Estimates of the prevalence of myopia across the world vary between 15 to 49 per cent with many individuals also having astigmatism. Traditionally, ametropia has been corrected for many hundreds of years with spectacles and contact lenses. Despite their longstanding use, there are disadvantages in both forms of optical correction. Although arguable, spectacles have a negative cosmetic appearance for some patients, causing confidence issues and stereotyping, particularly for higher refractive errors with thicker and more magnifying or minifying lenses. There are also issues such as inconvenience with sports, increased reflections and the physical weight of the spectacles on the patient's face. Contact lenses also have a variety of disadvantages, such as cost, disruption of the normal physiology of the ocular surface, risk of infection and discomfort. Despite these disadvantages, significant developments have occurred in contact lens manufacturing, such as the introduction of daily disposables and silicone hydrogels with ever-increasing power ranges. The disadvantages of spectacles and contact lenses as well as the psychological factors have played a part in the decision of the vast numbers of patients who undergo refractive surgery to free themselves of spectacle or contact lens dependence. Refractive surgery can be broadly classified into keratorefractive surgery, which may be achieved by incisional, laser, thermal, implants or lamellar surgery and lenticular surgery, such as clear lens extraction, phakic, multifocal and pseudo-accommodative intraocular lenses.
There have been many historical corneal refractive techniques and procedures developed over the years. From early techniques of radial keratotomy to modern excimer laser techniques, the field of refractive surgery is one of the most rapidly developing in ophthalmology. This review details the historical aspects of the many early techniques up to current techniques used on millions of eyes around the world.
Early refractive surgery suggestions
The first suggestion of refractive correction was by Hermann Boerhaave in 1708, when he suggested that high myopia could be corrected by couching the clear crystalline lens. Although this may have been first performed by von Haller in 1746 and subsequently performed by others,[7, 8] the first reports in the literature were not until the 1890s with clear lens extraction. Despite this, this form of refractive surgery was rarely performed until recent times.
The first suggestions of corneal surgery to alter the refractive power of the eye were by Dutch ophthalmologist Snellen, in 1869. Snellen documented the possible correction of corneal astigmatism, based on prior observations by Donders, of whom Snellen was a student, that corneal scars following cataract surgery increased astigmatism. Clinical reports surfaced later in the 1880s and 1890s.[12-16] Norwegian physician, Hjalmar Schiötz was the first to perform astigmatic keratotomy for the correction of 19.50 dioptres (D) of with-the-rule corneal astigmatism post-cataract surgery with the use of a 3.5 mm penetrating corneal incision. In this case, astigmatism was reduced to 7.00 D. The first cases of non-penetrating astigmatic keratotomy in the correction of astigmatism occurred later in the 1890s in the USA, the Netherlands and Italy.[13-15] Experimental work in the rabbit eye by Dutch physician, Lans, followed in 1898. This work revealed many important concepts, such as coupling, whereby a corneal incision will flatten the cornea along the incised meridian and steepen the orthogonal, flatter meridian, thereby maintaining the average corneal curvature. It also revealed that deeper and more central incisions and scars have greater effects. The major breakthrough in refractive surgery was with the introduction of radial keratotomy (RK), initially with reports by Sato in 1939 and later with Yenaliev, Fyodorov and Durnev in the former Soviet Union.
Tsutomu Sato, a Japanese ophthalmologist, observed the flattening effect following acute hydrops in keratoconics. Sato subsequently produced horizontal breaks in Desçemet's membrane (and the endothelium) of keratoconic eyes initially using a posterior approach. Sato conducted further experimental work with both anterior and posterior approach keratotomy in the 1940s reporting promising results for up to 4.00 D of myopia.[18-20] In the early 1950s, hundreds of patients underwent anterior and posterior keratotomies with the results of 32 eyes published in 1953. Later in the 1950s, Sato ceased to perform the surgery due to the introduction of contact lenses; however, due to the lack of knowledge of the importance of the corneal endothelium, many patients subsequently developed corneal decompensation in later years. Of the retrieved medical records of patients who underwent surgery at Juntendo University between 1953 and 1959, 78.6 per cent had bullous keratopathy occurring at an average time of 26.9 years after surgery. Svyatoslav Fyodorov brought the Sato-style radial keratotomy to the Soviet Union but encountered poor results. In 1969, Yenaliev, also in the Soviet Union, performed radial keratotomy using four to 24 anterior incisions, finding that 73 per cent of the 426 eyes operated on, remained stable with 27 per cent regressing. Throughout the 1970s further refinements to the technique were established with improved results.[24-26] Leo Bores brought radial keratotomy to the USA in 1978, followed by a small number of other ophthalmologists.
