Abstract and IntroductionAbstractDry eye is the most common post-operative complication in patients who undergo laser-assistedin situkeratomileusis and other photorefractive procedures. Epidemiological studies have found that almost all patients experience some form of dry-eye-related discomfort in the post-operative period. This review seeks primarily to identify patient factors, which predispose to this complication, as well as outline the possible interventions clinicians can consider to avoid, prevent and treat this complication. Numerous pre-, intra- and post-operative guidelines are provided. The ideal method of post-laser-assistedin situkeratomileusis dry eye prevention is a meticulous peri-operative management plan, as opposed to post-operative management alone. Newer modalities of photorefractive surgery may have differing effects on the ocular surface.IntroductionDry eye disease is defined as a multifactorial disease of the ocular surface and tear film that results insymptoms ofdiscomfort, visual disturbance and tear film instability. It is characterized by hyperosmolarity of the tear film and inflammation of the ocular surface.[1]Photorefractive surgery induces dry eye or exacerbates pre-existing dry eye by causing increased tear osmolarity and inflammation of the ocular surface via various mechanisms.[2]The three predominant techniques of photorefractive surgery now used in clinical practice are laser-assistedin-situkeratomileusis (LASIK), photorefractive keratectomy (PRK) and laser epithelial keratomileusis (LASEK). LASIK continues to be the most commonly performed surgery of the three.[3]This discussion is hence centered upon LASIK, but still includes a study of some recent variants of laser corneal refractive procedures. While it is acknowledged that this topic has been extensively reviewed previously,[4]this article focuses on providing concise, evidence-based guidelines to clinicians on how best to prevent or treat post-LASIK dry eye. This begins from a process of prudent patient selection combined with peri-operative treatment of the conditionEpidemiologyDry eye is a common complication after photorefractive surgery. The incidence of post-LASIK dry eye ranged between 8.3 and 48.0% based on symptomatic and/or objective findings assessed at least 6 months post-operatively.[59]However, comparison of these studies is not possible due to their differing diagnostic criteria for dry eye.To date, no study has looked at the incidence or prevalence of chronic, persistent post-LASIK dry eye beyond the 6-month post-operative mark. It is uncertain if incidence of post-operative dry eye in the short term (1 day to 1 month) is a predictive factor for the development of chronic dry eye in the longer term (more than 6 months).PathophysiologyThe pathophysiologic mechanisms behind post-LASIK dry eye have been previously reviewed,[2,10]and are summarized below with updates included:Disruption of Afferent Corneal Sensory NervesMaintenance of a healthy tear film is achieved by a constant feedback mechanism between the ocular surface, brainstem and lacrimal glands, collectively called the Lacrimal Functional Unit.[1]Photorefractive surgery compromises the sensory nerve supply of the cornea, resulting in impaired sensation. Decreased afferent input to the lacrimal functional unit results in decreased tear secretion, leading to a deficient aqueous component of the tear film.Usingin vivoconfocal microscopy of 65 human corneas, decreases in length and degree of interconnectedness of corneal sub-basal nerve fiber layers have been observed in post-LASIK corneas at 6 months post-operatively.[11]Such abnormal nerve morphology is correlated with corneal hypoesthesia (assessed by Cochet-Bonnet esthesiometry). Post-LASIK corneal sensory threshold was as high as 160 mg/0.0113 mm2at 2 weeks after LASIK, though this resolves to the normal threshold of approximately 11 mg/0.0113 mm2at 6 months.While corneal sensation has been found to recover by 6 months after the procedure,[11]the morphology of the sub-basal nerve plexus seems to require at least 5 years before returning to pre-surgical levels of nerve density.[12]Other anatomical defects in corneal innervation have also been identified after LASIK, more specifically decreased length, width and tortuosity of sub-basal nerve fibers.[13]In this study, tortuosity returned to a pre-operative state by 3 months post-operatively, while decreases in length and width persisted even after 6 months of follow-up. The time required for sub-basal nerves to recover to its pre-operative length and width is unknown.Decreased afferent input can also cause decreased blink frequency and increases the inter-blink interval. There are also previous reviews that have explored the fact that LASIK can cause incomplete blinking, leading to exposure keratopathy.[14]Overall, the increased exposure time of the ocular surface to the environment leads to greater evaporative loss of the tear film, contributing to dryness.[10]Dry eyes are associated with minute punctate epithelial erosions of the cornea, usually detected by fluorescein or Rose Bengal staining of the ocular surface. This is seen in post-LASIK patients due to impaired healing of the epithelium.Numerous small peptides released by sensory nerve endings play a role in supporting overlying epithelium.[15]Beyond the anesthetic effect caused by sensory nerve damage, disruption of corneal innervation also deprives the epithelium of epitheliotrophic factors such as substance P and insulin-like growth factor-1 that play a role in maintaining a healthy epithelium and wound healing.[16]Studies in mice have shown that innervation is important in maintaining limbal corneal stem cells.