The human cornea is a densely innervated tissue that provides a high level of sensitivity for ocular protection through the detection of foreign objects or noxious substances. Corneal innervation also plays an important role in the trophic maintenance and repair of the cornea. Any alterations to normal innervation of the cornea will not only lessen the ability to detect objects or substances that could damage the eye, but also reduce its wound-healing ability.
Reduction in corneal sensitivity may occur from the desensitization of nerve fibers, such as during contact lens wear, or from nerve damage during the progression of specific corneal and ocular diseases. The treatment can potentially cause further compromise of the existing corneal innervation. In most cases, however, there are complex processes of reinnervation during the recovery stage after treatment, which may be partial or complete, but which commonly occurs over a prolonged period.
Recent times have seen a proliferation in the variety of procedures for the treatment of ocular disease, conditions, and refractive error. Current surgical techniques, however, still impact on corneal sensitivity, having different effects on corneal sensation that depend on the location, size, depth, and orientation of surgical incisions to the ocular surface.
CORNEAL INNERVATION AND MEASUREMENT OF SENSITIVITY
The cornea is a highly specialized tissue that performs four roles in the eye: (1) transparency, allowing light to enter the eye; (2) refraction, focusing the light entering the eye; (3) containment of intraocular fluid and support of structures; and (4) protection of the eye against trauma. The protection of this essential organ is achieved in a gross manner by the eyebrows, eyelids, and eyelashes, and avoidance responses to objects seen to approach the eye. Also of importance is the extremely sensitive network of fine nerve endings within the corneal epithelium. These nerve endings detect any potential noxious agent present on the corneal surface, stimulating lid closure and tear production.
The quality of the epithelial nerve sensitivity can be assessed by measuring how well the nerves respond to various stimuli, such as mechanical probing, in the form of a nylon thread,1,2 a thermally cooling air pulse,3 or to mechanical, thermal (warming), or chemical stimuli presented pneumatically.4,5 The ability to assess corneal sensitivity has allowed for the investigation of various different physiological, pathological, and surgical factors on corneal nerve function.6–9
During surgery, damage to nerve function can be minimized by using short, shallow, linear incisions that avoid cutting across the radially oriented corneal nerves. Shorter incisions reduce both the damage caused and the extent of healing required in the cornea postoperatively. However, most incisions are circumferential, which can sever many nerve fiber bundles. Excimer laser refractive surgery (photorefractive keratectomy [PRK], laser in situ keratomileusis [LASIK], and laser subepithelial keratomileusis [LASEK]) affects the cornea and its sensory nerve network in a very different way. The reshaping of the anterior corneal surface involves the removal of a large volume of corneal tissue, over a wide surface area.10,11 As a consequence, the epithelial sensory nerves are significantly affected within the treatment zone.
Innervation of the Cornea
The corneal epithelium has the highest nerve density of free nerve endings of any tissue in the body: 300 to 600 times that of the skin, and 20 to 40 times that of the dental pulp.12 This extensive network of fine nerve endings produces an exquisitely sensitive response to any mechanical, thermal, or chemical stimulus.12 The nerves also play a role in the maintenance and health of the corneal epithelium. A reduction in corneal nerve supply will result in impaired wound healing, decreased epithelial metabolism, and reduced epithelial cell adhesion (e.g., neurotrophic keratopathy).13,14 In addition, impairment of the corneal nerves disrupts the feedback loop for basal tear production, leading to diminished lacrimal secretion and blink reflex, with subsequent drying of the ocular surface.15–18
Derivation of the Corneal Nerve Supply
The corneal nerves are derived from the nasociliary nerve, which is a branch of the ophthalmic nerve, derived from the first division of the Vth cranial nerve (trigeminal). The nerves supplying the cornea pass along the long ciliary nerve, which is a branch of the nasociliary nerve. They penetrate the posterior sclera, and then pass between the sclera and choroid, coursing anteriorly to provide the sensory supply for the cornea, iris, ciliary body, trabecular meshwork, and sclera.
On reaching the corneal limbus, the nerves produce an annular limbal plexus, and then join one of two nerve systems. Approximately 50 to 90 deeper nerve trunks enter the mid-stroma radially, at an average depth of 293±106 μm, from various sites around the corneal circumference. More superficial nerves enter the posterior epithelium as finer nerves that contribute to the peripheral subbasal nerve plexus.19 Each mid-stromal trunk contains 900 to 1,200 myelinated and unmyelinated axons of diameter 0.5 to 5 μm, which travel centripetally, mainly in the superficial 150 μm of the anterior stroma.20 The posterior stroma contains only small-to-medium diameter nerve bundles and scattered individual axons.21 However, this lower nerve density is still sufficient to provide axons from which new nerves can reinnervate the remaining cornea after anterior stromal surgery.
