Principles of photodisruption

Outline

Laser-tissue interactions Photodisruption

Laser principles

optical breakdown and plasma formation mechanisms of damage

Instrumentation Clinical applications

posterior capsulotomy

iridectomy and other anterior segment applications

posterior segment New laser techniques

Conclusions and future developments

Laser-tissue interactions

The effect of laser radiation on a particular target depends on the properties of both the laser and the target. The most important laser output parameters are wavelength, duration, and power. Wavelength is a function of the laser cavity’s excited medium, which is a gas in argon, krypton, and excimer lasers, a liquid in dye lasers, a semiconductor in diode lasers, and a solid state material in the neodymium:yttrium aluminum garnet (Nd:YAG) and other lasers that will be examined in greater depth in this chapter. According to the principle of wave-particle duality, radiation is propagated in the form of both waves and discrete quanta, or photons. As such, radiation of a given wavelength is associated with photons of a corresponding energy, such that E = hν = hc/λ, where h = Planck’s constant, ν = frequency, c = speed of light, and λ = wavelength. Thus, frequency and energy increase as

wavelength decreases. The visible spectrum extends approximately from 380-760 nm. The first law of photochemistry (Grotthus-Draper) states that photons must be absorbed by a target in order to initiate a chemical reaction.1 A chromophore is a molecule, or a portion thereof, that absorbs a photon of a particular energy. Depending on the photon’s energy, a chromophore can undergo bond-breaking, ionization, or various types of molecular excitation.

The ability of a target, which may or may not be of a homogeneous composition, to absorb radiation is measured by the attenuation in incident radiation after a certain length of the material has been traversed. The absorbence, A, of a material is defined as A(d) = log[I0/I(d)] = εcd, where I0 = initial intensity, I(d) = intensity at distance d, ε = absorptivity of the material, and c = molarity of the material. Transmission is that fraction of the incident energy that is not absorbed after traversing a particular target thickness. It is usually written in the form of Beer’s law, T(d) = 10-A(d) = e-αd, where αd = 2.3A defines the absorption coefficient α. α is generally given in units of cm-1 and represents the fraction of incident energy that is absorbed per unit length of target material. Absorption length is defined as α-1, or that distance at which e-1 = 0.368 of incident energy is transmitted, corresponding to 63.2% absorption. The thermal susceptibility of the irradiated tissue is denoted by the thermal relaxation time, τ, which gives an indication of the time required for the irradiated tissue to carry away heat energy from the target site. It is wavelengthdependent, and is proportional to 1/4α2κ, where κ measures the tissue diffusivity in cm2/sec.

The absorption maximum of a compound is that wavelength in a given portion of the spectrum which has the highest probability of absorption. A plot of

absorption versus wavelength yields an absorption spectrum that is characteristic of the chemical composition of that compound. Quantum yield is a measure of the efficiency with which absorbed radiation produces chemical changes, while an action spectrum is a plot of the relative efficiency of the photoreaction versus wavelength.

Photodisruption

Photodisruption is the use of high peak-power ionizing laser pulses to disrupt tissue. Energy is concentrated in space and time to create optical breakdown, or ionization of the target medium, with formation of a plasma, seen as a spark. The use of optical radiation to produce a plasma became possible only after the development of lasers capable of emitting high power through very brief radiation pulses. Although the first lasers were too weak to achieve optical breakdown, in 1962 Hellwarth developed the method of Q-switch- ing, which allowed the creation of very brief but large ruby laser pulses over 10-50 nanoseconds (nsec, 10-9 sec), with maximum powers in the tens of megawatts.2

In 1972, Krasnov reported the first use of clinically desirable intraocular photodisruption, treating the trabecular meshwork of eyes with open-angle glaucoma.3 To emphasize the relative importance of nonthermal acoustic mechanisms in creating these tissue effects, he used the term ‘cold laser’, which ignores the fact that plasma formation causes very localized temperature increases greater than 10,000EC. Further work demonstrated that, because of the ruby laser’s high-order mode structure (which limits the minimal spot size that can be achieved) it is not the ideal source for a clinically practical ophthalmic photodisruptor. Although by 1979 Gaasterland succeeded in building a Q-switched ruby laser capable of membranectomy, the required energy and waiting time between laser shots were too great to make this technique clinically useful. However, the increasing popularity of extracapsular cataract extraction (ECCE) and the pioneering research of Aron-Rosa et al.4 and Fankhauser et al.5 in the early 1980s with Nd:YAG lasers, soon combined to make laser photodisruption a reality.

Laser principles

Laser power can be increased by either increasing energy or, more practically, by decreasing the period over which the energy is delivered. The two principal means of compressing the laser output in time to achieve high-peak power are mode-locking and Q-switching. Mode-locking is comparable to the audible summation of musical tones with similar frequencies, known as beating, which is heard as a periodic surge in intensity. The phase relationships in lasers are synchronized by a shutter near one of the cavity mirrors. For ophthalmic applications, the most common shutter is a saturable dye, employed in a proc-

ess known as passive mode-locking. The dye absorbs low-power radiation pulses, but becomes transparent on exposure to high-power ones.

The Q-switch is an intracavity shutter which requires an active medium that allows atoms to remain in the high-energy state for a relatively long time to create high-peak power. Solid state media such as Nd:YAG are particularly well-suited for this process. At the appropriate time, the Q-switch shutter is opened, exposing the mirror. Oscillation and stimulated emission follow quickly, with emission of a single brief high-power pulse. Methods of Q-switching include saturable dyes, rotating mirrors, and acoustooptic modulators. Pockel’s cell, an electro-optic modulator that is the most common Q-switch, applies voltage across a crystal to vary polarization. Polarity can be rapidly changed by 90E, making the cell either opaque or transparent to the polarized laser beam. The ‘Q’refers to the quality factor of the laser cavity, which is defined as the energy stored in the cavity divided by the energy lost per cycle. Rapid extraction of high power is accomplished as the Q-switch changes the quality factor of the cavity from a high to a low Q.

Whereas typical mode-locked laser output consists of a train of seven to ten 25-picosecond (psec, 10-12 sec) pulses, at intervals of 5 nsec and contained within a 35-50 nsec envelope, Q-switched laser output generally consists of a single 2-30 nsec pulse. The total energy required for a single Q-switched pulse and a train of mode-locked pulses is the same, but the peak power necessary to cause avalanche ionization must be 100-1000 times greater for mode-locked than Q- switched lasers.6,7 Maximum outputs of most ophthalmic models are approximately 10-30 mJ and 5 mJ for Q-switched and mode-locked lasers, respectively, but because of the greater control and relative safety of the Q-switch, those models employing mode-lock- ing have largely fallen out of favor.

Optical breakdown and plasma formation

When a target is heated by absorbing radiant energy, the effect is linearly proportional to the cause. In contrast, nonlinear effects are sudden all-or-nothing phenomena. Optical breakdown, a nonlinear reaction, occurs when the laser output is sufficiently condensed spatially and temporally to achieve high irradiance. It is manifested by a spark and accompanied by an audible snap, producing dramatic target damage. When focused to a small spot, typically less than 50 m in diameter, short-pulsed Nd:YAG lasers can produce enough irradiance, usually 1010-1011 W/cm2, to induce optical breakdown, dissociating electrons from their atoms and creating a plasma. Q-switched pulses cause ionization mainly by focal target heating, in a process called thermionic emission, whereas modelocked ones rely primarily on multiphoton absorption.8 In either case, once the initial free electrons have been generated, plasma expands via electron avalanche or cascade if the irradiance is adequate to cause rapid ionization. Plasma absorbs and scatters incident

radiation, thereby shielding underlying structures. Plasma radiation absorption and growth both occur through inverse bremsstrahlung, the process of photon absorption and electron acceleration in the presence of an atom or ion.

Mechanisms of damage

In biological systems, thermal denaturation of protein and nucleic acids is theoretically confined to a radius of 0.1 mm for a 1 mJ pulse.9 As such, although high local temperatures exist briefly, total heat energy is low, and significant clinical photocoagulation does not occur.

Several mechanisms combine to generate pressure waves radiating from the zone of optical breakdown, the foremost of which is the rapid plasma expansion that begins as a hypersonic wave.10,11 A secondary source of hypersonic and sonic waves is stimulated Brillouin scattering, in which the laser light generates the pressure wave that scatters it.12 The focal heating may lead to vaporization, melting, and thermal expansion, generating acoustic waves.13 If sufficiently strong, the radiation’s electric field will deform a target through electrostriction, which causes simple Brillouin scattering, and radiation pressure induced by momentum transfer from photons to atoms in inverse bremsstrahlung.

