In the developed world, cataract surgery has become a routine

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1 REVIEW ARTICLe The Complexities of Negative Dysphotopsia Ivayla I. Geneva, MD, PhD,* and Bonnie A. Henderson, MD Abstract: The appearance of a dark shadow in the temporal periphery, otherwise known as negative dysphotopsia, continues to be a problem for some patients after routine uncomplicated cataract surgery. Etiologies include type and design of intraocular lens (IOL), anatomical features and dimensions of the eye, pupil size, angle kappa, relationship of the optic to the anterior capsule, and the position of the optic/haptic junction of the IOL. Although the primary etiology remains controversial, it is clear that the cause is multifactorial. All of the factors should be considered when attempting to prevent or treat this phenomenon. Key Words: negative dysphotopsia, photopsias, cataract surgery, shadow (Asia-Pac J Ophthalmol 2017;6: ) In the developed world, cataract surgery has become a routine procedure that can be safely accomplished in the outpatient setting. In the United States alone, there are nearly 4 million such surgeries performed each year with about 9000 cataract surgeons actively practicing in the field. 1 The number of available intraocular lenses (IOLs) is similarly large, with new designs and materials emerging every year. 2 Although the majority of cataract surgeries leave the patient entirely satisfied, the postsurgical outcomes continue to be hampered by photic phenomena. 3,4 Of these, positive dysphotopsia is the more extensively studied variant and is characterized by bright artifacts such as arcs, streaks, and halos that appear in the midperiphery or center of the retina of affected individuals. 5 7 First described in 1993 by Masket et al, 8 positive dysphotopsia is quite common, affecting up to 49% of cataract surgery patients immediately after the procedure 9 but then the incidence decreases to 0.2% to 2.2% over the following year, where the resolution is believed to depend on various factors including the IOL type. 10 Although positive dysphotopsias may be more common, negative dysphotopsia (ND) represents a bigger challenge when it persists. 3,11 It has been the focus of research since ; however, the etiology remains elusive and is likely multifactorial. 3 It affects up to 15.2% of patients immediately after surgery and similar to positive dysphotopsia, the incidence of ND declines over time. Approximately 2 3% of patients complain of permanent symptoms, requiring invasive procedures From the *Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY; and Department of Ophthalmology, Tufts University School of Medicine, Boston, MA. Received for publication March 17, 2017; accepted May 29, The authors have no funding or conflicts of interest to declare. Reprints: Bonnie An Henderson, MD, Ophthalmic Consultants of Boston, 52 Second Avenue, Suite 2500, Waltham, MA E mail: bonnieanhenderson@ gmail.com. Copyright 2017 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO including IOL exchanges. Negative dysphotopsia manifests as a dark shadow in the peripheral vision, which is perceived by some patients as severely as a retinal detachment or vascular occlusion, 9 whereas others seek extensive neurological evaluation. 12 This article provides a comprehensive review of the intriguing field of negative dysphotopsia. materials and methods All published articles up to March 2017 were identified and reviewed. The key words negative dysphotopsia and the search engines PubMed, Google Scholar, and Retina Medical were employed. Additionally, the references in all identified papers were evaluated for additional published material. The discussion focus was aimed at full papers, case series, and case reports. However, if judged to contain significant new material, information from published commentaries and replies was also included. Origin The first published manuscript on negative dysphotopsia by Davison 10 in 2000 included hand drawings by patients suffering from dark shadows in their peripheral vision that appeared shortly after cataract surgery. It is now appreciated that the shadows can occur in the form of an arc or a crescent, but in either case are always in the temporal-most part of the visual field. The interest in negative dysphotopsia over the years has been growing in the cataract surgery community, with the number of publications (research articles, correspondences, case series, case reports, and reviews) steadily increasing each year (Fig. 1). In addition to these full papers, the topic of ND has been often the focus of discussion in the Journal of Cataract and Refractive Surgery (JCRS) consultation section, along with comments and replies. 50 Diagnosing Negative Dysphotopsia It is well established that ND occurs shortly after surgery and is usually documented on the first postoperative day when the patient starts complaining of visual deficits in peripheral vision, which are perceived as dark shadows. Experimental studies by Osher 51 involving several patients with ND demonstrated that the shadow can change in shape and severity as the direction of gaze changes. Namely, the shadow is perceived as more intense when the eye adducts and may disappear when it abducts or when the temporal field is shielded with a hand. Further, the same study along with a report by Trattler 52 found that the shadow can thicken when the gaze is directed into a mirror. Negative dysphotopsia can also be stimulated by a peripheral point source. 53 Interestingly, ND has a tendency to occur in both eyes of affected individuals, 52,54 56 which has been linked to person-specific anatomical predisposing factors, which will be discussed later in this review. Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017

