Dislocated Intraocular Lens

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Article initiated by:
Christopher Garabet, Frank S. Hwang, MD, Soungmin Cho, MD, Suzie A. Gasparian, MD
All contributors:
Frank S. Hwang, MD, Alpa S. Patel, M.D., Derek W DelMonte, MD, Suzie A. Gasparian, MD, Jonathan C. Tsui, MD, Sadiqa K Stelzner, MD, FACS, Joseph Christenbury, MD
Assigned editor:
Joseph Christenbury, MD
Review:
Assigned status Up to Date
 by Joseph Christenbury, MD on November 13, 2024.


Fundus photograph demonstrating late spontaneous IOL-capsular bag complex dislocation following cataract surgery.

Introduction

Background

Dislocated intraocular lens (IOL) is a rare, yet serious complication whereby the intraocular lens moves out of its normal position in the eye. IOL dislocation has been reported at a rate of 0.2% to 3%.[1] [2] [3] [4] It may occur as a result of an early or late complication of cataract surgery, prior vitreoretinal surgery, trauma, or an inherent pathological process or connective tissue disorder contributing to lens zonular weakness.[5] Dislocation may present as phacodonesis, simple decentration within the bag or in the sulcus, partial subluxation, or complete dislocation of the lens within and outside of the bag. Decentration usually refers to loss of IOL centration without zonular or capsular instability. Subluxation refers to partial zonular or capsular instability. Dislocation is due to total zonular or capsular instability. However, the terms are commonly interchanged. Once the dislocated IOL is identified, there are several possible management options.

Etiology/Risk factors

IOL dislocation is typically related to the integrity of the capsular bag and its support system (zonules) and their ability to support an IOL. There are many predisposing conditions that increase the risk of capsular bag instability and zonular weakness including cataract surgery, prior vitreoretinal surgery[6] [7] [8], aging[7], axial myopia[8][9], inflammation/uveitis [8][10], trauma [6][11], retinitis pigmentosa[4] [8], diabetes mellitus[12], atopic dermatitis[11], mature cataract[8], previous episodes of acute angle-closure attack[13], connective tissue disorders e.g. pseudoexfoliation syndrome (being the most common risk factor with more than 50% of cases), Marfan syndrome, homocystinuria, hyperlysinemia, Ehlers-Danlos Syndrome, scleroderma, Weill-Marchesani syndrome, ectopia lentis et pupillae [4] [6] [7][14] [15].

With relation to cataract surgery, IOL dislocation may be categorized based on the timing of its presentation – early if it occurs within three months of IOL placement, and late if it occurs three months after IOL placement. Early dislocation of the lens may occur with poor fixation of the IOL or capsular and/or zonular rupture during cataract surgery.[5] Zonular rupture usually occurs from posterior pressure on the lens and the capsule while performing "can-opener style" capsulotomy, phacoemulsification of the nucleus, or IOL implantation.[12] Late dislocation of the lens typically occurs due to progressive zonular insufficiency and contraction of the anterior capsule.[5] Progressive zonular weakness has been associated with previous vitreoretinal surgery, uveitis, trauma, high myopia, retinitis pigmentosa, aging, diabetes mellitus, atopic dermatitis (e.g. repeated eye rubbing), previous acute angle-closure attacks, and connective tissue disorders.[5] [6][16] [17]


Capsular opening contraction is commonly observed after cataract surgery and can be accompanied by continuous curvilinear capsulorrhexis. Trauma caused by capsulotomy of the anterior capsule leads to proliferation and metaplasia of the lens epithelial cells on the capsular margins into myofibroblasts, which subsequently creates a contraction force. This centripetal force overcomes the centrifugal zonal force and leads to constriction of the capsulotomy.[18] In patients with weaker zonules, as seen in pseudoexfoliation syndrome, retinitis pigmentosa, and diabetes mellitus, the constriction that occurs is more pronounced.[19] Increased epithelial cell proliferation seen in posterior capsular opacification (PCO) may contribute to the IOL and capsular bag weight, which leads to increased zonular stress.[20] The impact of neodymium:YAG (Nd:YAG) laser for treatment of PCO may be the trigger point for subluxation.[4] [6]

Diagnosis

History, signs, and symptoms

Given that there are many predisposing conditions that increase the risk of IOL dislocation, a thorough history is necessary in patients. Patients with a dislocated IOL may experience a decrease or change in vision, diplopia, and/or glare.[5] Additionally, they may report ocular pain or headaches from intermittent angle-closure and/or inflammation. Some patients also report seeing the edge of the IOL.