The shock wave begins immediately with plasma formation, and expands at a hypersonic velocity of 4 km/sec, falling to sonic velocity within 200 m. The acoustic transient lasts 50 nsec at a distance of 300 m from the focal point, while the pressure falls from 1000 to 100 atm within 1 mm.14 The next process is cavitation, or vapor bubble formation. This be-

gins within 50-150 nsec after breakdown in water, expands rapidly for the first 20 sec, reaches a maximum size of approximately 0.6 mm at 300 sec, and

collapses within 300-650 sec.10,11 Cavity propagation velocity is about 20 m/sec at 300 m from the breakdown.15 Many shock waves may be generated along the laser beam’s path as impurities are encountered.16 Damage zone size depends on the irradiance and total energy, the plasma’s duration, and the mechanical properties (including density, mass, tensile strength, and elasticity) of the target tissue.17-20

For many years, most cataract operations have included the insertion of intraocular lenses (IOLs), which were mostly made initially of glass, then polymethylmethacrylate (PMMA), and most recently are typically composed of silicone or other foldable materials. These lenses can affect the intraocular use of lasers, especially for posterior capsulotomy (see below) where occasional damage takes different forms characteristic of the IOL material.21 Such damage is typically more significant for rigid IOLs, which can develop microcracks, melted voids, and large pulverized regions. Unlike the situation in liquids, optical breakdown in rigid lenses may be associated with selffocusing and self-trapping with both nsec and psec pulses.22 The damage threshold for glass is approxi-

mately 100 times greater than that for PMMA, but once glass damage occurs, it tends to be more extensive.23 As damage tends to be cumulative, IOLs may be harmed more by bursts of laser shots than by single pulses. Various rigid IOL designs, including the use of spacers to increase the separation between the IOL and the posterior lens capsule, have been created in the attempt to minimize damage from photodisruption.

The threshold for retinal laser injury is inversely proportional to the laser’s wavelength and pulse duration and directly proportional to spot size.24 Since clinical applications of Nd:YAG photodisruption involve energies significantly above retinal damage thresholds, it is important to consider how the retina is protected during these laser procedures. Beam divergence, i.e., the angle formed by the cone of light converging on and diverging from the laser system’s focal point, is the most important element in retinal protection. The border of the laser beam is described as either the 1/e or 1/e2 points of the solid angle. Commercial ophthalmic Nd:YAG lasers usually broaden the laser beam with an inverse galilean telescope and then employ a large-diameter, high-power final focusing lens to achieve the desired combination of cone angle, minimal spot size, and comfortable working distance. As such, for retinal injury to occur during Nd:YAG laser posterior capsulotomy, 96 mJ, some 20 times the energy clinically used, would have to be incident on the cornea.

Plasma formation is a secondary factor in retinal protection during photodisruption in the pupillary plane. It absorbs and scatters incident radiation, thereby diminishing the transmission of radiant energy along the beam path. Plasma shielding assumes a more important role in retinal protection during vitreous photodisruption. Nevertheless, the pressure waves still propagate unattenuated, and may cause retinal or choroidal damage even in the absence of suprathreshold radiation levels.

Instrumentation

Although photodisruption is possible with other lasers and at other wavelengths, including some Nd:YAG harmonics, the fundamental Nd:YAG output at 1064 nm is virtually the only one used in commercial ophthalmic photodisruptors (Fig. 1). Most clinical Nd:YAG lasers employ the fundamental TEM00 mode, so that the spot size, and consequently the energy required for optical breakdown, can be minimized. Beam divergence is generally 0.5-3.0 mrad. The lasers are cooled by ambient air or internally recirculated water, and require only standard 110 V outlets. Whereas 5 mJ is sufficient for most applications, many ophthalmic Q-switched Nd:YAG lasers are capable of producing up to 30 mJ. Higher energies may be needed to cut very dense material and in cases of hazy media, such as corneal edema or blood in the anterior chamber.

Fig. 1. YC-1600 portable Nd:YAG laser. (Reproduced by courtesy of Nidek, Inc., Fremont, CA.)

An aiming beam is required to guide the pulsed, invisible Nd:YAG output. This is achieved with a continuous wave helium:neon (He:Ne) laser that produces 632.8 nm output coaxial with the Nd:YAG’s and below the retinal injury threshold. Since high-peak power pulses cannot be satisfactorily transmitted via fiberoptics, ophthalmic Nd:YAG lasers employ fixed mirrors to guide the output to the patient, who is generally seated opposite the surgeon at a specially configured slit-lamp biomicroscope. The larger the solid cone angle, the lower the energy required for optical breakdown and the risk of IOL or retinal damage, but the greater the chances of beam vignetting during some applications. The slit-lamp design limits the angle to approximately 20°, and most systems employ one of 16E. A ‘heads-up’ feature, available on most current Nd:YAG laser systems, displays important information about treatment parameters.

While contact lenses are generally not required for simple posterior capsulotomy, they may be helpful to stabilize the eye, prevent blinking, and maintain a regular optical surface. A suitable lens may have a radius of curvature similar to the cornea’s (8-12 mm), with an additional central high plus power button lens to enhance beam convergence and magnify the surgeon’s view (e.g., the central Abraham lens with a 66D button, Fig. 2A). However, such lenses also provide a smaller field of view through the button lens and limit illumination.

A peripheral Abraham button lens (Fig. 2B) is helpful for peripheral iridectomy, since it enhances visualization and control of the photodisruption. Standard mirror lenses such as the Goldmann three-mirror contact lens can be used for gonioscopy treatments, although pupillary treatment with the planosurface would eliminate the beam convergence of the cornea and hence risk retinal injury. Moreover, improperly

focused high-irradiance pulses can damage the mirrors. Special Nd:YAG gonioscopic lenses are now available that enable better angle visualization and treatment within a short working distance (Fig. 2C). Compact laser contact lenses with anterior curvatures ranging from flatter than the cornea to planoanterior are used for midand deep-vitreous work (Fig. 2D).

Clinical applications

Posterior capsulotomy

Cataract surgery has largely changed from intracapsular cataract extraction (ICCE), in which the entire lens capsule is removed together with the opaque lens, to extracapsular cataract extraction (ECCE) and phacoemulsification, in which the posterior lens capsule is left in place. This serves to both reduce the incidence of postoperative vitreoretinal complications, such as cystoid macular edema (CME), and to provide support for posterior chamber IOLs. Unfortunately, this membrane often also opacifies over a period of months to years, diminishing the improved vision afforded by removal of the primary cataract.25

Several factors may contribute to optical compromise of initially clear posterior lens capsules. In the early postoperative period, fibrosis can manifest as a gray-white band or plaque-like opacity. Months to years following surgery, opacity may be caused by migration of epithelial cells with formation of small Elschnig’s pearls and bladder cells. Capsular wrinkling can develop as either broad undulations or fine wrinkles. It has been suggested that secondary cataract formation is somewhat less with silicone than with PMMA IOLs,26 although whether this is due to differences in the IOL material or the initial surgical technique remains to be determined. Until the advent of photodisruption, an opacified posterior lens capsule was ruptured by introducing a needle into the eye with the patient seated at the slit-lamp, with all the attendant risks of any invasive procedure. The Nd:YAG laser has proven so successful at sectioning these membranes that it has completely replaced traditional surgical discission.

Posterior capsulotomy is associated with a high degree of visual improvement, but is not without occasional complications. These may include IOL marking, retinal detachment, rupture of the anterior hyaloid face, and bleeding from diabetic rubeosis iridis and neovascular glaucoma in diabetics. The heparin coating with which many IOLs are now made may also be compromised.27 However, by far the most commonly encountered difficulty is a transient rise in intraocular pressure (IOP),28 probably caused by impaired aqueous outflow resulting from capsular debris, acute inflammatory cells, and high-molecular- weight proteins.29

In an early study on the safety and efficacy of Nd:YAG laser posterior capsulotomy, Keates and as-

months following laser capsulotomy. Only three patients had at least 3D of myopia, and all eight were treated with scleral buckle. That three patients’ detachments developed more than a year after laser treatment implies that the laser did not directly cause the detachments and highlights the need for long-term follow-up. Seven patients (0.8%) developed new, persistent glaucoma following laser capsulotomy. Mean IOP was 18.7 mmHg before ECCE and 19.6 mmHg before capsulotomy, but reached a mean maximum of 25 mmHg during the first post-laser week. Mean IOP at six months was 22.3 mmHg on medication, and at an average last follow-up of 28.3 months it was 20.4 mmHg. Laser trabeculectomy was necessary in one patient. A posterior chamber IOL may be associated with a lower incidence of transient IOP rise, but does not necessarily protect against persistent IOP elevation.

All prospective laser capsulotomy patients require a thorough medical and ophthalmological history and physical. Direct ophthalmoscopy is the most reliable technique for assessing capsular opacity. While secondary cataracts can substantially diminish vision, their removal does not guarantee normal vision. Especially in older patients, concomitant ocular pathology (such as macular degeneration or CME) may impair vision even after capsulotomy. The laser interferometer and potential acuity meter can penetrate mild to moderate capsular opacity and assess macular function. In cases where decreased visual acuity is disproportionate to capsular opacity, a useless or even deleterious procedure may be avoided.

Dilatation facilitates laser capsulotomy, but may be omitted in the absence of a miotic pupil. Before dilatation, it may be useful to place a marker shot, to aid subsequent identification of the true visual axis. To prevent iris capture of a posterior chamber IOL, a single drop of 2.5% phenylephrine, together with a drop of 0.5-1% tropicamide if necessary, is advisable. Topical anesthesia is usually required only when using a contact lens. A retrobulbar injection may be needed for akinesia in rare cases such as patients with nystagmus.