The myelinated nerves lose their myelin sheath soon after entering the stroma.22 As these axons pass toward the epithelium, they ramify and divide to form a poorly characterized subepithelial plexus in the superficial stroma.12,19,23 Anteriorly directed nerves emerge from the subepithelial plexus, at an average of 204±58 sites, to enter the basal epithelial cell layer.19,24 As they do so, the nerve bundles lose their remaining Schwann cell coverings. These nerves then combine in bundles with peripheral nerves from the limbal plexus, which enter the basal epithelium from the limbus, to form the subbasal nerve plexus.25 The subbasal nerve plexus lies between the epithelial basal cells and Bowman layer, and typically runs parallel to the corneal surface in a whorl-like pattern.26 In some cases, the path of the nerve fibers deforms the lateral or basal borders of the basal cells, such that the fibers seem to be fully enclosed. Each nerve fiber contains 1 to 40 axons.24,25 The fibers are of four different types—mechanosensory, polymodal, mechanoheat and “cold” neurons—and are arranged within the corneal epithelium according to their type.27–29 For the measurement of corneal sensitivity, there are two principal nerve types that mediate the corneal nerve response: A∂ fibers that remain in the subbasal nerve plexus, and C fibers that turn upward from this plexus toward the surface.30 A∂ fibers are large-diameter (8–10 μm), straight nerves that respond primarily to mechanical stimuli, whereas C fibers are small-diameter (5–8 μm), beaded nerves that respond to thermal and chemical stimuli (Fig. 1).5,27,31–33
Within the epithelium, the anteriorly oriented fibers in the basal epithelial layer pass through the wing-cell layer toward the superficial cells, where they end in fine, unspecialized nerve endings. These free terminals are usually swollen and can be found throughout the depth of the epithelium. Some of the nerve endings in the superficial layer can extend up to the last desmosomal junction between two superficial cells and are separated from the external environment only by this junction.12,23,34
Corneal Nerve Repair Mechanisms
The repair of the corneal nerve supply generally occurs in two phases, although the pattern and timing of the process varies with the type and extent of initial tissue damage.35–37 The first phase involves nerves from the undamaged epithelium surrounding the wound, and the second phase originates in the undamaged stroma deep to the wound. During each phase, reinnervation occurs by an initial degeneration of the original fibers within or close to the wound, followed by the regeneration of new terminals and axons into the healing tissue.7
With a purely epithelial wound, degeneration of damaged nerves occurs rapidly, and any nerves within the wound area will have degenerated by 24 hr after the trauma. By 48 hr, further degeneration of the nerves in the undamaged stromal plexus occurs, up to approximately 0.5 mm from the wound margin.35,38 Simultaneously, at around 16 hr, the first collateral nerve sprouts start growing from the intraepithelial axons in the undamaged cornea adjacent to the wound. By 24 hr, a dense hyperplasia of these neurites can be seen. The nerve sprouts completely surround the wound and orientate themselves perpendicularly to the edge. Terminals from these sprouts then grow horizontally to enter the basal cell layer of the newly repaired epithelium within the wound area. The purpose of these temporary neurites is not known, but they may result from the increased release of epithelial neurotrophic factor.36,39
The second phase of the reinnervation process begins around 7 days after the injury and can extend for 14 to 21 days depending on the extent of the original injury. New nerve growth develops in the stromal plexus of the surrounding undamaged cornea. New terminals grow obliquely into the newly formed, reorganized epithelium from the damaged stumps of the original axons that had innervated the area. At the same time as these new nerve endings are developing, the nerve sprouts formed in the first phase begin to degenerate and disappeared entirely by 3 weeks. The second-phase reinnervation reestablishes a normal pattern of corneal epithelial innervation within about 4 weeks, although tactile sensitivity would still be below normal levels for some time.36,40
Perilimbal and deeper stromal wounds that damage the main ciliary nerve bundles at the limbus (e.g., cataract surgery) or portions of the stromal nerve supply (e.g., penetrating keratoplasty [PK]) will inevitably produce longer-lasting damage to the epithelial nerve supply. All those nerves distal to the incision will degenerate, producing an immediate loss of corneal sensitivity. Collateral growth of new nerve sprouts from undamaged axons occurs, but is much reduced and nearly all of the new nerve growth develops from the stromal nerve stumps that pass through the wound scar. The remodeling takes at least 60 days to occur, and the resulting innervation density will be lower than normal. The whole nerve supply architecture will remain distorted even after 30 months.35,40 The recovery of sensitivity will be slow, and may never return to previous levels, depending on the type and extent of the damage.41
Measurement of Corneal Sensitivity
The Cochet–Bonnet Aesthesiometer (CBA) is the most common method for assessing corneal sensitivity.2 Introduced in 1960, the instrument uses a thin nylon thread (diameter 0.12 mm) to apply a direct mechanical stimulus to the corneal nerves. The technique relies on the resistance of the thread to bending. As the thread is gently pressed against the corneal surface, the force required to bend the thread is transferred to the cornea. A variation in the intensity of this stimulus is achieved by varying the length of the nylon thread, which in turn alters the force that must be applied to produce a bend in the thread—the shorter the thread, the greater the force required.