[17]Nerve growth factor (NGF) has been highlighted as a major factor in promoting epithelial healing by promoting cell migration via the upregulation of matrix metalloproteinase-9 and cleavage of beta4 integrins.[18]It has been found to be elevated in post-PRK and LASIK eyes and is likely to be the predominant neuropeptide in promoting epithelial healing after the procedure.[19]Lower levels of post-operative NGF are associated with poorer post-operative tear function.[19]Deficiency of NGF expression may hence be the pathophysiologic basis of LASIK-induced neurotrophic epitheliopathy (LNE),[20]in which a persistent corneal epithelial defect forms, regardless of tear production status.The healing process after photorefractive surgery is initiated by epithelial migration, followed by epithelial proliferation and stromal regeneration.[21]Expression of cytokines involved in wound-healing such as TNF-, PDGF, VEGF and TGF-1 is part of the keratocyte's innate response to insult. After LASIK, the expression of these cytokines was not impaired.[2225]This seems to support LNE as the primary cause of poor epithelial healing in post-LASIK corneas.Unlike keratocyte-derived growth factors, lacrimal secreted glycoproteins and cytokines may be impaired after LASIK. Lacritin for instance is produced almost exclusively by the lacrimal gland.[26]After secretion, it can drive further lacrimal secretion and acinar proliferation. Post-LASIK hyposecretion of tears leads to decreased delivery of lacritin to the ocular surface. This may contribute to poor epithelial healing or dry eye, though this has to be confirmed by studies. There have been no studies investigating transferrin or lactoferrin levels in post-LASIK eyes.Increase in Ocular Surface InflammationInflammation is a key characteristic of dry eye. While tear hyperosmolarity remains the most well-documented trigger of ocular surface inflammation, other triggers have gained prominence in light of recent findings.Decreased blink rate[27]and tear fluorescein clearance[28]is detectable after LASIK, even at 12 months after surgery. As a result, the lacrimal functional unit that normally ensures constant dilution and removal of inflammatory cytokines from the ocular surface may be impaired. This can explain the tear hyperosmolarity observed in patients that underwent LASIK and PRK.[29]The resultant tear hyperosmolarity causes inflammation via epithelial stress signaling, which drives the accumulation of inflammatory mediators such as IL-1, and matrix metalloproteinase 9 (MMP-9), which is seen in dry eye.[30]However, a recently published study disputed that tear osmolarity increased significantly after LASIK, especially when patients are compliant to lubricant drops.[31]Neurogenic inflammation is defined as the phenomenon of vasodilation, increased vascular permeability and hypersensitivity of end-organ tissues as a result of pro-inflammatory mediators released by afferent nerve endings.[32]During LASIK, the neuropeptides substance P, neuropeptide Y and calcitonin gene-related peptide (CGRP) are released into the corneal stroma by damaged corneal nerves, both at the boundaries of the flap as well as the ablation surface. They cause mast cell degranulation and recruitment of polymorphonuclear leukocytes and monocytes/macrophages to the ocular surface.[33]The threshold for detection of painful stimuli may have been altered after the LASIK surgery. The neuropeptides mentioned above have been implicated in lowering nociceptive thresholds, possibly contributing to more readily perceived symptoms of inflammation such as dryness and discomfort after LASIK.[34]Laser-induced inflammation of the cornea occurs due to excimer laser ablation of the corneal stroma, and femtosecond laser flap creation. In such cases, a sequential cascade of keratocyte apoptosis, activation and differentiation into myofibroblasts occurs.[35]The pattern of inflammation has been found to be significantly different between LASIK and PRK, first in the type of cytokine responses elicited, and second in the intensity and site of inflammatory response. Laser-induced inflammation associated with PRK occurs predominantly at the corneal sub-epithelial layer and anterior stroma, while laser-induced inflammation in LASIK is more confined to the deeper stroma.[36]Cytokines such as IL-1, IL-6, IL-8 and monocyte chemotactic protein-1 were expressed by human corneal fibroblasts at 24 h after exposure to the excimer laser.[37]They contribute to polymorphonuclear leukocyte and monocyte/macrophages recruitment to the ocular surface and inflammatory changes. The inflammatory cytokines can contribute to corneal scarring and haze,[38]particularly in PRK.[39]Alteration of Ocular Surface AnatomyImmobilization of the eye via a suction ring is usually done to restrict eye movements during surgery. In a rabbit model (n = 30),[40]this has been shown to cause inflammatory cell infiltration, blood vessel dilation and congestion, apoptosis and thinning of epithelium of the conjunctiva detected by histological examination. AB2.5-PAS (for distinguishing acidic and neutral mucins) and AB1.0-PAS staining (for distinguishing sulfated acid mucin and non-sulfated acid mucin) both revealed statistically significant reduction in conjunctival goblet cell density. These changes were observed to be present at 3 days after suction ring application and resolved at 7 days. Impression cytology also detected significant reduction in peri-flap goblet cell density in human subjects 1 week to 1 month after LASIK.