Refinements to the surgical procedure, in addition to advances in guarded knives and microscopes, improved accuracy. An increased number of incisions induced greater refractive effects up to approximately 16 incisions, with a greater number of incisions found to provide no additional effect and potentially an opposing effect. Most performers used four or eight incisions, depending on the refractive error for the correction of up to 6.00 D of myopia (Figure 1). Using 16 incisions over eight incisions had only a 5–10 per cent further effect. The radial keratotomy incisions result in peripheral elevation, which in turn causes central corneal flattening. An increased effect occurs with deeper and more central incisions. Further modifications to increase the refractive effect included multizone RK. Incisional direction also varied. Typically, the incisional direction was from the optical zone to the limbus in America but limbus to optical zone in the Soviet Union. In 1981, the Prospective Evaluation of Radial Keratotomy (PERK) study commenced which involved a nine-centre clinical trial in the USA. The 10-year follow-up data from this study, despite variable optical zones and non-use of nomograms, found that 38 per cent were within 0.50 D and 60 per cent within 1.00 D. Hyperopic shifts are a common feature of radial keratotomy, occurring in 43 per cent of eyes in the PERK study along with diurnal variation. Regression is expected in the early stages due to corneal wound healing, hence overcorrection is performed. Neovascularisation along the radial incisions may also induce regressive effects. The diurnal variation is also expected in the early stages after surgery resultant to corneal oedema. Quality of vision problems are a common side effect of radial keratotomy, resulting in symptoms such as glare and haloes, which are related to the optical zone size. There is also an increased vulnerability to traumatic lesions and globe rupture due to the reduced biomechanical strength of the cornea.[30, 31]
Hexagonal keratotomy was first performed in Mexico by Antonio Méndez for the correction of up to +4.00 D of hyperopia using circumferential connecting hexagonal incisions. The incisional configuration induced central corneal steepening, hence reducing hyperopia. In 1992, Casebeer and Phillips devised a modification to the technique with non-connecting incisions; however, this surgery was found to be associated with high complication rates and refractive instability.[33, 34] For astigmatic corrections, astigmatic keratotomy was one of the first adaptations to radial keratotomy, which involved two tangential incisions on each side of the optical zone as well as interrupted transverse (T) incisions. Thornton and Saunders described the straight T cut incision for the correction of myopia and Ruiz described the stepladder procedure for larger astigmatic corrections, both of which were practised widely in the 1980s. Tangential T-cuts were associated with a small myopic effect, which was not a problem with the arcuate T-cuts. Radial keratotomy and hexagonal keratotomy have essentially been discontinued owing to their aforementioned complications and lack of refractive accuracy and stability; however, ARC-T or limbal relaxing incisions are commonly used at the time of cataract surgery and following keratoplasty aiming to reduce corneal astigmatism. A lot of the advances in astigmatic correction stem from the work of Richard Troutman, particularly principles in astigmatic keratectomy, such as incisional placement on the steepest corneal meridian to reduce astigmatism and corneal wedge resection for astigmatic control.[39-42] Further developments in the analysis and treatment planning of astigmatism include the work of Noel Alpins, notably, ‘The Alpins Method’ which is applicable to both incisional and laser paradigms.[43-48] For a detailed review on the advances in astigmatic correction, the reader is directed to the chapters on astigmatism in the recent book by Benjamin Boyd.
Lamellar refractive surgery
A huge advance in the refractive surgery field is accredited to Spanish ophthalmologist José Ignacio Barraquer. In 1948, he observed an advanced case of keratoconus, which was unsuitable for penetrating keratoplasty. Instead, he performed an 11 mm diameter lamellar keratoplasty, resulting in a near emmetropic refraction. In 1949, following experimental studies in rabbit eyes, Barraquer published the results of a study, which indicated that by flattening or steepening the central corneal curvature, refractive correction could be achieved with a procedure termed refractive keratoplasty. Although initial research by Barraquer was in Spain, most of his work in the field of refractive surgery was conducted in Bogotá, Colombia. Barraquer's continued research lead to two major contributions in this field, namely, keratomileusis and keratophakia.[51-53]
Keratomileusis originates from the Greek words keras (κέρας) meaning hornlike and smileusis (σμίλɛυσις) meaning carving. The original technique of myopic keratomileusis by Barraquer was performed freehand with a Paufique knife. Due to the technical difficulty of this, Barraquer designed a manual microkeratome to enable improved and easier lamellar resection and corneal disc carving. The microkeratome consisted of applanator lenses and suction rings of various heights, realising the importance of contact between the suction ring and the microkeratome to enable a smooth lamellar dissection. Freeze keratomileusis involved the use of a microkeratome to remove a central section of the cornea which was then frozen with liquid nitrogen or solid carbon dioxide. It was cryolathed on its posterior surface, thawed, returned to the cornea and sutured in place. Freeze keratomileusis was capable of correcting myopia up to -15.00 D and hypermetropia up to +8.00 D but was generally unsuccessful for the correction of astigmatism. It also had other disadvantages, such as slow recovery time, in part due to corneal oedema and de-epithelialisation caused by dead keratocytes and damaged lamellar architecture from the freezing process. It was also associated with irregular astigmatism and corneal haze.[56-59] Owing to these disadvantages, non-freeze modifications were developed, such as the Barraquer-Krumeich-Swinger (BKS) non-freeze technique. This technique avoided the loss of fibroblasts and brought less post-operative discomfort due to a viable epithelium. Instead of freezing the resectioned cornea, the corneal cap was placed on a suction mould based on the attempted refractive correction for the microkeratome to make the refractive cut. Unfortunately, it too was unsuccessful at correcting astigmatism but on the plus side, it was associated with fewer complications than freeze techniques.[57, 60]
In 1964, Krwawicz in Poland followed Barraquer's work with what was termed ‘stromectomy’, which involved two separate manual stromal cuts with the second cut being discarded, although he had previously attempted to modify corneal curvature with other techniques.[50, 51] Pureskin in Russia followed Krwawicz's technique with the use of a trephine to demarcate the resection. Similar work was followed by Elstein and colleagues. In 1985, Hoffman devised a method of stromectomy using double suction rings and curvature templates called keratokyphosis; however, none of these techniques proved to be particularly successful.
