16 The Femtosecond Laser in the Surgical Treatment of Presbyopia in the Lens: Options and Limitations

Mateusz M. Kecik and Ronald R. Krueger

Keywords: presbyopia correction, accommodation restoration, femtosecond lenticular photodisruption, Phaco-Ersatz, lens refilling

16.1 Introduction

Presbyopia is a naturally occurring process, associated with aging, and involves biochemical, structural, and anatomical changes in the crystalline lens, zonules, and ciliary muscle. It provokes a progressive loss of accommodation, and decreases the near focus when distance corrected, profoundly impacting the quality of life among frustrated patients. In 2011, there were an estimated 1.272 billion cases of presbyopia worldwide, resulting in a potential productivity loss of US$ 25.367 billion. ¹

The first attempt at describing accommodation by crystalline lens movement was attempted by Kepler in 1611. Next came the conception of a more accurate theory by Hermann Ludwig von Helmholtz in 1855, and the 1864 publication of the highly acclaimed “On the anomalies of accommodation and refraction of the eye” by Franciscus Cornelis Donders, where he identified refractive errors and presbyopia.

Initially, presbyopia was managed with optical aids such as magnifying lenses and monocles, but later bifocal glasses were invented by Benjamin Franklin in 1784. Now, more than 230 years later, most presbyopic patients still use bifocals or reading glasses, demonstrating both the utility of Franklin’s invention and the fact that the quest for true accommodation restoration is considered the “Holy Grail” of modern ophthalmology and refractive surgery.

Current surgical approaches at either pseudoaccommodation or true accommodation restoration can be divided into three groups: corneal-, scleral-, or crystalline-based procedures. The creation of picosecond and femtosecond lasers enabled surgeons to deliver ultrashort, high-power, low-energy pulses deep into the crystalline lens to enable a new and novel possibility for accommodation restoration in the aging lens. ² The old paradigm “don’t touch a noncataractous, clear lens” seems to be a thing of the past, as femtosecond laser pulses are now being used, not only to sculpt the lens prior to a refractive lens exchange, but also, when appropriately applied, to offer the promise of enhancing the internal flexibility of the aging lens without inducing a progressive or vision-threatening cataract. Furthermore, these femtosecond lasers are adding more precision to existing cataract surgical techniques, and providing a key solution to futuristic concepts, like Phaco-Ersatz, whose early days seemed to be limited by the surgeon’s inability both to remove the cataract through a small capsular opening and to create this peripheral anterior opening, of less than 1 mm in diameter, with high circularity and reproducibility.

16.2 The Anatomy and Physiology of Accommodation and Presbyopia

The Helmholtz theory of accommodation accurately describes basic mechanisms behind the accommodative response. Helmholtz argued that the contraction of the ciliary muscle decreases zonular tension, which in turn allows the crystalline lens to increase its curvature and thickness while decreasing equatorial diameter. Simply put, lens moves away from the sclera during accommodation. Difference in angles of anterior and posterior zonular insertion into the crystalline lens and varying densities of nucleus and cortex result in a more pronounced curvature modification of the anterior than the posterior lenticular surface. Those changes result in an increase in lens optical power and near focus. The study of accommodation with ultrasound biomicroscopy (UBM) found the anterior and posterior surfaces to contribute to 63 and 37% changes in lens thickness during accommodation, respectively, and demonstrate a subsequent anterior movement of the lens’ geometric center. ³ Another accommodative change is the decrease in anterior chamber depth (ACD) and intraocular pressure (IOP). The cornea is static and undergoes no changes during accommodation. ⁴

The ability of the eye’s optical system to increase its power is reduced with age, resulting in presbyopia. The reduction is said to occur at a rate of about –0.19 D a year, with a complete loss of accommodation around the age of 55 years. ^{3,​ 5} The cause of presbyopia is multifactorial and not yet entirely understood. It involves subtle changes in the zonules, crystalline lens, and the ciliary muscle.

The equatorial fibers of anterior zonules decrease in number with age and the zonular insertion progressively shifts anteriorly, changing the mechanical interactions between the crystalline lens and the ciliary muscle. ⁶ The accumulation of Ca²⁺ and lipids contribute to zonular fragility.