In most instances, a posterior capsule can be opened with minimal pulse energies of 1-2 mJ from the Nd:YAG laser. Shots are placed along tension lines, as indicated by capsular wrinkles, to create the most efficient opening. Except in patients at high risk for retinal detachment or others in whom a smaller capsulotomy opening may be safer, the opening should be as large as the pupil in ambient light. Figure 3 shows a posterior capsulotomy behind a posterior chamber IOL. Several steps can be employed to minimize IOL damage, including using the lowest possible energy settings, stabilizing the eye with a contact lens, beginning treatment in areas of capsule-IOL separation, and in some cases focusing in the anterior vitreous and allowing the anterior radiation of the shockwave to rupture the capsule. Some surgeons have reported displacement of foldable IOLs into the vitreous following capsulotomy.34 In aphakic patients, focusing

Fig. 3. Secondary cataract after Nd:YAG laser capsulotomy. The IOL edge and haptic are visible. (Reproduced by courtesy of Roger Steinert, MD.)

anterior to the capsule may help preserve the anterior hyaloid membrane.

Post-laser pharmacotherapy varies widely, but typical practice includes the use of a topical steroid (e.g., prednisolone acetate 1% or dexamethasone 0.1%) and a pressure-reducing medication (e.g., β-blocker or apraclonidine) immediately following treatment. Patients with an increase of at least 5 mmHg above baseline IOP or those with pre-existing glaucoma require more aggressive prophylaxis and frequent IOP checks. However, prophylactic treatment (e.g., 1% apraclonidine35 or 0.5% levobunolol36) prior to laser capsulotomy offers the best insurance against IOP spikes. Pre-laser oral (acetazolamide) and topical (2% dorzolamide) carbonic anhydrase inhibitors have been shown to provide comparable prophylaxis.37

Fankhauser and associates5 were the first to use the Q-switched Nd:YAG laser to cut pupillary membranes. Though less common than posterior capsulotomy, membranectomy can optically clear the pupil in eyes with significant pathology that are poor candidates for surgery or would otherwise require major operations. In contrast to posterior capsules, membranes have little or no elastic properties and may have to be chipped away at the edges with pulses of 4-12 mJ. Dense membranes may need multiple treatment sessions.

Iridectomy and other anterior segment applications

Argon laser iridectomy has largely supplanted the traditional surgical approach, but there remain many instances in which its use is problematic. The argon laser relies on coagulation, vaporization, and necrosis to cut through tissue, and light blue or gray irises may not absorb sufficient energy. Conversely, the strong absorption by dark brown irises may generate a char that impedes further penetration. Since photodisruption does not depend on target pigmentation, the short-pulsed Nd:YAG laser represents an attractive alternative for creating iridectomies. This was verified in clinical studies, which demonstrated that the Q-switched Nd:YAG laser can create openings in the

iris that, unlike some openings created with the argon laser, do not gradually close.38

The Fankhauser group5 performed the first Q- switched Nd:YAG laser iridectomy. Some phakic patients experienced opacification for 1-2 mm in the underlying anterior lens capsule, but this response was transient, and there was no cataract formation. Aside from small self-limited hemorrhages that are occasionally encountered with the Nd:YAG laser,39 complications with that laser are usually of equal or less severity than with the argon laser. However, as with all photodisruption procedures, the Nd:YAG would be unable to coagulate any significant bleeding that might occur. Unlike cutting through the iris sphincter, where hemorrhage is expected, peripheral iridectomy seldom causes bleeding. Full-thickness iridectomy is achieved more quickly B usually with just a single shot B and reliably with the Nd:YAG laser than with the argon laser. Both lasers are associated with a small IOP rise that resolves within several hours. Nd:YAG laser iridectomy has proved effective in cases in which the argon laser has failed,40 while use of the two lasers together on dark irises may allow less energy to be employed than with either laser alone.41,42

To facilitate laser iridectomy, the iris is drawn taught by instilling miotic drops, such as pilocarpine 4%. Following administration of topical anesthetic, an Abraham lens with a peripheral 66D button lens is applied. Treating the basal iris is safest as it is not directly apposed to the crystalline lens. Penetration is facilitated and bleeding avoided by targeting a thin area, such as a crypt. Openings are often achieved with a laser energy of 4-8 mJ; although a single shot is desirable, up to four are often needed. A burst setting of more than several pulses risks injury to the underlying crystalline lens capsule. With the proper technique, the loss of corneal endothelial cells overlying the treatment site can be minimized.43 Strong topical steroids four times a day are begun immediately following the laser iridectomy. If significant inflammation or bleeding is present and the iridectomy is definitely patent, intermittent short-term dilatation may help prevent synechia formation.

Corneal edema and haze, anterior chamber reaction, and iris congestion may make argon laser iridectomy impossible in aphakic and pseudophakic patients with acute angle-closure glaucoma. Photodisruption with the Nd:YAG laser is the treatment of choice, even in instances in which the argon laser can penetrate the iris. The Nd:YAG laser’s success in creating an ‘anterior hyaloidectomy’ to cure malignant (ciliovitreal block) glaucoma demonstrates the pathophysiological role of the anterior hyaloid face.44 To ensure the long-term patency of at least one iridectomy as the iris bombé is relieved, at least three iridectomies should be made. The laser is then aimed at the anterior vitreous through the iridectomy or pupil. Cycloplegia, mydriasis, and intensive topical steroid treatment is then begun.

The Q-switched Nd:YAG laser is useful in

coreoplasty, although rarely in phakic patients. Treatment is generally begun in the peripheral iris stroma, with numerous 6-10 mJ shots progressing toward the sphincter and pupil (and hence likely causing hemorrhage) only at the end of the treatment session. Additional anterior segment applications of Nd:YAG laser photodisruption include severing of retained anterior capsule tags following ECCE, creating corneal stromal puncture in cases of refractory traumatic recurrent erosion,45 zonulysis of subluxated crystalline lenses (e.g., in individuals with Marfan’s syndrome),46 synechialysis (especially in relatively unpigmented tissue that would not be amenable to therapy with the argon laser), and anterior vitreolysis in patients with CME and Irvine-Gass syndrome.47,48

Posterior segment

While technically more demanding and potentially more dangerous, Nd:YAG laser photodisruption may also be applicable to pathology in the posterior segment. Relatively avascular vitreous membranes associated with significant retinal traction can be cut with this laser.49,50 Experimental vitreous membranes in rabbits have been successfully sectioned with 4 mJ pulses as close as 4 mm to the retina, without retinal injury.51 Since these membranes may be complex and fibrous, hundreds or thousands of pulses, often in multiple sessions, may be necessary. Nd:YAG laser photodisruption of the anterior surface of preretinal hemorrhages has allowed absorption of blood into the vitreous.52 Aside from the risk of retinal or choroidal hemorrhage, which rises exponentially with proximity to the retina, a lens (crystalline or IOL) may also be damaged if work is performed too close to its posterior surface. However, despite initial concern that photodisruption of the posterior lens capsule or vitreous may cause liquefaction and other vitreous disturbance, Krauss et al.53 employed MRI and other techniques to demonstrate that this process does not significantly affect the structural integrity of the normal vitreous body.

New laser techniques

The Q-switched Nd:YAG laser is the quintessential ophthalmic photodisruption laser. However, there are several other photodisruption lasers that have been used in the lab or clinically whose mechanisms of tissue interaction are less consistently described. Such nebulous terminology may be a matter of semantics, but it does have some basis in biophysics. While the argon and other lasers with msec or longer output have almost exclusively thermal (photocoagulation) effects, the ultrashort-pulsed Nd:YAG laser with nsec or shorter output has mechanical (photodisruption) effects, and the excimer laser (which also has nsec output) vaporizes tissue via ablation, there are other lasers with intermediate or variable pulse durations and unique properties whose efficacy may indeed be based

on a combination of mechanisms. Two lasers in the last category are the erbium:yttrium aluminum garnet (Er:YAG) and neodymium:yttrium lithium fluoride (Nd:YLF). The Er:YAG laser at 2.94 µm and output in the µsec range has been tested on virtually every portion of the eye. Although it is sometimes described as causing photodisruption, the Er:YAG is more commonly said to effect ablation. Its various applications B most notably vitreolysis and ‘photophacoablation’ of cataractous lenses B are described elsewhere in this volume. The Nd:YLF laser, with primary emission at 1053 nm and pulses ranging from psec to fsec, has similarly been said to cause ablation, but its interaction with tissue is more accurately described as photodisruption, and hence this laser will be considered here.