Automated lamellar keratoplasty (ALK) was developed by Luis Ruiz also in Bogotá, Colombia, following his invention of an improved automated microkeratome. This was also a non-freeze technique involving a primary keratectomy with an automated microkeratome, which was followed by a second pass of the automated microkeratome to the stromal bed, removing a section of the cornea to achieve the desired refractive effect. The primary corneal cap was then replaced. The microkeratome removed central corneal tissue in the correction of myopia but it was also used for correcting hyperopia. For hyperopic correction, a thick flap was created at approximately 300 μm and then replaced. This caused the cornea to become ectatic, which reduced the level of hyperopia. The reduced biomechanical strength of the cornea following the deep flap creation allowed for this ectatic process (Figure 2). The level of hyperopic correction is proportional to the diameter of the flap if the flap depth is kept constant. Despite good initial results for hyperopic correction, Lyle and Jin highlighted long-term refractive instability with 26 per cent of eyes developing iatrogenic keratoconus; however, this was later revealed to occur only in eyes which had previous radial keratotomy.[58, 59] Homoplastic automated lamellar keratoplasty has been performed for higher degrees of hyperopia and it involves the removal of a small disc of 80 to 100 μm in thickness and five to seven millimetres in diameter, which is then replaced by a donor lenticule of approximately 350 to 400 μm thick. The efficacy and safety of homoplastic automated lamellar keratoplasty has not been fully ascertained. The use of automated lamellar keratoplasty went out of favour with the introduction of the excimer laser to ablate corneal tissue, which provided improved accuracy in refractive correction.
Keratophakia was developed for the correction of high hyperopia or aphakia, which was then a comparatively common need compared to the present time. The procedure was developed by Barraquer involving an initial keratectomy of the patient's cornea using a microkeratome. Frozen donor corneal tissue, including the epithelium, Bowman's layer and the anterior stroma, was implanted intrastromally into the recipient cornea with the original keratectomised corneal cap being sutured in place. The additional corneal tissue increased the anterior corneal curvature and hence increased the refractive power of the eye; however, similarly to freeze keratomileusis, due to the cryolated corneal tissue, recovery was slow with recovery times of up to six months. Synthetic intracorneal lenses have attempted to overcome the limitations with frozen donor tissue and limited availability of donors. Early work in this area was promising but a recent study of 15 patients implanted with the PermaVision (ReVision Optics Inc) found nine of the patients elected to have the implant removed, with dissatisfaction with the quality of vision as the most frequent reason for removal.
Epikeratophakia was introduced in 1980 by Herbert Kaufman for the correction of large ranges of myopia and hyperopia. The procedure involves sewing a human donor lenticule to the anterior surface of the prepared eye. The preparation of the recipient eye involves the removal of the epithelium followed by a peripheral annular keratotomy, allowing the frozen donor edges to be tucked into the peripheral recipient cornea and sewn in place (Figure 3). The limited use of this procedure is due to its problems with epithelial recovery, interface scarring and clarity, reduced distance visual acuity, poor refractive predictability and refractive regression. It is still used occasionally for the correction of aphakia in children, where lens surgery is contraindicated or there is intolerance to spectacles or contact lenses or severe corneal thinning, where other forms of grafting procedures are not appropriate.
Intrastromal corneal ring segments
Intrastromal corneal ring segments are curved plastic inserts made from polymethyl methacrylate (PMMA), which are surgically inserted into the peripheral corneal stroma (Figure 4). This technique avoids contact with the central or paracentral corneal area. Gene Reynolds introduced the idea to modify the corneal curvature for the correction of myopia and hyperopia. His initial theory was to insert the segments and actively expand (myopic correction) or contract (hyperopic correction) them to achieve the desired refractive result. This method was further refined, leading to the realisation that the simple addition of an intrastromal ring caused central corneal flattening. The segment thickness had a direct effect on the degree of flattening and the initial expanding/contracting method initiated by Reynolds was not achievable.