Although this instrument has become the standard method for assessing corneal sensitivity, there are major deficiencies in its design and this has led to the development of newer instruments.42–44 The Draeger45 Electronic-Optic Aesthesiometer used a fine metal wire attached to a solenoid motor to apply varying stimulus intensities to the cornea. It produced a stimulus similar to the CBA, but was less affected by ambient, environmental influences. The Belmonte Aesthesiometer uses pressurized air mixes, released at the cornea through an air jet, to stimulate the corneal nerves.46 In a series of experiments, this instrument has been used to show that the corneal nerve fibers respond to different stimulus modalities.32,47,48 The Non-Contact Corneal Aesthesiometer (NCCA) uses a controlled air pulse, of predetermined pressure and duration, aimed at the anterior ocular surface to produce a localized cooling of the tear film.3,49 This cooling is transferred to the corneal epithelium where it is detected by the nerves. Mechanical techniques, such as the Cochet–Bonnet and Draeger Aesthesiometers, stimulate the A∂ fibers, whereas the NCCA, which produces cooling, predominantly stimulates the C fibers of the corneal innervation.
Corneal sensitivity can be assessed at various locations on the corneal surface, depending on the area of interest. For example, in LASIK, a comparison is often made between the center of the flap and the paracentral area of the flap adjacent to the hinge. However, for the majority of assessments, only the central cornea is measured.
EFFECTS OF OCULAR SURGERY ON CORNEAL SENSATION
All types of corneal surgery inevitably alter corneal sensitivity because the corneal nerve supply will be damaged. The pattern of loss and recovery produced will depend on the type (linear incision, laser excision, and thermal laser), depth, location, and extent of wound made because these influence the number of nerve fibers damaged or severed, and on the healing response of the patient. Other types of ocular surgery, such as retinal detachment repair or squint surgery, can also affect the corneal nerve supply.6,9
In cataract surgery, the cloudy lens is removed and a new intraocular lens is inserted through an incision at or just anterior or posterior to the limbus. As the technique has evolved, it has been possible for the length of the incision to be reduced.
Large-Incision Cataract Surgery
In large-incision extracapsular cataract surgery, the nucleus is removed intact, requiring a full-thickness incision 12- to 13-mm long to be made circumferential to the limbus. Corneal sensitivity is severely reduced within the sector of the cornea central to the arc of incision.50–53 The incision cuts through both the limbal nerve plexus and the large centripetal nerve fibers. As a result, the corneal epithelium and stroma supplied by these nerves becomes denervated. After such a major insult, the recovery of sensation is slow. Little improvement occurs by 1 year postoperatively, and even at 2 years, sensitivity is below normal in the majority of cases.54–58
Manual Small-Incision Cataract Surgery
Manual small-incision cataract surgery is a technique mainly used in the developing world. It also delivers the nucleus whole, as in extracapsular surgery, but through a smaller, more posterior incision in the sclera. Scleral incisions generally produce less effect on the corneal sensation than corneal incisions.59 A straight or curved incision, 6- to 8-mm long, is made 3 to 4 mm behind the limbus, and a tunnel is fashioned to enter the anterior chamber at the level of Schwalbe's line. No significant reduction in corneal sensitivity occurs in the central or 4 mid-peripheral quadrants in the first 2 weeks postoperatively.60
Rarely, patients undergoing cataract extraction cannot be given an intraocular lens, in which case they may be fitted with a contact lens. Both rigid gas-permeable lenses and soft lenses reduce corneal sensation;6,61 so, it is important to monitor corneal health in these patients as for any other contact lens wearer.
With the advent of phacoemulsification and foldable intraocular lenses, cataract surgery can be performed through a small 2- to 3-mm tunnel incision. This still reduces corneal sensitivity, but over a much smaller area and is possibly followed by a quicker recovery.62 This pattern is also evident in patients who undergo a surgical iridectomy, or a trabeculectomy which is performed in the anterior sclera. The smaller incision arc causes less nerve damage, and the sensitivity loss is generally limited to corneal locations at the central and peripheral cornea adjacent to the incision site.63 Recovery to preoperative normal levels usually occurs between 3 and 9 months.56,64,65 This is delayed by the presence of dry eye disease before surgery66 and accelerated with the topical applications of cyclosporine-A postoperatively to treat dry eye.67 Recovery does not seem to be influenced by the mechanism of phacoemulsification occurring at the tip, as shown in a recent study that compared torsional technology with conventional longitudinal movement of the tip.68
Small Corneal Tunnel Incision for Phacoemulsification Surgery
Small-incision cataract surgery is sometimes combined with limbal relaxing incisions to address preexisting corneal astigmatism. These arcuate incisions at 90% depth can also produce a sector of reduced corneal sensation, in a similar way to more central arcuate keratotomies (see below).
The reduction in sensitivity after corneal transplantation depends on the depth and thickness of the tissue removed and replaced. There is a spectrum of procedures ranging from full-thickness PK, through lamellar procedures in which the anterior or posterior layers are replaced, to overlays (tectonic grafts or epikeratophakia) with minimal removal of tissue. In all these procedures, the donor cornea inevitably has no innervation immediately after surgery.
