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

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 Cochet-Bonnet 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 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-α, PDGF, VEGF and TGF-β1 is part of the keratocyte's innate response to insult. After LASIK, the expression of these cytokines was not impaired.[22–25] 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 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 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 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]

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