Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Clinical background

Accommodation refers to a process whereby a change in position as well as increased curvature of the crystalline lens increases the conjugation power of the eye, i.e., its ability to converge an image to focus on the retina. This process allows for the focus of a near object of regard on the retina. The first well-recognized and now widely accepted theory of accommodation was proposed by Hermann von Helmholtz in 1856. Helmholtz’s theory posits that accommodation occurs through a relative rounding of the lens due to relaxation of the zonules, the fibrous elements that suspend the lens in place. The ciliary muscle attaching to the fibrous zonules contracts during accommodation, leading to relaxation of the zonules and therefore rounding of the crystalline lens. The change in shape of the lens leads to increased conjugation power of the eye, and therefore enhanced focus at near (Figure 35.1).

As humans age, a well-established age-correlated decrease in accommodation occurs starting at just over the age of 40. This process is known as presbyopia. The causes of presbyopia are varied and include changes in the lens shape, size and compliance, as well as changes in the ciliary body and zonular structure.

Based on the various etiologies of presbyopia, multiple surgical approaches have been introduced for restoring accommodation in the presbyopic or pseudophakic population with variable effectiveness. These procedures can be broadly categorized into two groups: procedures intended to enhance the change in crystalline lens shape during accommodation that is attenuated in presbyopia, and procedures whereby the rigid and enlarged crystalline lens is removed and replaced by a multifocal or accommodative intraocular lens (IOL).

Pathology

Lens changes in presbyopia

The lens increases in thickness with age, with a 60-year-old lens having on average one-third greater volume than a 30-year-old lens (Box 35.1). This is demonstrated by exten-

sive cadaveric analysis, ultrasound, and scheimpflug biomicroscopy.1,2 In theory, a larger lens is more difficult to deform than a smaller lens. Mimicking zonular forces, Glasser and Campbell3 demonstrated that older lenses exhibit less change in focal length when stretched radially, both with and without the lens capsule. Fisher4 has studied in great detail changes in the elasticity and water content of the lens substance, and has demonstrated constant water content with increased stiffening of the lens substance with age. By Fisher’s mathematical modeling,4 these lens changes contribute 55% of presbyopia.

Ciliary body changes in presbyopia

An age-dependent decline in ciliary body movement, amplitude, and velocity was demonstrated by Croft et al5 through dynamic real-time videography in monkeys. This finding suggests that decreased functioning of the ciliary body itself may contribute to presbyopia. Poyer et al,6 however, found no evidence of variable muscle function with age by observing in vitro ciliary muscle contractility induced by cholinergic agents. Examination of rhesus monkey eyes by biomicroscopy and electron microscopy revealed that posterior tendons of ciliary muscle in older monkeys exhibited increased fibrillar material compared to those of younger monkeys. Increased mechanical stiffness of the posterior insertion of the muscle with age with preserved muscle contractility may therefore contribute to presbyopia.7

Lens capsular changes in presbyopia

Fisher4 postulated that, if the lens capsule is truly elastic, it can transmit radial forces from zonules to the lens and alter the lens shape during accommodation without requiring an anteroposterior force, such as vitreous pressure. Fisher4 demonstrated that the lens capsule does have elasticity sufficient to deform the shape of the lens anteroposteriorly, as shown by centrifuging lenses to create a radial force mimicking zonules. Fisher’s work demonstrated that this elasticity appears to decrease precipitously with age, a process thought to contribute at least 40% of presbyopia. The lens capsule’s ability to mould the lens necessitates compliance of the lens matrix as well as sufficient force generated from the capsule. Both of these factors appear to decline with age.2,4

Figure 35.1  Diagram of the Helmholtz theory of accommodation. (A) A cross-section of the anterior segment during relaxation of accommodation.

(B) Accommodation leads to contraction of the ciliary body muscle leading to relaxation of the zonules and rounding of the lens. The increased anteroposterior thickness of the lens increases the converging power of the eye.

Box 35.1  Anatomical changes in the eye with age

•Thickness of the crystalline lens increases

•The ciliary body muscular insertion becomes stiffer with age but the muscle itself retains contractility. Overall ciliary body muscle function decreases

•The lens capsule decreases in elasticity

•Zonular attachments migrate anteriorly

Box 35.2  Schachar’s theory

•Zonular tension increases during accommodation. Increased lenticular size with age decreases zonular tension, leading to presbyopia

Zonular changes in presbyopia

With age, the zonular attachments to the lens migrate anteriorly, likely due to the expansion of the lens size. With a greater tangential orientation of the zonules to the lens, zonules are less able to generate force, contributing to presbyopia.2

Alternative theories of presbyopia

In 1994, Schachar8 proposed a theory of accommodation that rebukes the widely accepted Helmholtz theory (Box 35.2). According to Schachar’s theory, zonular tension primarily increases during accommodation. As the anterior and posterior surfaces of the lens round during accommodation, the anterior and posterior zonules, those that are visualized by biomicroscopy in vivo, relax. Meanwhile, the more important equatorial zonules increase in tension during accommodation with contraction of the ciliary body. This leads to relative flattening of the peripheral lens, but steepening of the central lens. Following this theory, increased lenticular size with age decreases equatorial zonular tension, leading to presbyopia. Scleral expansion surgery may counteract presbyopia by reinstating equatorial zonular tension.