While the ArF excimer laser at 193 nm remains the paramount refractive laser, researchers continue to examine other lasers that may offer certain clinical or technical advantages. One early focus of such work was intrastromal treatment, since before widespread adoption of LASIK, excimer laser photorefractive surgery necessarily involved removal of the epithelium and obliteration of Bowman’s membrane. Since there is rapidly increasing corneal transmission beginning at about 300 nm, ultra-short-pulsed lasers with emission between approximately 400 and 1500 nm would be able to non-invasively cause photodisruption at any specifically targeted corneal level, rather than relying on absorption by corneal chromophores.54 Indeed, Nd:YAG laser photodisruption with nsec pulses can create intrastromal vacuoles, albeit on a scale of negligible clinical value.55 Although Nd:YAG laser psec pulses have an optical breakdown threshold of only about 20 J and appear to cause correspondingly less shockwave emission and cavitation bubble expansion than nsec pulses do,56,57 they are still incapable of equalling the precision of the excimer laser.58

The Nd:YLF is another solid state laser that has been investigated for a variety of ophthalmic applications. Nd:YLF has a larger fluorescence bandwidth than does Nd:YAG and hence can produce pulses of shorter duration. Some researchers used early Nd:YLF laser prototypes experimentally for iridectomy, pupilloplasty, posterior capsulotomy, and vitreolysis, but results were generally not as good as with other laser or conventional surgical techniques.59,60 As such, most studies using the Nd:YLF laser have continued to concentrate on potential corneal applications.

Initial results using the Nd:YLF laser operating in the psec domain for intrastromal photodisruption in animal and cadaver eyes were unsatisfactory.61-66 Given the even further reduction in shockwave and cavitation effects B and hence localized tissue damage B caused by photodisruption pulses in the fsec (10-15 sec) range,67 studies with the Nd:YLF laser have increasingly focused on fsec technology. A group at Saint Louis University has extensively studied corneal applications of Nd:YLF laser photodisruption.

They found that while the Nd:YLF laser producing psec pulses (with energies of 25 J and spot separations of 10-20 m) could serve as a non-invasive microkeratome and create corneal flaps for LASIK with the excimer laser,68 the Nd:YLF laser operating in the fsec range (with pulse energies of only 4-8 J and spot separations of 10-15 m) produced far smoother lamellar surfaces that required no additional mechanical dissection.69

A couple of companies now manufacture fsec Nd:YLF lasers primarily as alternatives to the traditional surgical microkeratome. Figure 4 shows the Pulsion FS laser from IntraLase Corp., a company founded in 1997 by two University of Michigan researchers. As of mid-2002, this device has received 510(k) clearance from the Food and Drug Administration for testing in 13 sites in the USA. The laser produces fsec pulses focused to a spot size of approximately 3 m. The device attaches to the patient’s eye via a suction ring, but IOP is only elevated to about 30-40 mmHg. A scanning system strings the pulses together at a rate of 10,000 Hz, creating intrastromal lamellar incision planes, and ultimately a flap, in 3060 sec in preparation for excimer LASIK (Fig. 5). Flap creation is one of the most problematic steps in conventional LASIK, the most common complication of which is irregular astigmatism. The fsec laser virtually eliminates the risk of flap-associated complications such as decentered flaps, epithelial ingrowth, epithelial abrasion, or perforations. In principle, flap thickness, diameter, edge bevel, and hinge location can all be adjusted by customizing the laser pulse pattern. The Pulsion FS laser has also been used in

Fig. 4. Pulsion FS femtosecond laser. (Reproduced by courtesy of IntraLase Corp., Irvine, CA.)

early clinical trials to create channels for placement of intrastromal corneal ring segments, affording greater precision and flexibility than is possible with manual dissection using a diamond knife.

Conclusions and future developments

Photodisruption with the Nd:YAG laser is now a relatively mature procedure, although techniques continue to be refined. No current laser is likely to supplant the Nd:YAG for its full range of applications. Diode lasers, aided by advances in endoprobes and indirect ophthalmoscopy, are already being used to treat a variety of vascular diseases, and are becoming the treatment of choice for retinopathy of prematurity. Diode laser technology is constantly improving, with output at higher energies and shorter pulse durations and wavelengths. New diode lasers may continue to replace larger, more expensive ophthalmic lasers, conceivably someday including the Nd:YAG photodisruptor.

Laser photorefractive surgery has obvious considerable clinical and commercial value, and many lasers at a variety of wavelengths and pulse durations have been touted as potential alternatives to the ArF

excimer. With further refinement in equipment and technique, Nd:YLF intrastromal photodisruption may represent a single-step alternative to traditional excimer LASIK by directly reprofiling the cornea. Another solid state fsec laser that has been the subject of recent pre-clinical studies for intrastromal photodisruption is the titanium-sapphire laser, with output at 780 nm and 200 fsec.70,71

Laser technology in general, and ophthalmic lasers in particular, are dynamic fields that are the subjects of active basic and clinical research. New laser instruments and techniques are continually being developed, and few go untested for potential ophthalmic use. The pace and scope of progress suggest that the field of ophthalmic lasers, including photodisruption, will continue to evolve.

References

1.Longsworth JW: Photophysics. In: Regan JD, Parrish JA (eds) The Science of Photomedicine, p 43. New York, NY: Plenum 1982

2.McClung FJ, Hellwarth RW: Giant optical pulsating from ruby. J Appl Phys 33:828-831, 1967

3.Krasnov M: Laser-puncture of the anterior chamber angle in glaucoma. Vestn Oftalmol 3:27-31, 1972

4.Aron-Rosa D, Aron JJ, Greisemann J et al: Use of the neodymium-YAG laser to open the posterior capsule after lens implant surgery: a preliminary report. J Am Intraocul Implant Soc 6:352-354, 1980

5.Fankhauser F, Roussel P, Steffen J et al: Clinical studies on the efficiency of a high power laser radiation upon some structures of the anterior segment of the eye. Int Ophthalmol 3:129-139, 1981

6.Steinert RF, Puliafito CA, Trokel S: Plasma formation and shielding by three ophthalmic Nd-YAG lasers. Am J Ophthalmol 96:427-434, 1983

7.Fradin DW, Bloembergen N, Letellier JP: Dependence of laser-induced breakdown field strength on pulse duration. Appl Phys Lett 22:635-637, 1973

8.Ready JF: Effects of High-Power Laser Radiation, pp 133143, 215-217. New York, NY: Academic Press 1971

9.Hu CL, Barnes FS: The thermal-chemical damage in biological material under laser irradiation. IEEE Trans Biomed Eng 17:220-229, 1970

10.Felix MP, Ellis AT: Laser-induced liquid breakdown: a step- by-step account. Appl Phys Lett 19:484-486, 1971

11.Lauterborn W: High-speed photography of laser-induced breakdown in liquids. Appl Phys Lett 21:27-29, 1972

12.Brewer RJ, Rieckhoff KE: Stimulated Brillouin scattering in liquids. Phys Rev Lett 13:334-336, 1964

13.Cleary SF, Hamrick PE: Laser-induced acoustic transients in the mammalian eye. J Acoust Soc Am 46:1037-1044, 1969

14.Van der Zypen E, Fankhauser F, Bebie H et al: Changes in the ultrastucture of the iris after irradiation with intense light. Adv Ophthalmol 39:59-180, 1979

15.Fujimoto JG, Lin WZ, Ippen IP et al: Time-resolved studies of Nd:YAG laser induced breakdown: plasma formation, acoustic wave generation, and cavitation. Invest Ophthalmol Vis Sci 26:1771-1777, 1985

16.Carome EF, Carreira EM, Prochaska CJ: Photographic studies of laser-induced pressure impulses in liquids. Appl Phys Lett 11:64-66, 1967

17.Mainster MA, Sliney DH, Belcher CD et al: Laser photodisruptors: damage mechanisms, instrument design, and safety. Ophthalmology 90:973-991, 1983

18.Taboada J: Interaction of short laser pulses with ocular tissues. In: Trokel S (ed) YAG Laser Ophthalmic Microsurgery, pp 15-38. Norwalk, CT: Appleton-Century-Crofts 1983

19.Smith WL, Liu P, Bloembergen N: Superbroadening in water and deuterium by self-focused picosecond pulses from a neodymium doped YAG laser. Phys Rev (A) 15:2396-2403, 1977

20.Anthes JP, Bass M: Direct observation of the dynamics of picosecond-pulse optical breakdown. Appl Phys Lett 31:412414, 1977

21.Dick B, Schwenn O, Pfeiffer N: Extent of damage to different intraocular lenses by neodymium:YAG laser treatment: an experimental study. Klin Mbl Augenheilk 211:263-271, 1997

22.Ashkinadze BM, Vladimirov VI, Likhachev VA et al: Breakdown in dielectrics caused by intense laser radiation. Sov Phys JETP 23:788-797, 1966

23.Loertscher H: Laser-induced breakdown for ophthalmic applications. In: Trokel S (ed) YAG Laser Ophthalmic Microsurgery, p 39. Norwalk, CT: Appleton-Century-Crofts 1983

24.Gibbons WD, Allen RG: Retinal damage from suprathreshold Q-switch laser exposure. Health Phys 35:461-469, 1978

25.Sinskey RM, Cain W: The posterior capsule and phacoemulsification. J Am Intraocul Implant Soc 4:206-207, 1978

26.Pradella SP, Taumer R: Frequency of Nd:YAG capsulotomy

after implantation of PMMA and silicone intraocular lenses. Ophthalmologe 95:482-485, 1998