Diagnostic procedures

A complete ophthalmologic exam is necessary in diagnosis of a dislocated IOL including an anterior and posterior segment exam. A detailed dilated retinal exam with scleral depression is important. If a detailed exam is not feasible, Bscan echography and/or an anterior segment OCT/ultrasound biomicroscopy (UBM) may be helpful in evaluating a posteriorly dislocated lens behind the iris in the anterior aspect of the vitreous cavity.

Types of IOL dislocation

IOL dislocation may present as phacodonesis, simple lens decentration within an intact capsular bag or in the sulcus, partial lens subluxation out of the capsular bag, or complete dislocation of the lens within or outside of the bag into the anterior or posterior chamber. If there is a posterior capsule defect or tear, the IOL may slide out of the bag, hence out-of-the-bag dislocation. If there is a defect in the stability of the capsular bag support system e.g. zonular weakness, the entire IOL with the capsular bag may dislocate, hence in-the-bag dislocation.

Treatment options

Observation

Observation may be a possible management option in cases where IOL subluxation is minimal without a significant impact on vision and damage to surrounding ocular structures. Those with pseudophacodonesis and without inferior dislocation are usually asymptomatic and tend to be such candidates.[21] In such cases, refraction may help sharpen the patient’s vision with close monitoring thereafter. Close follow-up is imperative to ensure patients do not develop potential IOL dislocation sequelae that may necessitate surgical intervention.

In cases where vision is affected and/or there is damage to surrounding ocular structures, surgery plays a large role in IOL dislocation management. The most common indications for surgery are decreased visual acuity, monocular diplopia, and halos.[4] Less commonly, retinal detachment[12], glaucoma[15], and/or Uveitis-Glaucoma-Hyphema (UGH) syndrome[14] portend surgical intervention. Several surgical options exist in management of dislocated IOL and should be tailored to each individual. Surgery typically includes pars plana vitrectomy to remove the dislocated lens with either an IOL cutter or through a scleral tunnel or sclerocorneal incision. This is followed by secondary IOL implantation.

IOL exchange

IOL exchange is possible, and likely the most common surgical option. The dislocated IOL is removed and decision to place an IOL in the anterior or posterior chamber becomes a matter of the integrity of the capsular bag. If there is adequate capsular support, an IOL may be placed in the posterior chamber and repositioned in the ciliary sulcus. If there is not enough capsular support, an IOL can be placed in the anterior chamber (ACIOL) or sutured in place to either the sclera or iris. There seems to be insufficient evidence, in terms of relative safety or efficacy, to support ACIOL vs scleral or iris-supported PCIOLs.[22] [23]

IOL fixation procedures

IOL fixation procedures provide surgical options in cases where there is not enough capsular bag support. Depending on the eye anatomy including the status of the cornea, iris, and sclera, ocular pathology, and comfort of the surgeon, decision for which fixation procedure can be tailored to the individual. IOL fixation procedures include transscleral suture fixation, transscleral haptic fixation, and iris fixation.

Transscleral Suture Fixation

Transscleral suture fixation is a possible option in patients without sufficient capsular bag support. This may be achieved either through an ab interno or ab externo approach whereby the sutures are passed either from inside to outside blindly or from outside to inside the eye, respectively. With both approaches, the lens is placed between the iris and the anterior vitreous cavity and is fixated by sutures from opposite sides. The sutures are then buried within the sclera. Different lenses and sutures are used depending on the surgeon's comfort level and experience.

CZ70BD (Alcon) is a non-foldable, polymethyl methacrylate (PMMA) single-piece IOL with eyelets on each side, which facilitate secured suturing. The size of the lens is 12.0mm in length with an optic diameter of 7.0mm. Because of its non-foldable nature of the IOL, larger incisions are required.