Penetrating and Deep Anterior Lamellar Keratoplasty
In PK, removal of the central corneal button from the host will damage the remnant nerves in the adjacent host corneal tissue. Although the host corneal epithelium and the subepithelial nerve plexus quickly recover, reinnervation of the stroma takes longer.69,70 In nerve regeneration after simple corneal incisions, new nerves grow toward the central cornea along the channels that the degenerated nerves had used. This speeds the regenerative process, and ensures that the new nerve ends do not have to burrow through the densely packed stromal collagen lamellae to establish a new path. However, when the tissue is replaced, as in transplantation, the nerves that are present in the peripheral host cornea do not align with the channels in the graft. Reinnervation is severely restricted and any recovery of sensation occurs slowly, being initiated at the periphery, with a gradual progression toward the center of the graft.70–75 This pattern emphasizes the importance of a fully functional stromal nerve supply, in addition to the subepithelial plexus, in the recovery of a normal corneal sensitivity.
Although some reinnervation of the corneal epithelium over the graft must occur from the undamaged peripheral corneal epithelium, this is insufficient to provide a full level of sensation. The earliest that central corneal sensitivity is detectable within the graft is 18 months postoperatively. In a study by Macalister et al.,76 66% of subjects had no central sensitivity and only 9% had normal sensitivity at 4 years postoperatively. By 7 years, 39% were still without any measurable sensitivity. Rao et al.72 found that the graft can remain completely anesthetic, or hypoesthetic, even 32 years after transplantation.
Two studies have shown that there is no difference in the rate of recovery of sensation between PK and deep anterior lamellar keratoplasty (replacement of 90%–96% of corneal thickness). In both procedures, Lin et al.77 found that sensitivity was reduced 12 months postoperatively, and Ceccuzzi et al.78 reported a 91% recovery to presurgery levels 2 years postoperatively. Darwish et al.,79 however, measured sensitivity changes using the NCCA (which stimulates C fibers rather than A∂ fibers) and found levels not significantly different to presurgery baseline at 12 months. This suggests that recovery rates differ between the different nerve fiber types. Al-Aqaba et al.80 performed a histochemical analysis on 12 failed full-thickness corneal grafts of mean survival duration of 6.4 years. The study found evidence of abnormal architecture and orientation of corneal nerves that persisted 14 years after surgery. It also showed that regenerated stromal nerves remained in the stroma, and did not contribute to epithelial innervation. Long-term alterations in corneal nerve morphology were confirmed in studies using in vivo confocal microscopy.81,82 One study found that the subbasal nerve density was still reduced 40 years after surgery.81 It seems that patients can expect some neural recovery, but that the majority will be left with a subnormal level of sensitivity.76,83
Posterior Lamellar Keratoplasty
A posterior lamellar or endothelial keratoplasty is used in conditions where there is purely an insufficiency of the endothelium, such as Fuchs corneal dystrophy. The host Descemet membrane and endothelium are replaced by those from a donor, thereby retaining the neural structure of the anterior host cornea after surgery. Only two studies have investigated the effect of this procedure on corneal sensitivity. Kumar et al.84 demonstrated relative preservation of corneal sensitivity after Descemet stripping automated endothelial keratoplasty technique. However, Ahuja et al.85 found that sensitivity was reduced compared with preoperative levels using a similar surgical technique (Descemet stripping endothelial keratoplasty). The same study found that although sensitivity recovered to presurgery levels within 3 years, it did not improve to levels similar to normal corneas.85 This suggests that nerve loss in the host periphery before surgery due to persistent edema or scarring was long-lasting.
Patients awaiting corneal transplant and suffering from symptomatic bullous keratopathy may have recurrent corneal erosions treated with anterior stromal puncture. This promotes new adhesion complexes between the epithelium and underlying stroma from the secretion of extracellular matrix proteins.86 In these cases, there is relief of symptoms, particularly pain, presumably from fewer bullae ruptures. Interestingly, corneal sensitivity improves after the procedure,87 suggesting recovery in nerve morphology with the improved corneal surface.
An arcuate keratotomy incision is a short (3–7 mm) circumferential corneal incision addressing astigmatism, for example, after corneal transplantation. It is made at a diameter of 6 to 7 mm and to only 90% to 95% depth. There is a sectoral loss and recovery of sensitivity confined to the portion of the cornea central to the incisions, as in cataract surgery. Shivitz and Arrowsmith88 found that, with an incision of less than 80% corneal thickness, 72.8% of patients had a normal sensitivity after 1 year, whereas with 90% corneal thickness incisions, no recovery of sensation was measured after the same period. Increasing the number of incisions also slows the recovery. However, in general, corneal sensitivity returns to normal levels by 1 year postoperatively.38,83,88,89 Studies involving animals have shown the faster recovery of experimentally damaged nerves with the topical application of therapeutic agents, such as semaphorin 3A inhibitor,90 pituitary adenylate cyclase–activating polypeptide,91 macrophage migration inhibitory factor,92 nerve growth factor,93 drug FK962,94 and pigment epithelial–derived factor plus docosahexaenoic acid.95
Tectonic Overlay Grafts and Epikeratophakia
A tectonic corneal graft is performed when a patch of donor tissue is transplanted onto the surface of a host cornea that has an actual or threatened perforation. This typically occurs as a result of severe corneal inflammation or previous infection, and the aim is to restore the integrity of the globe. There are no studies of corneal sensitivity after such procedures, but we can extrapolate from studies on epikeratophakia and cryo-keratomileusis. Epikeratophakia is a refractive surgery technique that involves the grafting of a lenticule of donor tissue to the anterior surface of the cornea, but is rarely performed these days. Cryo-keratomileusis is similar, but involves the removal, freezing, reshaping, and reattachment of a portion of the host cornea. After epikeratophakia, the new anterior surface has no nerve supply and a new innervation must develop in much the same way as that after PK. As a result, the pattern of sensitivity recovery measured is much the same.96–99 With cryo-keratomileusis, the reshaped corneal button has undergone freezing in addition to removal from the donor, both of which would have destroyed the corneal nerves. Reinnervation of the corneal button and sensation recovery will also be limited, in a similar manner to keratoplasty.99–103 For example, at 5 years after epikeratoplasty, only minimal corneal sensitivity was measured in the central zone, but by 10 years postoperatively, it had significantly returned. However, only 17.7% of eyes at 10 years had a normal central corneal sensitivity.104 Epikeratoplasty may also include a centrally placed keratectomy, but no difference in loss and recovery has been found between those patients with a keratectomy and those without.