27.Kohnen T, Dick B, Jacobi KW: Effects of Nd:YAG microexplosions on heparin-coated PMMA intraocular lenses. Ophthalmologe 92:293-296, 1995

28.Parker WT, Clorfeine GS, Stocklin RD: Marked intraocular pressure rise following Nd-YAG laser capsulotomy. Ophthalmic Surg 15:103-104, 1984

29.Epstein DL, Jedziniak JA, Grant WM: Obstruction of aqueous outflow by lens particles and by heavy molecular-weight soluble lens proteins. Invest Ophthalmol Vis Sci 17:272277, 1978

30.Keates RH, Steinert RF, Puliafito CA et al: Long-term follow-up of Nd-YAG laser posterior capsulotomy. J Am Intraocul Implant Soc 10:164-168, 1984

31.Magno BV, Datiles MB, Lasa MS et al: Evaluation of visual function following neodymium:YAG laser posterior capsulotomy. Ophthalmology 104:1287-1293, 1997

32.Richter CU, Arzeno G, Pappas HR et al: Prevention of intraocular pressure elevation following neodymium-YAG posterior capsulotomy. Arch Ophthalmol 103:912-915, 1985

33.Steinert RF, Puliafito CA, Kumar SR et al: Cystoid macular edema, retinal detachment and glaucoma after Nd:YAG laser posterior capsulotomy. Am J Ophthalmol 112:373-380, 1991

34.Levy JH, Pisacano AM, Anello RD: Displacement of bagplaced hydrogel lenses into the vitreous following neodym- ium-YAG laser capsulotomy. J Cataract Refract Surg 16: 563-566, 1990

35.Pollack ID, Brown RH, Crandall AS et al: Effectiveness of apraclonidine in preventing the rise of intraocular pressure after neodymium-YAG laser posterior capsulotomy. Trans Am Ophthalmol Soc 86:461-472, 1989

36.Silverstone DE, Novack GD, Kelley EP et al: Prophylactic treatment of intraocular pressure elevations after neodym- ium-YAG laser capsulotomies and extracapsular cataract extraction with levobunolol. Ophthalmology 95:713-718, 1988

37.Ladas ID, Baltatzis S, Panagiotidis D et al: Topical 2.0% dorzolamide vs oral acetazolamide for prevention of intraocular pressure rise after neodymium:YAG laser posterior capsulotomy. Arch Ophthalmol 115:1241-1244, 1997

38.Del Priore LV, Robin AL, Pollack IP: Neodymium-YAG and argon laser iridotomy: long-term follow-up in a prospective, randomized clinical trial. Ophthalmology 95:12071211, 1988

39.Schwartz L: Laser iridectomy. In: Schwartz L, Spaeth G, Brown G (eds) Laser Therapy of the Anterior Segment: A Practical Approach, pp 29-58. Thorofare, NJ: Charles B Slack 1984

40.Robin AL, Pollack IP: Q-switched neodymium-YAG laser iridotomy in patients in whom the argon laser fails. Arch Ophthalmol 104:531-535, 1986

41.Zborwski-Gutman L, Rosner M, Blumenthal M et al: Sequential use of argon and Nd:YAG lasers to produce an iridotomy: a pilot study. Metab Pediatr Syst Ophthalmol 11:58-60, 1988

42.Lim L, Seah SK, Lim AS: Comparison of argon laser iridotomy and sequential argon laser and Nd:YAG laser iridotomy in dark irides. Ophthalmic Surg 27:285-288, 1996

43.Panek WC, Lee DA, Christensen RE: The effects of Nd:YAG laser iridectomy on the corneal endothelium. Am J Ophthalmol 111:505-507, 1991

44.Epstein DL, Steinert RF, Puliafito CA: Neodymium-YAG laser therapy to the anterior hyaloid in aphakic malignant (ciliovitreal block) glaucoma. Am J Ophthalmol 98:137-143, 1984

45.Geggel HS: Successful treatment of recurrent corneal erosion with Nd:YAG anterior stromal puncture. Am J Ophthalmol 110:404-407, 1990

46.Tchah HW, Larson RS, Nichols BD et al: Neodymium:YAG laser zonulysis for treatment of lens subluxation. Ophthalmology 96:230-234, 1989

47.Katzen LE, Fleischman JA, Trokel S: YAG laser treatment of cystoid macular edema. Am J Ophthalmol 95:589-592, 1983

48.Steinert RF, Wasson PJ: Neodymium:YAG anterior vitreolysis for Irvine-Gass cystoid macular edema. J Cataract Refract Surg 15:304-307, 1989

49.Jagger JD, Hamilton AM, Polkinghorne P: Q-switched neodymium-YAG laser vitreolysis in the treatment of posterior segment disease. Arch Clin Exp Ophthalmol 228:222225, 1990

50.Berglin L, Stenkula S, Crafoord S et al: A new technique of treating rhegmatogenous retinal detachment using the Q- switched Nd:YAG laser. Ophthalmic Surg 18:890-892, 1987

51.Puliafito CA, Wasson PJ, Steinert RF et al: Nd-YAG laser surgery on experimental vitreous membranes. Arch Ophthalmol 102:843-847, 1984

52.Iijima H, Satoh S, Tsukahara S: Nd:YAG laser photodisruption for preretinal hemorrhage due to retinal macroaneurysm. Retina 18:430-434, 1998

53.Krauss JM, Puliafito CA, Miglior S et al: Vitreous changes after neodymium-YAG laser photodisruption. Arch Ophthalmol 104:592-597, 1986

54.Krauss JM, Puliafito CA, Steinert RF: Laser interactions with the cornea. Surv Ophthalmol 31:37-53, 1986

55.Taboada J, Poirier RH, Yee RW et al: Intrastromal photorefractive keratectomy with a new optically coupled laser probe. Refract Corneal Surg 8:399-402, 1992

56.Vogel A, Busch S, Jungnickel K et al: Mechanisms of intraocular photodisruption with picosecond and nanosecond laser pulses. Lasers Surg Med 15:32-34, 1994

57.Vogel A, Capon MR, Asiyo-Vogel MN et al: Intraocular photodisruption with picosecond and nanosecond laser pulses: tissue effects in cornea, lens, and retina. Invest Ophthalmol Vis Sci 35:3032-3044, 1994

58.Vogel A, Asiyo-Vogel M, Birngruber R: Intrastromal refractive corneal surgery with pico-second Nd:YAG laser pulses. Ophthalmologe 91:655-662, 1994

59.Cohen BZ, Wald KJ, Toyama K: Neodymium:YLF picosecond laser segmentation for retinal traction associated with

proliferative diabetic retinopathy. Am J Ophthalmol 123:515523, 1997

60.Geering G, Roider J, Schmidt-Erfurt U et al: Initial clinical experience with the picosecond Nd:YLF laser for intraocular therapeutic applications. Br J Ophthalmol 82:504-509, 1998

61.Remmel RM, Dardenne CM, Bille JF: Intrastromal tissue removal using an infrared picosecond Nd:YLF ophthalmic laser operating at 1053 nm. Lasers Light Ophthalmol 4:169173, 1992

62.Brown DB, O’Brien WJ, Schultz RO: Nd:YLF picosecond laser capabilities and ultrastructure effects in corneal ablations. Invest Ophthalmol Vis Sci 34(Suppl):1246, 1993

63.Itoi M, Bassage S, Del Cerro M et al: Corneal incisions utilizing the 1053 nm picosecond Nd:YLF ophthalmic laser. Cornea 15:2-8, 1996

64.Krueger RR, Quantock AJ, Juhasz T et al: Ultrastructure of picosecond laser intrastromal photodisruption. J Refract Surg 12:607-612, 1996

65.Ito M, Quantock AJ, Malhan S et al: Picosecond laser in situ keratomileusis with a 1053-nm Nd:YLF laser. J Refract Surg 12:721-728, 1996

66.Gimbel HV, Coupland SG, Ferensowicz M: Review of intrastromal photorefractive keratectomy with the neodymium: yttrium-lithium-fluoride laser. Int Ophthalmol Clin 37:95102, 1997

67.Juhasz T, Kastis GA, Suarez C et al: Time-resolved observations of shock waves and cavitation bubbles generated by femtosecond laser pulses in corneal tissue and water. Lasers Surg Med 19:23-31, 1996

68.Krueger RR, Marchi V, Gualano A et al: Clinical analysis of the neodymium:YLF picosecond laser as a microkeratome for laser in situ keratomileusis. J Cataract Refract Surg 24:1434-1440, 1998

69.Kurtz RM, Horvath C, Liu HH et al: Lamellar refractive surgery with scanned intrastromal picosecond and femtosecond laser pulses in animal eyes. J Refract Surg 14:541548, 1998

70.Lubatschowski H, Maatz G, Heisterkamp A et al: Application of ultrashort laser pulses for intrastromal refractive surgery. Graefe’s Arch Clin Exp Ophthalmol 238:33-39, 2000

71.Heisterkamp A, Ripken T, Lutkefels E et al: Optimizing laser parameters for intrastromal incision with ultra-short laser pulses. Ophthalmologe 98:623-628, 2001

History

The transparency of the cornea of the eye provides an opportunity for intraocular surgical interventions with a laser beam without opening the bulbus. In 1973, two groups of scientists described methods to reduce the intraocular pressure (IOP) by irradiation of the trabecular meshwork using a laser.

