Corneal Refractive Surgery-related Dry Eye
Numerous studies have looked into how position, width and angle of flap creation can affect post-operative dry eye. Other factors to take into account include the need for refractive enhancement surgeries and use of the suction ring.
After flap creation, only the nerve bundles passing through the flap hinge avoid transection and are preserved for the innervation of the corneal epithelium. There have been contrasting findings on how differing hinge position influence post-operative corneal sensitivity and dry eye outcomes, summarized in Table 1.
It has been suggested the long posterior corneal nerves predominantly enter the cornea at the limbus at the 3 and 9 o'clock positions, and that a nasal/horizontally positioned hinge will hence preserve more of the major nerve trunks compared to a superiorly/vertically positioned hinge. These studies quoted a schematic of corneal nerve architecture by Muller et al. published in 1997. However, Muller later published a review in 2003 that revised their previous findings. The most updated schematic postulated that corneal nerves entered the corneal limbus in an equal distribution along the circumference of the limbus, implying that differing hinge position has minimal impact on the extent of post-LASIK corneal denervation.
The two prospective studies, which concluded that a horizontally positioned hinge was superior to a verticallypositioned hinge only, reported their results up to a period of 2 months and 6 months, respectively. A 2013 systematic review and meta-analysis of eight randomized-controlled trials (including some of those listed in Table 1) also reported worse corneal staining score, tear secretion, tear film stability and loss of corneal sensitivity in cases of vertically positioned hinges than horizontally positioned hinges, but this difference was only significant at 3 months post-operatively and had resolved by 6 months. None of these studies included comparisons of dry eye symptomology after LASIK. Dry eye symptoms, assessed by the ocular surface disease index questionnaire, have been found to be similar in patients regardless of hinge position by three separate prospective studies.
In summary, we are of the opinion that hinge position has a minimal, if any, effect on the severity of dry eyes in the immediate post-operative period.
There is also no evidence whatsoever that hinge position has an effect on the risk of LASIK-related dry eye in the long run. This is highlighted most by Mian et al., which included 56 eyes in their study on a 12-month follow-up. This was the study with the longest follow-up period, and showed that hinge position had no effect on corneal sensitivity or dry eye outcomes at any given time point after LASIK.
A narrow hinge width (3.00–5.50 mm) was also reported to be associated with slower recovery and greater severity of post-operative loss of corneal sensitivity, and more severe dry eye symptoms than a wider hinge width (6.00–7.50 mm).
Differences in hinge angle and flap thickness were not found to affect post-operative corneal sensitivity and dry eye at any given time point within 12 months. Enhancement surgeries with flap lifting at a mean of 1 year after the initial procedure, which could damage healed corneal nerves, also did not lead to an increased incidence of post-operative dry eye.
As elaborated in the 'Pathophysiology' section, intra-operative application of a suction ring on the ocular surface would reduce goblet cell density in the conjunctiva for up to 1 month after LASIK.
Different modalities of flap creation, namely microkeratome and different platforms of femtosecond lasers, have also been investigated for their effects on post-operative dry eye.
One study (which included 183 eyes) reported that compared with microkeratome LASIK, femtosecond laser LASIK led to lower incidence and severity of punctate epithelial erosion and dry eye symptoms, as well as lesser use of cyclosporine A for post-LASIK dry eye treatment at 1 month post-operatively.
In contrast, two other studies, with sample sizes of 102 and 274, reported no significant difference in both tear function and symptoms between microkeratome or femtosecond laser procedures. These two studies had longer follow-up times (12 months and 3 months). Some clinicians may favor the use of femtosecond lasers over the microkeratome, but the difference in dry eye outcomes is once again unlikely to be substantial regardless of modality used, especially beyond the first month of post-LASIK recovery.
Among femtosecond laser flap-creation systems, there was no association between the types of femtosecond lasers, namely lasers of frequency (500 vs 60 kHz) and machines (VisuMax vs Intralase), and post-operative dry eye.
Use of different ablation laser platforms also had no effect on post-LASIK dry eye (summarized in Table 2), though more research has to be done to draw any meaningful conclusions.
PRK, LASEK and epipolis laser in-situ keratomileusis (Epi-LASIK) are common alternatives to LASIK for corneal refractive surgeries. Literature has reported different risk profiles for these alternatives, and they are summarized below:
Photorefractive keratectomy PRK patients have better post-operative tear function, but suffer more severe dry eye symptoms and poorer wound healing.