By Schachar’s theory, increased equatorial zonular tension during accommodation should pull the lens equator toward the sclera. Glasser and Kaufman’s work9 contradicts Schachar’s theory by demonstrating in vivo that the lens

Box 35.3  Coleman’s catenary theory

•Differential pressures in the anterior and posterior chambers are created during ciliary body contraction, creating a reproducible shape of the anterior lens surface important for accommodation

Box 35.4  Etiologies for loss of accommodation

•Normal aging process

•Pseudophakia

•Aphakia

•Changes in ciliary body functioning (spasm, paralysis, or atony)

•Cranial nerve 3 palsy

equator moves away from the sclera during accommodation in monkeys induced by Edinger–Westphal stimulation as well as local pharmacologic agents. Their work also revealed a downward sag of the lens with gravity during accommodation, which further challenges Schachar’s theory.

Coleman proposed a theory in 197010 supporting a role for vitreous pressure in the processes of accommodation and presbyopia (Box 35.3). His catenary theory states that the lens, zonules, and vitreous act as a diaphragm controlling differential pressures in the anterior and vitreous chambers. Ciliary body contraction during accommodation initiates movement of the diaphragm, creating a differential pressure gradient in the eye between the anterior chamber and the vitreous cavity. Coleman asserts that this pressure gradient is crucial in establishing a reproducible “catenary” shape of the anterior lens surface during accommodation. Coleman’s theory is supported by a mechanical model and demonstration of differential pressures in the two chambers during accommodation. By Coleman’s model, the development of more flexible IOLs may provide some degree of accommodation.11,12

Mathematical modeling suggests that posterior pressure by the vitreous may be important in the process of accommodation, supporting Coleman’s theory.13 However, recent modeling with a two-dimensional axisymmetric model did not reveal an increase in refractive power with posterior lenticular pressure.14

Etiology

Loss of accommodation most commonly occurs by three primary mechanisms: presbyopia as a normal process of aging, pseudophakia (lens extraction followed by implantation of an artificial lens without the ability to accommodate), and aphakia (lens extraction without replacement). Less commonly, premature loss of accommodation can occur secondary to paralysis, spasm, or atony of the ciliary muscle. For example, cycloplegia with a pharmacologic agent such as atropine will paralyze the ciliary muscle and inhibit accommodation. A cranial nerve 3 palsy also paralyzes accommodation via loss of neurologic innervation of the ciliary muscle (Box 35.4).

Box 35.5  Helmholtz theory

•The equatorial zonules relax during accommodation, leading to rounding of the central lens curvature, increasing the converging power of the eye

Pathophysiology

The lens

According to the Helmholtz theory of accommodation, the equatorial zonules maintain tension on the lens at rest, allowing for a relative flattening of the central curvature of the lens and an enlarged diameter. An effort to focus at near induces ciliary body contraction which paradoxically relaxes the zonules due to a centripetal movement of the muscle (Figure 35.1). In turn, the zonules release tension on the equator of the lens, allowing the lens to round up at the anterior and posterior surfaces, increasing in thickness and therefore the converging power of the eye (Box 35.5).15

In the modern era, through ultrasound biomicroscopy and goniovideography, Glasser and Kaufman9 have been able to substantiate the Helmholtz theory and further characterize the accommodative process in monkeys. These investigators have documented that not only does the lens equator move away from the sclera radially during accommodation, but it also moves anteriorly due to a forward migration of the ciliary body during contraction. The contracting ciliary body, anchored to the scleral spur, trabecular meshwork, and peripheral cornea, acts as a sling to bring the lens forward during accommodation. Conversely, the elastic choroid and posterior zonules pull the lens posteriorly during relaxation of accommodation.

In addition to intraocular changes altering the lens, a number of other intraocular and extraocular changes are known to occur during accommodation to assist with viewing objects at changing distances. These factors are not considered true components of accommodation by its strict definition.