The ciliary muscle has been demonstrated to develop connective tissue within it with age. ⁷ It is, however, believed to be the result, not the cause, of presbyopia. As the lens grows, it displaces the uveal tract anteriorly and inward, which in turn makes the ciliary muscle contraction irrelevant. ⁵ The theory that connective tissue development is a secondary occurrence seems to be proven by the fact that the ciliary muscle contraction is undiminished throughout life, and was even demonstrated to increase in presbyopic subjects. ⁷ This phenomenon may be the vain effort of the ciliary muscle to overcome ever-increasing lens stiffening.

The crystalline lens undergoes the most notable changes, and is regarded as the chief culprit of presbyopia. Its capsule is made up of type IV collagen, which is subjected to a natural process of cross-linking and glycation with age. This results in the doubling of the capsular thickness between the first and the eighth decades with a concomitant reduction of capsular elasticity ⁸. The lens itself is characterized by its lifelong growth. Lens epithelial cells (LEC), located on the anterior lens surface, lose their organelles and differentiate to form lens fiber cells, which are characterized by their high protein concentration and lack of cellular structures. ⁵ Old fiber cells are progressively pushed to the center and compacted by the ever-increasing new layers, similar as in a pearl. This lifelong accumulation of LEC fibers results in an increase in lens thickness, with little change in equatorial diameter, and a progressive decrease in elasticity due to lens compaction. The most pronounced changes occur within the lens nucleus, as it becomes harder and more compact, while the cortex, inversely, becomes more flexible. Overall, the growing lens assumes a lower axial position in the eye.

Although many components play a role in presbyopia, the modification of overall lenticular stiffness seems to be the main limiting factor in the loss of accommodation in presbyopic subjects. A rotational method of assessing the lens’ elasticity, introduced by Fischer in 1971, quantified the age-dependent axial deformation of rotating cadaver lenses. ⁹ A different stretching method, proposed by Adrian Glasser in 1998, investigated the changes in lenticular curvature and the focusing of light rays while stretching the ciliary body, zonules, and lens complex of dissected cadaver eyes, where the dissected scleral band is mounted onto a stretching apparatus. ¹⁰ Both of these studies identified the stiffening of the lens to be the limiting factor in lens deformation with age. A different method for investigating the lens’ mechanical properties employs a mechanical compressive device, which tests the lens’ resistance to a gradually increasing external compressive force. Unfortunately, all those methods are invasive and can be only performed ex vivo.

In vivo testing of accommodation, on the other hand, is tricky, because the iris compromises the visibility of the human accommodative apparatus from outside investigation. Imaging methods like UBM, magnetic resonance imaging (MRI), and Scheimpflug imaging have been used to visualize ocular structures during different accommodative states. Baikoff et al studied accommodation in an albino subject with optical coherence tomography (OCT), and they were able to directly confirm and visualize anterior segment modifications as described by Helmholtz over 150 years ago. ¹¹

16.3 Crystalline Lens Photodisruption for Accommodation Restoration

16.3.1 Basic Concepts

As stated earlier, the crystalline lens seems to be the natural and most obvious target of accommodation restoration procedures. Techniques like Phaco-Ersatz and clever accommodative IOL designs have been proposed in order to make use of the eye’s accommodative apparatus after cataract surgery, unfortunately with inconsistent results. Up until this time, there has been no proposed technique involving a modification of the crystalline lens that does not require its extraction. Even with the first symptoms of presbyopia beginning near the age of 44 to 45 years, and with a definite loss of accommodation between 50 and 55 years, it would still be many years before the development of a vision-compromising cataract that would warrant intraocular surgery. Ideally, a fast, safe, and minimally invasive procedure could benefit those in both the presbyopic and the prepresbyopic ages.