2 Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 Negative Dysphotopsia figure 1. Publications regarding negative dysphotopsias. Although ND is easy to diagnose, the incidence rates vary widely from 0% to 15.2%. 9,48,51,55,57 60 These differences could be attributed to the use of a variety of IOLs and different surgical approaches. Additionally, it is believed that higher incidence rates are related to actively asking the patient about the symptoms the day after surgery. 51 More objective findings to confirm the diagnosis can be generated by a computerized visual field exam that would show a temporal scotoma, first reported by Marques et al 61 in 1 patient with ND. A more recent prospective case-controlled study by Makhotkina et al 62 demonstrated that in at least 3 out of the 11 studied eyes with ND, there was a relative scotoma that matched the ND symptoms. Multifactorial Etiology Over the past 1.5 decades a number of associations have been made between the occurrence of ND and possible predisposing factors. Although there is evidence supporting these associations, as will be illustrated shortly, there are also numerous reports of exceptions, thus rendering the prediction of which patient will develop ND quite challenging. IOL Material and Design With the introduction of the term negative dysphotopsia by Davison 10 in 2000 also came the first proposed etiology. Davison studied the postoperative outcomes of 6668 consecutive eyes implanted with the sharp-edged acrylic IOLs Acrysof MA30 and MA60 (Alcon Laboratories, Inc) starting in Davison concluded that it was this particular edge design and the acrylic material with its higher refractive index (1.44 to 1.55) as compared with silicone (1.41 to 1.46) 63 that predisposes to ND. The incidence of ND Davison reported in his inaugural paper was only 0.2%, yet this was a photic phenomenon previously unknown to his highvolume practice. It was around the same time, in the mid-1990s, when acrylic IOLs became popular among cataract surgeons as they offered 2 much sought after characteristics: the acrylic material results in lower rates of capsulorrhexis diameter shrinkage as compared with silicone IOLs 64 and the truncated edge design is associated with lower rates of posterior capsule opacification Unfortunately, the number of reports of negative dysphotopsia associated with this IOL type was growing. In a study published 2 years later, Davison 55 reported ND incidence of 0.73% among 2044 eyes implanted with Alcon esa30al and 0.85% among 586 eyes implanted with SA60AT (Alcon). Narvarez 58 reported ND incidence of 6.7% among 30 eyes implanted with the squareedged Tecnis Z9000 silicone IOL (Abbott Medical Optics). Radford 59 reported an incidence of 13.2% in 32 eyes implanted with AcrySof SN60AT (Alcon). Wei 48 reported an incidence of 0.7% among 467 eyes implanted with SA60AT (Alcon). Bournas 9 reported an initial incidence of 8% for Meridian HP60M (Bausch and Lomb), 7.3% for Acrysof MA60BM (Alcon), and 2.7% for Acrysof MA30BA (Alcon), where each IOL type was implanted into 150 eyes. Osher 51 reported, in a prospective study of 250 consecutive eyes, an ND incidence of 15.2% when the single-piece acrylic SN60WF or SN60AT (Alcon) were implanted. Wenzel et al 70 reported a 1% incidence of ND among 800 cataract surgery eyes using the acrylic Acrysof SA60AT or SN60WF IOLs. Vamosi et al 60 demonstrated an ND incidence of 0.13% among 3806 eyes with 610 HPS. Smaller single cases or case series were reported to result in ND when using SN60AT (Alcon), 54 SN60WF (Alcon), 56 Acrysof SA60AT (Alcon), 71 Acrysof SN60WF, 72 Akreos Adapt AV, 72 ZCBOO (Abbott Medical Optics), 72 and spherical single-piece acrylic IOLs (Alcon SN60AT). 40 In addition to the above reports of ND cases, cataract surgeons have expressed their support of the IOL sharp-edge design contributing to the development of ND symptomatology inside the consultation sections of the JCRS 18 20,23 and in comments. 73 As mentioned earlier, the great variability among reported ND incidence rates is most likely due to different surgical techniques employed, different IOL designs and material, wide variety in sample sizes, and the fact that incidence rates are strongly influenced by whether the patients are actively asked about symptoms. Although the above were all mainly observational studies, the likely mechanisms were explored later on in ray tracing modeling by Holladay, 11 Hong, 47 and Simpson. 74 The calculations carried out by Holladay 11 revealed that in the pseudophakic eye a light ray discontinuation can occur because the rays that arrive at the posterior sharp or truncated IOL edge will be refracted more posteriorly than the rays that pass through the posterior surface of the IOL that is immediately adjacent to the IOL edge (Fig. 2A). Holladay referred to this phenomenon as type 3 shadow and believed that it is the cause of ND. The ray tracing experiments also demonstrated that if the IOL edge is round, it will disperse the incoming light rays (Fig. 2B), thus blurring the shadow and making it harder for the patient to perceive. Nevertheless, roundedged IOLs could also lead to ND as long as the edge corner radius is smaller than 0.05 mm, which leads to decreased dispersion. Further, Holladay s calculations provided support for the role of the larger refractive index in the development of ND. It was already suspected based on clinical experience that a larger distance between the back of the iris and the anterior capsule of the lens predisposes to ND. 26,30,60 Indeed, Holladay calculated that the distance range that allows for the shadow is significantly larger for acrylic IOLs (0.06 to 1.23 mm) as compared with silicone IOLs (0.06 to 0.62 mm). Therefore, a cataract surgical procedure using a higher refractive index IOL is more likely to result in ND when compared with an otherwise identical procedure where a lower refractive index IOL is implanted. Simpson 74 also performed ray tracing calculations and concluded that the reason for ND development is the difference in lens diameter between the implanted lens (around 6 mm) and the natural human crystalline lens (around 9.5 mm). The simulations showed that at large angles of more than 60 or 70 degrees some of the incoming light rays 2017 Asia-Pacific Academy of Ophthalmology 365