Implants modify the central corneal curvature through the addition of tissue or material as opposed to tissue removal which often occurs with other refractive surgery procedures. When implanted, the peripheral cornea pushes the peripheral anterior and posterior corneal surfaces outwards (circumferential centrifugal expansion), requiring compensatory central corneal flattening.
Early implantation with an intrastromal ring segment was well tolerated with little host reaction in blind and sighted eyes.[77-79] Removal of the implants indicated the potential for restoring the normal histology of the cornea and in some cases, the central cornea returned to its pre-operative curvature. Reversibility has been demonstrated after explantation of both hydrogel inlays and intrastromal ring segments.[80, 81]
The first human trial was conducted in 1991 in Brazil with intracorneal rings implanted into the non-functional eyes of three patients. In this study the intracorneal rings were 360 degrees, 0.30 mm thick and the outer diameter was 7.70 mm. In all three cases, no significant complications were encountered within one year post-operatively and one implant was successfully explanted. The average corneal flattening was 2.00 D and the eye that underwent implant removal returned to its original curvature. Numerous modifications and trials occurred over the years and in April 1999, the Federal Drug Administration approved the use of 150-degree paired intrastromal ring segments under the name of IntacsTM (Addition Technology Inc). Various sizes are available but the FDA has only approved thicknesses of 0.25 mm, 0.30 mm and 0.35 mm. IntacsTM are approved for patients with low myopia (-1.00 to -3.00 D) with less than 1.00 D of astigmatism. The refractive error must be stable and the patient must be at least 21 years old.
In 1998, Joseph Colin from Brest University Hospital in France proposed intrastromal ring segments in keratoconic eyes. Since then, a large amount of work and published studies have investigated their use in keratoconus, forme fruste keratoconus, pellucid marginal degeneration and post-laser in situ keratomileusis (LASIK) ectasia. Mechanical and femtosecond laser-assisted implantation have demonstrated visual, refractive and topographic improvements; however, a higher incidence of intra-operative and post-operative complications has been reported with the mechanical procedure, according to evidence found in the peer-reviewed literature.
At present in the United Kingdom, the National Institute for Clinical Excellence (NICE) has concerns about the safety of the procedure for patients with refractive errors, which can be corrected by other means, such as spectacles, contact lenses or laser refractive surgery. Their guidance is that corneal implants should not be used for the treatment of refractive errors in the absence of other ocular pathology such as keratoconus.
Ferrara ring segments are similar to IntacsTM, however, they have a 1.5 mm radius of curvature instead of the 3.5 mm radius as with IntacsTM and they have a triangular anterior shape. It has been postulated that Ferrara ring segments might have a stronger effect on central corneal flattening in keratoconic eyes. The Ferrara ring tips lift anteriorly after implantation, which adds an extra flattening effect in the meridian opposite the implantation site.[84, 85]
One of the main disadvantages of intrastromal ring segments, as a refractive surgery alternative, is the limited refractive range of correction and predictability. Comparative studies with techniques such as LASIK have shown better predictability and quicker recovery with LASIK.
Excimer laser refractive surgery
Laser (light amplification by stimulated emission of radiation) is a method for emitting electromagnetic (EM) radiation via stimulated emission. Lasers were developed following initial work on microwave amplifying devices (masers). In 1960 Theodore Maiman developed the first laser following the earlier work of Schawlow and Townes. The emitted EM radiation is usually spatially coherent, monochromatic and of low-divergence, enabling it to be manipulated. This means that the emitted EM radiation is in waves of one wavelength, equal frequency and phase, which can be easily re-directed. The atom, the basic unit of matter, consists of a central nucleus, which contains positively charged protons and neutral neutrons. The nucleus of an atom is surrounded by negatively charged electrons bound to the atom via EM force. These electrons have both kinetic and potential energy due to their motion and electrostatic attraction to the nucleus, respectively. Each atom has a defined set of energy levels with electrons able to receive or lose discrete ‘packets’ of energy to move energy levels. When an electron receives the required energy, it is able to move further from the atom's nucleus, to a more distant excited state. When electrons return to a lower energy level, energy is released in the form of a photon of light. The frequency and hence the wavelength of this emitted photon of light can be calculated via Planck's equation, E = hf, where E is the known energy, h is Planck's constant (≈6.6 × 10-34 J·s) and f is the frequency. The wavelength, λ, of the emitted photon can then be calculated from the formula λ = c/f, where c is the speed of light (≈3 × 10 m/s). This process of electrons changing energy levels may occur in three differing situations: photo absorption, spontaneous emission and stimulated or induced emission. Stimulated emission is employed in the use of lasers, where a photon of exactly the correct amount of energy passes an excited atom forcing an electron to drop down energy levels and in the process emitting a photon with the same phase, wavelength, frequency and direction of the passing photon. The passing photon remains undisturbed and the emitted photon follows it in the same pattern, thus providing two identical photons.
