Table 2.

Summary of dry eye interventions and impact on HOAs

Reference/study	Country	Study design	Intervention	Follow-up period	HOA measuring device	Level of evidence	Parameters for efficacy	Main result	Remarks
A preliminary investigation into the effects of ocular lubricants on higher order aberrations in normal and dry eye subjects McGinnigle et al. 2013 [24]	UK	Randomized controlled trial (RCT)	Unpreserved Hypromellose drops vs Tears Again™ liposome spray vs combination in normal and dry eyes	60 min after instillation	Measured using Nidek OPD-Scan III (Nidek Technologies, Gamagori, Japan)—dual OCT and ray tracing	Level 1	Strehl ratio for HOAs Total aberrations Spherical aberrations Coma	Hypromellose drops led to a significant decrease in HOAs immediately after but no difference 1 h post intervention in both normal and dry eyes. Liposome spray caused no significant difference at any time point in both eyes. Combination has no significant difference at any point in both eyes Hypromellose drops increased total aberrations immediately after but decreased proportionally after an hour for both eye types. Liposome spray had no effect on total aberrations for each eye type. Combination had no effect for each eye type There were no significant changes in spherical aberrations for each intervention type (drops, spray, and combination) for each eye type There were no significant changes in coma for each intervention type (drops, spray, and combination) for each eye type	HOAs were higher at baseline in the dry eye group The increase in total aberrations with Hypromellose drops was insignificant compared to baseline
Effects of 3% diquafosol sodium ophthalmic solution on higher-order aberrations in patients diagnosed with dry eye after cataract surgery Inoue et al. 2016 [3]	Japan	RCT	3% diquafosol sodium (DQS) ophthalmic solution vs artificial tears (ATs) in dry eyes after cataract surgery	4 weeks	Measured using a wavefront analyzer (KR-1 W; Topcon Corp, Tokyo, Japan)—dual OCT and ray tracing	Level 1	Tear film metrics: tear breakup time (TBUT), fluorescein staining, and Schirmer test scores HOA Fluctuation index (FI) and stability index (SI)	TBUT was significantly decreased in both DQS and AT groups compared to preoperative BUT baseline values. BUT was significantly increased after 4 weeks of DQS instillation Corneal and conjunctival fluorescein staining was significantly increased in both groups postoperatively. DQS significantly reduced fluorescein staining after 4 weeks of instillation There was no significant change 4 weeks after cataract surgery in both groups HOAs trends showed upward curves in both groups 4 weeks after surgery. DQS treatment stabilized the pattern whereas AT treatment continued to have an upward curve pattern FI was significantly lower in the DQS group compared to the AT group SI was significantly lower in the DQS group compared to the AT group	4 weeks of AT instillation did not significantly increase BUT 4 weeks of AT instillation did not significantly reduce fluorescein staining There was no significant difference in the FI before and after 4 weeks of instillation for both DQS and AT groups There was no pre- and postoperative difference in SI for the DQS group but the AT group showed a significant increase in SI postoperatively after 4 weeks of instillation
Effects of sodium hyaluronate on wavefront aberrations in dry eye patients Lekhanont et al. 2014 [25]	Thailand	RCT	100 eyes from 50 patients 0.18% sodium hyaluronate (SH) vs 0.9% sodium chloride in patients with dry eye	1 min, 10 min, 30 min, 1 h, and 2 h after instillation	Measured using a Zywave II aberrometer (Bausch & Lomb, Irvine, CA, USA)—ray tracing device	Level 1	Baseline characteristics HOAs Coma and spherical aberrations Eye symptoms Adverse events	No significant differences in baseline characteristics of Schirmer test value, TBUT, corneal fluorescein staining, pupil diameter, HOAs, and severity of dry eye symptoms At baseline, HOAs were not significantly different in both treatment and control eyes There was a significant decrease from baseline in spherical aberrations in the treatment group 1 min after instillation but this gradually increased back to baseline at later time points The treatment group showed significant reductions in visual analogue scale (VAS) for 6/12 symptoms: scratchiness, dryness, grittiness, burning, ocular fatigue, and photophobia No reported ocular or systemic adverse events or complications with treatment	No patient had associated rheumatic disease There was no significant difference in HOA at any time point in both eye groups There was no significant difference in coma aberrations after treatment compared to baseline This was a double-blind study and significant improvement was found at all time points for treated eyes