3 Geneva and Henderson Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 All in all, ND has been observed to develop using all types of lenses, including those with low refractive index and rounded edges. And though the design of the IOL and the refractivity of the IOL material likely play an important role, there seem to be additional risk factors that determine the etiology of ND. A figure 2. Ray tracing of the type 3 shadow of negative dysphotopsia showing both the sharp edge (A) and round edge (B), as described by Holladay et al. 11 Reprinted with permission from J Cataract Refract Surg 2012;38: miss the implanted lens and create a second image perceived in the far periphery by the patient. When this second peak overlaps with the image created by the light rays that are passing through the IOL, a portion of the light waves cancel out and a shadow can be perceived by the patient. However, this same phenomenon was already described by Holladay 11 and is what Holladay called type 2 shadow. This shadow was discarded as an unlikely cause of ND because it forms too far peripherally, which renders it outside the functional human retina. In a later comment, Simpson 73 agreed that because the shadow occurs very far peripherally, most individuals lack sufficient resolution in this region and the ocular media may not be entirely clear; thus the shadow cannot be perceived by most people. Interestingly, further ray tracing analysis by Hong 47 showed that when using the silicone lens and if the light rays are traced further behind the iris (ie, further than Holladay did) they will form a nonshaded area reminiscent of positive dysphotopsia. It should be noted that despite the available clinical and theoretical data in support of high refractive index IOLs with sharp truncated edges as the culprits for ND, there are a number of published exceptions. For instance, Trattler 52 presented case series of eyes with ND where sharp truncated-edge acrylic IOLs [SA60AT (Alcon), MA60AC (Alcon), and Sensar AR40e (Abbott)] and square-edged silicone IOLs (Phacoflex SI-40NB) were used. Further, Masket and Fram 53 published a case report where the roundedged silicone AQ2010V (Staar Surgical) was implanted after the extraction of the square-edged acrylic Acrysof SA60AT in the hopes that the ND symptoms would resolve. However, the ND symptoms persisted even with the round-edged low refractive index IOL. Further, it is important to note that the IOLs available on the market are not simply divided into the 2 sharp truncated-edge and round-edge categories. Instead, some IOLs have a rounded anterior edge and a square posterior edge, whereas others have a rim around the edge of the optic. 75 Furthermore, there is a geometric variety among different makes and models of square-edged IOLs such as slightly different angles from the typical 90-degree square edge. 76 Finally, even multifocal IOLs have been shown to result in ND, as shown by DeVries et al 57 who reported an ND incidence of 2.6% among the studied 76 eyes B Interaction Between the Anterior Capsulotomy and the IOL Masket and Fram 53 introduced the idea of ND being caused by a reflection of the anterior capsulotomy edge that is projected onto the peripheral portion of the nasal retina. In their paper, they presented several cases of ND that were successfully treated, to full or partial symptom resolution, by placing a piggyback IOL or by reverse optic capture, whereas there was no improvement in symptoms if the second IOL was placed in the bag or if iris suture fixation of the capsular bag IOL complex was done. This study provided evidence of the need for the IOL optic to be anterior to the anterior capsulotomy edge to prevent or treat ND. Further, the authors concluded that simply reducing the posterior chamber depth was not sufficient to prevent ND in the IOL exchanges, nor was the use of IOLs with lower refractive index. Ray tracing calculations by the same authors 77 provided theoretical support for their anterior capsulotomy IOL interaction hypothesis. Additional reports have been published to demonstrate ND resolution after in-the-sulcus IOL implantation. 49,60,72 However, it should be noted that in-the-sulcus positioning by definition results in decreased iris-to-iol distance 11 and, as discussed earlier, it has been demonstrated that decrease in this distance leads to decrease in the chance for ND. Therefore, the cause and effect relationship is not straightforward in the Masket and Fram paper. Further critique stems from the study by Holladay et al 11 where the authors believe that ND resolution is brought about by opacification of the anterior nasal capsule that overlaps the nasal IOL edge. The anterior capsulotomy opacification results in light being more diffused, making the dark shadow less distinct. This is what Holladay referred to as type 1 shadow, which is in fact different from the ND phenomenon (type 3 shadow), as the former appears in the 35-degree region whereas the ND shadow appears in the 90-degree region. This type 1 shadow was also calculated to decrease upon pupil constriction and indeed the opacification of the anterior nasal capsule is functionally similar to pupil constriction. On the other hand, the ND shadow becomes less intense with mydriasis as will be explained in the next section. The calculations by Holladay et al 11 were also in disagreement with Masket and Fram s conclusion 53 that ND does not occur with in-the-sulcus IOL implantation because ND is still possible as long as the space behind the iris exceeds 0.06 mm, which can occur even with inthe-sulcus positioning. Further, consultation responses by several cataract surgeons 21,45 and several case series 72,78 claimed that ND can develop even in patients with perfect overlap of the IOL edge by the anterior capsule (Fig. 3). Despite the controversies, it is generally well accepted that the cataract surgeon should aim for a complete anterior capsule overlap of the IOL edge to prevent stray light rays from entering the optical system and reaching the retina. 13,22,27,31 Pupil Size Ever since the discovery of ND, pupil size has been suspected to play a role in the moderation of the symptoms. Initially, it was believed that a smaller pupil should decrease the ND 2017 Asia-Pacific Academy of Ophthalmology