Stimulated or induced emission rarely occurs as few atoms are in an excited state; they tend to remain in ground state with lower energies. Therefore, to achieve a situation with many excited atoms to evoke stimulated emission, a large quantity of energy is required within the laser medium. When a photon is released from an electron, dropping energy levels, it will induce stimulated emission in a neighbouring atom, which in turn will release an identical photon, which continues in a chain reaction. Laser systems also use internal mirrors, which reflect photons, which in turn induce further photon release. One of these mirrors is partially reflective, enabling a small percentage of photons to be released, hence forming a coherent and monochromatic laser beam. This allows photons in phase and of equal wavelength to arrive at the same position in the target tissue at one time.
The excimer laser, also known as the exciplex laser, is an ultraviolet (UV) laser, first described by Basov and colleagues in 1970. Excimer is short for ‘excited dimer’ and exciplex is short for ‘excited complex’. The excimer laser operates by combining an inert gas and a reactive gas. In 1981, the first reports of the use of excimer lasers with the eye emerged from Taboada, Mikesell and Reed from the Laser Effects branch of the Radiation Sciences Division, US Air Force School of Aerospace Medicine. This study involved the exposure of a rabbit cornea to a 248 nm krypton laser causing either opacification or de-epithelialisation to that area of the cornea. A subsequent study investigated the 193 nm argon fluoride laser; however, it was physical engineer and ophthalmologist, Stephen Trokel who developed the use of the excimer laser for refractive correction. Trokel collaborated with photochemist, Rangaswamy Srinivasan, who was working with the argon fluoride excimer lasers to etch microprocessors at IBM Thomas J Watson Laboratories. Srinivasan demonstrated that ablative photodecomposition of a human hair with the excimer laser could accurately remove organic tissue without collateral damage. Further collaborations with Ronald Krueger, an electrical engineer and a medical student at the time and John Marshall from the Institute of Ophthalmology in London, helped to investigate histopathological and ultrastructural features of corneal ablation (Figure 5).[93-95] These studies improved understanding of the nature of the effect of the excimer laser on the cornea, and initially it replaced the knife in radial keratotomy and astigmatic keratotomy. It was also used for trephination in keratoplasty and for the treatment of superficial corneal pathologies, in the form of phototherapeutic keratectomy (PTK).
In refractive surgery, the inert gas used is argon and the reactive gas is halogen fluorine, hence the common name of the argon-fluoride (ArF) excimer laser. Under high pressure in controlled conditions, argon partially ionises. Electrical stimulation of argon associated with fluorine, produces unstable compounds which rapidly dissociate and release photons (laser light) in the UV range at a wavelength of 193 nm. At this specific wavelength, the peptide bond linking collagen amino acids selectively absorbs the photons. Unlike cutting or burning tissue, the excimer laser disrupts the molecular bonds on the surface of the tissue, which disintegrate into the air in a very controlled manner via ablation. Hence, this gives the excimer laser an advantage, in that it can selectively remove fine amounts of tissue with virtually no thermal effect and no change in surrounding tissue. It is reassuring that the 193 nm ArF excimer laser has a low mutagenic potential due to absorption by the cytoplasm, which protects the DNA within the cell nucleus.[96, 97]
In 1985, optical engineer, Charles Munnerlyn with his colleagues, submitted a manuscript introducing photorefractive keratectomy (PRK), which was published in 1988. This article also introduced the relationship between the corneal tissue ablation and the size of the optical zone to the intended refractive correction. The formula is theoretical and assumes a spherical cornea and spherical ablation profile for myopic corrections.
The Munnerlyn approximated formula is as follows:
where OZ is the optical zone size in millimetres and D is refractive correction in dioptres.
Further work by Marshall and colleagues demonstrated clear corneal transparency in monkey corneas eight months following PRK. The first large area excimer laser ablation procedure on a human living eye was performed by Theo Seiler in Germany in 1985 to remove a corneal scar. Interest in the field grew rapidly and Marshall, Trokel and Seiler organised the first congress in Berlin, Germany, in 1986. Since then, laser technology has advanced, extending to correct all forms of ametropia accompanied by improved efficacy, predictability, safety and stability.
Since the advent of lasers, they have been closely associated with ophthalmology. In retinal photocoagulation, photons of light cause molecular vibration, which in turn increases the temperature of the tissue, causing vaporisation to protein denaturation. The neodymium:yttrium-aluminum-garnet (Nd:YAG) 1064 nm laser was introduced as the first non-thermal laser used in ophthalmology. It works by photodisruption, whereby at the point of focus of the laser beam it causes ionisation and is often used nowadays to perform capsulotomies in the case of posterior lens capsule opacification or iridotomies. More recent developments include diode lasers, semi-conductors, solid state technology and femtosecond lasers.
