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Abstract and Introduction

Abstract
Dry eye is the most common post-operative complication in patients who undergo
laser-assisted in situ keratomileusis 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-assisted in situ keratomileusis 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.

Introduction
Dry eye disease is defined as a multifactorial disease of the ocular surface and tear
film that results in symptoms of discomfort, 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-assisted in-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 condition

Epidemiology

Dry 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).

Pathophysiology
The 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 Nerves


Maintenance 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.
Using in vivo confocal 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 CochetBonnet esthesiometry). Post-LASIK corneal sensory threshold was as high as 160
mg/0.0113 mm2 at 2 weeks after LASIK, though this resolves to the normal threshold
of approximately 11 mg/0.0113 mm2 at 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 LASIKinduced 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 Inflammation


Inflammation 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 proinflammatory 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 Anatomy


Immobilization 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 nongoblet 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 & Assessment


Prior 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 Factors


Age, female gender and East Asian race are possible predisposing factors to postoperative 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 postLASIK 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 postLASIK 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 TGF1 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 History


Pre-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 wellcontrolled 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 graftversus-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 Function


The 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 preoperative 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 postoperative 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 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 postoperative 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.[66,74] These studies quoted a schematic of
corneal nerve architecture by Muller et 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 metaanalysis 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 postoperatively 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 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 (3.005.50 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 postoperative 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 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.[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 in Table 2), though more research has to be done to draw any
meaningful conclusions.[87,88]

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.[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 reepithelialization is not required after LASIK due to replacement of the flap. This

prolonged period of post-operative wound healing may contribute greatly to postPRK 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[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,
Dooley et 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.
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,[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 Feng et
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 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.

Patient Selection & Management


Pre- & Intra-operative Steps of Dry Eye Prevention
Patient 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 four patient
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]
Solomon et 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 postoperatively. While it may be beneficial for the patients to do so, it is impractical given
the day surgery setting 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 Eye


Pre-operative treatment should not be stopped after surgery. A trial [106] found that preoperative 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 of dry 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 Hessert et
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 noncontrolled 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 Research


Several 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 reepithelisation of the cornea. However, it has limited efficacy in improving postoperative 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 longterm 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 Commentary
Prevention 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 postoperative 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 View
Current 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 its low cost and 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 a femtosecond 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 femtoLASIK 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 Eye


Risk Factors and Management

Louis Tong, Yang Zhao, Ryan Lee


Disclosures

Expert Rev Ophthalmol. 2013;8(6):561-575.

Sidebar
Key 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-assisted in 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 preoperative 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.

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