Available studies revealed that PRK offered better post-operative tear function, in terms of higher Schirmer score and TBUT, and lower tear osmolarity, than LASIK at up to 3 months following surgery. Symptoms were not investigated in these studies.
However, symptomatic dry eye seemed to be worse in patients who have undergone PRK rather than LASIK. One study assessed dry-eye symptoms in post-LASIK and PRK patients by using a questionnaire, which enquired about major symptoms such as frequency of dryness, tenderness of the eyelid and the sensation of eyelid stickiness. It reported a higher frequency of dry-eye symptoms in patients who underwent PRK as compared with LASIK, for at least 6 months post-operatively. In another randomized trial, while symptoms of dryness and foreign body sensation were not significantly different between procedures, patients with PRK reported a higher frequency of visual fluctuation at 1 month after operation.
The reason behind this discrepancy between signs and symptoms can be explained by the differing effects PRK and LASIK have on corneal sensitivity, and the greater degree of wound healing necessary in PRK. A study that compared PRK and LASIK patients for up to 3 months post-operatively found that corneal sensitivity was more significantly impaired in LASIK patients. Hence, while patients may have poorer tear function after LASIK, their corneas are less sensitive to irritating or painful stimuli, hence they suffer less symptoms. Moreover, due to the stripping of the corneal epithelium during the PRK procedure, re-epithelialization of the cornea to pre-operative thickness requires about 6 months. In contrast, this process of re-epithelialization is not required after LASIK due to replacement of the flap. This prolonged period of post-operative wound healing may contribute greatly to post-PRK dry eye.
Laser epithelial keratomileusis LASEK has very similar effects on post-operative dry eye as LASIK.
LASEK, compared with LASIK, has shown better post-operative tear secretion in patients and was found in a separate study to lead to earlier recovery of corneal sensitivity, which was shown to be correlated with the sub-basal nerve fiber and keratocyte density at time of measurement. However, dry eye symptomology was not investigated in these studies.
Four other studies have demonstrated contrasting results. In particular, Dooley et al. took the most holistic approach of investigating both signs and symptoms of dry eye in a prospective controlled cross-sectional study. This study of 85 eyes over a 12-month period showed no differences between LASEK and LASIK in dry eye symptoms (ocular surface disease index score), tear function (Schirmer score and tear osmolarity) and incidence of dry eye.
EpiLASIK EpiLASIK seems to be intermediate between LASIK and PRK in terms of induction of dry eye.
The mechanics of the EpiLASIK procedure (creation of a sub-epithelial flap, ablation of the superficial stroma) is a combination of elements from both LASIK and PRK. Its post-operative effects on the ocular surface are also likely to be that between the profiles of LASIK and PRK.
In a rabbit model, early post-operative increase in NGF was found to be higher in the EpiLASIK group than the LASIK group, implying that corneal nerve regeneration is faster in EpiLASIK. This is consistent with research in human eyes, where on-flap EpiLASIK was shown to offer faster recovery of corneal sensitivity over a 6-month period. Tear function, which was assessed by TBUT and Schirmer II, was also found to be superior in EpiLASIK in the same study.
Another human study found no significant differences in incidence of post-operative dry eye between patients who underwent either LASIK, LASEK or EpiLASIK. However, this study only assessed their patients up to 1 week post-operatively.
For EpiLASIK, flap-off procedures were shown to be superior to flap-on procedures as they resulted in faster epithelial healing and were associated with a reduced expression of tear cytokines such as IL-8, TNF-α, PDGF-BB, bFGF, compared with on-flap procedures. This is supported with a meta-analysis published by Feng et al. in 2012.
In comparing EpiLASIK with PRK, this difference in flap-off or flap-on seemed important. Flap-off EpiLASIK patients experienced slightly less post-operative pain over 4 days compared with PRK patients, while flap-on EpiLASIK patients experienced greater post-operative pain, poorer wound healing and poorer visual recovery than PRK patients.
The severity of dry eye varies in different variations of LASIK and these are summarized in Figure 1A & B.
(Enlarge Image)
Figure 1.
The relationship between different photorefractive modalities and its patient outcomes. (A) Photorefractive procedures ranked by length of time before relief in pain or dry eye symptoms, in ascending order. (B) Photorefractive procedures ranked by severity of tear dysfunction, in ascending order.
