. 2019 Oct 11;8(Suppl 1):15–31. doi: 10.1007/s40123-019-00210-3

Table 1.

Summary of most recently published results for CXL plus protocols in the treatment of keratoconus

Authors	Protocol	No. of eyes	Study design (level of evidence^b)	Follow-up (months)	VA outcomes	Keratometry outcomes	Complications
Combined CXL + PRK
Kanellopoulos and Binder [36]	Athens	32	Prospective case series (level 4)	27 (range 6–59)	27/32 eyes with UCVA and BCVA improved better than 2.25 logMAR	Minimal reduced K in 30/32 eyes	6.25% haze, 6.25% progress
Kanellopoulos and Asimellis [39]	Athens	231	Prospective case series (level 4)	36	UCVA improved 0.38 ± 0.31, BCVA improved 0.20 ± 0.21 logMAR^a	Flat K reduced −3.34 D^a	None
Kanellopoulos [40]	Athens (simultaneous vs. sequential)	127 simultaneous, 198 sequential	Retrospective, comparative (level 4)	36 ± 18 (range 24–68)	Sequential: UCVA improved 0.41, BCVA improved 0.25 logMAR Simultaneous: UCVA reduced 0.66, BCVA improved 0.28 logMAR	Sequential: mean K reduced 2.75 ± 1.3 D Simultaneous: mean K reduced 3.5 ± 1.3 D	19 eyes with haze (17 of sequential, 2 of simultaneous)
Tuwairqi and Sinjab [43]	Athens	22	Prospective case series (level 4)	12	Improved UCVA and BCVA^a	K values reduced in all, significant in 55%^a	None
Alessio et al. [44]	Athens	34 (17 CXL only, 17 PRK + CXL)	Prospective, non-randomized trial (level 3)	24	CXL only: UCVA improved 0.07, BCVA improved 0.04 logMAR PRK + CXL: UCVA improved 0.44, BCVA improved 0.03 logMAR^a	CXL only: mean K reduced −1.15 D PRK + CXL: mean K reduced −2.07 D^a	None (32.35% haze resolved)
Ohana et al. [45]	Athens	98	Retrospective case series (level 5)	25.3 ± 11.5 (range 12–36)	UCVA improved 1.23 logMAR, BCVA no improvement	Mean K reduced −4.03 D^a	5% significant haze
Iqbal et al. [46]	Athens	125 (58 CXL only, 67 PRK + CXL)	Prospective, non-randomized trial (level 3)	24	CXL only: SE reduced 2.25 D, UCVA improved 0.54 logMAR^a PRK + CXL: SE reduced 2.31 D, UCVA improved 0.68 logMAR^a	CXL only: mean K reduced −2.12 D^a PRK + CXL: mean K reduced −1.44 D^a	CXL only: 12.1% haze resolved, 1.7% stromal scar CXL + PRK: 5.9% haze resolved, 1.3% stromal scar
Gore et al. [48]	Athens	47	Prospective, non-randomized trial (level 3)	24	BCVA improved 0.13 logMAR in PRK + CXL group^a	Steep K reduced −5.4 D^a, flat K reduced −1.1 D	1 eye microbial keratitis
Nattis et al. [54]	Sequential CXL then TG-PRK	62 (34 refractive PRK, 28 topographic PRK)	Retrospective, comparative case series (level 5)	6 after PRK	Refractive: UCVA improved 20/100–20/60^a, BCVA improved 20/50–20/30 Topographic: UCVA and BCVA no improvement	Refractive: mean K reduced −0.36 D Topographic: no change in K	None
COMBINED CXL + PTK
Kymionis et al. [56]	Cretan	38 (19 PTK + CXL, 19 CXL only)	Prospective, comparative randomized trial (level 2)	12	PTK + CXL: UCVA improved 0.36, BCVA improved 0.12 logMAR^a CXL only: UCVA and BCVA no improvement	PTK + CXL: steep K reduced −2.07 D^a CXL only: steep K reduced −0.34 D	None
Kymionis et al. [57]	Cretan	23	Prospective case series (level 4)	24–48	UCVA improved 0.38, BCVA improved 0.10 logMAR^a	Steep K reduced −3.40 D, flat K reduced −1.60 D^a	None
Kapasi et al. [58]	Cretan	34 (17 PTK + CXL, 17 CXL only)	Retrospective, comparative case series (level 5)	1	PTK + CXL: BCVA improved 0.33 lines CXL only: BCVA decreased −0.58 lines	Not reported	None
Kymionis et al. [52]	Cretan plus	31	Prospective case series (level 4)	19.53 ± 3.97 (range 12–25)	UCVA improved 0.46, BCVA improved 0.084 logMAR^a	Steep K reduced −2.35 D, flat K reduced −1.18 D^a	50% posterior haze
Grentzelos et al. [59]	Cretan plus	55	Prospective case series (level 4)	12	UCVA improved 0.59, BCVA improved 0.12 logMAR^a	Steep K reduced −4.03 D, flat K reduced −2.16 D^a	7.3% significant haze
COMBINED CXL + ICRS
Chan et al. [66]	Intacs alone vs. same-day Intacs + CXL	25 (12 Intacs only, 13 Intacs/CXL)	Retrospective, comparative case series (level 5)	3 (Intacs alone: 102 ± 39 days, Intacs/CXL: 97 ± 38 days)	Intacs: UCVA improved 0.93 ± 0.89, BCVA improved 0.13 ± 0.20 Intacs/CXL: UCVA improved 0.76 ± 0.80, BCVA improved 0.11 ± 0.12 logMAR	Steep and mean K reduced more in Intacs/CXL group vs. Intacs only^a	None