Excimer laser properties
The laser beam energy density is greatest and most constant in the central area of the beam with variable cold and hot spots, which become more of a problem with the degradation of the providing gases. Homogenisation consists of narrowing the emergent laser beam to maximise cross-sectional uniformity with the use of mirrors, lenses, prisms and diffuser plates. The beam homogenisation process constitutes a reduction in energy with smaller numbers of optical interferences resulting in less power loss. Following beam homogenisation, the laser beam is delivered by full beam, scanning slit delivery or flying spot. Full beam or broad delivery systems were used in first-generation laser platforms. An ablative mask or diaphragm was used and customisation was possible. Despite excellent smooth surface ablation, a higher frequency of central islands resulted, secondary to ablation plume. The main advantage was their speed of delivery.
Scanning slit systems involve the use of a diaphragm creating rectangular beams, which are capable of rotating in different directions. This improves homogeneity yet maintains a rapid delivery.
Flying spot systems use small circular spots of variable diameter with only the most homogenous central portion of the laser beam being used. A high frequency is used to maintain rapid delivery, with delivery being achieved with x- and y-axis pivoting mirrors. Each pulse removes a very small volume of tissue and hence many pulses are applied to ablate the cornea. The configuration of the location of the spots is important, as they need to be optimally spaced to avoid thermal effects. A Gaussian profile is usually employed in flying spot systems, where adjacent pulses are offset by half the diameter of the beam. This provides an even ablation rate with a regular ablation substrate. Most modern excimer laser systems are flying spot, enabling more complex treatments such as wavefront or topographically guided treatments.[103, 104]
Eye trackers are used to compensate for both involuntary and voluntary eye movements during surgery. Active systems will track the eye with the laser beam, re-adjusting its position depending on the position of the eye. Passive systems function when eye movements exceed a preset threshold, and in this case the ablation will automatically stop. Eye movements may be horizontally in the x–y plane, vertically in the z-plane or cyclo-torsional, which may occur in posture change from upright to supine or due to pre-existing cyclophoria or cyclotropia. The laser beam itself has a number of parameters, which are displayed and described in Table 1.
|Laser beam parameter||Description|
|Pulse frequency||High frequency induces thermal effects whereas low frequency results in slow delivery. A compromise is required and is usually between 10 and 400 Hz.|
|Pulse energy||Ranges between 10 and 250 mJ, with possible variations of up to 10 per cent between pulses, which may cause small refractive effects.|
|Pulse duration||Ranges between 10 and 20 ns. Short duration limits thermal effects.|
|Ablation rate||Ranges between 0.25 to 0.6 μm. Dehydration increases ablation rate which can impact the refractive correction by up to 15 per cent. The stroma ablates approximately 30 per cent more rapidly than Bowman's layer. Healthy stroma ablates quicker than scarred stromal tissue.|
|Fluence||The amount of laser energy per unit area. Ranges between 160 to 250 mJ/cm2. The photoablative threshold at the cornea is 50 mJ/cm2 and if the fluence is below this threshold, it will cause irregular and incomplete ablations. Above this threshold, each laser pulse will ablate a precise amount of corneal tissue with the amount of ablation increasing non-linearly up to approximately 600 mJ/cm2.|
The response of the cornea to the excimer laser is complex, with the main issue being the cellular interaction between the corneal epithelium and the underlying stroma. Hence, with more superficial ablations, there is a greater wound-healing response from the eye. Trauma to the epithelium causes the release of cytokines in the tear film, which gains access to the stroma. These pro-inflammatory cytokines induce keratocyte apoptosis. Further wound-healing inflammatory cells lead to further keratocyte necrosis. This will provoke healthy keratocyte migration and proliferation. Some of the healthy keratocytes will transform to myofibroblasts, which will manipulate the remodelling of corneal tissue. Myofibroblasts are reflective to illumination and are often seen as subepithelial haze shortly after surface refractive procedures.
The PRK procedure involves the removal of the corneal epithelium which is most commonly performed mechanically (for example, an Amolis brush) with prior application of 18–20 per cent alcohol to loosen the epithelium. After epithelial removal, the cornea is ablated with the excimer laser. Antibiotic and steroid drops are usually instilled following ablation, along with a bandage contact lens.
Photorefractive keratectomy has remained a popular procedure, as it avoids the production of a corneal flap and hence eliminates potential flap-related complications. Other reasons for its popularity include cases of thin corneas, epithelial dystrophies, recurrent erosions and dryness. PRK is typically indicated for low degrees of myopia and hyperopia. The long-term studies for low to moderate myopia indicate refractive stability at one year, which was maintained at 12 years.[104, 105] These studies demonstrated there were no significant hyperopic shifts, regression or fluctuation with 65–81 per cent of eyes achieving a refractive outcome within 1.00 D. Stability was observed between three and six months; however, this was longer for higher degrees of ametropia. These long-term studies have used standard laser treatment profiles and when comparing these results with those of more recent procedures, the technological advances in laser systems should be taken into consideration. In terms of hyperopia, a recent study by Leccisotti in Italy compared hyperopic PRK with and without mitomycin C. The study found that mitomycin C prevented haze formation and improved predictability and efficacy.