Pupil size

The pupil becomes smaller with accommodation effort by way of parasympathetic innervation of the iris sphincter from the Edinger–Westphal nucleus via the third cranial nerve.16,17 Such a process is known to enhance depth of focus that assists with near viewing.18 Recent work has demonstrated that the dynamic pupil near response does not change appreciably with age, and therefore likely does not contribute to or counteract presbyopia.19 Static pupil size tends to decrease with age.17

Restoration of accommodation

Box 35.6  Extraocular changes that occur with

accommodation

•Pupil size decreases

•Convergence

Box 35.7  Stimuli for accommodation

•Retinal disparity between the two eyes

•Change in angular size of an object

•Image blur

Neural pathways in accommodation

Accommodation is initiated by voluntary effort to focus on near objects. Multiple stimuli for accommodation have been identified, but not all are well understood. It is likely that the most powerful stimulus for accommodation is retinal disparity between the two eyes as they focus on an object at varying distances. Monocular accommodation is driven by other cues for distance. For example, a change in angular size of an object has also been shown to induce accommodation even in the absence of actual distance change if all else is kept constant.21 Image blur also induces accommodation. Placing minus lenses in front of the eye, with angular size maintained constant, appears to induce accommodation by way of blur. This effect is diminished when blur cues are blunted, such as with decreased illumination or increased depth of focus with a pinhole.22 The mechanism by which the brain appears to recognize the appropriate direction of accommodation with blurring is unknown. Simply blurring an object without changing the refractive status of the eye or the object distance does not induce accommodation (Box 35.7).21

Neuronal pathways in the brain controlling accommodation are not fully understood but appear to involve primarily the Edinger–Westphal complex in the midbrain. The Edinger–Westphal complex receives inputs from the ventral and rostral midbrain, the likely location for receipt of accommodative cues such as retinal image disparity. From the Edinger–Westphal complex, the parasympathetics and thirdnerve fascicles leave and synapse at the ciliary ganglion. Postsynaptic fibers continue to join the posterior ciliary nerves reaching the iris sphincter for control of pupil size as well as the ciliary body for control of accommodation17 (Figure 35.2).

Tonic accommodation occurs at all times without any neural stimulus. Presumably baseline innervation from the midbrain is constantly firing. In a completely darkened room and without cognitive near cues, young adults are found on average to accommodate approximately 1.00 D.20

Convergence

Changes in stimulation of the rectus muscles bilaterally allow for convergence of the eyes to focus on objects binocularly at varying distances. Stimuli for accommodation, both binocular and monocular, initiate convergence (Box 35.6). Therefore, accommodation within the eye and ocular convergence occur in parallel.20

Restoration of accommodation

Scleral expansion surgery

Scleral expansion surgery is based on Schachar’s theory8 of accommodation that postulates that equatorial zonules increase in tension during accommodation. By this theory,

ract development with this treatment. In favor of the treatment, however, use of the femtosecond laser on live rabbit lenses resulted in intralenticular bubble formation that resolved without cataract formation after 3 months.29 Further studies in humans are necessary to understand both the safety and efficacy of this treatment approach.

Intraocular lens surgery

Replacement of the lens substance by capsule-filling gel

Given that loss of lens matrix compliance appears to be in large part responsible for presbyopia, replacing the lens with pliable material has been explored extensively as a strategy to combat presbyopia. Two methods have been devised to refill the lens. By one method, a viscous material is injected into the capsule after removing the lens from a small opening in the capsule.30,31 A second method involves insertion of a balloon filled with the viscous material into the empty capsule. Kessler first devised a method in 1964 by which the empty lens capsule is injected with a polymer mimicking the youthful crystalline lens.32 Since then, multiple attempts have been made to achieve results for capsular refilling in animal models. Haefliger and Parel33 have investigated direct capsule bag refilling in a primate model, and reported change in anterior-chamber depth representing accommodation under pilocarpine stimulation. Their method of evaluating accommodation has been refuted more recently because change in anterior-chamber depth may actually represent pilocarpine’s effect on the position of the lens–iris diaphragm rather than definitive evidence of accommodation.34 Nishi et al35,36 were able to demonstrate refractive changes suggesting a small amount of accommodation by automated refractometry with pilocarpine after capsular refilling with injectable silicone in both rabbits and monkeys. Nishi’s method utilized a silicone plug to prevent leakage of the injected silicone.

To avoid the technical challenges of removing a cataract from a small capsular opening and to prevent leakage of liquid from the capsular bag, a fluid-filled balloon was devised to contain the liquid artificial lens material. In rabbits, this technique failed to improve accommodation substantially and also resulted in capsular opacification.37 Monkeys demonstrated only a modest improvement in accommodation that decreased with time with fibrosis of the lens capsule.38

Hettlich et al31 devised a method of injecting a monomeric material that can be polymerized inside the capsular bag by short light exposure to avoid risk of fluid leaking out of the lens after the surgery. Containment of the artificial lens material with a balloon is no longer necessary by this method. However, beyond initial safety studies in animals, no further developments have been made using this technique.