[41]The mucin layer of the tear film is hence likely to be compromised, leading to tear film instability, which contributes to dry eye.Other morphological changes include a decreased nuclear-cytoplasmic ratio of non-goblet conjunctival epithelial cells,[42]but the significance of this alteration is not known.Photorefractive surgery involves excising stromal tissue that results in flattening of the central cornea post-surgery. This is postulated to be detrimental to the eyelid's interaction with the ocular surface as well as surface tension of the tear film.[29,43]This in turn leads to incongruent interaction between the posterior lid margin and the cornea surface during blinking.Irregularities in the corneal surface have also been found after photorefractive surgery. Striae detectable by slit-lamp examination and microfolds detectable by confocal microscopy have both been documented in the Bowman's layer after LASIK.[44]Some cases of corneal striae are severe enough to cause refractive error and were persistent even at 15 months after LASIK.[45]Microfolds are also consistently found in almost all post-LASIK eyes, with some being discovered 2 years after LASIK.[44,46]It is postulated that these irregularities contributes to impaired tear spreading with tear instability and resultant post-LASIK dry eye.[47]Pre-operative Risk Factors & AssessmentPrior to any corneal refractive surgery, it is crucial to take a comprehensive history during the consultation and to assess the patient's existing tear function or dry eye status. Demographic factors, lifestyle, medical and surgical history should be elicited to understand the risk profile of the patient seeking refractive surgery.Demographic & Lifestyle FactorsAge, female gender and East Asian race are possible predisposing factors to post-operative dry eye. Age was found to be inversely associated with corneal sensitivity,[48]but older age was not correlated to the development of post-operative dry eyes.[49]The age range examined in the studies was from 27 to 47 years. Female gender and East Asian ethnicity (in contrast to Caucasian ethnicity) are risk factors for post-LASIK dry eye, as evidenced by more severe symptoms and poorer tear function post-operatively.[7,48]In a separate study, age and gender were not found to predispose to post-LASIK dry eye, but this study diagnosed dry eye purely on corneal fluorescein staining.[8]Ethnicity as a risk factor may be confounded by other factors. These include racial differences in lid and orbital anatomy, blinking dynamics; higher pre-operative myopia and attempted refractive correction; and poorer pre-existing tear film parameters in East Asians. The effects of age, gender and race have been reviewed elsewhere and similar conclusions were obtained.[8,50,51]History of contact lens wear is also important. Patients with contact lens intolerance may have underlying dry eye. Long duration of contact lens use is a risk factor for otherwise normal individuals to develop dry eye[2,52]and similarly predisposes post-LASIK patients to chronic dry eye defined as dry eye persisting beyond 6 months.[49]The duration of contact lens wear in this study ranged from 3 to 23 years.Cigarette smoking should also be considered. A study published in 2013 discovered that contact lens wear and chronic cigarette smoking positively correlate with TGF-1 and VEGF tear levels and delayed corneal re-epithelialization.[53]There is no evidence that smoking cessation improves the tear outcome after LASIK.Medical & Surgical HistoryPre-operative assessment should also focus on these factors: previous diagnosis of dry eye, frequency and intensity of symptoms of pre-operative dry eye disease, severity of pre-operative myopia, presence of other ocular inflammatory disease, collagen vascular disease (CVD) (especially Sjogren syndrome) and history of prior blepharoplasty.Increased severity of pre-operative myopia was shown to be a risk factor for chronic post-LASIK dry eye, defined as a corneal fluorescein staining score of three or more[8](relative risk of 0.88 per diopter increase in pre-operative spherical equivalent). This study examined -1 to -7D of myopia in 35 adults. Studies have shown that incidence of dry eye is greater in patients with a history of allergy. This was concluded in a retrospective study of 572 individuals in an elderly population (age range: 4386).[54]Incidence or prevalence of dry eye in atopic individuals has not been documented. The higher incidence of inflammatory complications of LASIK, such as Diffuse Lamellar Keratitis, in atopic patients suggests that these patients have an abnormally strong inflammatory response to LASIK.[55]Caution is advised in performing LASIK on patients with history of atopic conditions such as asthma, atopic dermatitis and rhinoconjunctivitis due to possible shared pathways of pathophysiology between atopy and post-LASIK dry eye. Evidence of common pathways includes NGF hyperexpression, which has been documented in patients with Vernal Keratoconjuncitivitis.[56]However, more extensive studies have to be done to establish how the mechanisms of ocular allergy and post-LASIK dry eye overlap and interact. Given the possibility of increased risk in atopic patients, it is advisable to control and stabilize the patient's allergic condition before performing LASIK.The FDA has named CVD a LASIK contraindication, as many CVDs can have a component of dry eye[57]and usually of higher severity, as reported in patients with rheumatoid arthritis.