In 1973, Krasnov1 described a ‘microrupture’ technique using a Q-switched ruby laser in open-angle glaucoma patients. His technique attempted to provide a direct opening pathway into Schlemm’s canal. A temporary reduction of IOP in all patients, accompanied by improved outflow facilities, was noted.

In that same year, Worthen and Wickham2 described the morphological effects of argon laser irradiation of the trabecular meshwork in the monkey. Later on, Wise and Witter3 accomplished lowering of the IOP in primary open-angle glaucoma patients by irradiation of the trabecular meshwork without perforating Schlemm’s canal, using an argon laser. This method of argon laser trabeculoplasty (ALT) is now used world-wide in the treatment of open-angle glaucoma (for a review, see Reiss et al.4 and Brilakis et al.5).

Wavelength dependence

Argon (wavelength 488-514 nm), Nd:YAG (523 nm), diode (810 nm), holmium, erbium:YAG, and other laser wavelengths are used for irradiation of the trabecular meshwork.7-14

CW lasers (10 ms - 0.5 s) produce coagulation by heat which is visible by an increased intensity of staining in histological sections (Figs. 1 and 2).

The argon laser does not cause very deep tissue damage (Fig. 1). Ultrastructural analysis shows that the collagen fibrils disintegrate into subfibrillar fragments, which lose their periodicity. Such changes correspond to an exposure of about 200°C, as systematic comparative analysis of heat-induced phenomena has shown.15,16,24 It has been found that penetration of heat induced by the Nd:YAG laser is six times deeper than that induced by the argon laser (Fig. 2).16 Nevertheless, in general, it can be assumed that trabecular photocoagulation is not a process that depends upon wavelength.17

Effects of dependence on pulse duration

There are significant differences regarding irradiation with cwor Q-switched lasers. Using a cw Nd:YAG laser for irradiation of the iris, a predominantly thermal coagulation effect is induced (Fig. 3). Collagen fibrils are damaged and degenerate into subfibrillar fragments, loosing their periodicity. The deepness of the crater generated depends on exposure time and mean power. Using a Q-switched laser, an eruption of the tissue may be observed (Fig. 4), predominantly caused by physical forces such as shock waves. The most conspicuous ultrastructural changes are vacuolation, disruption, and fragmentation of melanin granules.15 From consideration of these different morphological effects, it can be assumed that the micropuncture technique described by Krasnov,1 using a Q-switched ruby laser, corresponds to a microexplosion effect with mechanical destruction of the trabecular meshwork, including the inner wall of Schlemm’s canal. In contrast ALT, conceived by Wise and Witter,3 is based on a coagulation effect and does not injure Schlemm’s canal.

Fig. 2. Trabecular meshwork of a human autopsy eye near Schwalbe’s line, treated by free-running Nd:YAG laser (exposure duration: 10 ms; pulse energy: 2 J). The penetration of heat induced by the Nd:YAG compared to the argon laser is five times greater. Semithin section stained with azure-II- methylenblue; negative magnification ×64. (Reproduced from Van der Zypen and Fankhauser16 by courtesy of the publisher.)

The deepness of the coagulation effect depends on exposure time and mean power.

The shortand long-term effects of both methods of irradiation of the chamber angle have been proved by our group in monkeys.

Origins of glaucoma

Up to the present, the origins of the primary openangle glaucoma are not well understood. An accumulation of intercellular material within the juxtacanalicular region of the trabecular meshwork usually is found in open-angle glaucoma.18 It is thought that the large accumulation of basement membrane-like material with heparin sulfate-type proteoglycans could be one of the causes of the increase of IOP in glaucoma.19 The increase of collagen IV, laminin, and fibronectin found in the basement region of the inner wall and at the juxtacanalicular tissue may be another reason for the increase in IOP.5,20 The aim of laser treatment of the chamber angle in primary open-angle glaucoma may be degradation of the extracellular juxtacanalicular proteoglycans or stimulation of the turnover of the extracellular matrix. ALT is also thought to stimulate the degradation of juxtacanalicular material. In organ cultures of the trabecular meshwork, stromolysin is thought to degrade the trabecular proteoclycans. The expression and secretion of stromolysin is thought to be stimulated by ALT.21,22

Morphological effects of trabeculopuncture

By irradiating the chamber angle of monkey eyes (Macaca speciosa) using a Q-switched Nd:YAG laser (exposure duration 30 ns), mechanical destruction of the trabecular meshwork, including the opening of Schlemm’s canal in the anterior cham-

ber, may be produced (Fig. 5). Then a widely gaping of Schlemm’s canal is created.23,52 Similarly, the endothelial cells of the outer wall are destroyed to a large extent (Fig. 6). However, the scleral spur usually remains intact. The width of the opening between the lamellae results from retraction of the disrupted trabecular lamellae at the ciliary muscle.

Collapse of Schlemm’s canal can be observed at the border of the irradiated area, and the inner wall of the canal is in close contact with the outer wall.

In trabeculopuncture of the monkey eye using a Q-switched laser, damage to the corneal endothelial cells and Descemet’s membrane inevitably occurs. This injury to the peripheral cornea leads to stimulation of the corneal endothelial cells, which grow into the damaged area. Eighteen months after

opening Schlemm’s canal in Macaca speciosa eyes, the original site of perforation is covered by an continuous layer of corneal endothelial cells (Figs. 7 and 8). No gaps were seen in this tight cell layer.53 On transmission electron microscopy, pigment granules were observed in some of these endothelial cells, which covered tight collagen scar tissue.24

In human eyes, Schlemm’s canal is located in a more posterior direction towards the equator. For

this reason, it could be possible that, in trabeculoplasty of human eyes, the corneal endothelium is better preserved than in monkey eyes, in which Schlemm’s canal is located near Schwalbe’s line (Fig. 9). In glaucomatous human eyes, no scar formation or endothelium proliferation was seen up to three years after laser trabecular ablation with removal of trabecular tissue and opening of Schlemm’s canal using an erbium:YAG laser (pulse energy: 5-7 mJ; pulse duration: 200 sec).14

Morphological effects of cyclodialysis

By aiming the laser beam at the center of the uveal trabecular meshwork between the iris root and the posterior rim of the cornea (Fig. 9), cyclodialysis is created (Fig. 10). However, Schlemm’s canal is not opened with this technique.25 Histological investigations have shown that the sclera only appears to be slightly damaged. Bundles of collagen fibers are formed the bottom of Schlemm’s canal.

In long-term studies (16 months after cyclodialysis), it has been observed that the cyclodialysis canal remains open (Fig. 11). The border of the canal is covered by a monolayer of connective tissue cells (Fig. 12). Collagen fibers are seen among the cell processes of the fibroblasts, which means that the cellular wall of the cyclodialysis canal is discontinuous, which enables the aqueous humor to enter deeper tissue compartments.

Three routes for the aqueous humor to flow out,

Fig. 9. Semi-schematic view of the angle of an anterior chamber of a monkey (Macaca speciosa). T: uveal trabecular meshwork; S: Schlemm’s canal with collector channel; P: scleral spur with insertion of the outer portion of the ciliary muscle (M); A: sclera; B: supraciliary space; F: ciliary folds; I: iris. Two sites of impact of the laser beam, either opening Schlemm’s canal or the supraciliary space can be seen. (Reproduced from Van der Zypen and Fankhauser25 by courtesy of the publisher.)

propagating from a cyclodialysis canal, can be seen when HgS particles are used as a tracer substance.24,25,26 Tracer substances leak between the collagen fiber bundles of the sclera and are absorbed by branches of the vortex veins (Fig. 13). Thirty percent of the aqueous humor normally leaves the

anterior chamber via a uveoscleral pathway.38,39 The second route leads to the veins of the ciliary muscle. Therefore, HgS particles can be found between the bundles of the ciliary muscle (Fig. 14). The third route is of some interest, but is speculative. HgS particles can be found in the supraciliary space, which is continuous with the suprachoroidal space up to the optic nerve head. The optic nerve outside the

bulbus is surrounded by the three layers of the meninges (Figs. 15a and b). The subarachnoid space containing cerebrospinal fluid extends from the brain and passes around the optic nerve up to the ocular bulbus. Tracer substances are found in the subrachoroid space and the tissue of Elschnig which borders the optic nerve head (Figs. 15a and b). Tracer substances are also found in the subarachnoid space

of the optic nerve (Fig. 16). Finally, tracer substances can be identified within the granulations of Pacchioni and pass from here into the superior sagittal sinus of the cranial dura mater. This pathway from the supraciliary via the suprachoroid into the subarachnoid space in enucleated human eyes can also be marked in the opposite direction. Tracer substances injected at high pressure into the subarachnoid space

of the optic nerve of human eyes can also be found in the suprachoroid space.