Lens refilling by either liquid polymer injection or balloon insertion has several important drawbacks (Box 35.10). It is difficult to achieve a specific lens power with liquid polymer injection. The range of accommodation in animal models is most often minimal and frequently unpredictable. The accommodative effect appears to be unstable and short-lived due to capsular fibrotic changes. More importantly, posterior

Restoration of accommodation

Box 35.10  Lens refilling with a gel

•Methods include liquid polymer injection and liquid-filled balloon insertion

•Use of balloons or silicone plugs helps counteract risk of postoperative leakage

•Animal studies show only modest refractive results in restoring accommodation with significant capsular lens opacification postoperatively

•Refractive results are unpredictable

Box 35.11  Multifocal intraocular lenses

•Utilize concentric rings of differential power to allow for far, near, and intermediate vision

•Well-established improvement in near vision with implantation of these lenses

•Decrease in contrast sensitivity is a significant side-effect that limits use

and anterior capsular opacification is an almost universal complication in both monkeys and rabbits in lens refilling by 3 months following surgery. Performing YAG capsulotomy may result in herniation of the lens material, negating the refractive benefits of the initial surgery.39

Multifocal intraocular lenses

While not actually restoring accommodation by its strict definition, multifocal IOLs have been utilized extensively to enhance near vision while maintaining distance acuity. These lenses employ concentric rings of differential refractive or diffractive power in the optic to allow for far, near, and in some cases intermediate vision (Box 35.11). Some lens designs exploit pupil size changes that naturally occur with changing distance of focus effort by assigning the lens center to near focus. While demonstrated to be effective in improving near vision and pseudoaccommodation by defocus curve analysis and subjective near vision testing, the almost universal prominent decrease in contrast sensitivity has encouraged the development of alternative modalities for restoration of accommodation.40

Accommodative intraocular lenses

As an alternative to capsular bag filling, Hara and colleagues proposed the implantation of a rigid optic lens implant that moves with accommodation to change the refractive status of the eye.41 These investigators devised an implant known as the “spring IOL” with two optics connected by a polypropylene coil spring. The two optics are compressed by the capsular bag and then separated with ciliary body constriction as tension on the capsular bag is released. A modification of the original design consisted of two optics separated by four peripheral polyvinylidene fluoride haptics. The posterior optic is plano while the anterior optic contains the appropriate power for the lens complex. The haptics transmit the movement of the capsular bag due to changes in zonular tension during near activity.41 Initial rabbit studies failed to demonstrate accommodation with these devices, likely due to species-specific limitations.42

Subsequent developments of accommodating IOLs have relied on similar principles to the “spring IOL,” utilizing a pair of hinged optics that harness the force of ciliary body contriction for axial movement and refractive change in the eye during near work. Changes in posterior vitreous pressure, as described by Coleman,12 may also play a role in accommodating IOL movement. Clinical trials with these devices have demonstrated a modest degree of accommodation in humans. Some of these devices are still in the early stages of clinical evaluation and show promise for clinical efficacy, while others have received Food and Drug Administration approval and have entered clinical practice. See Figure 35.4 for various accommodating IOL schematics and photographs and Box 35.12.

In a recent meta-analysis of accommodating IOLs,43 five randomized controlled trials and 15 nonrandomized con-

272

trolled trials were identified assessing the clinical success of the HumanOptics (Erlangen, Germany) 1CU implant (Figure 35.4A). Three of the five randomized controlled trials found a statistically significant improvement in distance corrected near visual acuity compared to control subjects with monofocal implants. Nonetheless, the mean distance corrected near visual acuity from all 20 studies is only J7. Several of these studies demonstrated axial movement of the IOL with instillation of pilocarpine, supporting the principles of design. Unfortunately, neither a mean axial movement of 1 mm or less nor a mean distance corrected near visual acuity of J7 in these studies would accomplish the goal of freedom from reading glasses.43

Seven nonrandomized studies of another accommodating IOL, the AT-45 Crystalens (Eyeonics, , Aliso Viejo, CA), found highly variable results in clinically demonstrated

Box 35.12  Accommodative intraocular lenses

•HumanOptics (Erlangen, Germany) 1CU implant: randomized controlled trials in humans show significant improvement in near vision and appropriate movement of lens with pilocarpine; however, most patients still require reading glasses

•AT-45 Crystalens (Eyeonics, Aliso Viejo, CA): nonrandomized controlled trials in humans show improvement in near vision to J3 in over 90% of subjects; however, variable movement of lens with pilocarpine