[58]However, research has produced conflicting evidence on the safety profile of LASIK on this group of patients. One paper[57]has reviewed studies on LASIK in patients with CVDs, in particular the four major diseases: Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus and seronegative spondyloarthropathies. This study concluded that together with stringent selection of only patients with mild, stable and well-controlled systemic condition, LASIK surgery may be safe in most patients with CVD with the exception of Sjogren's syndrome.Even in cases of Sjogren syndrome with severe dry eyes diagnosed prior to LASIK, good post-operative refractive power and tear function outcomes were achieved when these patients were appropriately managed pre- and post-operatively with artificial tears, topical autologous serum and punctal occlusion.[59]However this was observed in a study of very small sample size (3 patients, 6 eyes). One case report has described two cases of early-stage Sjogren syndrome patients who were well-controlled for both systemic condition and dry eye, but still suffered from severe post-LASIK dry eye complicated with punctate epithelial erosion and regression of the initial refractive error at 2 and 15 months post-operatively. Despite 10 months of intensive dry eye treatment, the patients' dry eye, improved only marginally.[60]There are no previous studies on post-LASIK dry eye in thyroid disease patients or graft-versus-host disease patients.Despite the numerous studies supporting that LASIK is safe in patients with CVD, it is still advisable to avoid photorefractive surgery in these patients. If patients insist on surgery, they should be counseled about their risk profile, as well as briefed about the importance of compliance to pre- and post-operative management with artificial tears, topical autologous serum, punctal occlusion, etc. Consultation with the rheumatologist is also necessary to assess the severity and stability of the patient's condition.While no studies have been conducted to assess the risk of post-LASIK dry eye in patients with a history of blepharoplasty, we believe patients who have had previous blepharoplasty should be stringently assessed before proceeding with LASIK, as dry eye may be a common complication after blepharoplasty.[61]In the lateral view, a vertical line dropped from the supraorbital rim to the infraorbital rim is usually in tangent with the corneal surface. If the corneal surface protrudes beyond this line, it is termed a negative vector.[62]Looking out for a negative vector of the orbit may also be helpful in assessing risk of dry eye. A negative vector is associated with greater incidence of scleral show and lower lid descent after lower lid blepharoplasty. Nocturnal lagophthalmos can occur after blepharoplasty[63]and should also be assessed in patients.Assessment of Pre-operative Tear & Cornea FunctionThe clinical examination should include factors aggravating dry eye, such as reduced corneal sensitivity, conjunctival hyperemia, chemosis, and lid disease such as blepharitis or meibomian gland disease. Abnormal lid anatomy and blink dysfunction (e.g., reduced blink rate) must be actively searched for during the pre-operative period. Lagophthalmos may occur for various reasons including facial nerve palsy.Pre-existing dry eye disease is a major risk factor for post-LASIK dry eye of higher severity.[10,42,48,50,64]As such, for these patients, pre-operative optimization of the ocular surface must be performed so that any negative impact of the surgery on dry eye will be minimized.[10,50,65,66]Ocular surface optimization, including the treatment of contributing conditions like meibomian gland dysfunction (MGD), will be covered under the 'Management' section.Objective dry eye signs can be measured with the traditional tear and corneal function tests, consisting of Schirmer's test to assess tear secretion (basal and reflex); tear break-up time (TBUT) to assess tear film stability; and corneal fluorescein dye staining to assess corneal epithelial integrity. They have all been demonstrated to be relevant risk factors for chronic post-LASIK dry eye.[48]Among these, the pre-LASIK Schirmer score is of particular importance and its pre-operative value is significantly correlated with post-operative TBUT (r = 0.504, p = 0.02) for up to 9 months in a study.[42]Schirmers I of less than 10 mm (at 5 min) was associated with increased risk (relative risk: 1.58; 95% CI: 1.102.26) of post-operative dry eye at one month post-operatively.[64]There has been no study using a receiving operating curve approach to examine the optimal Schirmer test threshold to detect post-LASIK dry eye.Certain groups performed Rose Bengal dye staining of the conjunctiva.[20,27,42,59,67]This has not proven to be mandatory for the purpose of routine assessment. It is also a potential source of ocular irritation, and hence its use does not seem warranted.Corneal sensitivity, although not a routine component of dry eye diagnosis, is valuable because of its role in the pathogenesis of LASIK-induced dry eye as previously mentioned. Assessment is performed using the Cochet-Bonnet esthesiometer. Three studies used non-contact gas esthesiometers for corneal sensitivity assessment.[6870]Though these are proven to give results that are consistent with those of Cochet-Bonnet esthesiometry, the gas esthesiometers may not be widely available for use in LASIK clinics due to their cost. There have been no studies that found correlation between pre-operative corneal sensitivity and post-operative tear function.InflammaDry, a rapid point-of-care diagnostic test to detect elevated matrix metalloproteinase 9 levels, has shown good sensitivity (85%) and specificity (94%), in detecting dry eye.[71]However, it should be noted that the diagnostic criteria for dry eye were strict in this study, and required positive OSDI, TBUT, Schirmer's test and corneal staining findings for dry eye. In the context of post-LASIK dry eye, InflammaDry may have a role in patient selection for pre-operative ocular surface optimization and for anti-inflammatory dry eye treatment.