Morphological effects of trabeculoplasty

Trabeculoplasty performed using a cw ALT, freerunning Nd:YAG laser light, or a diode laser shows

similar morphological reactions. In clinical applications, when comparing argon and Nd:YAG lasers, the final reduction of IOP using either method was found to be identical.27 However, the effect of argon laser light is more superficial compared to Nd: YAG laser light. Irradiation with an argon laser (pulse power 0.5 W; pulse duration: 0.1 s; focus spot diameter: 50 µm; Fig. 17) or a free-running Nd:YAG laser (energy: 200 mJ; pulse duration; 10 ms; focus spot diameter: 50 µm; Fig. 18) produces superficial coagulation of the inner layers of the uveal trabecular meshwork.8,28 Some of the inner trabecular sheets are disrupted, and the solid cell processes of the trabecular endothelial cells broken up. Collagen fibrils of the trabecular cores disintegrate into the subfibrillar structures, loosing their periodicity (Fig. 19). In analogy, if collagen fibrils of the iris

are heated up, it can be assumed that temperatures of up to 70-90°C will be reached within the center of impact during irradiation with the Nd:YAG laser (energy: 200 mJ; pulse duration: 10 ms).15,24 In deeper regions of the trabecular meshwork, the collagen fibrils within the trabecular cores were only partially dissolved; in many cases, they showed a normal cross-section, but had shortened periodicity (Fig. 20). Long-spacing fibers (curly collagen), which are often observed within the trabecular cores of glaucomatous human eyes, but more rarely in monkey eyes, degenerate. The light bands of these collagen fibrils disintegrate and exhibit tree-like ramifications (Fig. 21). Within the juxtacanalicular (cribriform) region of the trabecular meshwork, no conspicuous changes of the structures are observed immediately after ALT. When using the Nd:YAG

laser for trabeculoplasty, only a small number of collagen fibrils dissolve.

In long-term observations, most morphological investigations of the trabecular meshwork after ALT demonstrate the more or less complete closure of the inner trabecular spaces in the zone of impact, due to scar formation.31-33,51 This scar formation is thought to be the result of thermal injury to the trabecular meshwork. These findings are in agreement with our investigations.6,28,29,34,35 Four weeks after

irradiation, activated cells, with morphological features similar to those of the corneal endothelium and connected to them, migrate from Schwalbe’s line and cover the inner iridocorneal trabeculae (Fig. 22). These cells close the irradiated zone by building a hexagonal monolayer which also expands into neighbouring untreated zoned, occluding the intertrabecular spaces. In monkey eyes, cells in the operculum were also stimulated to migrate into the damage zone.35 The operculum consists of a group of cells

near the anterior insertion of the trabeculae, and is not seen in human eyes.

It may be that vasoactive intestinal protein (VIP, 28-aminoacid neuropeptide) stimulates the proliferation of migrating cells.36

Both ALT and Nd:YAG laser trabeculoplasty are accepted clinical methods for lowering IOP.4,9-11,13 It has been speculated that shrinkage of the collagen arising at the impact zone causes dilatation and elevation of the intertrabecular spaces near to the scar.3

In contrast to the scar formation at the inner trabecular meshwork, degeneration of cells and intercellular material can be seen within the juxtacanalicular region.28,34,35 In this zone, accumulation of basal lamina-like material with heparin sulfate-type proteoglycans is found in glaucomatous human eyes.19 Degeneration of the cells starts with lysis of the cell organelles, dilatation of the cell nucleus, and accumulation of DNS material. Cell membranes remain intact for a long time (Fig. 23).

At the end of the degeneration process (from 13 weeks to seven months after irradiation with the Nd:YAG and argon lasers, respectively), most of the trabecular endothelial cells at the juxtacanalicular region have degenerated near the impact zone. The final organization of the cellular network has come to an end after degeneration of the basement mem-

brane, which can withstand the degenerative process for a long period of time (Fig. 24).

Apart from this degenerative process, phagocytosed cells migrate into the juxtacanalicular region of the irradiated zone. These cells phagocytize and digest collagen fibrils (Fig. 25). The collagen fragments are pressed together within a voluminous

vacuole (Fig. 26). The accumulation of acid phosphatase, which is an important enzyme for digestion is indicative of the degradation process within the vacuoles (Fig. 27).28,29,34

As well as this process of degradation, fibroblasts, which are active in collagen synthesis, migrate into the zone of dissolution.6,37 The activity of these fibroblasts in collagen synthesis is shown by the expansion of the rough endoplasmic reticulum (Fig. 28).

In summary, an active process based on the turnover of cells and intercellular substances can be seen

from 13 weeks to seven months after irradiation (i.e., the end of the period of observation). The most prominent feature is the degenerative processes. These may be responsible for the postoperative decrease of IOP. Later on, it may be that regenerative processes come into play that cause the re-elevation of the IOP. Remodelling of the juxtacanalicular extracellular matrix may be initiated by the expression of cytokines in the juxtacanalicular region. Such cytokines have been found in organ cultures of the trabecular meshwork after ALT.22

Conclusions and perspectives in glaucoma surgery

ALT would seem to be the most important method for lowering IOP, with the exception of perforating methods such as Elliot-type procedures. Scar formation may prevent the long-term success of ALT in lowering IOP. More recently, alternative methods have been advanced.

Viscocanalostomy has been reported to lower IOP without creating a filtering bleb.40 With this technique, following removal the deep scleral layers, Schlemm’s canal is cannulated and is expanded with a viscoelastic material. Complications such as hypotony and hyphema, which may compromise the operative results, may be avoided.40,41 Variations of this procedure include removing the inner wall of

Schlemm’s canal and the adjacent meshwork, while leaving the inner meshwork intact and placing a collagen implant into the filtration bed in order to prevent episcleral fibrosis.42 A more likely explanation of the working mechanisms of this operative procedure is the expansion of the canal ruptures and the disruption of both the inner and outer endothelial walls of Schlemm’s canal.43 This disruption may extend into the juxtacanalicular tissue and may also rupture some of the uveal meshwork.

Another surgical method for lowering IOP is the

manipulation of Descemet’s membrane, which is not normally permeable to the aqueous humor. However, if Descemet’s membrane has become thin or is partially removed, its permeability may increase.44

Laser sclerostomy ab interno may also be a successful approach in the treatment of open-angle glaucoma.45 The failure of this and of other filtering surgery methods may be caused by the extensive wound healing process.46 However, scar formation can be suppressed by the use of antifibrotic agents such as 5-fluorouracil or mitomycin C.47-50 Mitomy-

cin C was noted to suppress the migration and proliferation of fibroblasts and macrophages for more than ten weeks after Nd:YAG laser sclerostomy ab interno in rabbits. Repolymerization of heat-dam- aged collagen was also unsuccessful in these experiments, and no neosynthesis of collagen fibrils was observed.50

Selective trabeculoplasty10 is a novel method using a Q-switched, frequency-doubled (KTP) laser, which it is claimed drastically reduces radiation damage to the trabeculum, while maintaining equally good results as standard ALT.10

References

1.Krasnov MM: Laseropuncture of the anterior chamber angle in glaucoma. Am J Ophthalmol 75:674-678, 1973

2.Worthen DM, Wickham MG: Laser trabeculotomy in monkeys. Invest Ophthalmology Vis Sci 12:707-711, 1973

3.Wise JB, Witter SL: Argon laser therapy for open-angle glaucoma. Arch Ophthalmology 97:319-322, 1979

4.Reiss GR, Wilensky JT, Higginbotham EJ: Laser trabeculoplasty. Surv Ophthalmol 35:407-428, 1991

5.Brilakis HS, Hann CR, Johnson DH: A comparison of different embedding media on the ultrastructure of the trabecular meshwork. Curr Eye Res 22:235-244, 2001

6.Fankhauser F, Van der Zypen E, Kwasniewska S: Argon and Nd:YAG laser trabeculoplasty: the relevance of ultrastructural findings for the evaluation of therapeutic effectiveness. New Trends Ophthalmol 2:238-245, 1987

7.McMillan TA, Stewart WC, Legler UF, Powers T, Nutaitis MJ, Apple DJ: Comparison of diode and argon laser trabeculoplasty in cadaver eyes. Invest Ophthalmol Vis Sci 35:706-710, 1994

8.Hollo G: Argon and low energy, pulsed Nd:YAG laser trabeculoplasty: a prospective, comparative clinical and

morphological study. Acta Ophthalmol Scand 74:126-131, 1996

9.Englert JA, Cox TA, Allingham RR, Shields MB: Argon vs diode laser trabeculoplasty. Am J Ophthalmol 124:627631, 1997

10.Latina MA, Sibayan SA, Shin DH, Noecker RJ, Marcellino G: Q-switched 532 nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology 105:2082-2088, 1998

11.Wang RF, Schumer RA, Serle JB, Podos SM: A comparison of argon laser and diode laser photocoagulation of the trabecular meshwork to produce the glaucoma monkey model. J Glaucoma 7:45-49, 1998

12.Kim YJ, Moon CS: One-year follow-up of laser trabeculoplasty using Q-switched frequency-doubled Nd:YAG laser of 523 nm wavelength. Ophthalmic Surgery Lasers 31:394-399, 2000

