Dry eye disease (DED) is one of the most prevalent eye conditions with 10-30% of the worldwide population diagnosed with DED.1 The Dry Eye Workshop2 defined dry eye as ‘a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface’. DEWS sub-committees have recently been working towards DEWS II, an updated report, which is due for publication in 2017.
In recent years, clinicians and researchers have tried to better understand the underlying causes of dry eye. Increased tear osmolarity, tear film irregularity, ocular surface injury and inflammation are frequently discussed factors in DED.2 Dry eye can be classified into evaporative dry eye and aqueous deficient dry eye. Briefly, evaporative dry eye is typically caused by meibomian gland dysfunction and aqueous deficient dry eye is caused by a reduction in lacrimal tear secretion.
DED is especially common in females and in adults over 50 years of age.3 Various factors are known to increase the likelihood of DED including age, medication use (eg antihistamines), hormonal changes, some systemic (eg diabetes and irritable bowel syndrome) and inflammatory conditions. Cataract surgery and corneal refractive surgery have also been associated with the development or exacerbation of DED.
The aim of this review is to consider the possible causes of DED following cataract surgery and corneal laser refractive surgery. A brief overview of the impact of DED on the outcomes of surgery and treatment options is also given.
Cataract surgery and dry eye
Cataract is treated surgically by removing the crystalline lens and replacing it with an intraocular lens (IOL). Cataract surgery is now one of the most frequently performed surgical procedures in the world.4 When the crystalline lens is replaced for the purpose of correction of refractive error, rather to remove a cataractous lens, the term refractive lens exchange or clear lens exchange is used.
During cataract surgery, a local anaesthetic is normally applied and small incisions (usually between 1.5 and 3mm) are made to access to the anterior chamber.5 An opening in the anterior capsular bag called a ‘capsulorrhexis’ is created. An ultrasound probe is then used to break up the lens and remove it in small pieces from the capsular bag (phacoemulsification).4,6 Finally, an intraocular lens is implanted using an injector.
More recently, femtosecond technology has been used for some steps in cataract surgery. Specifically, the laser can be used to create the corneal incisions, to create the capsulotomy and also to fragment the crystalline lens prior to the phacoemulsification procedure.4,7
The pre-operative medications used in cataract surgery include anaesthetic and pupil dilating agents. There are various options regarding the approach to anaesthesia including topical, sub-Tenon’s, peribulbar, retrobular and general anaesthetics.
The choice of pre and post-operative medications will depend on surgeon preference as well as patient-specific factors.8 Topical and subconjunctival antibiotics are used to prevent infection. Intraoperatively, dilute povidone-iodine solution is widely used at the start of the procedure in many countries for skin and conjunctival antisepsis.9 Prophylactic intracameral agents such as cefuroxime or vancomycin are used at the close of surgery to reduce the risk of endophthalmitis.10
Post operatively, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are among the other agents that may be used often for days to weeks as prophylaxis against post-operative infection and inflammation. While corticosteroids are effective on the inflammatory mediators, NSAIDs act by blocking cyclooxygenase enzymes and prostaglandin synthesis.11,12 NSAIDs are applied to reduce pain and inflammation.13 Diclofenac, ketorolac, bromfenac and nepafenac are examples of topical NSAID.14 Repeated use of preserved ophthalmic medications can have an adverse impact on the ocular surface.
Figure 1: Blepharitis can impact on quality of life
DED impacts on visual performance and quality of life, and depression and anxiety are more prevalent in blepharitis (figure 1).15 DED can also adversely impact vision and comfort following cataract surgery. Preoperative tear film quality can have an impact on the accuracy of preoperative measurements such as ocular biometry which is used to calculate IOL power to a high degree of accuracy, and DED could therefore affect the postoperative refractive outcome. Furthermore failure to manage blepharitis prior to referral can lead to postponement of surgery due to the potential increased risk of infection.16 A possible risk factor for endophthalmitis is thought to be local eyelid disease attributable to the patient`s own flora.16 Therefore, efforts should be made to optimise the ocular surface prior to and following cataract and refractive lens surgery.