[72]Other diagnostic aids to consider include tear osmolarity testing with the TearLab Osmolarity System. Use of this device to diagnose and assess dry eye has been reviewed favorably,[73]and has been found to be useful in assessment of LASIK-related dry eye.[31]Intra-operative FactorsHinge Properties, LASIK Enhancement, Suction Ring ApplicationNumerous studies have looked into how position, width and angle of flap creation can affect post-operative dry eye. Other factors totake into accountinclude 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 inTable 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.[66,74]These studies quoted a schematic of corneal nerve architecture by Mulleret al.published in 1997.[75]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,[15]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[76]and 6 months,[74]respectively. A 2013 systematic review and meta-analysis of eight randomized-controlled trials (including some of those listed inTable 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.[77]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.[7880]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 Mianet 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 (3.005.50 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 (6.007.50 mm).[66,81]Differences in hinge angle[79]and flap thickness[79,82]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.[83]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.[41]Variations of LASIKDifferent 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 dryeye treatmentat 1 month post-operatively.[5]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.[84,85]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.[86]Use of different ablation laser platforms also had no effect on post-LASIK dry eye (summarized inTable 2), though more research has to be done to draw any meaningful conclusions.[87,88]Alternatives to LASIKPRK, LASEK and epipolis laserin-situkeratomileusis (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 keratectomyPRK 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.[29,89]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.[9]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.[90]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.[91]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.[92]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 keratomileusisLASEK has very similar effects on post-operative dry eye as LASIK.LASEK, compared with LASIK, has shown better post-operative tear secretion in patients[89]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.[93]However, dry eye symptomology was not investigated in these studies.Four other studies[9396]have demonstrated contrasting results. In particular, Dooleyet al.[94]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.EpiLASIKEpiLASIK 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,[97]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.[98]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.[96]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-, PDGF-BB, bFGF, compared with on-flap procedures.[99]This is supported with a meta-analysis published by Fenget al.in 2012.[100]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,[101]while flap-on EpiLASIK patients experienced greater post-operative pain, poorer wound healing and poorer visual recovery than PRK patients.[102]Summary of Variations of LASIKThe 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.Patient Selection & ManagementPre- & Intra-operative Steps of Dry Eye PreventionPatient selection is vital for safety and management considerations and should be guided by the risk profile gathered from the elicited history, pre-operative tear and corneal function, and choice of surgical procedure. The ocular surface must be stabilized in at-risk patients with artificial tears and a combination of other modalities, namely punctal occlusion, topical autologous serum, cyclosporine A, nutritional supplementation and lid hygiene and lid warming, on indication based on the underlying risk factors.For most types of treatment (except cyclosporine) there has been no previous recommendation for how long treatment should be administered before photorefractive procedures are performed. As a general guide, it is best to delay any form of surgery until tear function is significantly improved.[10,50,66]The period of time before expected improvement depends on the dry eye treatment modalities used and number of modalities.In patients where no significant improvements in ocular surface conditions are observed despite meticulous pre-operative treatment, the risks and benefits should be clearly discussed with the patient before undergoing the procedure. There is an option to continue with the planned surgery provided that patient understands that there is a higher risk of post-operative dry eye.Our recommendation is supported by a retrospective study of fourpatient groups(untreated controls (n = 53), PRK (n = 51), LASIK without ocular surface management (n = 53) and LASIK with ocular surface management (n = 140)) that showed pre-operative treatment reduces post-operative symptoms (when after LASIK) and achieved higher goblet cell densities as compared to controls without pre-operative treatment.[103]Although no specific evidence that pre-operative signs of inflammation such as conjunctival redness and meibomian gland disease are risk factors for post-LASIK dry eye, we do recommend that topical Cyclosporine A should still be given to patients with obvious signs of ocular surface inflammation, given the role of inflammation in causing dry eye.