Laser in situ keratomileusis
In 1989, Ioannis Pallikaris from the University of Crete, Greece was the first to perform LASIK on a blind eye with human studies beginning in 1990.[108, 109] The concept evolved from a patent filed by Gholam Peyman describing the use of the excimer laser to sculpt the corneal stroma on the back surface of the corneal flap. Two ophthalmologists, Razhev and Chebotaev from the Novosibirsk Institute in Siberia were the first to perform an excimer laser ablation on the stromal bed beneath a hand-cut flap and the use of a home-made excimer laser. Lucio Buratto from Milan, Italy created a free cap using a microkeratome and performed laser ablation on the underside of the stromal cap. George Waring and colleagues in Jeddah, Saudi Arabia and Stephen Brint in New Orleans, USA also attempted this approach by Buratto; however, Pallikaris deserves the credit for providing the LASIK procedure as it is known today with the use of a guarded microkeratome, hinged flap and stromal ablation. The Pallikaris group in Crete published their early experiences with LASIK in 1994, indicating excellent predictability and stability. LASIK has since become the most commonly performed laser refractive procedure around the world owing mainly to its predictability, speed of recovery and an absence of pain. It is routinely performed for refractive errors in the range of myopia up to -10.00 D, hyperopia up to +5.00 D and astigmatism up to 4.00 D.
The LASIK procedure consists of two main parts: the creation of a corneal flap followed by excimer laser ablation to the stromal bed. The flap creation is made with either a mechanical microkeratome or a femtosecond laser. Femtosecond lasers (wavelength of 1,053 nm) have a variety of theoretical advantages over mechanical microkeratomes, such as the reduced risk of intra-operative flap complications. Flap creation with a mechanical microkeratome can increase intraocular pressure in excess of 60 mmHg, whereas the femtosecond laser can create the corneal flap with much lower intraocular pressure increases, which reduces the risk of optic nerve head damage and ischaemia; however, the femtosecond laser procedure is of longer duration and some studies have suggested a higher incidence of diffuse lamellar keratitis along with other complications.
Long-term results for LASIK appear promising in terms of visual and refractive outcomes. Alió and colleagues recently published 10-year results of LASIK for myopia up to -10.00 D. Seventy-three per cent of eyes were within 1.00 D and 92 per cent within 2.00 D. A mean myopic regression of -0.12 D ± 0.16 per year was noted. Fifty-three per cent of patients demonstrated an increase in visual acuity (VA) and 35 per cent demonstrated no change. Further advances in LASIK continue with the introduction of thin flap techniques known as sub-Bowman keratomileusis (SBK) and inverted side cuts with femtosecond laser to reduce loss of corneal biomechanical strength which occurs with thick-flap LASIK.[114, 115]
Laser epithelial keratomileusis (LASEK)
LASEK can be described as a variant of PRK. Instead of the complete removal of the corneal epithelium as performed with PRK, a dilute alcohol solution is used to loosen the epithelial adhesions with the underlying stroma. Then the loosened epithelium can be brushed to the side and laser ablation is applied to the exposed stroma. The corneal epithelium is then repositioned. The first procedure was performed in 1996 by Azar and colleagues in the Massachusetts Eye and Ear Infirmary, Boston, USA. Camellin coined the term LASEK for laser epithelial keratomileusis, with alternative expressions, including laser subepithelial keratomileusis, subepithelial photorefractive keratectomy,[117, 118] epithelial flap photorefractive keratectomy, laser-assisted subepithelial keratectomy, excimer laser subepithelial ablation, epithelial laser in situ keratomileusis (epi-LASIK) and advanced surface laser ablation (ASLA).
Excellent visual and refractive results have been found with LASEK for myopia.[122, 123] In comparison to PRK, a recent meta-analysis found no clinical differences between the two procedures. In comparison to LASIK, marginally better visual and refractive results are found for LASEK in low myopic corrections. The mean logMAR uncorrected vision was 0.01 ± 0.08 and 0.06 ± 0.12 for the LASEK and LASIK groups, respectively. The mean post-operative spherical equivalent was -0.15 ± 0.40 D and -0.37 ± 0.45 D for the LASEK and LASIK groups, respectively, with no eyes losing two or more lines of VA in either the LASEK or LASIK groups.