•Synchrony lens (Visiogen, Irvine, CA): has a high-powered plus anterior optic coupled with a compensatory minus posterior optic. Early pilot study controlled trials show 96% of subjects with J3 or better near vision; however further studies are needed

•BioComFold IOL 43E (Morcher, Stuttgart, Germany): has a peripheral bulging ring that pushes the intraocular lens forward with ciliary body constriction. Significant appropriate movement of the lens seen with pilocarpine; however no significant difference in accommodation

accommodation.43 (Figure 35.4B). The largest study of 246 subjects found 90.1% of subjects with this lens showing a best distance corrected near visual acuity of J3 or better.44 Biometric studies of IOL movement with pilocarpine 2% revealed conflicting results, however, with one study showing a backward movement of the IOL.43 Although promising, randomized clinical trials with appropriate control groups are necessary to assess the AT-45 Crystalens definitively.

Utilizing a dual-optic single-piece silicone IOL design, the Synchrony lens (Visiogen, Irvine, CA) has a high powered plus anterior optic coupled with a compensatory minus posterior optic (Figure 35.4C). By ray tracing analysis, this design enhances the accommodative power of the eye without requiring an increased axial movement of the IOL.45,46 In the pilot clinical study of 24 subjects with the Synchrony lens implant, 96% of subjects had a best distance

Key references

corrected near visual acuity of J3 or better. Subjects with the Synchrony lens implant had significantly greater accommodation measured by defocus curves compared to a control group with monofocal implants (3.22 D, range 1.00–8.00 D, compared to 1.65 D, range 1.00–2.50 D). While these results are promising, biomicroscopy to demonstrate IOL movement as well as larger clinical trials are needed to establish the efficacy of this accommodating IOL.

The BioComFold IOL 43E (Stuttgart, Germany) has a peripheral bulging ring that pushes the IOL forward with ciliary body constriction (no picture shown). Among 15 subjects implanted with the BioComFold IOL, the lens was shown to shift anteriorly to a greater degree than monofocal lenses with instillation of pilocarpine (0.72 ± 0.58 mm compared to 0.28 ± 0.38 mm); however no significant difference in accommodation measured by defocus curves was seen between the two groups.47

Conclusions

Restoration of accommodation is an exciting and dynamic field today. Various approaches to the reversal of presbyopia are currently in development. More sophisticated techniques accompanied by future human safety and efficacy trials are needed to elucidate the utility of modification of the crystalline lens as a technique for presbyopia reversal. Scleral expansion surgery continues to be a controversial technique and has an uncertain future. Multifocal lenses, while somewhat effective, are limited by quality of vision issues and loss of contrast sensitivity. While lens refilling techniques have largely been abandoned due to poor results in animal trials, advances in material and control of lens epithelial cell proliferation may improve performance. Multiple accommodating IOL designs are now entering the market with promising results in human clinical trials. Larger randomized controlled trials are needed to establish that these lenses provide adequate visual function to allow patients to forgo spectacle correction for the broad range of daily tasks.

3.Glasser A, Campbell MC. Presbyopia and the optical changes in the human crystalline lens with age. Vision Res 1998;38:209–229.

4.Fisher RF. The elastic constants of the human lens. J Physiol 1971;212:147–180.

8.Schachar RA. Zonular function: a new hypothesis with clinical implications. Ann Ophthalmol 1994;26:36–38.

9.Glasser A, Kaufman PL. The mechanism of accommodation in primates. Ophthalmology 1999;106:863–872.

10.Coleman DJ. Unified model for accommodative mechanism. Am J Ophthalmol 1970;69:1063–1079.

15.Helmholtz Hv. Treatise on Physiological Optics. New York: Dover Publications, 1962.

23.Kleinmann G, Kim HJ, Yee RW. Scleral expansion procedure for the correction of

presbyopia. Int Ophthalmol Clin 2006;46:1–12.

26.Mathews S. Scleral expansion surgery does not restore accommodation in human presbyopia. Ophthalmology 1999;106:873–877.

27.Myers RI, Krueger RR. Novel approaches to correction of presbyopia with laser modification of the crystalline lens.

J Refract Surg 1998;14:136–139.

32.Kessler J. Experiments in refilling the lens. Arch Ophthalmol 1964;71:412– 417.

33.Haefliger E, Parel JM. Accommodation of an endocapsular silicone lens (PhacoErsatz) in the aging rhesus monkey. J Refract Corneal Surg 1994;10:550–

555.

40.Leyland M, Pringle E. Multifocal versus monofocal intraocular lenses after

cataract extraction. Cochrane Database Syst Rev 2006;CD003169.