[104]Future directions in research include the possible correlation of pre-operative tear cytokine levels with post-operative dry eye.Moreover, topical cyclosporine A's beneficial effect on nerve regeneration[10]makes it appropriate for post-LASIK dry eye caused by the loss of corneal sensitivity. Autologous serum may also be considered.During the procedure, hydration and surface integrity of the cornea should be maintained. A trial showed that intra-operative use of carboxymethylcellulose (CMC) artificial tears (continued post-operatively) was superior in preserving tear stability and reducing epithelial erosion compared with normal saline.[105]Solomonet al.[66]compiled the following recommendations: Delivery of a glycerine-containing topical anesthetic such as proparacaine over two doses, one immediately upon arrival of the patient, and one immediately before the procedure; Application of CMC 1% drops to the corneal surface immediately after flap replacement. This hydrates the cornea; Application of a non-preserved non-steroidal anti-inflammatory drug, prednisolone acetate 1% and a fluoroquinolone antibiotic before lid speculum removal; Closing the patient's eyes for 15 min before flap examination; Solomon also recommended that patients kept their eyes closed for 4 h post-operatively. While it may be beneficial for the patients to do so, it is impractical given theday surgerysetting of all photorefractive procedures. We hence recommend; Instruct the patient to close their eyes for the duration of observation after surgery, and to avoid strenuous activity of the eye for the rest of the day.Post-operative Management of Dry EyePre-operative treatment should not be stopped after surgery. A trial[106]found that pre-operative use of cyclosporin A, BID, continued till 3 months post-operatively led to improved outcomes of visual acuity and dry eye parameters.The role of post-operative management in treating post-LASIK dry eye has been reviewed extensively[30,50,52,66,103,107]and is generally agreed to lead to quicker recovery of tear and corneal function and resolution ofdry eye symptoms.We support the notion of combination therapy similar to that of treating routine dry eye, consisting minimally of the use of preservative-free artificial tears. CMC artificial tears, such as Refresh Plus (Allergan) or Cellufresh (Allergan), demonstrated better early post-operative tear film stability and less ocular surface staining than HPMC artificial tears, such as Bion tears (Alcon). These conclusions were made by an unmasked, randomized study, which monitored dry eye symptoms and signs in 18 eyes of 10 patients for a period of 1 month.[108]If there are additional contributing factors such as MGD or aqueous tear deficiency, additional treatment modalities targeting the specific pathology can be administered. To date, no study has looked specifically at how pre-operative MGD contributes to post-LASIK dry eye, but it can be assumed that these patients will have more severe tear film dysfunction after surgery. Hence, it will be best to address MGD and observe for improvement in the patient's condition before proceeding to photorefractive surgery.In MGD, the use of lid hygiene, warm compress and lid warming, nutritional supplement, topical azithromycin and oral doxycycline have been described by various authors for post-LASIK patients.[4,51,109]In particular, a lid warming device, Eyefeel (Kao, Inc.), was shown to improve post-operative symptoms (OSDI), tear film stability (TBUT) and tear lipid layer thickness (interferometry).[110]In this study, these post-LASIK patients were not examined for MGD before operation, but only 16 out of 17 of them had dry eye symptoms before LASIK. They all presented with persistent dry eyes for more than one year post-operatively with signs of lipid layer deficiency. Their condition responded well to lid warming therapy, with a reduction of symptoms and increase in thickness of the lipid layer, suggesting that MGD was the underlying cause of their dry eyes.In aqueous tear deficiency, post-operative use of punctal plugs has showed faster recovery toward a stable tear film and symptom relief, as well as the improvement of both quantitative and functional visual acuity.[111113]In dry eye, irregularity of the tear film induces wavefront aberrations. Patients with high amounts of wavefront aberrations pre-operatively continue to have aberrations, which were not caused by the refractive procedure. The aberrations experienced by such patients, measured by a Shack-Hartmann wavefront sensor (Zywave, Bausch and Lomb), were reduced with the use of post-operative punctal plug insertion at day 1.[111]However, a case report warned that plug insertion after LASIK carries the risk of causing canaliculitis, even among the new generation SmartPLUG (Medennium Inc.).[114]Findings from a rabbit study showed that autologous serum inhibited cytokine release and migration of inflammatory cells. It also decreased keratocyte apoptosis and promoted migration of fibroblast and myofibroblast to the wound site following surgery.[115]Topical autologous serum was shown in a trial of 27 men to reduce corneal epithelial erosions and improve post-operative tear film stability more effectively than artificial tears at up to 3 and 6 months, respectively.[116]However the high cost and limited availability of this modality continues to limit its clinical use.Topical cyclosporine A (CsA) given twice a day may be incorporated into standard treatment [104,106,117119]. A randomized controlled trial comprising 21 patients with pre-existing dry eyes showed that CsA, given at 1 month before operation, discontinued for 48 h post-operatively then continued for another 3 months in addition to artificial tears as needed, showed greater tear secretion in patients between 1 and 6 months post-operatively compared with artificial tears alone.