There have been few published studies on the outcomes of LASEK for the treatment of hyperopia. O'Brart and colleagues investigated LASEK for the correction of hyperopia up to +5.00 D. This study used non-cycloplegic refractive techniques to determine the subjective refraction and did not use mitomycin C during LASEK procedures. They found that hyperopic LASEK provides excellent refractive and visual outcomes with minimal complications. At 12 months, the mean refractive error was +0.09 D with 100 and 86 per cent of eyes within 1.00 D and 0.50 D of emmetropia, respectively. Forty-seven per cent of eyes gained an improvement in VA, 43 per cent had no change and 10 per cent lost one line. McAlinden and Moore investigated hyperopic treatments up to +4.50 D with mitomycin C finding excellent results with a mean one-year post-operative spherical equivalent of 0.03 D.
Epithelial laser in situ keratomileusis
Epi-LASIK is a more recent refractive surgical procedure, developed by Pallikaris and colleagues from the University of Crete, Greece in 2002. PRK is associated with post-operative pain and corneal haze. LASIK overcame these complications but introduced its own, in the form of flap-related complications and ectasia. These disadvantages led to the development of LASEK. However, LASEK has its own disadvantages similar to PRK, such as slower visual recovery, post-operative pain and the risk of haze. Hence epi-LASIK was developed to separate the epithelial flap without the use of alcohol with the aim of maintaining a viable flap and providing faster recovery and less haze.
The procedure involves the use of an epikeratome with a blunt plastic blade, mechanically separating an epithelial sheet above Bowman's layer but below the basement membrane, which is followed by photoablation. The epithelial flap may be returned or discarded. The procedure theoretically avoids flap complications, which may be encountered with mechanical microkeratomes and avoids alcohol-related cellular changes (Figure 6).
Studies have reported good visual and refractive outcomes with this procedure[129-131] but similar to LASEK. In a comparative study between epi-LASIK, LASEK and PRK for myopia, results indicated that significantly less pain was experienced with epi-LASIK in the first few hours after surgery but at four hours all patients had the same levels of pain, which improved to minimal or no pain at 24 hours. No significant differences were noted among groups for vision, refractive error and haze; however, this study did report a high rate of flap failure (33 per cent), which was subsequently converted to PRK. Torres and colleagues found epi-LASIK and PRK induce similar pain on post-operative day one but epi-LASIK demonstrated statistically more pain than PRK on days three and six. Studies comparing on- and off-flap epi-LASIK have generally found the off-flap method provides faster visual recovery and less post-operative pain than the on-flap method,[135, 136] whereas other studies found no differences. Further research into the role of the epithelium will hopefully address these issues. Overall, the published results indicate that epi-LASIK is a potentially good alternative surface ablation procedure but further research is required, along with addressing the high rate of flap creation failure and the added expense over PRK or LASEK.
Thermal procedures involve the delivery of thermal energy to the peripheral cornea, which causes collagen shrinkage, hence increasing central corneal curvature and power. Radial intrastromal thermokeratoplasty was developed by Fyodorov in 1981 in the former Soviet Union and worked similar to radial keratotomy only with the use of a thermal probe tip rather than incisions. This technique was effective in the initial correction of hyperopia but poor predictability and regression were frequent problems.[138-141] Similar procedures, such as laser thermokeratoplasty have been applied using solid-state infrared lasers, such as the holmium:YAG laser in the treatment of hyperopia and diode lasers: diode laser thermal keratoplasty.[142, 143] Conductive keratoplasty is a more recent technique which was originally conceived as an alternative to thermokeratoplasty by Antiono Mendez. It is a non-ablative technique which uses radiofrequency energy applied to the stroma with a probe tip. It has been approved by the American Food and Drugs Administration for the treatment of hyperopia and presbyopia. The probe is inserted at a number of points in the periphery of the cornea in a circular pattern, usually six to eight millimetres in diameter. Following the procedure, stromal tissue remodels forming a scar in the peripheral location of the probe entry point. More recently, the technique has gained interest in the treatment of keratoconus.[144-148]
From the first suggestion of refractive correction by Hermann Boerhaave in 1708, corneal refractive surgery has come a long way. Tsutomu Sato introduced RK and José Barraquer pioneered keratomileusis with further major breakthroughs in the 1980s with the introduction of the excimer laser for PRK and then for LASIK. This saw a rapid increase in the use of the excimer laser over incisional radial keratotomy and it now dominates refractive surgery. Many remarkable technological advances make this field one of the most rapidly developing in health care. Further advances in recent years have provided improved clinical outcomes with improved surgical procedures, such as LASEK, the use of femtosecond lasers, thin flap LASIK (sub-Bowman's keratomileusis), improved laser delivery systems, improved eye trackers, wavefront-guided and topography-guided lasers. These remarkable advances coupled with improved visual outcomes, refractive predictability and fewer complications, have given rise to laser refractive surgery becoming an acceptable alternative to spectacles and contact lenses.
Grants and Financial Assistance
Part funding was provided by the Department for Employment and Learning (DEL), Belfast, Northern Ireland, UK.