The short term effect of trehalose and different doses of sodium hyaluronate on anterior corneal aberrations in dry eye patients Yildirim et al. 2021 [26]	Turkey	Prospective comparison study	0.15% SH vs 0.2% SH vs trehalose + 0.15% SH in patients with dry eye	Immediately after and 10 min after instillation	Measured using a Pentacam Tomography imaging (PTC, Oculus Inc, Lynnwood, WA, USA; version: 1.21r41)—OCT device	Level 2	Baseline characteristics Total root mean square (RMS), lower order aberration (LOA), HOAs, and spherical aberrations	No significant differences in baseline characteristics of Schirmer test value and TBUT Total RMS, LOA, HOAs, and spherical aberrations after each treatment group were significantly decreased compared to baseline. In 0.15% SH and 0.2% SH groups, vertical trefoil was significantly increased after treatment compared to baseline. Horizontal coma was increased after treatment in all groups compared to baseline	Protection and prevention of histological changes caused by NMDA There was no significant difference between different treatment groups
The effect of lifitegrast on refractive accuracy and symptoms in dry eye patients undergoing cataract surgery Hovanesian et al. 2020 [27]	USA	Prospective comparison study	5% lifitegrast ophthalmic solution in patients with dry eye undergoing cataract surgery	28-day course of intervention	Measured using the Zeiss Atlas topographer (Dublin, California, USA)—OCT device	Level 2	Anterior corneal power measurements HOAs Standardized patient evaluation of eye dryness (SPEED) questionnaire Corneal staining TBUT Conjunctival redness	Eyes treated with 5% lifitegrast for 28 days had more significantly accurate predicted spherical equivalent (SE) refraction for the lens actually implanted when measured There was a significant improvement in HOAs in 65% (44/77) of patients after the first course of treatment. There was a significant improvement in HOAs in 54% (27/77) of patients after the full course of treatment measured postsurgery and compared to baseline There was a significant improvement in SPEED questionnaire from baselines scores of 8.1 ± 6.6 to 4.0 ± 3.2 after preoperative treatment and second round postsurgery Corneal staining measured with the Oxford scale was significantly reduced after pre- and postoperative courses of treatment There was a significant improvement in TBUT after the pre- and postoperative courses of treatment Conjunctival redness was measured with the Schulze scale and there was significant improvement after the pre- and postoperative courses of treatment	There was also a significant increase in HOAs in 26% (13/77) of patients after the full course of treatment measured postsurgery and compared to baseline SPEED scores > 10 are considered symptomatic of dry eye disease
Clinical effects and safety of 3% diquafosol ophthalmic solution for patients with dry eye after cataract surgery: a randomized controlled trial Park et al. 2016 [28]	South Korea	RCT	3% DQS vs 0.1% SH in patients with dry eye after cataract surgery	12 weeks	Measured using a KR-1W wavefront analyzer (Topcon Medical System, Inc, Tokyo, Japan)—dual OCT and ray tracing	Level 1	Mean changes in ocular surface disease index (OSDI) TBUT Schirmer test Fluorescein staining Conjunctival lissamine (LG) staining HOAs Trefoil, coma, tetrafoil, and second astigmatism Uncorrected distance visual acuity (UDVA) Anterior chamber inflammation	OSDI scores were significantly lower in both treatment groups compared to baseline after 12 weeks TBUT was significantly longer in the DQS group than in the SH group Schirmer test values with DQS treatment were significantly higher compared to SH treatment Corneal fluorescein staining was significantly lower in the DQS group than in the SH group but both groups showed significant improvement compared to baseline after 12 weeks LG staining was significantly