Prevalence of dry eye after cataract surgery
Patients who have undergone cataract surgery, may complain of ocular discomfort due to dry eye,17 although the reported prevalence of DED is variable due, in part, to the lack of universally agreed diagnostic criteria. One study focused on the diagnosis of dry eye and its prevalence in a cohort of 50 eyes of 37 patients who underwent cataract surgery.18 The authors used the Ocular Surface Disease Index (OSDI) questionnaire, corneal and conjunctival fluorescent staining, tear break-up time (TBUT), Schirmer test and impression cytology in the diagnosis. Dry eye was observed in almost all patients using these techniques. Cho et al19 studied 70 eyes of 35 patients, who did not experience dry eye prior to surgery.
Dry eye indicators worsened after cataract surgery, however, follow-up intervals were only one to 10 days and so it was not possible to comment on whether it improved with time. However, Li et al20 found after 30 days that 19.3% of patients showed a reduced TBUT.20 Kasetsuwan et al17 studied 92 patients free from ocular disease other than cataract. The results of the tests for dry eye conducted seven days after cataract surgery had altered compared to pre-operatively. The incidence of dry eye diagnosed with TBUT postoperatively was 68.4%, with Schirmer test it was 11.9%, with the Oxford Schema Staining it was 58.7% and with the OSDI the prevalence was 9.8%.17 The variation in prevalence from these tests is partly due to differences in the test sensitivity.17
Dry eye and FLACS
Femtosecond laser assisted cataract surgery (FLACS) aims to improve precision in creating the corneal incisions and anterior capsulotomy and reduce the ultrasound energy required in removing the lens.21 However, the pressure associated with the suction ring and the additional laser procedure could theoretically disturb the ocular surface and tear film.21 To date, only a few studies have analysed the occurrence of dry eye after femtosecond laser assisted surgery in comparison to standard cataract surgery.
Yu et al21 studied 137 subjects to compare dry eye after cataract surgery performed using traditional phacoemulsification and using femtosecond laser assisted surgery. They concluded that patients who underwent FLACS are more prone to dry eye than patients undergoing traditional phacoemulsification surgery. The study followed patients for one month, and further research is required to allow conclusions to be drawn on possible longer term effect of femtosecond laser assisted surgery on DED.
Aetiology of dry eye after cataract surgery
The underlying mechanism of DED following cataract surgery could be related to disruption of corneal nerves and the corneal epithelium due to;
- disruption of corneal nerves and the corneal epithelium due to the incisions.
- Intraoperative irrigation of the ocular surface.
- Light from the operating microscope.
- Elevation of inflammatory mediators in the tear film.
- The application of anaesthetic agents and postoperative eye drops (active agents and/or preservatives).17,19
The cornea is a remarkably sensitive tissue due to a high density of nerve endings.22 The sensory innervation of the cornea is provided by the ophthalmic branch of the trigeminal nerve. From the limbus nerve structure is spread in the anterior stroma and ends in the subbasal nerve plexus which is located between the basal epithelial cells and Bowman’s layer. Due to transsection of the nerve fibres, a decrease in corneal sensitivity is observed after corneal refractive surgery with a reduction of tear secretion.23 The reduction of corneal sensitivity affects the supply of fundamental components such as epidermal growth factors and vitamin A.24
Corneal incisions are also thought to be a possible contributory factor for a postoperative dry eye in cataract surgery. Any disruption of the corneal nerves could impair corneal sensitivity, epithelial wound healing, epithelial permeability and alter corneal metabolic function.46,47 The effect of corneal incision size has been explored with smaller incisions reducing corneal nerve disruption and its deleterious effects.26
Inflammation is another potential reason for postoperative dry eye and inflammation is associated with both types of dry eye (evaporative and aqueous deficient dry eye). To some extent, inflammation is a natural response to surgery.27 Inflammation induces many metabolic processes such as inflammatory cell migration, increased inflammatory cytokines, chemokines and different enzymes.28,29 The pathophysiology depends on various mediators30,31 and ocular surface damage and hyperosmolarity are possible factors in activating these mediators.31,32
Topical medications could also lead to dry eye which may be due to the use of preservatives in multi-dose eye drops.27 Studies have shown that preservative-free eye drops provide better results in terms of preventing ocular inflammation and reducing the risk of dry eye after surgery.33,34 Jee et al33 studied 0.1% sodium hyaluronate and 0.1% fluorometholone eye drops without preservatives and found an improvement in the signs and symptoms of dry eye after cataract surgery.