4 Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 Negative Dysphotopsia and the extent of functional retina by using, for example, Goldmann perimetry for retina mapping. figure 3. Example of a pseudophakic eye with complete overlap of the optic by anterior capsule. symptoms and thus patients were prescribed miotic eye drops. 15,23,24 As this treatment led to no consistent benefit, the attitude toward pupil size began to change, with surgeons starting to express their doubts. 16,27 Moreover, case series were published claiming that ND symptoms can be decreased by taking an opposite approach, namely, pupil dilation. 52,53 Ray tracing theoretical calculations by Holladay et al 11 supported those clinical studies by showing how a constricted pupil will act like a pinhole and lead to an increase in the level of contrast between the shadow region and the light rays adjacent to it. Hong et al 77 also used ray tracing to show that smaller pupils, in addition to clear capsular bags and small capsulorrhexis, increase the chance of developing ND symptoms. Predisposing Patient Anatomy The observation that negative dysphotopsia has a tendency to occur bilaterally more often than would be expected by chance alone is perhaps the strongest argument for the existence of patient-specific anatomic predisposing factors. Among the 2630 eyes studied by Davison, 55 less than 1% developed ND; however, among those who developed ND, the phenomenon was bilateral in 44%. Less objective findings include a report of 3 patients with bilateral ND by Trattler 52 and 2 reports of 1 patient each with bilateral ND by Cooke 54 and Zeldovich. 56 It should be noted, however, that in the latter 2 reports it is uncertain what the incidence of bilateral ND had been because the unilateral cases, if any, in the authors practices during the same time period were not included in the papers. Nevertheless, over the years, a number of cataract surgeons have expressed their belief in anatomic predisposition. 51,52,55,79 Nasal Retina The most obvious anatomic predisposition, and in fact an absolute prerequisite, for the development of ND is the presence of functional nasal retina because light needs to form a discontinuity on the far nasal retina for a shadow to be perceived in the far peripheral visual field. It is well known that in humans the retina extends farther in the nasal than in the temporal direction, which is believed to be the reason why the ND shadow is perceived only in the far temporal periphery. 31 Despite the obvious nature of this requirement, to our knowledge, there have been no studies carried out to demonstrate a correlation between the rate of ND incidence Facial Characteristics Other anatomical features that are believed to predispose to ND are having a prominent globe or a shallow orbit. Yet, there is scant objective evidence in support of this theory. For instance, Osher 51 carried out a prospective study of 250 cataract surgery eyes where all of the 8 eyes that developed persistent ND for over 1 year belonged to individuals with the above characteristics. However, there have been reports where patients who developed ND lacked the above facial features. 54 Unfortunately, the contributions of facial anatomy have not been well studied in ray tracing simulations or in the clinic. Except for the Osher paper in 2008, all the ND reports published to date do not contain exophthalmometry data. Further, facial anatomy has been reported only in cases of persistent ND, which is by far the minority of patients suffering from ND symptoms. Iris Color Lighter-colored eyes have been proposed to predispose to the development of ND by Miyoshi. 34 However, similar to the facial features above, there is no evidence, either theoretical or clinical, to support possible mechanisms. Further, the iris color dependence would likely be confounded by race-specific facial features. For instance, the dark-eyed population referred to by Miyoshi is of Asian origin and therefore may have different orbital dimensions with difference in the prominence of the globe, as compared with other races. Angle Alpha Based on ray tracing simulations, Holladay et al 11 proposed that ND can be induced when the eye is turned temporally and there is an angle alpha (the angle between the visual and optical axes) of 5.2 degrees. The mechanism is believed to be an increased exposure of the nasal retina with the above configuration. Further, if the pupil is displaced by 2.6 degrees nasally, which corresponds to 0.3 mm on the corneal surface, the pupil will be closer to the nasal edge of the IOL that will result in an alteration of the retinal field angle, which also translates into increased exposure of the nasal retina. The Neuroadaptation Hypothesis A few years after the discovery of ND, Coroneo 15 proposed that the shadow may constitute a manifestation of a large-scale antagonistic receptive-field center-surround arrangement. This is a well-studied phenomenon where a stimulation of the retina in 1 location results in surround inhibition, which allows for increased contrast and the perception of a sharper image. 80 Coroneo proposed that ND could stem from similar differential neural adaptation where light rays incident on the nasal periphery would reach the nasal edge and the periphery of the IOL and would be focused by the anterior segment to produce zones of intense nasal retina illumination (ie, a series of secondary images that could be perceived as positive dysphotopsia). However, the area between these high-intensity images can undergo center-surround inhibition and be perceived as a dark shadow. Over time, the brain adapts and the shadow may no longer be perceived, which is in accordance with the clinical observation that ND symptoms decrease and usually disappear over time, as demonstrated by the 2017 Asia-Pacific Academy of Ophthalmology 367