Akreos AO60 (Bausch + Lomb) is a foldable acrylic single-piece IOL. As it is a foldable lens, the incision site can be made smaller, which facilitates better maintenance of the anterior chamber and globe structure during the surgery and leads to less wound leakage.[24] The lens has two eyelets on each opposite side, allowing for a 4-point fixation. It is theorized that the 4-point fixation provides improved stability to help decrease tilting, although there is no study that directly compares CZ70 and Akreos AO 60 IOLs. Additionally, there have been reports that there is increased risk of calcification and opacification of the Akreos AO60 through calcium salt deposition with exposure to intraocular air or gas.[25]

MX60 enVista (Bausch + Lomb) is a foldable acrylic IOL. This IOL can be inserted with a smaller incision, and the eyelets are located on each side at the haptic-optic junction. Unlike Akreos AO60 IOL, MX60 enVista is a hydrophobic lens, and there is less concern for opacification. Furthermore, with uniform center-to-edge power, decentration is thought to be less of a concern. This IOL comes in a toric form for patients with astigmatism.

There have been reports of single-piece toric IOLs that have been inserted with transscleral suture fixation.[26] [27] The IOLs that were used for transscleral suture fixation were Centerflex 570T (Rayner) and SN6AT5 (Alcon). The Centerflex 570T is a foldable IOL. It has two closed loops where the sutures were fixated.[26] The SN6AT5 IOL does not have loops or eyelets, so the sutures had to be secured in a "lasso-type" fashion.[27]

A variety of sutures are currently used for transscleral suture fixation. These sutures include 10-0 polypropylene, 9-0 polypropylene, and CV-8 Gore-Tex. 10-0 polypropylene has traditionally been the suture of choice. However, IOL dislocations secondary to suture erosions and breakages have been reported.[28] [29] [30] These suture breakages have been associated with how long the sutures had been in place. The mean time from surgery until breakage ranged from four to six and a half years. These reports suggest utilization of a thicker suture such as 9-0 polypropylene, which is reported to have higher tensile strength to withstand the biodegradation seen in 10-0 polypropylene.[28] However, there is another study that questions the superiority of 9-0 over 10-0 polypropylene and the potential increased risk of endophthalmitis owing to the larger suture size and erosion into the sclera.[31]

Recently, Gore-Tex has also been selected as a suture of choice due to its high tensile strength and longevity to decrease risk of suture breakage.[24][32] While the long-term complications and outcomes of the scleral fixation have not been shown to date, several studies have shown success in utilizing Gore-Tex sutures for scleral fixation with minimal suture complications.[32] However, longer-term studies are needed for better comparison.

Transscleral Haptic Fixation

Transscleral haptic fixation is a possible option in patients without sufficient capsular bag support that is a modification of sutureless intrascleral 3-piece IOL fixation. The double-needle flanged IOL fixation, also known as the Yamane technique, is carried out via the conjunctiva with small incisions made by 30-gauge needles. The needles are inserted through the sclera, 2mm posterior to the limbus, and the 3-piece IOL haptics fed into the lumen of the needles, which are pulled out of the scleral tunnels, thereby fixating the haptics to the sclera without suture or glue by means of a flange at the end of the haptic for firm fixation in the scleral tunnel (protruding ends of haptics are cauterized to prevent haptic slippage into the eye). A peripheral iridotomy is then placed after miosis to avoid iris capture of the IOL. This double needle technique minimizes the sclerotomy and decreases risk of post-operative hypotony.[33]

IOL selection for the Yamane technique is crucial given that conventional PMMA haptics are reportedly prone to kinking, breaking, or disinsertion from the optic during intra-operative manipulation. AR40E (AMO Sensar) is a hydrophobic acrylic 3-piece IOL with PMMA angulated haptics. MA60AC (AcrySof) is an acrylic foldable 3-piece lens with PMMA haptics that may be folded prior to insertion. CT Lucia 602 (Carl Zeiss Meditec) is a hydrophobic acrylic lens typically recommended with the Yamane technique due to the durability of its haptics, which are composed of polyvinylidene fluoride.[34] [35]

Currently, there is no IOL specifically designed for the Yamane technique. One study compared the use of NX-70 IOLs and PN6A IOLs in the flanged IOL fixation technique and revealed no statistically significant differences; however, they noted less intra- and post-operative complications using NX-70 IOLs although PN6A IOLs were easer to maneuver in the anterior chamber with shorter operating times. In their study, they recommended use of strong jointed IOLs e.g. NX-70 IOLs to avoid detachment of the haptic from the optic.[36]

Fibrin-glue assisted sutureless posterior chamber IOL implantation is also an option in patients with deficient posterior capsules. This surgical technique utilizes two partial-thickness, limbal-based scleral flaps 180 degrees apart where the lens haptics are externalized with the use of forceps to place them inside the scleral tunnels beneath the scleral flaps. Fibrin glue is used to attach the haptics to the scleral bed beneath the flap.[37] This technique, like the Yamane technique, does not require sutures.