The idea of softening a hard nucleus with laser pulses in order to restore accommodation was first proposed in 1998. ¹² The aim was to enhance lens fiber sliding and in turn to rejuvenate the lens’ accommodative properties. The concept was truly ahead of its time, specifically in relation to the laser technology available and the complexity of three-dimensional and dynamic refractive correction. In 2001, the first in vitro evaluation of the concept was performed. Freshly excised cadaver lenses were first placed on a rotational device and their elasticity (rotational deformation) was studied using the Fisher method discussed earlier, confirming Fisher’s observations of lens stiffening with age. Next, neodymium-doped:yttrium aluminum garnet (Nd:YAG) laser pulses were applied in a central ring pattern (▶ Fig. 16.1) and rotational deformation was measured and compared with the contralateral, untreated lens. The experiment showed a significant increase of elasticity in the laser-treated group, with some lenses achieving a rotational deformation comparable with that of lenses 20 years younger. ¹³ These results seemed promising, but the nanosecond laser used in this study was only a crude energy source used to illustrate the possibility of accommodation restoration. Nevertheless, the experiment was an important milestone, and helped fuel the engineering research needed to design a shorter pulse, lower energy lasers that could be used in this application.

16.3.2 Cataractogenesis and Safety

The concept of using a laser for accommodation restoration in a clear lens makes sense only if it preserves good vision and does not induce vision-threatening or progressive cataracts. However, the very idea of surgically modifying the crystalline lens seems to be undermined by a deeply rooted belief, that any trauma to the crystalline lens induces a cataract. Certainly, the use of nanosecond lasers, with high-energy effects and extensive collateral damage to surrounding lens tissues, is not safe in clear lenses. Vogel et al observed that decreased laser pulse duration allows the use of less energy and therefore causes less collateral damage. ¹⁴ Based on this relationship, a much safer prototype picosecond laser and delivery system was created, allowing the studies on lenticular photodisruption to increase momentum. Later, the commercial femtosecond laser unit, developed for refractive laser-assisted cataract surgery, allowed for further refinement in energy delivery and treatment pattern design. By lowering the energy threshold needed for photodisruption, the three effects of photodisruption, plasma formation, shock wave generation, and cavitation bubble formation, are each minimized (▶ Fig. 16.2). Any heat generated by the ultrashort laser pulses is too low and the thermal diffusion is too slow to dissipate the energy by heat conduction. Instead, a rapidly expanding plasma provokes the creation of a minimal shock wave, which is atraumatic within the surrounding tissue and only leaves behind a small residual gas bubble, which can aid in separating that tissue. The above features make femtosecond lasers a unique and an essential tool in clear lens procedures.

In 2005, Krueger et al treated six living rabbit eyes with femtosecond laser pulses of 1 μJ/pulse and spacing of 10 um with the contralateral eye serving as control. After treatment, there was a presence of an array of intralenticular bubbles, which resolved with time, leaving only faint evidence of laser treatment pattern (▶ Fig. 16.3). The rabbits were followed for 3 months; one specimen developed cataracts in both treated and untreated eye, which was judged unrelated to laser treatment. All other remaining eyes showed good transparency, while several treated lenses showed even less light scatter than the respective control eye. Ultrastructural examination demonstrated an electron dense border of 0.5 to 1.0 um with surrounding lens fibers of normal architecture (▶ Fig. 16.4). ¹⁵

The first long-term studies involved nonhuman primates; ² seven rhesus monkeys were enrolled in a similar experiment with a follow-up time of over 4.5 years. The primates underwent total iridectomies to facilitate the visualization of the lens, zonules, and the ciliary body. The laser used in the study had a 10-ps pulse width and a wavelength of 1064 nm. Much higher pulse energy and total energy, compared to the rabbit study, were used, with pulses of 25 to 45 μJ and 2 to 10 million spots in each eye. Again, there was an immediate bubble formation (▶ Fig. 16.5) that disappeared within 24 hours. After 4.5 years, four of the original seven primates were still living; one never received any laser treatment, one received treatment in only one eye, and the remaining two received treatment in both eyes. The study concluded that progressive cataract does not occur in eyes that did not present a preexisting cataract. The slit lamp findings at 4.5 years after treatment included faint translucencies indicative of laser pulses, nevertheless allowing for excellent funduscopic images (▶ Fig. 16.6). Interestingly, the primate with preexisting cataract did not show any progression after laser treatment at the end of the follow-up; however, it did develop central opacities that did not prevent clear visualization of the posterior pole (▶ Fig. 16.7).

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