lower in the DQS group than in the SH group but both groups showed significant improvement compared to baseline after 12 weeks SH treatment significantly lowered HOAs compared to DQS treatment after 12 weeks There was no significant difference between the two groups for trefoil, coma, tetrafoil, and second astigmatism Both groups significantly improved UDVA by the 1-week mark postsurgery and sustained this improvement There was no significant difference in anterior chamber inflammation pre- and postoperatively and at any time points	There was no significant difference between the treatment groups and at the 1-week postsurgery there was an increased OSDI score that recovered towards baseline by 4 weeks TBUT at postoperative week 12 was significantly longer than at baseline for DQS treatment whereas SH treatment returned to baseline by 12 weeks There was no significant difference between pre- and postoperative measurements in the DQS group but the SH group never returned to baseline after 12 weeks There was no significant difference in pre- and postoperative HOAs for both groups There was no significant difference between the two groups though inflammation reached its peak 1-week postsurgery and declined to baseline by 12 weeks for both groups
Effectiveness and optical quality of topical 3.0% diquafosol versus 0.05% cyclosporine A in dry eye patients following cataract surgery Lee et al. 2016 [29]	South Korea	RCT	3% DQS vs 0.05% cyclosporine A in patients with dry eye after cataract surgery	3 months	Measured using a Hartmann–Shack wavefront aberrometer (WASCA; Carl Zeiss Meditec, Oberkochen, Germany)—ray tracing device	Level 1	TBUT Schirmer test Corneal staining OSDI HOAs Vertical coma	The DQS group had significantly better TBUT results at 1 and 3 months compared to the cyclosporine A group There was a significant improvement in Schirmer test scores at 2 and 3 months for the DQS group and 1 and 3 months for the cyclosporine A group compared to baseline There was a significant improvement ocular staining at all time points for both treatments compared to baseline All OSDI scores showed a decreasing trend but was not significant for either treatment group compared to baseline There was a significant improvement in HOAs in the cyclosporine A group at 2 and 3 months compared to baseline. Cyclosporine A treatment at 3 months was also significantly better than DQS Vertical coma significantly improved in the cyclosporine A group at 3 months compared to baseline and significantly compared to DQS treatment at 2 and 3 months	There was a significant difference in TBUT results compared to baseline at 1, 2, and 3 month time points in the DQS group but only at 2 months for the cyclosporine A group There was no significant difference in improvements between the two groups There was no significant difference between the two groups SPEED scores > 10 are considered symptomatic of dry eye disease There was no significant difference in DQS treatment compared to baseline All other optical aberration values showed no significant difference
The effect of punctal occlusion on wavefront aberrations in dry eye patients after laser in situ keratomileusis Huang et al. 2004 [30]	USA	Prospective comparison study	Punctal occlusion in patients with dry eyes post LASIK vs patients with non-dry eyes post LASIK	1 month	Measured using a Hartmann–Shack wavefront sensor (Zywave; Bausch & Lomb, Rochester, New York, USA)—ray tracing device	Level 2	Total RMS wavefront error values, lower order wavefront errors, defocus, and astigmatism Higher order RMS wavefront errors Third, fourth, and fifth-order aberrations HOAs Visual acuity	Dry eyes after 1 month post-punctal occlusion had significantly improved total RMS wavefront error values, lower order wavefront errors, defocus, and astigmatism compared to measurements pre-punctal occlusion There was a significant improvement in higher-order RMS wavefront error in patients after punctal plug insertion There was a significant reduction/improvement in RMS wavefront measures in the third, fourth, and fifth-order aberrations after punctal occlusion There was a significant reduction/improvement in coma and spherical aberration after punctal occlusion There was improvement in visual acuity in patients with punctal occlusion	There were no significant changes in trefoil after punctal plug These results were not determined to be significant