5 Geneva and Henderson Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 large prospective studies carried out by Osher 51 and Henderson et al. 81 A related hypothesis was put forth by Gosala 46 that involves the role of rod photoreceptors in the development of ND. Gosala reasoned that because the ND shadow forms in the far periphery and the human retina periphery is predominantly covered by rods, these cells could be involved. From a physiological standpoint, rods are much slower to adapt to overstimulation as compared with cones and will continue to generate negative afterimages in the periphery while at the same time the cone-rich more central retina would tire and lose sensitivity. A possible fault in this hypothesis stems from the well-known properties of rod photoreceptors with regard to the relationship between light levels and their functionality. Namely, rods only function in dim environments and any light levels beyond those experienced at dusk will result in complete saturation of the rod phototransduction cascade, leaving cone photoreceptors to be solely responsible for visual input to the brain. Therefore, if Gosala s hypothesis was indeed providing the main mechanism for ND, then one would expect ND to occur mainly in dimly lit environments. However, this is not the case. Interestingly, a new study by Wenzel et al 70 reported ND in 8 patients where the ND shadow was located more centrally than the usual range of degrees. The authors were able to find an association between the ND location and the location of the blind spot, with the shadow being directly adjacent to patients blind spot. It is well known that cataract surgery results in slight dislocation and magnification of the blind spot as the natural crystalline lens is replaced. Therefore, it stands to reason that a negative shadow may be perceived immediately after surgery and correspond to the presurgery blind spot. Neuroadaptation at the level of the brain over time would then result in the dissipation of the shadow. However, the type of shadow described by Wenzel et al is not the typical peripheral shadow that has been described in all previously published reports. Of course, these neuroadaptation hypotheses would only explain the phenomenon of transient ND, whereas persistent ND as described by Trattler et al, 52 Cooke, 54 Zeldovich, 56 and Folden 78 likely has a different etiology. Corneal Incision in Transient ND In 2006, Osher 82 put forth the hypothesis that transient ND could form in postoperative eyes because of the presence of edema at the incision site. Osher referred to this phenomenon as the shadow sign. Around the same time, Belucci 28 advised in a published consultation that in a patient with bilateral cataracts where the first eye developed ND, the surgeon should be mindful of the shape of the cornea when planning surgery for the second eye. However, Belucci did not elaborate as to the specifics for the role of cornea shape in the prediction of ND occurrence. Two years later, Osher 51 published a large longitudinal prospective study of 250 cataract surgery eyes to demonstrate that ND is likely to occur in eyes where the temporal corneal incision is not completely covered by the eyelid. There were 186 eyes with exposed temporal corneal incision after the surgery and of them 38 developed ND, which resolved within 1 year for the majority of the cases. On the other hand, among the 64 eyes in which the corneal incision was covered by the eyelid, none developed ND postoperatively. Although this etiology of transient ND is logically sound, it should be noted that in many cases of transient ND, such as those in the large prospective study by Henderson et al, 81 ND develops despite complete coverage of the corneal incision by the eyelid. Further, there are many other eye surgery types that require corneal incision, including laser in situ keratomilieusis flap surgery, radial or arcuate keratotomy, and penetrating or lamellar keratoplasty. However, to our knowledge, there have been no reports of ND developing after any eye procedure except for cataract surgery. Treatment Options and Challenges Counseling and Behavioral Approaches As is common in most fields of medicine, when given a choice, noninvasive treatment approaches are usually considered first. In the case of negative dysphotopsia, there are a number of such noninvasive options. One can start with counseling the patient. It is helpful to advise patients that ND symptoms are likely to dissipate over time as neuroadaptation occurs. 17,18,24,71 In the 6 to 12 months after surgery, posterior capsule opacification is expected to take place, which could eliminate or at least decrease the ND symptoms. 11,13,15,23,61,77 Potentially beneficial behavioral approaches include wearing sunglasses 15 when driving at night and on bright sunny days 15,19 to minimize the street lamp glare and sun rays, respectively. Also, one can try using glasses with thick frames, which are expected to block temporal light rays from entering the pupil. 43 It has also been proposed by Mackool 20 that in cases of bilateral cataracts after the first eye develops ND, one can expedite surgery in the second eye such that the patient has at least 1 eye with normal vision, thus perhaps making it easier for the patient to ignore the unilateral ND until it dissipates over time. Pharmacologic agents to induce mydriasis can also be tried as a noninvasive approach, as explained earlier. However, mydriasis can be quite inconvenient and interfere with daily activities such as reading and therefore would not be a satisfactory longterm solution for ND. 23 Nd:YAG Laser Anterior Capsulectomy As described earlier, one of the major theories of ND etiology involves the interaction between the anterior capsulotomy edge and temporal light rays resulting in reflection of the edge onto the nasal retina, creating the shadow. Accordingly, cataract surgeons have tried to treat ND by removing the nasal portion of the anterior capsule via Nd:YAG laser capsulectomy, with variable outcomes. The success rate in clearing ND has ranged from around 50% 78,83 to no success. 44 It should also be noted that the anterior capsulectomy causes anterior movement of the IOL, which decreases the distance between the back of the iris and the IOL. 14 Therefore, remembering Holladay s ray tracing result, 11 if the distance is decreased to less than 0.06 mm, ND would be expected to disappear, perhaps even without the anterior capsule rim being completely removed. Nevertheless, Nd:YAG laser anterior capsulectomy is considered to be the least invasive surgical treatment approach for negative dysphotopsia. 50 Reverse Optic Capture Masket and Fram 53 were the first to provide evidence for the utility of reverse optic capture in the treatment of negative dysphotopsia. They presented 3 ND eyes, in 2 of which the optic was 2017 Asia-Pacific Academy of Ophthalmology