43.Findl O, Leydolt C. Meta-analysis of accommodating intraocular lenses. J Cataract Refract Surg 2007;33:522– 527.

44.Cumming JS, Colvard DM, Dell SJ, et al. Clinical evaluation of the Crystalens AT-45 accommodating intraocular lens: results of the U.S. Food and Drug Administration clinical trial. J Cataract Refract Surg 2006;32:812–825.

46.McLeod SD. Optical principles, biomechanics, and initial clinical performance of a dual-optic accommodating intraocular lens (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2006;104:437–452.

Overview

Intraoperative floppy iris syndrome (IFIS) was first characterized by Chang and Campbell in 2005.1 It is associated with the use of systemic α-receptor blockers, such as tamsulosin (Flomax), used in the medical management of benign prostatic hyperplasia (BPH). The features of IFIS are seen during cataract surgery despite proper wound construction and compose of a triad of: (1) a flaccid iris that billows in response to normal intraoperative fluid currents; (2) a strong propensity for the iris to prolapse through any or all properly constructed incisions; and (3) progressive intraoperative pupillary constriction.1 This behavior of the iris creates a difficult situation for the surgeon and can potentially increase the complication rate. About 2% of the general cataract surgery population has some degree of IFIS.1 Since the syndrome was first described, surgeons have devised a variety of techniques to minimize the characteristics of IFIS.

Pharmacology

The iris is a complex structure mediated by the iris dilator smooth muscle and the sphincter muscle. When the α-receptors are stimulated, the dilator smooth muscle contracts to cause pupillary dilation, and conversely, when the α-receptors are blocked, the dilator smooth muscle relaxes, causing pupillary miosis.2 There are nine subtypes of

α-receptors: α1a, α1b, α1d, α2a, α2b, α2c, ß1, ß2, and ß3.2 Like most tissues, multiple subtypes of adrenergic receptors exist

in the iris smooth muscle. However, iris contraction is 100fold more sensitive to α1-antagonists than α2-antagonists, which suggests that α1-receptors predominate in mediating dilation.2 Molecular, protein, and functional assays have found that the α1a-receptor subtype mediates iris dilator smooth-muscle contraction in animal species.2 It is presumed that humans have a similar α1a-receptor profile in the iris dilator muscle.

Like the iris, the prostate smooth muscle is also mediated by a balance of sympathetic, parasympathetic, and other receptor systems (Box 36.1). BPH is associated with lower urinary tract symptoms such as nocturia, dysuria, and incomplete bladder emptying.3 The main α1-receptor subtype found in the smooth muscle of the prostate, urethra, and

Intraoperative floppy iris syndrome

Amy Lin and Roger F Steinert

bladder neck is the α1a-receptor.2 Blockage of the α1a-receptor relaxes the prostatic smooth muscle to relieve outflow obstruction, and enhances urine flow. Older α1-receptor blockers such as alfuzosin (Uroxatral), doxazosin (Cardura), and terazosin (Hytrin) bind all α1 subtypes equally.2 Tamsulosin (Flomax) is more uroselective,3 as it selectively binds α1a and α1d-receptors.2 However, because tamsulosin is a systemic drug, it is also selective for the iris dilator smooth muscle.

It is presumed that the lack of tone in the dilator muscle of the iris due to the highly selective α1a-receptor blockade is responsible for the signs of IFIS.4 However, several studies have found that only a portion of patients on tamsulosin develop the manifestations of IFIS, and that there is a continuum of the degree of manifestation.5–7 Of patients taking tamsulosin, the percentage of eyes of patients with no IFIS features has been found to range from 10% to 43%.5–7 The percentage of eyes with all three characteristics of IFIS, or severe IFIS, has been reported as 30–43%.6,7 Manivikar and Allen8 found that 31% of eyes were well dilated and remained so throughout the surgery, 22% were well dilated but constricted during the surgery, 38% were mid dilated and remained the same or constricted further during the surgery, and 9% were poorly dilated at the outset.8 IFIS can present in varying degrees even between the two eyes of the same patient. Complete IFIS has been reported to occur in the eye of one patient, when surgery in the fellow eye 1 week prior did not reveal any IFIS.9

While IFIS is clearly associated with tamsulosin, it is unclear whether or not other medications or systemic conditions can manifest an IFIS-like picture. Because the nonselective α-blockers have some affinity for the α1a-receptor, one can presume that these medications may cause a minor degree of IFIS; however, multiple studies have not found an association between the nonselective α-blockers and IFIS.1,5 It is possible that other medications may cause IFIS. Zuclopenthixol, an antipsychotic with dopaminergic, as well as α-adrenergic blockade, may be associated with IFIS.10 However, this was found in just one patient, and thus warrants further study. Patients with diabetes and pseudoexfoliation syndrome can have poor dilation; however, these disease processes have not been implicated in IFIS.5 Similarly, pilocarpine, a muscarinic receptor antagonist, which causes miosis, has not been associated with IFIS.5 Furthermore, it has been reported that patients may develop IFIS