[106]This is supported by a retrospective study of 45 patients, in which addition of CsA to standard treatment improved recovery of post-operative uncorrected visual acuity and better predictability of refractive correction.[118]Disappointingly, the benefits of CsA were not replicated in a prospective randomized controlled trial by Hessertet al.,[117]which had a larger sample size of 124 patients as compared with all previously quoted studies in CsA. Improvements in visual acuity, mesopic contrast acuity, dry eye symptoms and tear film inflammatory mediator levels were found to be similar compared with standard treatment without CsA at all time-points up to 3 months for both LASIK and PRK.Tacrolimus is an immunosuppressive agent similar to cyclosporine. In a non-controlled trial, tacrolimus eye drops were shown to improve tear film function and reduce corneal epitheliopathy in eight dry eye patients with Sjogren syndrome. Tear secretion and tear stability improved only at day 90 and day 28 of treatment while corneal staining was reduced by day 14 of treatment.[120]However, patients should be warned that tacrolimus can cause an uncomfortable stinging sensation.Therapeutic Agents Under ResearchSeveral newer modalities are also in the pipeline. Eye platelet rich plasma (E-PRP) has been shown to reduce punctate epithelial erosion,[121123]increase tear film stability[122]and improve best corrected visual acuity following surgery.[122,123]It has been suggested that it provides growth factors and bioactive proteins to stimulate re-epithelisation of the cornea. However, it has limited efficacy in improving post-operative corneal sensitivity, as the diffusion of these growth factors to the nerve fibers in the stroma is limited.[121]Given its low cost and its lack of known adverse events,[123]it may one day become a standard treatment.Ophthalmic gels consisting of protein-free calf blood extract and recombinant bovine basic fibroblast growth factor (r-bFGF) have been studied clinically for the treatment of LASIK-induced dry eye and have shown clinical efficacy.[124,125]However, the long-term safety profile of these bovine-derived products has not been reported.Finally, several compounds are still being put through basic research and their potential may be better understood in the future. Their common mechanism of action is through stimulating corneal nerve regeneration. Both the NGF[126]and the bioactive N-terminal peptide from adenylate cyclase-activating polypeptide (PACAP27)[127]have demonstrated that they increased the speed of recovery of corneal sensitivity and induced growth of neurite extensions. However, the tear NGF is usually already raised after LASIK. Theoretically, this treatment modality may only be effective in patients with deficient NGF expression.FK962 (N-[1-acetylpiperidin-4-yl]-4-fluorobenzamide) has also shown increased corneal nerve regeneration in rat trigeminal ganglion cells and recovery of corneal sensitivity in rabbits[128]and its mechanism using the rat trigeminal ganglion cell model is shown to likely involve glial derived neurotrophic factor that induces neurite elongation but is independent of NGF.[129]Another compound, leukemia inhibitory factor (LIF), when compared with balanced saline, showed accelerated corneal nerve regeneration and better post-operative tear function (Schirmer I and TBUT) for at least 3 months in rabbits.[130]Expert CommentaryPrevention of dry eye lies clearly in the identification of patients at risk of such a complication, using the risk factors outlined earlier in this review. From there, a proper post-operative management of the patient can be planned, such as the use of cyclosporine A together with lubricant drops in patients with high risk of dry eye.Patient counseling is a key component of pre-operative management. Patient satisfaction will be less affected if patients are given a more accurate prognosis of their post-operative discomfort. We also urge clinicians to extend the concept of post-operative care to peri-operative care in patients with especially high risk profiles, and that surgery should only proceed once there is significant improvement in ocular surface conditions.Intra-operative factors, in general, seem inconsequential if the patient is properly managed for their dry eyes. Studies have not proven that differences in hinge position, type of procedure, or ablation systems have any drastic effect on post-operative dry eye. Clinicians hence need not be too concerned of the risk of dry eye in their selection of photorefractive procedure and laser ablation platforms, and should be free to choose the procedure, which is most suitable for the patient, considering his/her corneal thickness and magnitude of refractive error. Important exceptions are ablation depth and hinge width, which should be minimized in patients with a high risk profile for post-operative dry eye.Research in the area of photorefractive surgery has always been influenced by substantial commercial interests. Negative findings may be under-reported and downplayed. The authors encourage researchers to publish even their negative findings such that literature in this field will be reliable and complete.Five-year ViewCurrent research findings suggest that post-LASIK dry eye is but a transient problem after the procedure and will resolve with time. The proportion of patients that go on to develop persistent, chronic dry eye problems