6 Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 Negative Dysphotopsia entirely prolapsed anterior to the capsule and in the third eye there was only partial reverse optic capture, with only the nasal edge of the optic being prolapsed anterior to the capsule. All 3 eyes were free of ND symptoms after the procedure. Inspired by that study, Narang and Narang 84 prophylactically implanted the second eye of 5 patients whose first eye had developed ND using a squareedged acrylic IOL and primary reverse optic capture. None of the 5 eyes developed ND postoperatively. Given the previously described ND tendency for bilaterality, this successful preventive approach is significant. The utility of this surgical approach is further supported by ray tracing simulations performed by Hong et al 77 and Holladay et al. 11 There is only 1 published consultation where Davison 36 claims that, likely based on his surgical experiences, reverse optic capture can sometimes fail. Piggyback IOLs Adding a second plano IOL, the piggyback IOL, in the sulcus of patients with ND achieves 3 goals. First, it results in decreased iris-to-iol distance; second, it covers the capsulorrhexis; and third, it provides another surface for internal reflection that is expected to create more scattering of the light rays incident on the IOL edge. All 3 are expected to interfere with the formation of a temporal shadow. This approach has been validated by several cataract surgeons: Ernest 85 reported 1 successful piggyback surgery, Masket and Fram 53 reported 7 cases, and Makhotkina 86 reported 9 such cases. Further, a large number of cataract surgeons provided their support of the piggyback approach in published commentaries and reviews. 27,28,30,37,44,56 Ray tracing experiments by Hong et al 77 and Holladay et al 11 are also in agreement. The excitement about the piggyback approach has been so great that it was even suggested as a preventive measure in high-risk eyes, such as the second eye of a patient who developed ND in the first eye. 29 Nevertheless, some surgeons are doubtful of its usefulness as it can lead to IOL decentralization and to iris chafing, leading to pigment dispersion. 36,85 IOL Exchange What many cataract surgeons consider the last resort, and certainly the most invasive approach, is removing the offending IOL and replacing it with an IOL that is possibly less likely to cause ND, such as the round-edged silicone implants ,23 26,54,55 However, successful exchange with square-edged acrylic IOLs has also been reported to resolve ND. 72,87 Therefore, it was proposed by Masket and Fram 88 that it is not the IOL design but the implantation location that determines the likelihood for ND formation, where implantation in the bag predisposes to ND whereas implantation in the sulcus is protective. Indeed, there have been a number of reports demonstrating that in-the-sulcus implantation after IOL exchange leads to ND resolution: Vamosi et al 60 presented 2 successful cases, Weinstein 49 presented 2 successful cases, and Burke 72 presented 5 successful cases. However, there have been a number of reports demonstrating that in-the-bag placement after IOL explantation can also eliminate ND symptoms: Davison 10 reported 5 successful cases, Cooke 54 reported 2 successful cases, Weinstein 49 reported 18 successful cases, and Taubenslag 87 reported 10 cases, 7 of which resulted in complete resolution of ND and 3 in partial resolution. It should be noted that there have indeed been a few reports of unsuccessful re-implantations in the bag: Vamosi et al 60 reported 1 such case and Masket and Fram 53 reported 3 more cases. The likely mechanism behind the success of the in-the-sulcus approach is the associated reduction in the iris-to-iol distance, which was elaborated on earlier. Given the reduction in the iris-to-iol distance, the same complications as in the case of piggyback IOLs are expected to apply here. Preventive Approaches Given the invasive nature of many of the treatment options for negative dysphotopsia, a robust prevention strategy would be invaluable. A recent prospective randomized patient-blinded clinical trial by Henderson et al 81 demonstrated that the incidence of ND can be decreased 2.3-fold if the IOL is implanted with the optic-haptic junction placed inferotemporally, an orientation that is often referred to as horizontal. Using the square-edged acrylic Acrysof SN60WF IOL, the 163 eyes implanted horizontally had ND incidence of only 6%, whereas the 114 control eyes that were implanted vertically had an incidence of 14% on the day after cataract surgery. Further support for horizontal implantation stems from a report on IOL exchanges by Taubenslag et al. 87 In this study 10 eyes with ND underwent IOL exchange with reimplantation using the square-edged acrylic Softec HDO (Lenstec, Inc), where implantation of the IOL horizontally led to complete resolution in 7 eyes and to a decrease in ND symptoms in the remaining 3 eyes. The mechanism responsible for the success of this approach likely involves refraction of incident light rays by the inferotemporal haptic position that posteriorly displaces the minimum limiting ray just missing the optic by approximately half the thickness of the haptic, which in turn reduces or eliminates the