Box 36.2  Long-lasting effects of tamsulosin

•Stopping tamsulosin preoperatively does not affect the severity of intraoperative floppy iris syndrome

•Previous use of tamsulosin even years before surgery does not eliminate the manifestation of intraoperative floppy iris syndrome

without any known reason.5 There may be other issues at play in IFIS besides a simple α1a-blockade of the iris dilator muscle.

Preoperative intervention

Many solutions have been proposed to minimize the effects of IFIS. The first seemingly obvious solution was to remove the offending medication. The half-life of tamsulosin is 48–72 hours.1 Stopping tamsulosin use prior to cataract surgery may have a slight effect on improving preoperative dilation, but does not affect IFIS severity.6 Patients have been reported to have varying degrees of IFIS even if they had not taken tamsulosin for 1–10 years.1,7,9 It is thought that a relatively constant α1a-receptor blockade while patients are on tamsulosin therapy can lead to disuse atrophy of the iris smooth muscle.1 A lack of iris rigidity would explain the billowing of the iris to the point of prolapse through all wounds. The progressive miosis may be the natural response of the iris to its own billowing in the midst of normal irrigation currents. It is not known how long patients have to be taking tamsulosin before exhibiting the features of IFIS. It has been reported to occur after 3 months of use,7 but there have been anecdotal reports of occurrence after less than 1 month of therapy. Currently, most surgeons do not advocate discontinuing the drug before cataract surgery because of lack of evidence of any benefit (Box 36.2).

Intraoperative measures

Prior to the description of IFIS, there were various techniques for enlarging a poorly dilated pupil. These methods included pupil stretching, sphincterotomies, and pupillary restraints such as iris hooks and pupil expansion rings (Box 36.3). As reported in Chang and Campbell’s original article,1 pupil stretching and sphincterotomies did not prevent iris prolapse or progressive pupil constriction. This phenomenon was thought to occur because the IFIS pupillary margin remained elastic, and snapped back to its original size. The authors recommended iris hooks or expansion rings for maintenance of a sufficiently large pupil. It was further rec-

Figure 36.1  Oetting’s diamond configuration of iris retractors. (Redrawn with permission from Oetting TA, Omphroy LC. Modified technique using flexible iris retractors in clear corneal surgery. J Cataract Refract Surg 2002;28:596–598.)

Box 36.3  Interventions that may minimize the manifestations of intraoperative floppy iris syndrome

•Pupil expansion rings or iris hooks with subincisional placement

•Healon 5 to dilate pupil and tamponade iris anteriorly

•Topical atropine prior to surgery

•Intracameral phenylephrine or epinephrine

ommended that the iris hooks be oriented in the diamond configuration described by Oetting and Omphroy,11 which has an iris retractor placed subincisionally (Figure 36.1). This technique minimizes further iris prolapse and damage to the iris by the phacoemulsification needle, as well as increasing the space accessible by the phacoemsulsification needle.

Since the original IFIS article, surgeons have proposed a multitude of additional ways to maximize pupil size and prevent iris billowing and prolapse. A super-cohesive visco­ elastic, such as sodium hyaluronate 2.3% (Healon 5, Advanced Medical Optics, Santa Ana, CA) has been used to augment pupil dilation intraoperatively, as well as tamponade the peripheral iris to block iris prolapse. At low flow and vacuum rates, Healon 5 resists aspiration and can stay within the eye.4 Aspiration of the Healon 5 can be further prevented by keeping the phacoemulsification needle at, or posterior to, the level of the pupil. If aspiration does occur, the anterior chamber can be reinjected with more Healon 5, or a dispersive viscoelastic such as sodium hyaluronate 3%– chondroitin sulfate 4% (Viscoat) can be injected centrally following the initial peripheral Healon 5 injection, helping to resist aspiration and keep the original Healon 5 over the peripheral iris.4

If Healon 5 alone is used prior to the capsulorrhexis, capsule tearing can be more difficult because of the increased resistance within this viscoelastic environment. Arshinoff had already devised a method, termed the ultimate soft-shell technique, to simplify this step.12 Healon 5 is injected in the anterior chamber to about 60–80% full. Then the rest of the

anterior chamber is slowly filled with balanced salt solution (BSS) by aiming the injection cannula at the surface of the lens capsule, near the center. This keeps the anterior lens capsule well tamponaded during the capsulorrhexis, yet with minimal resistance to tearing.12