The single dose versions of unpreserved eye drops are often more expensive than preserved eye drops and some preparations can be difficult to instil. Multi-dose eye drops could be used with microbial filtration and adsorption on a membrane or could be applied with a valve system preventing contamination.27 Ideally clinicians should prescribe preservative-free eye drops where feasible, particularly for patients with moderate/severe ocular surface disease.3
Park et al35 evaluated meibomian gland function, changes to tears, ocular surface parameters and tear inflammatory mediators following cataract surgery in a group of patients with pre-existing dry eye and another group without pre-existing dry eye. They found that meibomian gland function can alter after cataract surgery and that this correlates with ocular symptom scores.
The authors discussed that although antibiotics can suppress bacterial lipases preventing degradation of normal meibum, the antibiotic and steroid used postoperatively did not improve lid margin abnormalities or meibomian gland secretions. They speculated that possible contributory factors in MGD after surgery were decreased corneal sensitivity altering blink rates, use of a lid speculum and/or the use of the agents. They emphasised the importance of careful evaluation of the meibomain glands pre and post-operatively (figure 1).
Goblet cells, located in the conjunctiva, are responsible for mucin secretion which allows adherence of the tear film to the hydrophobic cornea. Loss of goblet cells could lead to evaporative dry eye.22 Researchers have observed a decline in goblet cell density after cataract surgery.18,36 For instance, Li et al18 found a decrease in goblet cells even three months after surgery. The reason behind the decrease in goblet cells after surgery remains unclear, potential causes may be related to the antiseptic agents used, the ocular medications and inflammatory responses.18,36,37
Implications of DED prior to surgery
The refractive predictability of cataract surgery depends on the accuracy of the preoperative power calculation of the intraocular lens (IOL) which is based on keratometry and biometry readings.38,39 However, these calculations require a stable tear film. If the tear film is not stable, the accuracy of the measurements can be reduced, which can result in deviation from the predicted post-operative refraction.39 Therefore, preoperative diagnosis and management of dry eye is important for cataract patients. However, no universally accepted diagnostic criteria for dry eye has been established.40
Tear meniscus height, tear break-up time and tear osmolarity are key characteristics of tear film assessment. Increased tear osmolarity is one indicator of dry eye disease. This could arise from excess evaporation, or decreased flow of tears. An increase in osmolarity can cause inflammation and cell death at the ocular surface.41 The TearLab Osmolarity System (figure 3) is an option to measure the osmolarity of the tear film. It is rapid to administer, requires a small tear volume sample, and demonstrates good specificity compared to some other tear assessment techniques such as tear meniscus height, tear break-up time, Schirmer test and grading of staining.42,43
Figure 3: TearLab Osmolarity System
Using this approach researchers showed that hyperosmolar subjects had more variability in keratometry readings with significant differences in IOL power variability. They suggested measuring tear osmolarity when planning cataract surgery may help identify patients at higher risk of unexpected refractive outcome. Despite these advantages, a recent study indicates tear osmolarity has to be measured at least three times in order to achieve reliable results.44
In summary, it is recognised patients may experience dry eye and symptoms of irritation following cataract surgery and efforts to optimise the ocular surface can improve the visual and refractive outcomes for patients. The cause is probably multifactorial and further research is required to better understand the aetiology and which of the modifiable factors is likely to be most impactful on patient outcomes.