Effect of instillation of eyedrops for dry eye on optical quality Koh et al. 2013 [11]	Japan	Prospective comparison study	0.3% SH vs 3% DQS vs 2% rebamipide drops in healthy eyes	1 min, 5 min, and 10 min after instillation	Measured using a custom-developed Hartmann–Shack wavefront aberrometer (Topcon Corp., Tokyo, Japan)—ray tracing device	Level 2	Coma-like aberrations, spherical-like aberrations, and total HOAs Forward light scatter	There was a significant increase in coma, spherical, and total HOAs immediately after instillation for all 3 drops compared to baseline. SH had significantly higher values immediately after instillation compared to DQS, rebamipide, and control There was a significant increase in forward light scatter immediately after rebamipide instillation compared to baseline and compared to all other groups	At 5 and 10 min after instillation, there were no significant differences in the HOA components among all groups At 5 and 10 min after instillation, there were no significant differences in forward light scatter among all groups
Effects of lipid- versus sodium hyaluronate-containing eye drops on optical quality and ocular surface parameters as a function of the meibomian gland dropout rate Miháltz et al. 2018 [31]	Austria	RCT	Artelac Lipid vs 0.2% SH in patients with dry eyes	3 months	Measured using the iTrace VFA—ray tracing device	Level 1	Schirmer test, TBUT, ocular surface staining, symptom score, meibomian gland (MG) dropout rate, corneal higher order RMS (HORMS), HO Strehl ratio, and HO modulation transfer function (MTF) HO Strehl ratio based on MG loss severity HORMS values based on MG loss severity	Both groups had significant improvement in Schirmer test, TBUT, ocular surface staining, and the symptom core after 3 months of treatment compared to baseline There was a significant improvement in SPEED questionnaire from baselines scores of 8.1 ± 6.6 to 4.0 ± 3.2 after preoperative treatment and second round postsurgery Corneal staining measured with the Oxford scale was significantly reduced after pre- and postoperative courses of treatment There was a significant increase in corneal HO Strehl ratio in patients with an MG dropout rate > 50% in the lipid group There was a significant decrease in corneal HORMS in patients with an MG dropout rate > 50% in the lipid group	Both groups had no significant changes to MG dropout rate, corneal HORMS, the HO Strehl ratio, and HO MTF. There was no significant difference when comparing treatment groups There was no significant difference in HO Strehl ratio in patients with an MG dropout rate > 50% in the SH group There was no significant difference in corneal HORMS in patients with an MG dropout rate > 50% in the SH group
Optical quality after instillation of eyedrops in dry-eye syndrome Montes-Mico et al. 2010 [32]	Spain	Prospective comparison study	Lubricating eye drops (Blink Intensive Tears) in patients with dry eyes	Immediately after and 10 min after instillation	Measured by computerized videokeratography (PCT 200, Optopol Technology S.A.)—OCT device	Level 2	Mean TBUT Corneal wavefront aberration contour plots Retinal point-spread function (PSF) Higher-order, spherical-like, and coma-like aberrations	TBUT was significantly lengthened the mean TBUT at 10 min compared to at 0 min (baseline) There was change in the number of contour lines between baseline and after artificial tear instillation There was an improvement in PSF after eye drop instillation Higher-order, spherical-like, and coma-like aberrations were all significantly decreased after drop instillation and this reduction was maintained and significant at 10 min	At 5 and 10 min after instillation, there were no significant differences in the HOA components among all groups This change in wavefront aberration contour plots was not qualitative and not quantified This change in PSF was not qualitative and not quantified There was no significant difference in reduction at 0 and 10 min