In radial keratotomy, typically 4 to 8 radial incisions are made in the cornea to flatten its center to treat myopia. The degree of flattening depends on the type, depth, and number of incisions made, and these factors also define the extent of sensitivity loss.38,41,105 The normal radial incisions are parallel to the axis of the radiating stromal nerve fibers and so produce minimal damage.
This surgical technique offers a reversible method for the correction of low myopic refractive errors, but is now more commonly used to stabilize the corneal profile in cases of progressive keratoconus. Small polymethylmethacrylate rings are inserted into a channel at two-thirds depth in the mid-peripheral stroma to produce an alteration to the shape of the anterior corneal surface. The epithelial nerves are not affected, and the stromal nerves are untouched superficial and deep to the ring segments. A small 2- to 3-mm radial incision in the cornea allows for insertion, but this produces no long-term reduction in corneal sensation, and sensitivity returns to preoperative levels after 1 year.106
Excimer Laser Surface Procedures
The excimer laser can remove tissue from a large area of the superficial cornea with extreme precision, and with minimal damage to adjacent tissue. It therefore affects the corneal nerve supply in a very different way to a scalpel incision.11,107–109 It has a role in refractive surgery, and is used to treat certain corneal surface diseases.
Photorefractive keratectomy uses excimer laser technology to directly alter the corneal refractive power over a large surface area. Myopic PRK procedures remove central corneal tissue over a typical treatment zone of 6- to 8.5-mm diameter110 to produce a saucer-shaped excision that is deeper centrally than peripherally. Hyperopic PRK has a wider “ring-donut” shaped treatment zone approximately 9 mm in diameter. The majority of tissue is removed in the mid-peripheral zone, with peripheral blending. In both procedures, the corneal epithelium is manually debrided in the treatment zone, and this removes all the sensitive epithelial nerve supply. The excimer laser then ablates the exposed stroma to a depth (10–150 μm) dependent on the dioptric correction required and the diameter of the ablation zone.111 This procedure removes a significant proportion of the anterior stromal nerve supply. As a result, when the corneal epithelium grows back over the exposed stroma, any reinnervation that takes place can only do so from the peripheral untouched epithelial supply and the remnant stromal supply deep to the excision.
The majority of research into the pattern of corneal sensitivity loss and recovery after PRK has been performed using the CBA or another similar mechanical stimulus, and have therefore considered the surgical effect on the A∂ fibers. There have only been a limited number of studies that have assessed the effect on the C fibers using a thermally cooling stimulus. The majority of studies have also only considered myopic PRK rather than hyperopic PRK.
Myopic Photorefractive Keratectomy
The majority of studies on myopic PRK used mechanical stimuli and found a short-term reduction in sensitivity.83,112–116 Sensitivity returned to preoperative levels by 6 months or even earlier, unless the ablation depth was very deep (approximately 100 μm, or corrections greater than −6.00 D). For the majority of refractive errors corrected, where the ablation depth was less than 100 μm, there was no relationship between the pattern of corneal sensation loss and recovery and ablation depth. By contrast, a study that assessed corneal sensitivity to a thermally cooling stimulus found that sensitivity did not recover until 1 year after surgery.117 This difference may be related to the different neural architecture of the two nerve types that mediate the two stimuli, and how this architecture is changed after PRK. An early histological study in rabbit eyes118 and in vivo confocal microscopy studies on human eyes119–121 have shown the recovery of corneal innervation after PRK to be disorganized. The crude lattice of nerves that reinnervates the corneal epithelium may provide a network more readily able to detect the mechanical surface deformation stimulus of the CBA. By contrast, the cooling stimulus of the NCCA may require a more complete reorganization of the corneal nerves, with a network of fine C fiber nerve endings arranged close to the epithelial surface. By necessity, this takes longer, and so, recovery of the C fiber sensation would take longer too.