Corneal refractive surgery
The connection between DED and corneal refractive surgery has been extensively investigated over the years.45-47 DED is considered a contraindication for corneal refractive surgery.48-51 Post-operatively DED can lead to visual discomfort, pain and sequelae of corneal infection.52-54 The surgical procedure, especially in LASIK surgery, temporarily reduces the nerve fibre density55 and it is assumed this reduces the corneal reflex which controls lacrimal gland secretion. After corneal ablation by a laser the interleukins present in the tear film and in the cornea react generating an amplified inflammatory response of the ocular surface.56 Newer techniques such as small incision lenticule extraction (SMILE – see figure 4) claim to reduce the prevalence of DED.57,58
Figure 4: Techniques such as SMILE claim to reduce the prevalence of post-operative dry eye disease. Image courtesy of Carl Zeiss Meditec AG
Current options for corneal refractive surgery
Corneal surface procedures include photorefractive keratotomy (PRK), laser-assisted subepithelial keratomileusis (LASEK) and epithelial laser-assisted in-situ keratomileusis (Epi-LASIK). Laser-assisted in-situ keratomileusis (LASIK) involves the creation of a flap either by a microkeratome or a femtosecond laser. SMILE is a relatively new development where a femtosecond laser creates a stromal lenticule that is removed through a small tunnel. Brief details of these procedures is given below:
Photorefractive keratectomy (PRK)
Topical anaesthesia is applied prior to de-epithelialisation of the cornea using a spatula followed by the excimer laser treatment to reshape the corneal stroma. Removal of the epithelium avoids the action of the excimer laser on the irregular thickness of the epithelium that could alter the treatment.59,60 To remove the epithelium, an alcohol solution61 (generally 20% ethyl alcohol) or a blade is used. PRK is the more painful laser vision correction technique and the post-operative recovery takes longer than LASEK, Epi-LASIK, and LASIK.62
The epithelium needs two to five days to recover and the surgeon often prescribes a bandage contact lens to protect the corneal surface63 followed by antibiotic and anti-inflammatory therapy. PRK causes a temporary reduction of subbasal corneal nerve density for up to a year, with complete recovery taking up to two years.64 However, studies23,65 suggest that corneal sensitivity could be re-established after only three months. During the period of nerve fibre regeneration, DED can manifest. Ozdamar et al66 reported that break up time (BUT) and Schirmer test results were reduced by about 50% compared to a control group six weeks after PRK.
Figure 5a and 5b: Patients with dry eye 1-2 weeks after femtoLASIK. Courtesy of Jay Bhatt and Jo-Shethal Thethy
Laser-assisted in-situ keratomileusis (LASIK)
Compared to PRK, LASIK preserves the epithelium during the excimer laser treatment by creating a corneal flap. Keeping the entire central epithelial surface in tact provides a better outcome in terms of short-term visual acuity and subjective comfort.67 To create the flap, the patient’s cornea is suctioned using approximately 65mmHg of vacuum. The flap can be created using a blade or a laser (see FemtoLASIK below). In terms of postoperative DED, LASIK shows a higher prevalence of dry eye compared to PRK. Potential reasons are the flap creation transsecting the subbasal, stromal and larger nerves55,64 and the effects of the excimer laser on the nerve plexuses. Reduced corneal sensitivity and reduced tear volume result in DED while the nerves regenerate.68
Laser-assisted sub-epithelial keratomileusis (LASEK)
This technique separates the epithelium from the underlying stroma using a dilute alcohol solution (concentration usually between 18% and 25%). Alcohol is applied to the corneal surface for approximately 30 seconds to weaken the adhesion of the epithelium to the underlying stromal layer.69 Using a spatula, the detached epithelium is moved to the periphery so that the stromal laser ablation can be performed. After the laser ablation, the epithelium is repositioned and a soft bandage contact lens is fitted to promote corneal wound healing. The repositioning of the epithelium helps to protect the anterior stromal tissue after ablation.70 There is some evidence that haze is reduced after LASEK (compared to PRK).71
FemtoLASIK
Femtosecond lasers used during LASIK to create the flap can reduce the complications observed with microkeratomes such as irregular flaps and epithelial defects. Compared to the microkeratome, femtosecond laser technology set new standards in terms of safety, predictability and accuracy,72-74 providing thinner and more uniform flaps.75,76
Refractive lenticule extraction (ReLEx)
Femtosecond lenticule extraction (FLEX) and small incision lenticule extraction (SMILE) are based on the application of a femtosecond laser to create a slice of stromal tissue called a lenticule. The lenticule is removed without affecting the anterior stroma. The main difference between FLEX and SMILE is the presence of the lifting flap: the FLEX technique involves a LASIK-like flap while the SMILE technique involves creating a side entrance (small incision) using a femtosecond laser. The tunnel allows the removal of the lenticule avoiding any flap complications. SMILE is indicated as an alternative to LASIK for myopia77 and studies for hyperopia are under way.78
Prevalence of dry eye after corneal refractive surgery
PRK
Thus corneal nerves play an important role in the secretion of tears: a partial alteration of the ocular nerve system is one of the main reasons for DED after PRK.79
Campos et al23 found in a small cohort (n = 14) that 96% of the PRK patients’ corneal sensitivity recovered after three months, which is in agreement with the work of Pérez-Santonja et al80 They showed in PRK patients (n = 18) that corneal sensitivity is reduced until three months after surgery. Bower et al81 found similar results: 5% of patients who had PRK (n = 73) developed chronic dry eye and 12% had transient dry eye after bilateral surgery. Recovery of corneal sensitivity in PRK patients was established one year after surgery.
