal scarring, and preservation of cross-linked corneal stromal tissue.[16] Over the last decade, the multiple studies that have been published on this subject proving the efficacy and safety of the procedure are reviewed by Kankariya VP et al.[22] The studies include prospective or retrospective series, have varied follow-up schedules ranging from 12-128 months, and include both sequential and simultaneous CXL after t-PRK. The review concludes that based on the published data, tPRK-CXL treatment stabilizes the disease progression, normalizes the corneal surface in keratoconic eyes by reducing the irregular astigmatism and potentially reducing the refractive error, and hence increases the visual acuity. We performed the similar procedure in eyes with grade 1-3 Keratoconus. In contrast to all the published literature above which was performed with the “T-CAT” algorithm on the WaveLight Allegretto Wave™ Excimer Laser System (WaveLight Laser Technologie AG), we present our technique of simultaneous same-day topography-guided PRK followed by accelerated CXL (Avedro Inc., Waltham, USA) using the Nidek CXIII excimer laser equipped with the customized aspheric treatment zone (CATz) algorithm. To our knowledge, this is the first such published study using this platform. Taking a clue of the name from the Athens Protocol which was performed in a hospital in Greece, we have named this as “Bharat Protocol” as it is done in the capital city of India (Bharat).

All of the patients in the published literature were patients with stage 1-3 keratoconus. The goal of this treatment was a better quality and quantity of vision, besides disease stabilization if the disease was progressing. Hence, at the time of inclusion in the present study whether the keratoconus was progressing or not was not studied as many patients underwent the procedure at the first diagnosis if the vision was poor qualitatively or quantitatively. This patient population was similar in age to the patients included in the previous studies.[22] The mean age of the patients in our study was 23.3 years. This was consistent with the patients in the keratoconus age group and was similar to the study population in the earlier reported literature. Although a maximum follow-up period is desirable, the minimum follow-up period in our study was 6 months with the maximum follow-up of 13 months. The follow-up period in the various published literature ranged from as low as 12 months to as high as 146 months.[2] Historically, the parameters included to assess the outcome of the procedure have included the UCVA, BCVA, keratometry, and refractive cylinder. Similar parameters were assessed pre- to post-op in our study too. We found statistically significant improvement in UCVA and BCVA with a more than two-line improvement in both in 23/30 and 17/30 cases, respectively. This was despite nonsignificant change in the refractive spherical equivalent or the topographic cylinder. This proved that a mild correction of only the irregular astigmatism in most cases resulted in better visual acuity parameters. The observation of a better UCVA and BCVA is consistent as reported previously.[22] Table 1 summarizes the results of our study. We also compared the visual outcome of patients in Athens Protocol study with ours. [Table 2] Though there were differences in the sample size and the follow-up, the results of the Athens Protocol study and our pilot study were similar with statistical improvements in UCVA and BCVA, and a decrease in flat and steep keratometry and pachymetry. What this proves is that the “Bharat Protocol” done on the Nidek system is giving consistent results as with the procedure already being performed on the Alcon platform worldwide.

Table 2.

Similarity/comparison of the outcome and the methodology of the Athens Protocol with our study. The data comparison shows that the outcomes with our protocol are similar to the Athens Protocol

Demography	Athens Protocol			Our Study (“Bharat Protocol”)
	Pre-op	Post-op (6 month)	P (95%CI)	Pre-op	Post-op (6 month)	P (95%CI)
n	231			30
Mean Age	30.1±7.5 years (range: 17 to 57 years)			23.33±6.07 years (range: 15-39 years)
Follow-up (months)	36 months			6 months
UCVA (Decimal)	0.18±0.2	0.55±0.29	P<0.0001	0.30±0.22	0.616±0.27	P<0.0001
BCVA (Decimal)	0.62±0.23	0.76±0.20	P<0.0001	0.601±0.292	0.794±0.23	P=0.0061
Flat K (D)	46.56±3.83	43.22±3.8	P<0.0001	46.94±4.5	43.89±4.36	P=0.0099
Steep K (D)	50.71	46.3		49.45±4.5	47.21±4.91	P=0.0411
Pachymetry (micron)	451.91±40.02	356.67±56.41	P<0.0001	464.93±29.905	413.86±36.24	P=0.0001

Scheimpflug imaging (Pentacam 70700: Oculus, Wetzlar Germany) in our study revealed a decrease in the steep, flat, and maximum keratometry and pachymetry. What was striking to note was that a significant change in the keratometric values was noted despite that in most cases only irregular astigmatism was targeted and an ablation for refractive error was done only in 7/30 eyes, that too of a magnitude of upto 1.5D only. A corresponding decrease in the pachymetry was also noted to the ablative LASER.

Similar to Shetty et al.,[23,24] we also studied the LOA, HOA, SA, and koma aberrations at 0 and 90°. Although they found significant reduction in the above, we found a reduction only in the RMS LOA, SA, and koma 90°. Furthermore, studies on the change in aberrations after TGPRK are required for a conclusion. A specific symptom outcome that we studied for the first time in our study was the distortion-induced eye pain that the patients of corneal ectasia classically complained of. Although at presentation 27/30 patients complained of severe afternoon–evening brow pain, this significantly reduced after the procedure. The reason hypothesized is the decrease in the corneal irregularity and hence a reduction in the visual distortion-induced pain. This finding has not been studied in the earlier reported literature.

Collagen cross-linking as performed with accelerated protocol in our study with the riboflavin soaking time of 15 minutes followed by UVA exposure of 9 mW/cm² for 10 minutes. While the previous reported literature has included CXL done both via the conventional Dresden Protocol and the accelerated protocol, we chose to use the high fluency accelerated protocol in all patients as this had been used in the study of the Athens Protocol previously.[20] It has also been shown earlier by Shetty et al.[23] that a fluency higher than 9 mW/cm² gave poorer results as compared to 3 mW/cm² or 9 mw/cm².

Ectasia stabilization was seen in all patients in our study and none of them progressed. This proved that besides being efficacious, “Bharat Protocol” was also a safe procedure to perform. A longer follow-up is however desirable for this assessment. There were no other complications noted.

This study demonstrates that topoguided PRK combined with collagen cross-linking for treatment of keratoconus is not limited to wavelight platform only and can be efficaciously performed on the Nidek platform too. This study shall encourage users of this platform to initiate this therapy with better visual outcomes for more number of patients worldwide. This pilot study is limited with the small follow-up. A larger multicentric study with larger sample size is desirable. Furthermore, due to the unavailability of the software to measure the epithelial thickness, a standard PTK of 45 micron was applied in all cases. This can be improved in further studies by incorporating the epithelial thickness maps and taking that into consideration for deciding the PTK thickness. Also, scleral contact lens were dispensed as peer need to a few patients amongst these. However, we have included the best-corrected visual acuity of the patients with spectacles for analysis purposes.

Conclusion

“Bharat Protocol” of topography-guided excimer laser ablation in conjunction with accelerated, high-fluence cross-linking in corneal ecstatic disease using the NIDEK CXIII equipped with CATz algorithm from the Final fit software is hence as safe and efficacious as the widely acknowledged Athens Protocol. To our best knowledge and PubMed research, this is the first such study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.