Additional pharmacologic measures to prevent IFIS manifestations have been reported. Preoperative use of topical atropine 1% twice a day for 10 days before surgery has been described to improve preoperative dilation over the standard drops of cyclopentolate and phenylephrine on the day of surgery. The dilation was maintained intraoperatively in most patients, with 19% (3/16) of patients requiring additional modifications of surgical technique.13

Intracameral pharmaceutical interventions for dilation have been explored. These methods may maximally stimulate the atrophic iris dilator smooth muscle. Manivikar and Allen8 employed standard topical dilating and nonsteroidal drops on the day of surgery, but also used intracameral preservative-free phenylephrine if the pupil was small or mid dilated at the start of surgery, or if there was significant pupil constriction or iris prolapse during the surgery.8 When intracameral phenylephrine was used at the start of surgery, there was a variable response, with some pupils staying the same size, and others dilating further. However, when intracameral phenylephrine was used when iris difficulties arose during surgery, it stopped the iris from prolapsing and dilated the pupil back to its preoperative size. This response took about 30–35 seconds for maximal effect.8

Because of the high acidity of dilating agents, there has been concern over toxicity. Manivikar and Allen8 were careful to use preservative-free phenylephrine diluted to a pH of 6.4. In a letter, Shugar14 described success in using intracameral epinephrine in the eyes of patients taking tamsulosin, with the thought that flooding the iris directly with epinephrine could overcome the α1a-receptor blockade. He evaluated the pH and performed rabbit studies to investigate any potential toxicity of his solution of 1 : 1000 bisulfite-free epinephrine mixed in a 1 : 3 dilution into his intracameral anesthetic mixture of BSS plus and preservative-free lidocaine (“Shugarcaine”: 3 parts BSS plus mixed with 1 part nonpreserved 4% lidocaine).14 The pH of his solution was 6.899, well within physiologic range. He injected the solution into the anterior chambers of rabbits, and found significantly less corneal edema than compared to bisulfite-containing solutions.

Masket and Belani15 reported success in using intracameral epinephrine diluted to 1 : 2500 in combination with topical use of atropine 1% for 2 days preoperatively. In 19 of 20 eyes, sufficient pupil dilation was achieved, without intraoperative constriction or billowing of the iris. One eye required iris hooks because no further dilation was achieved with intracameral epinephrine. Sodium hyaluronate 3%–chondroitin sulfate 4% (DisCoVisc), a mixed cohe-

sive as well as dispersive viscoelastic was used in all cases. The pharmacologic combination of atropine and epinephrine was postulated to have worked well because of the synergistic effect of blockage of the muscarinic receptors of the iris sphincter muscle, coupled with direct stimulation of the weakened iris dilator muscle with concentrated epinephrine. Use of DisCoVisc may have been of value as well, as it mechanically dilated the pupil further and also held the iris in a favorable position during surgery.

Bimanual microincisional cataract surgery may offer some benefit in IFIS cases, as it creates a small and maximally watertight seal to prevent iris prolapse, and has a separate irrigation port which can be kept anterior to the iris to prevent billowing. Chang and Campbell1 used this technique on four eyes, but it only helped in two of the cases. At the time of writing, there had not been any published studies regarding bimanual phacoemulsification and its role in IFIS.

Conclusions

There has been much interest in IFIS since it was first described. New techniques for preventing its manifestations continue to evolve. There are still questions surrounding the pathophysiology and variability of its clinical presentation, with ongoing studies in this area. Because of the potential increase in risk of complications during surgery, it is vital that all patients be screened for any past history of taking tamsulosin. Although tamsulosin is indicated for the treatment of BPH, it is also being used off-label in women for treatment of lower urinary tract symptoms. Knowledge of tamsulosin use is the first step in anticipating possible IFIS. A surgeon should be comfortable with various methods of dealing with IFIS to decrease the rate of complications.

Summary

IFIS has been associated with tamsulosin (Flomax), a highly selective α1-receptor drug for BPH. Because antagonism of the α1-receptors causes relaxation of the iris dilator muscle, it is thought that lack of iris tone causes the features of IFIS: a billowing iris, iris prolapse, and progression intraoperative miosis. There is a great variability of IFIS presentation, ranging from no manifestations to a severe degree of presentation. A patient with any present or previous history of taking tamsulosin is considered at risk for exhibiting IFIS. There are a variety of intraoperative maneuvers to help the surgeon achieve control over the abnormal iris, and thus prevent complications during cataract surgery. Anticipation of possible IFIS is the first step to a successful surgery in the setting of IFIS.

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