13.Blyth CPJ, Moriarty AP, McHugh JDA: Diode laser trabeculoplasty versus argon laser trabeculoplasty in the control primary open angle glaucoma. Lasers Med Sci 14: 105108, 1999

14.Dietlein TS, Jacobi PC, Mietz H, Kriegelstein GK: Morphology of the trabecular meshwork three years after erbium:YAG trabecular ablation. Ophthalmic Surg Lasers 32:483-485, 2001

15.Van der Zypen E, Fankhauser F, Bebie H, Marshall J: Changes in the ultrastructure of the iris after irradiation with intense light: a study of long-term effects after irradiation with argon-ion, Nd:YAG and Q-switched ruby lasers. Adv Ophthalmol 39:59-180, 1979

16.Van der Zypen E, Fankhauser F: Lasers in the treatment of chronic simple glaucoma. Trans Ophthalmol Soc UK 102: 147-153, 1982

17.McHugh D, Marshall J, Ffytche TJ, Hamilton A, Raven A: Ultrastructural changes of the human trabecular meshwork after photocoagulation with a diode laser. Invest Ophthalmol 33:2664-2667, 1992

18.Furuyoshi N, Furuyoshi M, Futa R, Gottanka J, LutjenDrecoll E: Ultrastructural changes in the trabecular mesh-

work of juvenile glaucoma. Ophthalmologica 211:140-146, 1997

19.Tawara A, Inomata H: Distribution and characterization of sulfated proteoglycans in the trabecular tissue of goniodysgenetic glaucoma. Am J Ophthalmol 117:741-755, 1994

20.Hann CR, Springett MJ, Wang X, Johnson DH: Ultrastructural location of collagen IV, fibronectin, and laminin in trabecular meshwork of normal and glaucomatous eyes. Ophthalmic Res 33:314-324, 2001

21.Parshley DE, Bradley JMB, Fisk A, Hadaegh A, Samples JR, Van Buskirk EM, Acott TS: Laser trabeculoplasty induces stromolysin expression by trabecular juxtacanalicular cells. Invest Ophthalmol 37:795-804, 1996

22.Bradley JM, Anderssohn AM, Colvis CM, Parshley DE, Zhu XH, Ruddat MS, Samples JR, Acott TS: Mediation of laser trabeculoplasty-induced matrix metalloproteinase expression by IL-1beta and TNFalpha. Invest Ophthalmol 41: 422-430, 2000

23.Van der Zypen E, Bebie H, Fankhauser F: Morphological studies about the efficiency of laser beams upon the structures of the angle of the anterior chamber. Facts and concepts related to the treatment of the chronic simple glaucoma. Int Ophthalmol 1:109-122, 1979

24.Van der Zypen E: The use of laser in eye surgery: morphological principles. Int Ophthalmol Clin 25:21-52, 1985

25.Van der Zypen E, Fankhauser F: The ultrastructural features of laser trabeculopuncture and cyclodialysis: problems related to successful treatment of chronic simple glaucoma. Ophthalmologica 179:189-200, 1979

26.Van der Zypen E, Fankhauser F: Der Abfluss des Kammerwassers aus dem Spatium suprachoroideale nach Cyclodialyse. Fortschr Ophthalmol 79:409-412, 1983

27.Belgrado G, Brihaye-van Geertruyden M, Herzeel R: Comparison of argon and cw.Nd.YAG laser trabeculoplasty. In Laser Technology in Opthalmology, John Marshall, editor, pp. 45-52. Kugler&Ghedini Publications, Amsterdam/Berkeley/Milano, 1988

28.Van der Zypen E: The effects of lasers on outflow structures. In: Kriegelstein GK (ed) Glaucoma Update III, pp 169-176. Springer-Verlag 1987

29.Van der Zypen E, Fankhauser F: Ultrastructural changes of the trabecular meshwork of the monkey (Macaca speciosa) following irradiation with the argon laser light. Graefe’s Arch Clin Exp Ophthalmol 221:249-261, 1984

30.Kramer TR, Noecker RJ: Comparison of the morphologic changes after selective laser trabeculoplasty and the argon laser trabeculoplasty in human eye bank eyes. Ophthalmology 108:773-779, 2001

31.Rodrigues MM, Spaeth, GL, Donohoo P: Electron microscopy of argon laser therapy in phakic open-angle glaucoma. Ophthalmology 89:198-210, 1982

32.March WF, Gherezghiher T, Koss M, Nordquist R: Ultrastructural and pharmacologic studies on laser-induced glaucoma in primates and rabbits. Lasers Surg Med 4:329-335, 1984

33.Ticho U, Cadet JC, Mahler J, Sekeles E, Bruchim A: Argon laser trabeculotomies in primates: evaluation by histological and perfusion studies. Invest Ophthalmol Vis Sci 17:667-674, 1978

34.Fankhauser F, Van der Zypen E, Kwasniewska S: Thermal effects on the trabecular meshwork induced by laser irradiation: clinical implications deduced from ultrastructural studies in the Macacca speciosa monkey. Trans Ophthalmol Soc UK 105:555-561, 1986

35.Van der Zypen E, Fankhauser F, England C, Kwasniewska

S:Morphology of the trabecular meshwork within monkey (Macacca speciosa) eyes after irradiation with the freerunning Nd:YAG laser. Ophthalmology 94:171-179, 1987

36.Koh SW, Yeh TH, Morris SM, Leffler M, Higginbotham EJ, Brenneman DE, Yue BY: Vasoactive intestinal peptide stimulation of human trabecular meshwork cell growth. Invest Ophthalmol 38:2781-2789, 1997

37.Van Buskirk EM: Pathophysiology of laser trabeculoplasty. Surv Ophthalmol 33:264-272, 1989

38.Bill A, Walinder E: The effect of pilocarpine on the dynamics of aqueous humour in a primate (Macaca irus). Invest Ophthalmol 5:170-175, 1966

39.Nilsson SF: The uveal outflow routes. Eye 11:149-154, 1997

40.Stegmann R, Pienaar A, Miller D: Viscocanalostomy for open-angle glaucoma in black African patients. J Cataract Refract Sur 25:316-322, 1999

41.Sayyad FE, Helal M, El-Kohilty H, Knall M, El-Mmaghraby

A:Nonpenetrating deep sclerectomy vs trabeculectomy in bilateral primary open-angle glaucoma. Ophthalmology 107:1671-1674, 2000

42.Mernoud A, Schnyder CC, Sickenberg M, Chiou AGY, Hediger SEA, Faggioni R: Comparison of deep sclerectomy with collagen implant and trabeculectomy in open-angle glaucoma. Ophthalmic Surg 15:734-740, 1984

43.Smit BA, Johnstone MA: Effect of viscocanalostomy on the histology of Schlemm’s canal in primate eyes. (Abstract 3071) Invest Ophthalmol Vis Sci 41(Suppl):5578, 2000

44.Splegel D, Schefthaler M, Kobuch K: Outflow facilities through Descemet’s membrane in rabbits. (Abstract 3071) Invest Ophthalmol Vis Sci 41(Suppl):5578, 2000

45.Fankhauser F, Dürr U, England C, Kwasniewska S, Van der Zypen E, Henchoz PD: Optical principles related to optimizing sclerostomy procedure. Ophthalmic Surg 23:752761, 1992

46.Iliev ME, Van der Zypen E, Fankhauser F, England C: The repair response following Nd:YAG laser sclerostomy ab interno in rabbits. Exp Eye Res 61:311-321, 1995

47.Yamamoto T, Varani J, Soong HK, Lichter PR: Effects of 5-fluorouracil and mitomycin C on cultured rabbit subconjunctival fibroblasts. Ophthalmology 97:1204-1210, 1990

48.Wand M: Minimizing conjunctival wound leaks in filtration surgery with mitomycin C. Ophthalmic Surg 24:708709, 1993

49.Pablo LE, Ramirez T, Alvarez R, Gonzalez I, Larrosa JM, Honrubia FM: Morphometric study of wound healing in a model of filtering surgery with mitomycin C. Eur J Ophthalmol 5:168-171, 1995

50.Iliev ME, Van der Zypen, E, Fankhauser F, England C: Transconjunctival application of mitomycin C in combination with laser sclerostomy ab interno: a long-term morphological study of the postoperative healing process. Exp Eye Res 64:1013-1026, 1997

51.Koller T, Sturmer J, Remé C, Gloor B: Membrane formation in the chamber angle after failure of argon laser trabeculoplasty: analysis and risk factors. Br J Ophthalmol 84:48-53, 2000

52.Van der Zypen E, Fankhauser F: Effekte eines neuartigen Lasertyps auf fixiertes Gewebe der Kammerwinkelregion des Affenauges. Klin Mbl Augenheilk 172:426, 1978

53.Van der Zypen E, Fankhauser F: Lasereffekte am Trabekelwerk: Ultrastrukturelle Untersuchungen am menschlichen und am Affenauge. In: Naumann GOH, Gloor B (ed) Wundheilung des Auges und ihre Komplikationen, pp 331-336. Munich: JF Bergmann Verlag 1880