Kilic et al. [67]	Same-day Intacs + epi-on CXL	131	Prospective case series (level 4)	7.07 ± 4.66 (range 1–25)	UCVA improved 0.26 ± 0.16, BCVA improved 0.24 ± 0.16 logMAR^a	Mean K reduced −4.47 D^a	None
Ertan et al. [68]	Sequential Intacs then epi-on CXL (mean 3.98 months between)	25	Retrospective case series (level 5)	3	UCVA improved additional 1.2, BCVA improved additional 0.36 Snellen lines after CXL^a	Mean K reduced −0.35 D, Steep K reduced −0.76 D after CXL^a	None
El Awady et al. [69]	Sequential ICRS then CXL	21	Prospective case series (level 4)	5.67 ± 1.89	UCVA and BCVA improved after ICRS, no significant improvement after CXL	Mean K reduced additional −0.09 D after CXL	None
Renesto Ada et al. [70]	Sequential riboflavin only vs. CXL then Intacs (3 months between)	39 (19 Intacs only, 20 CXL/Intacs)	Prospective, randomized, comparative trial (level 2)	24	Intacs: UCVA improved 0.16, BCVA improved 0.13 logMAR CXL/Intacs: UCVA improved 0.33, BCVA improved 0.22 logMAR (no difference between groups)	No difference between groups for all K values	None
Saelens et al. [75]	Same-day Ferrara ICRS + CXL	7	Retrospective case series (level 5)	11.7 ± 3.6 (range 5–17)	UCVA improved 0.50, BCVA improved 0.26 decimal^a	Mean K reduced −3.0 D, steep K reduced −3.6 D^a	1 explanted for migration
Coskunseven et al. [77]	Sequential CXL then ICRS vs. ICRS then CXL (mean 7 ± 2 months between procedures)	48 (24 CXL/ICRS, 24 ICRS/CXL)	Prospective, randomized, comparative trial (level 2)	13 ± 1	CXL/ICRS: UCVA improved 0.18, BCVA improved 0.17 decimal^a ICRS/CXL: UCVA improved 0.21, BCVA improved 0.33 decimal^a	CXL/ICRS: Mean K reduced −4.16 D^a ICRS/CXL: Mean K reduced −3.98 D^a	8 eyes with stromal edema (resolved by 3 months)
Multiple combined procedures
Iovieno et al. [80]	Sequential Intacs then same-day PRK + CXL (6 months between)	5	Prospective case series (level 4)	6	BCVA improved additional 0.2 after PRK + CXL^a	Mean K reduced additional −1.1 D after PRK + CXL^a	None
Kremer et al. [81]	Sequential Intacs then same-day PRK + CXL (> 6 months between)	45	Prospective case series (level 4)	12	UCVA improved 0.35, BCVA improved 0.19 decimal additional after PRK + CXL^a	Apex K reduced additional −4.30 D after PRK + CXL^a	11.1% mild haze, 8.9% epithelial hyperplasia
Coskunseven et al. [82]	Sequential ICRS then CXL then PRK (6 months between each)	16	Prospective case series (level 4)	6	UCVA improved 0.89, BCVA improved 0.62 logMAR^a	Steep K reduced −8.66 D, flat K reduced −3.11 D^a	None
Yeung et al. [83]	Simultaneous PTK + ICRS + conventional CXL	16	Prospective case series (level 4)	6.9 ± 4.6	UCVA improved 0.73, BCVA improved 0.16 logMAR^a	Mean K reduced −2.70 D, steep K reduced −5.78 D^a	None
Rocha et al. [84]	Simultaneous Intacs + PTK + conventional CXL	55	Retrospective case series (level 4)	6	UCVA improved 0.39, BCVA improved 0.08 logMAR^a	Cylinder improved 2.12 D^a	1 eye (2%) lost > 3 lines BCVA (haze)
Assaf and Kotb [85]	Sequential Athens protocol then PIOL (2–4 months between)	22	Prospective case series (level 4)	10.9 ± 1.6 (range 6–14)	UCVA improved 0.87, BCVA improved 0.34 logMAR^a	Mean K reduced −1.75 D^a	None

Studies were excluded from this table if they were case reports (≤ 2 eyes), non-keratoconic ectatic eyes were included in the treatment groups, or they were preliminary results (only most updated long-term follow-up outcomes included)

CXL corneal collagen cross-linking, TG-PRK topography-guided photorefractive keratectomy, PTK phototherapeutic keratectomy, ICRS intrastromal corneal ring segments, PIOL phakic intraocular lens, SE spherical equivalent, VA visual acuity, BCVA best-corrected visual acuity, UCVA uncorrected visual acuity, K keratometry, D diopter

^aDenotes a statistically significant value as established by the individual study's criteria

^bDenotes level of evidence as classified by the Oxford Centre for Evidence-based Medicine (2009)