shadow on the retina. Holladay and Simpson 89 have found via additional ray tracing studies that the benefit of horizontal positioning is actually due to the nasal optic/haptic junction rather than the temporal junction as stated by Henderson et al. 81 However, because the haptics are 180 degrees away from each other, the recommended position of the IOL remains the same. In the same theoretical study, Holladay and Simpson separated primary and secondary factors. Primary factors are smaller photopic pupil, higher angle kappa, equibiconvex shape with higher IOL power, and smaller axial location. Secondary factors include IOL design, overlap of the nasal edge of the optic by the anterior capsule, and the optic haptic junction positioning. There are also new IOLs under development, which are specially designed to prevent negative dysphotopsia. One such implant is the patented Masket ND IOL 90 whose design is based on the reverse optic capture concept and according to Masket, this new IOL features a peripheral groove placed anteriorly to accept the anterior capsulotomy, and a lip of the optic overriding the anterior capsule. Although the utility of the Masket ND IOL is still awaiting validation in a large clinical trial, the IOL has already been used in Europe. 90 Another potentially useful IOL is the oval-optic IOL, the Softec HDO (Lenstec, Inc), that is expected to minimize ND based on its larger size as compared with the mainstream IOLs, which renders it closer to the size of the natural crystalline lens. 91 Again, this lens has not yet been tested in a clinical trial. However, it was pointed out by Masket et al 92 in 2016 that this lens is prone to inducing positive dysphotopsia (PD). In their study, the authors report the need for explantation of this IOL for intractable PD, which resolved when the AQ2010V IOL (Staar Surgical) was implanted instead during the second surgery. Although the exact combination of risk factors to develop 2017 Asia-Pacific Academy of Ophthalmology 369

7 Geneva and Henderson Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 ND for a particular individual is not yet clear, we are beginning to understand the range of potential causes. Many of these causes are specific to the individual or to the eye and cannot be altered. However, due to the increased interest in pursuing the origins of this elusive disease, the ophthalmology community is closing in on the etiologies and possible treatments References Lindstrom R. Thoughts on cataract surgery: Rev Ophthalmol Randleman JB, Lockwood JC. Intraocular lens designs and materials. In: Randleman JB, ed. Intraocular Lens Surgery: Selection, Complications, and Complex Cases. New York, New York: Thieme; 2016: Henderson BA, Geneva II. Negative dysphotopsia: a perfect storm. J Cataract Refract Surg. 2015;41: Hood CT, Sugar A. Subjective complaints after cataract surgery: common causes and management strategies. Curr Opin Ophthalmol. 2015;26: Holladay JT. Evaluating the intraocular lens optic. Surv Ophthalmol. 1986; 30: Holladay JT, Bishop JE, Lewis JW. Diagnosis and treatment of mysterious light streaks seen by patients following extracapsular cataract extraction. J Am Intraocul Implant Soc. 1985;11: Holladay JT, Lang A, Portney V. Analysis of edge glare phenomena in intraocular lens edge designs. J Cataract Refract Surg. 1999;25: Masket S, Geraghty E, Crandall AS, et al. Undesired light images associated with ovoid intraocular lenses. J Cataract Refract Surg. 1993; 19: Bournas P, Drazinos S, Kanellas D, et al. Dysphotopsia after cataract surgery: comparison of four different intraocular lenses. Ophthalmologica. 2007;221: Davison JA. Positive and negative dysphotopsia in patients with acrylic intraocular lenses. J Cataract Refract Surg. 2000;26: Holladay JT, Zhao H, Reisin CR. Negative dysphotopsia: the enigmatic penumbra. J Cataract Refract Surg. 2012;38: Michelson MA, Holladay JT. The intersection of optics and neuroophthalmology: the enigma of pseudophakic dysphotopsia. J Neuroophthalmol. 2015;35: Arnold PN. Cataract surgical problem: August consultation #8. J Cataract Refract Surg. 2005;31: Cionni R. Cataract surgical problem: April consultation #6. J Cataract Refract Surg. 2005;31: Coroneo M. Cataract surgical problem: April consultation #3. J Cataract Refract Surg. 2005;31: Davison J. Cataract surgical problem: April consultation #9. J Cataract Refract Surg. 2005;31: Dewey S. Cataract surgical problem: April consultation #10. J Cataract Refract Surg. 2005;31: Erie J. Cataract surgical problem: April consultation #11. J Cataract Refract Surg. 2005;31: Franchini A. Cataract surgical problem: April consultation #7. J Cataract Refract Surg. 2005;31: Mackool R. Cataract surgical problem: April consultation #12. J Cataract Refract Surg. 2005;31: Masket S. Cataract surgical problem: April consultation #1. J Cataract Refract Surg. 2005;31: Menapace R. 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Cataract surgical problem: July consultation #9. J Cataract Refract Surg. 2013;39: Olson RJ. Refractive surgical problem: July consultation #7. J Cataract Refract Surg. 2013;39: Vamosi P. Cataract surgical problem: July consultation #6. J Cataract Refract Surg. 2013;39: Weinstein A. Cataract surgical problem: July consultation #4. J Cataract Refract Surg. 2013;39: Gosala S. Optical phenomena causing negative dysphotopsia. J Cataract Refract Surg. 2010;36:1620; author reply, Hong X, Liu Y, Karakelle M, et al. Negative dysphotopsia: differences in the studies of an enigmatic optic phenomenon. J Cataract Refract Surg. 2013;39: Wei M, Brettell D, Bhardwaj G, et al. Negative dysphotopsia with spherical intraocular lenses. J Cataract Refract Surg. 2010;36: Weinstein A. Surgical experience with pseudophakic negative dysphotopsia. J Cataract Refract Surg. 2012;38:561; author reply. 50. Holladay JT. Reply: Etiology of negative dysphotopsia. J Cataract Refract Surg. 2013;39:486, e1 e Osher RH. Negative dysphotopsia: long-term study and possible explanation for transient symptoms. J Cataract Refract Surg. 2008;34: Trattler WB, Whitsett JC, Simone PA. Negative dysphotopsia after intraocular lens implantation irrespective of design and material. J Cataract Refract Surg. 2005;31: Masket S, Fram NR. Pseudophakic negative dysphotopsia: surgical Asia-Pacific Academy of Ophthalmology