Hypersensitivity after PRK surgery has been reported in rabbits, which persisted for up to 10 weeks after surgery.122 No similar findings have been reported for studies on humans. However, hypersensitivity of regenerating corneal nerve C fibers has been reported,123 and a study by Gallar et al.124 found hypersensitivity after LASIK. This latter finding has been attributed to the greater stimulus resolution possible with the Belmonte aesthesiometer. It is, therefore, possible that there could be some short-term (1–2 weeks) hypersensitivity after PRK if measurements were made using a sufficiently sensitive device.
Hyperopic Photorefractive Keratectomy
Only one published article has considered the effect of low-powered hyperopic PRK correction on corneal sensation.125 This study used the cooling stimulus of the NCCA to assess the loss and recovery of C-fiber–mediated sensitivity. Although a similar result might be expected to that found with myopic PRK, sensitivity was found to not change significantly after surgery. This unusual result can be explained by again considering the effect of surgery on the corneal architecture. Unlike myopic PRK where a large, deep central ablation occurs, in hyperopic PRK, the central corneal stroma is preserved and a peripheral ring is ablated. Because the ablations attempted in the study were not deep (2–4 diopters), the deeper stromal nerve supply to the central cornea was most likely preserved. Even with the debridement or ablation of the central epithelial nerve supply, the virtually untouched stromal nerve supply is sufficient to maintain corneal sensation. However, for this to be confirmed, measurements of corneal sensation at both the central cornea and at the area of cornea where maximum ablation depth occurred would need to be taken. The authors also suggested that the short-term hypersensitivity of regenerating C fibers may have masked some of the initial sensitivity loss after corneal epithelium removal.
One other important use of excimer laser ablation is for phototherapeutic keratectomy (PTK). This procedure produces a broad excision of uniform depth, or masking fluid can be used during the removal of proud irregularities. It is used to treat superficial corneal pathological conditions and has a wide variety of indications including removal of band keratopathy or superficial scars and improving epithelial adhesion in recurrent erosion. No attempt is made to alter the patient's refraction. Removal of abnormal tissue can lead to an improvement in corneal sensation after PTK, both in terms of increased sensitivity and a reduction in discomfort. Creation of a smoother corneal surface may also improve tear film quality and conjunctival squamous metaplasia.126 Patients with herpetic corneal scarring commonly have reduced corneal sensitivity before the procedure, and therefore unsurprisingly, corneal sensitivity measurements are slightly lower at 6 months compared with other patients.
Excimer Laser Flap Procedures
In refractive procedures under a flap, a layer of epithelium or epithelium plus stroma is raised before the excimer laser refractive correction is applied to the stromal bed, and then the flap is replaced. In contrast to surface treatments, this provides the opportunity for some innervation of the surface layers to remain intact.
Laser In Situ Keratomileusis
Laser in situ keratomileusis is a development of PRK, in which a corneal flap is produced, which includes superficial stroma as well as epithelium. A microkeratome is used to cut through the superficial stroma, creating a thin (160–180 μm thick) flap. This is then peeled back, exposing the underlying stroma for ablation in a similar way to PRK. The flap is then carefully replaced over the treatment zone. An alternative method for the flap creation is the use of a femtosecond laser, creating a thinner (90–100 μm thick) flap. Further details are discussed below.
From the point of view of corneal innervation, the microkeratome cuts through the epithelial nerve supply in the periphery of the flap, and the deep nerve supply across the base of the flap. The only exception to this is in the 45° to 60° sector central to the hinge, where the epithelial supply is preserved. This is in contrast to the formally used procedures of epikeratophakia and cryo-keratomileusis, where the flap was totally removed without a hinge and no nerve supply to the flap was retained. In LASIK, the laser ablation will remove the central portion of the stromal nerve supply to an even greater depth.
This more complex surgical procedure has produced a mixed set of results. The majority of published studies have found less reduction in sensitivity after LASIK than with PRK.127–134 However, this reduction in sensitivity has a longer duration, up to about 6 months.115,116,130,135–137 Several studies found a greater initial loss of sensitivity with deeper ablations, but after 6 months, this difference no longer persisted.138–140 Topical application of cyclosporine141 and protein-free calf blood extract142 have been shown to speed the recovery of corneal sensitivity after LASIK.