Iris Suture Fixation

Iris-fixated IOLs were previously used in the form of claw-shaped haptic devices, however its high complication rate and suboptimal visual outcomes led to vault modifications from the original design whereby iris clip or iridocapsular lenses were used.[38] [39] Iris-claw IOLs are currently not only used for the phakic correction of myopia but also correction of aphakia in the absence of capsular support.[40]

An iris-claw IOL may be placed either in the anterior chamber or in the posterior chamber (retropupillary) to reduce the potential for complications seen with ACIOLs. Surgeons may choose anterior or posterior chamber placement depending on their experience and characteristics of the procedure.[41] For anterior chamber placement, the IOL is placed into the anterior chamber with the iris enclavated at its mid-peripheral region between claw haptics. For retropupillary fixation, one haptic of the IOL is introduced behind the iris, enclavated, followed by enclavation of the other haptic.[41] A peripheral iridectomy is performed for anterior implantation.

Out-of-the-bag dislocated IOLs may also be sutured to the iris, assuming that it is not damaged and is of the appropriate power. Techniques have included the optic of a dislocated 3-piece IOL prolapsed into the anterior chamber above the iris whilst the haptics are in the ciliary sulcus, emulating an optic capture. After miosis, four paracentesis wounds are utilized to fixate each of haptics to the peripheral iris. A modified McCannel iris suturing technique using the Siepser sliding-knot technique has reported success in suturing the haptics with McCannel polypropylene suture on a curved needle to the iris. The optic is then moved behind the iris.[42] [43]

Anterior Chamber Intraocular Lens (ACIOL) placement

In the absence of adequate capsular support, implantation of flexible open-loop anterior chamber intraocular lens (ACIOL) is an option.[44] [45] However, anterior chamber depth and anterior chamber angle support assessment is imperative. Currently, modern flexible open-loop haptics and anteriorly vaulted optics compose ACIOLs, which have been modified from previous designs to result in lower rate of complications.[46] [47] Footplates are incorporated into each haptic to provide stability, whilst decreasing the amount of contact with the angle.[48] Additionally, they have an anterior vault to decrease the risk of iris chafe and corneal touch.[49]

ACIOL placement typically involves placing the lens into the anterior chamber through a temporal scleral tunnel incision with assistance from a lens glide to rest footplates against the scleral spur. Consideration to avoidance of incarceration of iris tissue or rubbing against the corneal endothelium in the process is key.[38] Scleral tunnel incision is usually closed using 10-0 Nylon sutures.

It is important to choose the appropriate ACIOL power since they require less power than the more posterior IOL. Additionally, horizontal white-to-white measurement of the corneal width aids in ensuring the ACIOL is the proper size and fit for the patient. A peripheral iridectomy should also be performed to prevent pupillary block.

Complications

IOL dislocation may cause several complications such as recurrent IOL dislocation[8] [12] [50] [51], retinal detachment[2][8][12][51][52], infection/hypopyon[2], inflammation, bleeding, corneal damage[2], macular edema[2][8][12][53], and elevation in intraocular pressure[2][53]. Sight-threatening complications such as hyphema, secondary glaucoma, macular edema, and pupillary block tend to develop in anterior chamber and iris fixation IOL cases with iris fixation lenses having a higher incidence of lens dislocation and subsequent corneal decompensation.[2]

Transscleral suture fixation lenses run the risk of retinal detachment and intraocular hemorrhage given the passage of sutures through uveal tissue[21]. Additionally, exposed suture tracks may lead to suture knot and tissue erosion and increased risk for endophthalmitis[21][45], with late IOL dislocation or tilt a potential existing concern as a result of suture loosening or rupture.[21][38]

Transscleral haptic fixation lenses have the risk of intraocular hemorrhage as well given that they involve fixation of IOL haptics through uveal tissue and partial thickness scleral flaps or tunnels.[54]