A longitudinal study by Hong et al82 showed that 48% of eyes treated (n = 220) had a reduction in BUT after surgery and about 73% of those patients complained about dry eyes. Ozdamar et al66 also found a significant decrease in Schirmer test results and BUT in all eyes (n = 32) six weeks after surgery. Lee et al83 observed a reduction in Schirmer test results and BUT in 36 eyes three and six months after surgery. This is in agreement with Nejima et al84 who showed significantly reduced tear secretion after one and three months.
A questionnaire study revealed DED symptoms in about 43% of PRK patients (n = 231) specified as ‘ocular discomfort’.85 Also in a long-term PRK evaluation (12 years), the percentage of dry eye assessed by questionnaire was around 3% (n = 68).86
LASIK
In comparison to PRK, DED is more frequently observed after LASIK surgery (figure 2), although LASIK is less painful in the short postoperative period.67 LASIK performed in eyes with high myopia (mean -11.98 ± 3.45 dioptres) reduced tear secretion (operated versus unoperated eye) while BUT remained similar between the two eyes before and after surgery.87
Figure 2: Patient with MGD pre-operatively. Courtesy of Jay Bhatt
Hovanesian et al85 obtained a DED incidence rate of 48% (n = 550) six months after LASIK using a questionnaire sent by mail. DED could also be associated with neurotrophic epitheliopathy in which the corneal epithelium loses its trophic function after the transsection of the corneal nerves during the flap construction. When this is observed after LASIK, patients who did not report DED before the surgery did so after treatment. The condition resolves after approximately six months.88
Figure 6: Administration of a single dose preservative-free ocular lubricant
Toda et al89 reported that more than 75% of patients interested in LASIK surgery suffer from DED. When LASIK is performed on DED patients, dryness increases significantly (n = 543 eyes) and tear film quality and quantity is reduced (Schirmer test, BUT, rose Bengal and fluorescein staining). Also race could play a role in the prevalence of DED after LASIK surgery; 28% of Asian eyes suffer from chronic DED compared to 7% of Caucasian eyes.90 The level of myopia to be corrected is in relation to the depth of laser ablation55 and with increasing refractive error, more stromal tissue will need to be removed.
De Paiva et al91 found that 37% of patients (n = 35) experience DED at the six-month follow-up visit and observed differences in dry eye depending on the position of the flap hinge. DED can persist for more than six months after surgery as reported by Shoja and Besharati92 who observed chronic dry eye in 20% of LASIK patients in their study.
LASEK
In a comparative evaluation of LASEK and PRK, 184 eyes of 92 patients were enrolled in a 24-month follow up study. The authors did not find any postoperative complications, including dry eye problems.93 Another study assessed the prevalence of DED in 85 eyes undergoing corneal refractive surgery; of those eyes 41% who had LASEK had an improved postoperative Schirmer test compared to LASIK. This was also confirmed by a reduced OSDI score after three months.
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