This outcome after LASIK can be attributed to the greater preservation of the corneal epithelial and anterior stromal innervation through the hinge of the corneal flap. The sector central to the hinge has some reduction in corneal sensation, but this loss is not as severe, and recovery occurs more quickly than the center of the flap and those portions of the flap furthest from the hinge.129,143,144 There is some disagreement on the influence of hinge position on corneal sensitivity, with studies showing either less reduction,143,144 no difference,145–147 or greater reduction135 in nasal or temporal-hinged eyes compared with superior-hinged eyes. In addition, Donnenfeld et al.143 showed greater loss with a narrower hinge, whereas Mian et al.146 noted that hinge angle and thickness have no effect on sensitivity loss. Nevertheless, it is likely that the prolonged depression in sensitivity reflects the need of the regenerating neurons to repopulate the stromal flap rather than just the new epithelium. As such, it reflects the problems of reinnervation encountered with corneal transplantation. In general, corneal nerve regeneration after LASIK follows a slower pattern than that found after PRK, with a greater delay in the development of new nerve fibers. However, as the nerve fibers become better organized, sensitivity returns to normal levels.129,148,150
In recent years, alternative methods to conventional LASIK have developed with the advent of the femtosecond laser for refractive surgery. When used in place of the microkeratome for flap creation (i.e., FS-LASIK), femtosecond laser cuts have been shown to produce better uniformity and predictability of the flap thickness than conventional LASIK,149 which results in less damage to the corneal nerves.150,151 In the femtosecond lenticule extraction (FLEx) technique, the femtosecond laser is used to create a lenticule within the stroma that is removed with forceps after the flap is lifted. In small-incision lenticule extraction, the lenticule is removed through a 3 to 4 mm opening in the peripheral cornea, rather than a full flap. This has been shown to produce less subbasal nerve density loss, with faster recovery of corneal sensitivity,152 when compared with FS-LASIK153–155 and FLEx-treated eyes.156–158 Less reduction in corneal sensitivity and faster recovery are found when the standard 70° angled laser side cut flap is replaced with an inverted 130° cut,159 presumably because of improved wound healing and apposition of severed nerves from a more stable flap after surgery.160
Laser Subepithelial Keratomileusis
Laser subepithelial keratomileusis was developed for patients considering refractive surgery who have low myopia, thin corneas, or a predisposition to flap trauma. Laser subepithelial keratomileusis combines elements of both PRK and LASIK techniques. The hinged flap that is made and restored after ablation is only a thin epithelial sheet. It is separated from the cornea, using either the application of an alcohol solution161 or an epikeratome.162 The excimer laser ablation is then applied to the stromal surface in a similar way to PRK. The deeper stromal nerves are thus spared during the ablation process. Disruption to nerve fibers in the subbasal, subepithelial, and anterior stromal layers still occurs after surgery, with the reduction in corneal sensitivity correlating with ablation depth.163–165 Two studies showed that the initial reduction in corneal sensitivity was less and recovery was faster after LASEK than after conventional LASIK.166,167 Another study involving LASEK showed that corneal sensitivity recovered faster when the flap was created with an epikeratome compared with using alcohol solution.151 Darwish et al.,168 however, found no such difference between LASIK and LASEK when sensitivity was measured using the NCCA. In addition, Patel et al.169 found no difference in sensitivity changes between flaps created with the femtosecond laser and the microkeratome using the Belmonte aesthesiometer. Therefore, it seems that LASIK had a greater impact than LASEK on the damage and regeneration of A∂ fibers, whereas there was no difference between the two techniques on recovery of C fibers.
Dry eye is a common complaint after all types of photorefractive surgery. Several studies have speculated that postoperative reduction in corneal sensitivity disrupts the feedback loop for basal tear production, leading to diminished lacrimal secretion and poor tear film, which produces dry eye symptoms.170–174
Cross-linking is a relatively new procedure that can delay or prevent the progression of keratoconus. Debridement of the central cornea epithelium is followed by topical application of riboflavin solution and irradiation of the exposed corneal stroma with ultraviolet A radiation.175 This results in chemical bonding between adjacent collagen lamellae to prevent slippage leading to ectasia. Many studies show a significant loss of corneal sensitivity immediately after surgery, followed by a gradual recovery toward preoperative levels over the ensuing 6 to 12 months.176–181 Nerve morphology is affected over a similar time course. One study showed that subbasal nerve density recovers to preoperative levels after 7 to 12 months. However, normal levels were still not reached by 5 years postoperatively.182 Less reduction and more rapid recovery in corneal sensitivity is achieved when the epithelium is not removed, which is the recommended procedure for patients with less than 400-μm corneal thickness.183
This procedure is used to selectively damage the ciliary body to decrease production of aqueous humour, as a treatment for glaucoma. It is accomplished by directing the beam from a neodymium:yttrium-aluminium-garnet (Nd:YAG) laser perpendicular to the sclera at a point 1- to 2-mm posterior to the limbus. The beam passes through the sclera and is absorbed by melanin in the pigmented tissue.
Preexisting corneal conditions (e.g., long-term use of topical beta-blockers, corneal surgery with large incision, some corneal dystrophies, high myopia, anterior uveitis, or diabetes mellitus)184 may predispose the patient to neurotrophic cornea defects. In severe conditions, this can lead to corneal perforation.185 However, changes in corneal innervation or sensation can be reduced by good patient selection and avoidance of the 3 and 9 o'clock limbal regions.186 Subjects in this study were preselected to exclude corneas with previous complications, diabetes, rheumatoid arthritis, amyloidosis, or herpetic eye disease, and this may have removed those “at-risk” groups that developed neurotrophic defects observed in other studies. Not exceeding the recommended laser power level of 2,500 mW for 2.5 s has also been suggested to prevent neurotrophic keratopathy development as a result of nerve damage.184
By contrast, a study in dogs found a 27.4% overall reduction in corneal sensitivity in all areas of the cornea, from preoperative levels after 2 weeks.187 No measurement was made of recovery time. Immunohistochemical analysis of the nerve fibers reported a loss of the major nerve bundles, suggesting that the nerves in the area of laser application are destroyed.