years after surgery is poorly investigated. Even if such studies have been done, given the delay between the refractive procedure and onset of dry eyes in these patients, it is hard to prove that the refractive procedure contributed to dry eye.Of all the pathophysiologic mechanisms implicated in post-LASIK dry eye, most resolve within one year after surgery and cannot seem to account for cases of chronic, persistent post-LASIK dry eye. As mentioned earlier, however, nerve morphology and corneal irregularities seem to be persistent defects that last beyond one year after surgery, and should be investigated for its possible effects on dry eye.Future research in neural influences of sub-basal nerves on the corneal surface may consider investigating if nociceptive thresholds have been reduced in these cases of chronic post-LASIK dry eye, or if subtle changes in the biochemical make-up of the sub-basal nerves can account for the condition of these patients.Advances in interferometry allow detection and localization of tear film breakup. There have been previous studies implicating corneal irregularities as the focal point for tear breakup and postulating it as a cause for post-LASIK dry eye, but more studies have to be carried out in patients who have persistent post-LASIK dry eye to establish this theory as an etiology of chronic dry eye after LASIK.In the area of management, many novel therapeutic agents are currently in clinical trials, with many holding great promise. Of note will be E-PRP that may see greater acceptance and use in the years ahead due to itslow costand good safety profile.ReLEx SMILE (small-incision lenticule extraction) is a new photorefractive procedure, which is gaining popularity. This new procedure completely removes the need for flap creation or epithelial stripping, achieving the desired refractive correction by creating an intra-stromal lenticule with afemtosecond laser, and removing the lenticule thereafter by a small incision made at the limbus. Theoretically, this leaves most of the corneal nerves intact and should lead to superior post-operative preservation of corneal sensitivity than previous photorefractive procedures.Two trials, one randomized[131]and one non-randomized[132]found SMILE to have better dry eye outcomes to femtosecond LASIK (femto-LASIK). In one randomized trial involving 28 patients (28 eyes underwent SMILE, contralateral eye underwent femto-LASIK), SMILE was found to result in significantly higher corneal sensitivity for up to 3 months when compared with femto-LASIK. In another non-randomized trial involving 54 eyes for femto-LASIK and 61 eyes for SMILE, corneal sensitivity was found to be superior in eyes, which have undergone SMILE compared with femto-LASIK for up to 3 months, and a complete recovery to baseline corneal sensitivity was faster and could be achieved 3 months post-operatively.SMILE was also superior to Femtosecond Lenticule Extraction (FLEx) in preserving corneal sensitivity. Moreover, in a randomized self-controlled trial involving 35 patients,[133]sub-basal nerve density was better preserved in SMILE than FLEx at 6 months post-operatively. This corresponded to superior corneal sensitivity of SMILE to FLEx at 6 months in the same study.However, in both randomized trials, tear film parameters were not significantly different between the surgical methods, despite differences in post-operative corneal sensitivity. In the non-randomized trial, tear film parameters were not examined.Corneal Refractive Surgery-related Dry EyeRisk Factors and ManagementLouis Tong, Yang Zhao, Ryan LeeDisclosuresExpert Rev Ophthalmol.2013;8(6):561-575.SidebarKey Issues Dry eye is a common complication after photorefractive procedures, and most cases spontaneously resolve a few months after surgery. A subset of patients have persistent symptoms, and there is limited literature on this group of patients. The pathophysiologic basis of post-laser-assistedin situkeratomileusis (LASIK) dry eye can be summarized into three main mechanisms: disruption of afferent corneal sensory nerves, increase in ocular surface inflammation, alteration of corneal anatomy. It is best to avoid LASIK and other photorefractive procedures in patients with pre-operative dry eye, collagen vascular diseases and allergies. Most intra-operative factors such as hinge properties in LASIK, flap creation method and differing ablation platforms do not seem to influence post-operative dry eye outcomes, the exceptions being hinge width and ablation depth. As a general rule, LASIK causes poorer tear function but less dry eye symptoms, while PRK produces more severe symptoms related to dry eye or wound healing. Treatment of dry eye should be peri-operative in contrast to purely post-operative. Use of artificial tears, cyclosporine A, topical autologous serum, punctal plug occlusion, lid warming are all possible treatment options. Numerous novel therapeutic agents for dry eye are currently in research, with eye platelet-rich plasma showing the most promise of becoming a component of standard treatment in future. Future research should focus on investigating the prevalence of chronic dry eye lasting more than one year post-LASIK, and finding the specific etiology of this form of dry eye.References1. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007).Ocul. Surf. 5(2), 7592 (2007).2. Nettune GR, Pflugfelder SC. Post-LASIK tear dysfunction and dysesthesia.Ocul. Surf. 8(3), 135145 (2010).3. Kuo IC. Trends inrefractive surgeryat an academic center: 20072009.BMC Ophthalmol. 11, 11 (2011).4. Shtein RM. Post-LASIK dry eye.Expert Rev. Ophthalmol. 6(5), 575582 (2011).5. 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