ACIOLs are in close proximity to the cornea and anterior chamber angle, and thus have an increased risk of damage to the cornea, iris, and angle. There exists an increased risk of pseudophakic bullous keratopathy, glaucoma, UGH syndrome, pupillary block and peripheral anterior synechiae, cystoid macular edema.[21] [38] [47] Given concern for such complications, some studies recommend avoiding ACIOL in patients <50 years old.[55] Newer ACIOL models have flexible loops and highly polished surfaces thus are less likely to cause problems.[38]

Similar to ACIOLs, iris-sutured fixation lenses rest in close proximity to the cornea, increasing the risk of corneal decompensation.[56] Also, its proximity to the iris may disrupt the integrity of the iris leading to iris chaffing, pigment dispersion, and chronic inflammation, peripheral synechiae, bleeding from the iris, pupillary distortion, and limited pupillary dilation.[38][42] [57]

Prognosis

Most patients with IOL dislocation with any method of management do quite well with consideration to their visual acuity and post-surgical outcome.[4][45] Visual acuity results have demonstrated that at least 85% of IOL cases over all achieve 20/40 or better acuity.[1] [2] Increasing age, pre-existing ocular pathology e.g. pre-operative corneal disease, glaucoma, iritis, iris neovascularization, diabetic retinopathy, history of retinal detachment, macular degeneration, amblyopia, surgical problems, and complications such as corneal and/or macular edema portend unfavorable visual outcomes.[2] Nonetheless, close follow-up and management may allow for avoidance of complications. Cautious pre-, intra-, and post-operative assessment is imperative in achievement of good outcomes.