8 Asia-Pacific Journal of Ophthalmology Volume 6, Number 4, July/August 2017 Negative Dysphotopsia management and new theory of etiology. J Cataract Refract Surg. 2011;37: Cooke DL. Negative dysphotopsia after temporal corneal incisions. J Cataract Refract Surg. 2010;36: Davison JA. Clinical performance of Alcon SA30AL and SA60AT singlepiece acrylic intraocular lenses. J Cataract Refract Surg. 2002;28: Zeldovich A. Treatment of negative dysphotopsia with unique sulcus lens. Clin Experiment Ophthalmol. 2012;40: De Vries NE, Webers CA, Touwslager WR, et al. Dissatisfaction after implantation of multifocal intraocular lenses. J Cataract Refract Surg. 2011; 37: Narvaez J, Banning CS, Stulting RD. Negative dysphotopsia associated with implantation of the Z9000 intraocular lens. J Cataract Refract Surg. 2005;31: Radford SW, Carlsson AM, Barrett GD. Comparison of pseudophakic dysphotopsia with Akreos Adapt and SN60-AT intraocular lenses. J Cataract Refract Surg. 2007;33: Vamosi P, Csakany B, Nemeth J. Intraocular lens exchange in patients with negative dysphotopsia symptoms. J Cataract Refract Surg. 2010;36: Marques FF, Marques DM. Unilateral dysphotopsia after bilateral intraocular lens implantation using the AR40e IOL model: case report. Arq Bras Oftalmol. 2007;70: Makhotkina NY, Berendschot TT, Nuijts RM. Objective evaluation of negative dysphotopsia with Goldmann kinetic perimetry. J Cataract Refract Surg. 2016;42: Bellucci R. An introduction to intraocular lenses: material, optics, haptics, design and abberation. In: Guell JL, ed. ESASO Course Series. Basel: Karger; 2013: Hayashi K, Hayashi H, Nakao F, et al. Reduction in the area of the anterior capsule opening after polymethylmethacrylate, silicone, and soft acrylic intraocular lens implantation. Am J Ophthalmol. 1997;123: Hayashi H, Hayashi K, Nakao F, et al. Quantitative comparison of posterior capsule opacification after polymethylmethacrylate, silicone, and soft acrylic intraocular lens implantation. Arch Ophthalmol. 1998;116: Hollick EJ, Spalton DJ, Ursell PG, et al. The effect of polymethylmethacrylate, silicone, and polyacrylic intraocular lenses on posterior capsular opacification 3 years after cataract surgery. Ophthalmology. 1999;106:49 54; discussion, Nishi O. Posterior capsule opacification. Part 1: experimental investigations. J Cataract Refract Surg. 1999;25: Ram J, Apple DJ, Peng Q, et al. Update on fixation of rigid and foldable posterior chamber intraocular lenses. Part II: choosing the correct haptic fixation and intraocular lens design to help eradicate posterior capsule opacification. Ophthalmology. 1999;106: Ursell PG, Spalton DJ, Pande MV, et al. Relationship between intraocular lens biomaterials and posterior capsule opacification. J Cataract Refract Surg. 1998;24: Wenzel M, Menapace R, Eppig T, et al. Is the memory effect of the blind spot involved in negative dysphotopsia after cataract surgery? J Ophthalmol. 2015;2015: Mahar PS. Negative dysphotopsia after uncomplicated phacoemulsiphication. Pak J Ophthalmol. 2013;29: Burke TR, Benjamin L. Sulcus-fixated intraocular lens implantation for the management of negative dysphotopsia. J Cataract Refract Surg. 2014;40: Simpson MJ. Managing and understanding negative dysphotopsia. J Cataract Refract Surg. 2015;41: Simpson MJ. Double image in far peripheral vision of pseudophakic eye as source of negative dysphotopsia. J Opt Soc Am A Opt Image Sci Vis. 2014; 31: Nanavaty MA, Spalton DJ, Boyce J, et al. Edge profile of commercially available square-edged intraocular lenses. J Cataract Refract Surg. 2008;34: Werner L, Tetz M, Feldmann I, et al. Evaluating and defining the sharpness of intraocular lenses: microedge structure of commercially available squareedged hydrophilic intraocular lenses. J Cataract Refract Surg. 2009;35: Hong X, Liu Y, Karakelle M, et al. Ray-tracing optical modeling of negative dysphotopsia. J Biomed Opt. 2011;16: Folden DV. Neodymium:YAG laser anterior capsulectomy: surgical option in the management of negative dysphotopsia. J Cataract Refract Surg. 2013;39: Schwiegerling J. Recent developments in pseudophakic dysphotopsia. Curr Opin Ophthalmol. 2006;17: Mazade RE, Eggers ED. Light adaptation alters inner retinal inhibition to shape OFF retinal pathway signaling. J Neurophysiol. 2016;115: Henderson BA, Yi DH, Constantine JB, et al. New preventative approach for negative dysphotopsia. J Cataract Refract Surg. 2016;42: Osher RH. The circle and the shadow: 2 early postoperative findings. J Cataract Refract Surg. 2006;32: Cooke DL, Kasko S, Platt LO. Resolution of negative dysphotopsia after laser anterior capsulotomy. J Cataract Refract Surg. 2013;39: Narang P, Narang S. Primary reverse optic capture with implantation of capsular tension ring to prevent pseudophakic negative dysphotopsia. J Cataract Refract Surg. 2015;41: Ernest PH. Severe photic phenomenon. J Cataract Refract Surg. 2006;32: Makhotkina NY, Berendschot TT, Beckers HJ, et al. Treatment of negative dysphotopsia with supplementary implantation of a sulcus-fixated intraocular lens. Graefes Arch Clin Exp Ophthalmol. 2015;253: Taubenslag KJ, Groos EB, Parker MG, et al. Successful treatment of negative dysphotopsia with in-the-bag intraocular lens exchange using a wide ovoid IOL. J Cataract Refract Surg. 2016;42: Masket S, Fram NR. Sulcus-fixated IOLs for negative dysphotopsia. J Cataract Refract Surg. 2015;41: Holladay JT, Simpson MJ. Negative dysphotopsia: causes and rationale for prevention and treatment. J Cataract Refract Surg. 2017;43: Masket S. Solving the problem of negative dysphotopsia. Cataract Refract Surg Today. 2014(May): Addressing the negative dysphotopsia salute. Lenstec Web site. Available at: Accessed March 11, Masket S, Rubin D, Fram NR. Dysphotopsia and oval intraocular lenses. J Cataract Refract Surg. 2016;42: Asia-Pacific Academy of Ophthalmology 371