Effect of rebamipide ophthalmic suspension on optical quality in the short break-up time type of dry eye Koh et al. 2013 [33]	Japan	Prospective comparison study	2% rebamipide drops in patients with short breakup time (BUT) of the tear time type of dry eye	Baseline, 2 weeks, and 4 weeks	Measured using the KR-1W (Topcon, Tokyo, Japan)—dual OCT and ray tracing	Level 2	Tear film BUT Fluorescein staining scores Schirmer test scores HOAs—corneal, coma-like, and spherical-like Fluctuation index (FI) and stability index (SI)	There was a significant increase in tear film BUT at 2 and 4 weeks after treatment when compared to baseline There was no significant difference in fluorescein staining scores at 2 and 4 weeks after treatment There was a significant decrease in Schirmer test scores at 4 weeks but not at 2 weeks after treatment HOAs were recorded for 10 s and there was a significant upward trend at baseline during the 10 s recording for corneal, coma-like, and spherical-like aberrations There was a significant variation/increase in spherical-like aberrations at the 2 week period during the 10 s recording The FI before treatment was significantly higher than at the 2- and 4-week time points. The SI before treatment was significantly higher only compared to the 4-week time point	There were no significant changes at the 4-week period
Effect of diquafosol ophthalmic solution on the optical quality of the eyes in patients with aqueous-deficient dry eye Koh et al. 2014 [34]	Japan	Prospective comparison study	3% DQS drops in patients with aqueous-deficient dry eyes	15 min and 4 weeks after instillation	Measured using a custom-developed Hartmann–Shack wavefront aberrometer (Topcon Corp., Tokyo, Japan)—ray tracing device	Level 2	Dry eye symptoms Mean corneal staining scores Conjunctival staining Schirmer test scores Mean total HOAs, coma-like aberrations, spherical-like aberrations, FIs, and SIs	There was a significant improvement in dry eye symptoms after treatment There was a significant decrease in corneal staining scores after treatment There was no significant change in conjunctival staining There was no significant change in Schirmer test scores There were significant decreases in mean total HOAs and spherical-like aberrations at 4 weeks compared to baseline	There were no significant differences in mean total HOAs and spherical-like aberrations at 15 min compared to baseline. There were also no significant differences in coma-like aberrations, FIs, and SIs at any time points compared to baseline
Effects of diquafosol tetrasodium administration on visual function in short break-up time dry eye Kaido et al. 2013 [35]	Japan	Prospective comparison study	DQS drops in patients with symptomatic dry eye and short BUT vs patients without dry eye symptoms and short BUT	1 month	Measured using the Hartmann–Shack wavefront aberrometer (Topcon Corp., Tokyo, Japan)—ray tracing device	Level 2	BUT values logMAR functional, minimal and maximal visual acuities, and HOAs	There was a significant increase in BUT values in symptom-negative BUT patients treated with DQS Symptom-positive BUT patients treated with DQS had a significant decrease in logMAR functional, minimal and maximal visual acuities, and HOAs	There was an increase trend in symptom-positive BUT patients treated with DQS but this was not significant There was no significant change in symptom-negative BUT patients
Effects of preservative-free 3% diquafosol in patients with pre-existing dry eye disease after cataract surgery: a randomized clinical trial Jun et al. 2019 [36]	South Korea	RCT	3% DQS drops in patients with pre-existing dry eye disease after cataract surgery	1 and 3 months	Measured using the iTrace (Tracey Technology, Texas, USA)—ray tracing device	Level 1	TBUT OSDI scores Meibomian gland dysfunction (MGD) HOAs	TBUT was significantly improved in the preservative-free 3% DQS (group 1), and preservative-containing 3% DQS (group 2) groups compared to preoperative baseline after 1 month. Only group 1 remained significantly improved after 3 months OSDI scores were significantly improved in groups 1 and 2 at both 1 and 3 months MGD stage was significantly improved in group 2 compared to preoperative measurements after 1 month. However only group 1 showed significant improvement in MGD stage at 3 months HOAs were reduced for all 3 groups at all points throughout the study and there were no significant differences between the groups	The preservative-free 0.15% SA (group 3) group had no significant improvement at both 1 and 3 months postoperatively compared to baseline MGD staging was significantly lower in groups 1 and 2 when compared to group 3