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. 

In This Article

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 post-operatively. 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 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 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.[111–113] 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 [104,106,117–119]. 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 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 Research

Several newer modalities are also in the pipeline. Eye platelet rich plasma (E-PRP) has been shown to reduce punctate epithelial erosion,[121–123] 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]

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