Intra-operative Factors
Hinge Properties, LASIK Enhancement, Suction Ring Application
Numerous studies have looked into how position, width and angle of flap creation can affect post-operative dry eye. Other factors to take into account include the need for refractive enhancement surgeries and use of the suction ring.
After flap creation, only the nerve bundles passing through the flap hinge avoid transection and are preserved for the innervation of the corneal epithelium. There have been contrasting findings on how differing hinge position influence post-operative corneal sensitivity and dry eye outcomes, summarized in Table 1.
It has been suggested the long posterior corneal nerves predominantly enter the cornea at the limbus at the 3 and 9 o'clock positions, and that a nasal/horizontally positioned hinge will hence preserve more of the major nerve trunks compared to a superiorly/vertically positioned hinge. These studies quoted a schematic of corneal nerve architecture by Muller et al. published in 1997. However, Muller later published a review in 2003 that revised their previous findings. The most updated schematic postulated that corneal nerves entered the corneal limbus in an equal distribution along the circumference of the limbus, implying that differing hinge position has minimal impact on the extent of post-LASIK corneal denervation.
The two prospective studies, which concluded that a horizontally positioned hinge was superior to a verticallypositioned hinge only, reported their results up to a period of 2 months and 6 months, respectively. A 2013 systematic review and meta-analysis of eight randomized-controlled trials (including some of those listed in Table 1) also reported worse corneal staining score, tear secretion, tear film stability and loss of corneal sensitivity in cases of vertically positioned hinges than horizontally positioned hinges, but this difference was only significant at 3 months post-operatively and had resolved by 6 months. None of these studies included comparisons of dry eye symptomology after LASIK. Dry eye symptoms, assessed by the ocular surface disease index questionnaire, have been found to be similar in patients regardless of hinge position by three separate prospective studies.
In summary, we are of the opinion that hinge position has a minimal, if any, effect on the severity of dry eyes in the immediate post-operative period.
There is also no evidence whatsoever that hinge position has an effect on the risk of LASIK-related dry eye in the long run. This is highlighted most by Mian et al., which included 56 eyes in their study on a 12-month follow-up. This was the study with the longest follow-up period, and showed that hinge position had no effect on corneal sensitivity or dry eye outcomes at any given time point after LASIK.
A narrow hinge width (3.00–5.50 mm) was also reported to be associated with slower recovery and greater severity of post-operative loss of corneal sensitivity, and more severe dry eye symptoms than a wider hinge width (6.00–7.50 mm).
Differences in hinge angle and flap thickness were not found to affect post-operative corneal sensitivity and dry eye at any given time point within 12 months. Enhancement surgeries with flap lifting at a mean of 1 year after the initial procedure, which could damage healed corneal nerves, also did not lead to an increased incidence of post-operative dry eye.
As elaborated in the 'Pathophysiology' section, intra-operative application of a suction ring on the ocular surface would reduce goblet cell density in the conjunctiva for up to 1 month after LASIK.
Variations of LASIK
Different modalities of flap creation, namely microkeratome and different platforms of femtosecond lasers, have also been investigated for their effects on post-operative dry eye.
One study (which included 183 eyes) reported that compared with microkeratome LASIK, femtosecond laser LASIK led to lower incidence and severity of punctate epithelial erosion and dry eye symptoms, as well as lesser use of cyclosporine A for post-LASIK dry eye treatment at 1 month post-operatively.
In contrast, two other studies, with sample sizes of 102 and 274, reported no significant difference in both tear function and symptoms between microkeratome or femtosecond laser procedures. These two studies had longer follow-up times (12 months and 3 months). Some clinicians may favor the use of femtosecond lasers over the microkeratome, but the difference in dry eye outcomes is once again unlikely to be substantial regardless of modality used, especially beyond the first month of post-LASIK recovery.
Among femtosecond laser flap-creation systems, there was no association between the types of femtosecond lasers, namely lasers of frequency (500 vs 60 kHz) and machines (VisuMax vs Intralase), and post-operative dry eye.
Use of different ablation laser platforms also had no effect on post-LASIK dry eye (summarized in Table 2), though more research has to be done to draw any meaningful conclusions.
Alternatives to LASIK
PRK, LASEK and epipolis laser in-situ keratomileusis (Epi-LASIK) are common alternatives to LASIK for corneal refractive surgeries. Literature has reported different risk profiles for these alternatives, and they are summarized below:
Photorefractive keratectomy PRK patients have better post-operative tear function, but suffer more severe dry eye symptoms and poorer wound healing.