References

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  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Stark, W.J., et al., The FDA report on intraocular lenses. Ophthalmology, 1983. 90(4): p. 311-17.
  3. ↑ Kratz, R.P., et al., The Shearing intraocular lens: a report of 1,000 cases. J Am Intraocul Implant Soc, 1981. 7(1): p. 55-7.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Gimbel, H.V., et al., Late in-the-bag intraocular lens dislocation: incidence, prevention, and management. J Cataract Refract Surg, 2005. 31(11): p. 2193-204.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Ascaso, F.J., V. Huerva, and A. Grzybowski, Epidemiology, Etiology, and Prevention of Late IOL-Capsular Bag Complex Dislocation: Review of the Literature. J Ophthalmol, 2015. 2015: p. 805706.
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  9. ↑ Shigeeda, T., et al., Spontaneous posterior dislocation of intraocular lenses fixated in the capsular bag. J Cataract Refract Surg, 2002. 28(9): p. 1689-93.
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  21. ↑ 21.0 21.1 21.2 21.3 21.4 Lorente, R., et al., Management of late spontaneous in-the-bag intraocular lens dislocation: Retrospective analysis of 45 cases. J Cataract Refract Surg, 2010. 36(8): p. 1270-82.
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  31. ↑ Wasiluk, E., et al., The implantation of the scleral-fixated posterior chamber intraocular lens with 9/0 polypropylene sutures - Long-term visual outcomes and complications. Adv Med Sci, 2019. 64(1): p. 100-103.
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  33. ↑ Yamane, S., et al., Flanged Intrascleral Intraocular Lens Fixation with Double-Needle Technique. Ophthalmology, 2017. 124(8): p. 1136-1142.
  34. ↑ Roach, L. Intrascleral Haptic Fixation as an Alternative to Sutures. Clinical Update, EyeNet Magazine. 2018.
  35. ↑ Ayres B, Al-Mohtaseb Z, Safran S, Shah M. Pearls for the Yamane Technique. Retina Today. 2020.
  36. ↑ Miura, Y., Y. Harada, and Y. Kiuchi, Comparison of Different IOL Types in the Flanged IOL Fixation Technique. J Ophthalmol, 2020. 2020: p. 8534028.
  37. ↑ Agarwal, A., et al., Fibrin glue-assisted sutureless posterior chamber intraocular lens implantation in eyes with deficient posterior capsules. J Cataract Refract Surg, 2008. 34(9): p. 1433-8.
  38. ↑ 38.0 38.1 38.2 38.3 38.4 38.5 Por, Y.M. and M.J. Lavin, Techniques of intraocular lens suspension in the absence of capsular/zonular support. Surv Ophthalmol, 2005. 50(5): p. 429-62.
  39. ↑ Binkhorst, C.D., Results of implantation of intraocular lenses in unilateral aphakia. With special reference to the pupillary or iris clip lens--a new method of fixation. Am J Ophthalmol, 1960. 49: p. 703-10.
  40. ↑ De Silva, S.R., et al., Iris-claw intraocular lenses to correct aphakia in the absence of capsule support. J Cataract Refract Surg, 2011. 37(9): p. 1667-72.
  41. ↑ 41.0 41.1 Mora, P., et al., Comparative Analysis of the Safety and Functional Outcomes of Anterior versus Retropupillary Iris-Claw IOL Fixation. J Ophthalmol, 2018. 2018: p. 8463569.
  42. ↑ 42.0 42.1 Armonaite, L., S. Lofgren, and A. Behndig, Iris suture fixation of out-of-the-bag dislocated three-piece intraocular lenses. Acta Ophthalmol, 2019. 97(6): p. 583-588.
  43. ↑ Chang, D.F., Siepser slipknot for McCannel iris-suture fixation of subluxated intraocular lenses. J Cataract Refract Surg, 2004. 30(6): p. 1170-6.
  44. ↑ Kwong, Y.Y., et al., Comparison of outcomes of primary scleral-fixated versus primary anterior chamber intraocular lens implantation in complicated cataract surgeries. Ophthalmology, 2007. 114(1): p. 80-5.
  45. ↑ 45.0 45.1 45.2 Holt, D.G., et al., Anterior chamber intraocular lens, sutured posterior chamber intraocular lens, or glued intraocular lens: where do we stand? Curr Opin Ophthalmol, 2012. 23(1): p. 62-7.
  46. ↑ Sawada, T., et al., Long-term follow-up of primary anterior chamber intraocular lens implantation. J Cataract Refract Surg, 1998. 24(11): p. 1515-20.
  47. ↑ 47.0 47.1 Drolsum, L., Long-term follow-up of secondary flexible, open-loop, anterior chamber intraocular lenses. J Cataract Refract Surg, 2003. 29(3): p. 498-503.
  48. ↑ Dick, H.B. and A.J. Augustin, Lens implant selection with absence of capsular support. Curr Opin Ophthalmol, 2001. 12(1): p. 47-57.
  49. ↑ Apple, D.J., et al., Anterior chamber lenses. Part I: Complications and pathology and a review of designs. J Cataract Refract Surg, 1987. 13(2): p. 157-74.
  50. ↑ Kim, S.S., et al., Management of dislocated intraocular lenses. Ophthalmology, 2008. 115(10): p. 1699-704.
  51. ↑ 51.0 51.1 Jakobsson, G., et al., Surgical repositioning of intraocular lenses after late dislocation: complications, effect on intraocular pressure, and visual outcomes. J Cataract Refract Surg, 2013. 39(12): p. 1879-85.
  52. ↑ Mello, M.O., Jr., et al., Surgical management and outcomes of dislocated intraocular lenses. Ophthalmology, 2000. 107(1): p. 62-7.
  53. ↑ 53.0 53.1 Kristianslund, O., et al., Late In-the-Bag Intraocular Lens Dislocation: A Randomized Clinical Trial Comparing Lens Repositioning and Lens Exchange. Ophthalmology, 2017. 124(2): p. 151-159.
  54. ↑ Scharioth, G.B., et al., Intermediate results of sutureless intrascleral posterior chamber intraocular lens fixation. J Cataract Refract Surg, 2010. 36(2): p. 254-9.
  55. ↑ Elderkin, S., et al., Outcome of descemet stripping automated endothelial keratoplasty in patients with an anterior chamber intraocular lens. Cornea, 2010. 29(11): p. 1273-7.
  56. ↑ Fechner, P.U., Late loss of corneal endothelial density with refractive iris-claw IOLs. J Cataract Refract Surg, 2010. 36(2): p. 352-3.
  57. ↑ Hirashima, D.E., et al., Outcomes of iris-claw anterior chamber versus iris-fixated foldable intraocular lens in subluxated lens secondary to Marfan syndrome. Ophthalmology, 2010. 117(8): p. 1479-85.
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