Retinal Detachment Surgery
The impact of retinal detachment surgery, which commonly involves pars plana vitrectomy, is not immediately apparent. However, a significant decrease in sensitivity has been found in eyes treated with an encircling band. No significant decrease was found in eyes treated with localized radial or circumferential silicone or sponge explants alone. The mechanism is unclear, but may be due to surgically induced inflammation of the ciliary nerves as they course between the sclera and choroid, or due to damage produced by compression of the nerves from the scleral buckle or by surgical perforation. There may be a contribution from postoperative inflammation and surface irregularity because an encircling band requires a full peritomy, whereas local explants require only sectoral incisions of the conjunctiva at the limbus. It is also not clear whether the effect on sensitivity is long term because the pattern of recovery does not correlate with time postoperatively. However, there may be a lot of variations in the damage to extraocular tissue during similar operations. Most studies find that sensation eventually returns to normal levels.188–191 In eyes treated with circumferential laser photocoagulation, corneal sensitivity may be reduced for 6 months after surgery.192 Damage is thought to occur to ciliary nerves in the suprachoroidal space.193,194 One article has raised the possibility of whether the fine nerves in the subbasal nerve plexus could be damaged as the laser passes through the cornea, but there is no pigment in the cornea to absorb the energy, and the rays are not focused there.192
Ocular discomfort and dryness is a commonly reported symptom after strabismus surgery. In the first study to explore the relationship between ocular sensitivity and symptoms,195 no change in central corneal sensation was observed. However, conjunctival sensation was reduced after surgery, which persisted during the 3-month duration of the study. This effect was suggested to be due to electrocauterization of the circumlimbal blood vessels damaging the perilimbal nerve fibers. A later study found that goblet cell density was reduced up to 2 months after surgery, resulting in instability of the ocular tear film and hence, another possible cause of ocular irritation symptoms.196 A more recent study found more dry eye symptoms and tear film instability with a limbal incision technique than fornix incisions.197 Central corneal sensitivity was also reduced after limbal incisions, whereas it was unchanged with fornix incisions, which suggest that limbal incisions cause partial denervation of the cornea. Despite the detected adverse effects, all studies found that most ocular signs and symptoms recovered to baseline levels within 2 to 4 months after surgery.
Transient reductions in corneal sensitivity have been recorded after most types of corneal surgery. Incisions into the ocular surface damage the complex network of superficial nerve fibers and terminals, with greater reductions in sensitivity seen with a greater arc length and depth into the mid-stroma, and if incisions are circumferential rather than radial. Incisions or debridement of the corneal epithelium will result in temporary loss of corneal sensitivity from the damage or removal of the subbasal and subepithelial nerve plexi. Recovery of corneal sensitivity from such procedures to preoperative levels is generally expected within 6 months for mechanical stimuli, or up to 1 year for thermal or chemical stimuli. Circumferential stromal and limbal incisions, however, cut through deeper trunks of the neural supply to the corneal surface. Although sensitivity loss is confined to the sector of the cornea central to the arc of incision, recovery is generally slower than epithelial procedures. Procedures involving the transplantation of corneal tissue show the slowest recovery due to a lack of alignment of nerve channels between host and donor tissue. A subnormal level of sensitivity is commonly observed after many years postoperatively. Other types of surgery, such as for squint or retinal detachment, can alter corneal sensitivity by affecting the nerves as they travel toward the cornea. In such cases, the severity and recovery time are generally less in comparison with procedures that involve incisions to the ocular surface.
To summarize, all types of ocular surgery can affect corneal innervation. However, for the majority of patients, corneal sensitivity can be expected to return to normal levels with time, and only when the most severe damage to the corneal innervation occurs, will there be a permanent reduction or absence in corneal sensitivity. Nevertheless, a quick recovery of the corneal nerve function to normal levels is important in the continuing maintenance of a healthy cornea, as several cases of surgically induced neurotrophic epitheliopathy have been recorded,18,188 as well as secondary effects on the tear film and contact lens tolerance. It is therefore important that clinicians are aware of this to provide appropriate management, especially in the presence of preexisting disease that might delay or influence recovery of corneal sensation.
METHOD OF LITERATURE SEARCH
A systematic search was completed using several scientific publication databases. Articles were selected for inclusion that evaluated any aspect of corneal sensation change, as a result of ocular surgery, and each article was critically assessed for the contribution it gave to the understanding of this area. For articles published between 2000 and 2017, articles relevant to corneal sensitivity, ocular surgery interventions, and measurement techniques were found using the search terms outlined in the PubMed search strategy (available on request), which provides the detailed search strategy in PubMed and Ovid Embase. The languages of focus were: English, French, German, Polish, Japanese, Danish, and Russian; however, the database searches were not limited to these, and other languages were considered. Articles before 2000 were searched through Medline, ISI Web of Science, and other databases.
The authors thank Dr. Caroline LS Kilduff for her design and illustration of the corneal innervation diagram.
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