Available studies revealed that PRK offered better post-operative tear function, in terms of higher Schirmer score and TBUT, and lower tear osmolarity, than LASIK at up to 3 months following surgery. Symptoms were not investigated in these studies.
However, symptomatic dry eye seemed to be worse in patients who have undergone PRK rather than LASIK. One study assessed dry-eye symptoms in post-LASIK and PRK patients by using a questionnaire, which enquired about major symptoms such as frequency of dryness, tenderness of the eyelid and the sensation of eyelid stickiness. It reported a higher frequency of dry-eye symptoms in patients who underwent PRK as compared with LASIK, for at least 6 months post-operatively. In another randomized trial, while symptoms of dryness and foreign body sensation were not significantly different between procedures, patients with PRK reported a higher frequency of visual fluctuation at 1 month after operation.
The reason behind this discrepancy between signs and symptoms can be explained by the differing effects PRK and LASIK have on corneal sensitivity, and the greater degree of wound healing necessary in PRK. A study that compared PRK and LASIK patients for up to 3 months post-operatively found that corneal sensitivity was more significantly impaired in LASIK patients. Hence, while patients may have poorer tear function after LASIK, their corneas are less sensitive to irritating or painful stimuli, hence they suffer less symptoms. Moreover, due to the stripping of the corneal epithelium during the PRK procedure, re-epithelialization of the cornea to pre-operative thickness requires about 6 months. In contrast, this process of re-epithelialization is not required after LASIK due to replacement of the flap. This prolonged period of post-operative wound healing may contribute greatly to post-PRK dry eye.
Laser epithelial keratomileusis LASEK has very similar effects on post-operative dry eye as LASIK.
LASEK, compared with LASIK, has shown better post-operative tear secretion in patients and was found in a separate study to lead to earlier recovery of corneal sensitivity, which was shown to be correlated with the sub-basal nerve fiber and keratocyte density at time of measurement. However, dry eye symptomology was not investigated in these studies.
Four other studies have demonstrated contrasting results. In particular, Dooley et al. took the most holistic approach of investigating both signs and symptoms of dry eye in a prospective controlled cross-sectional study. This study of 85 eyes over a 12-month period showed no differences between LASEK and LASIK in dry eye symptoms (ocular surface disease index score), tear function (Schirmer score and tear osmolarity) and incidence of dry eye.
EpiLASIK EpiLASIK seems to be intermediate between LASIK and PRK in terms of induction of dry eye.
The mechanics of the EpiLASIK procedure (creation of a sub-epithelial flap, ablation of the superficial stroma) is a combination of elements from both LASIK and PRK. Its post-operative effects on the ocular surface are also likely to be that between the profiles of LASIK and PRK.
In a rabbit model, early post-operative increase in NGF was found to be higher in the EpiLASIK group than the LASIK group, implying that corneal nerve regeneration is faster in EpiLASIK. This is consistent with research in human eyes, where on-flap EpiLASIK was shown to offer faster recovery of corneal sensitivity over a 6-month period. Tear function, which was assessed by TBUT and Schirmer II, was also found to be superior in EpiLASIK in the same study.
Another human study found no significant differences in incidence of post-operative dry eye between patients who underwent either LASIK, LASEK or EpiLASIK. However, this study only assessed their patients up to 1 week post-operatively.
For EpiLASIK, flap-off procedures were shown to be superior to flap-on procedures as they resulted in faster epithelial healing and were associated with a reduced expression of tear cytokines such as IL-8, TNF-α, PDGF-BB, bFGF, compared with on-flap procedures. This is supported with a meta-analysis published by Feng et al. in 2012.
In comparing EpiLASIK with PRK, this difference in flap-off or flap-on seemed important. Flap-off EpiLASIK patients experienced slightly less post-operative pain over 4 days compared with PRK patients, while flap-on EpiLASIK patients experienced greater post-operative pain, poorer wound healing and poorer visual recovery than PRK patients.
Summary of Variations of LASIK
The severity of dry eye varies in different variations of LASIK and these are summarized in Figure 1A & B.
(Enlarge Image)
Figure 1.
The relationship between different photorefractive modalities and its patient outcomes. (A) Photorefractive procedures ranked by length of time before relief in pain or dry eye symptoms, in ascending order. (B) Photorefractive procedures ranked by severity of tear dysfunction, in ascending order.
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