THE INCIDENCE, PATHOGENESIS AND
`TREATMENT OF CYSTOID MACULAR EDEMA
`FOLLOWING CATARACT SURGERY‘
`
`BY Allan]. Flack, MD (BY INVITATION)
`
`INTRODUCTION
`
`Cystoid macular edema (CME) following cataract surgery was first recog-
`nized over 4 decades ago by Irvine.‘ Macular edema was mentioned in the
`20tl1 century, and CME was identified and studied earlier in the 20th cen-
`tury.” However, the report of Irvine represents the first clinical descrip-
`tion of CME following cataract surgery as a distinct entity.‘ Following this
`initial description, the syndrome was further studied and described with
`new methods including fluorescein angiograms.” Today, this postopera-
`tive complication is frequently referred to as the Irvine-Cass syndrome. It
`is recognized as the most common cause of decreased vision in patients
`following cataract surgery with or without the implantation of an intrace-
`ular lens.” This syndrome is responsible for a greater and a more fre-
`quent loss of vision than many of the more commonly discussed postoper-
`ative complications, including retinal detachment and endophthalmitis.‘°‘”
`Despite over 40 years of clinical and laboratory investigative effort, the
`incidence and pathogenesis of this syndrome remain obscure, and its treat-
`ment continues to be controversial.
`
`The purpose of this thesis is to provide a current and comprehensive
`review of the literature on the Irvine—Cass syndrome and to describe pre-
`viously unpublished investigations that extend our knowledge about the
`incidence, pathogenesis, and treatment of this syndrome. The literature
`review supports the hypothesis that the incidence, pathogenesis, and treat-
`ment of CME following cataract surgery are poorly understood. The over-
`all goal of the 7 laboratory and clinical studies described within this thesis
`is to provide new information concerning the incidence, pathogenesis, and
`treatment of CME following cataract surgery.
`
`‘From the Department of Ophthalmology and the Department of Veterans Affairs,
`University of California, San Francisco, Medical Center. Supported by a Merit Review grant
`from the Department of Veterans Affairs; a grant from That Man May See, Inc; a depart-
`mental core grant from the National Institutes of Health—University of California, San
`Francisco, Department of Ophthalmology; a research grant from Syntex, Palo Alto,
`California; an unrestricted research grant from Allergan; and a grant from Research to
`Prevent Blindness.
`
`Tn. AM. OPHTH. Soc. VOL. XCVI, 1998
`
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`SENJU EXHIBIT 2068
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`More specifically, the original results and data that are reported vvith—
`in the new investigations section following the literature review include:
`1.
`Incidence of CME Following Cataract Surgery
`II. Correlation of Anterior Ocular Inflammation with CME Following
`Cataract Surgery
`III. Topical NSAID Treatment of CME Following Cataract Surgery With
`Topical NSAIDs
`A. Comparison of Topical NSAIDs and Their Ability to Stabilize the
`Blood-Aqueous Barrier (BAB) of Rabbits Following Paracentesis
`B. Comparison of Ketorolac Tromethamine 0.5% and Diclofenac
`Sodium 0.1% Ophthalmic Solutions in Reducing Postoperative
`Inflammation After Cataract Extraction and Intraocular Lens
`
`Implantation
`C. The Effect of Patient Characteristics on Response to Topical
`NSAID Treatment of Chronic Clinical CME Following Cataract
`Surgery
`D.Treatment of Acute-Onset Clinical Cystoid Macular Edema
`Following Cataract Surgery With Topical NSAIDs
`IV. Oral Acetazolamide and the Treatment of Chronic Clinical CME
`
`Following Cataract Surgery
`These original laboratory and clinical efforts consist of 5 studies (I,
`IIIA, IIIB, IIID, IV) that have not been previously published. In addition,
`two studies (II, IIIC) are included that have been previously published in
`part. However, they are reported here in more detail and with a different
`emphasis in support of this thesis.
`A summary and conclusions section derived from both the literature
`review and the new investigations is placed at the end of this thesis. This
`section attempts to place the findings of the new investigations and their
`relationship to the literature review into perspective in a concise manner.
`
`REVIEW OF LITERATURE
`
`INCIDENCE
`
`Although CME following cataract surgery is recognized as the most com-
`mon cause of decreased vision in the postoperative period, the reported inci-
`dence of this postoperative complication has been and continues to be quite
`variable. Many review articles mention factors that may contribute to the
`difiference in the reported incidence of CME.“'‘'’‘’‘ These comments are
`derived from more than 60 published papers, each of which mentions or
`discusses the incidence of this syndrome. These publications are summa-
`rized in the Appendix of this paper.”-‘”"“”*°° In spite of the extensive effort
`reflected in these reports and reviews, the incidence of this syndrome
`remains uncertain. Furthermore, frequently the reasons for the differences
`
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`Cystoid Macular Edema Following Surgery
`
`559
`
`in reported incidence continue to remain a mystery. For example, 2 well-
`designed studies performed in the same city, including patients with similar
`characteristics who were operated on by the same surgeon using the same
`technique and medications, report an incidence of 5.6% and 18.8%, respec-
`tively, for angiographic CME in eyes with intact posterior capsules and
`intraocular lenses lacking UV filters.“‘9‘ The explanation for this difference
`in incidence is unclear.” Therefore, some of the coexistent variables that can
`affect the incidence of CME have not been identified.
`
`However, in spite of this uncertainty, it is important to recognize as
`many of the known variables as is possible for at least 2 reasons. First, it
`seems prudent to identify factors tending to increase the incidence of
`CME and to omit them in an attempt to minimize the incidence of this
`postoperative complication.” Second, it is important to identify these vari-
`ables and recognize their potential impact on the interpretation of results
`from therapeutic trials that evaluate potential treatments for CME. The
`presence of these variables and their potential influence on the observed
`incidence of CME make it unwise to use retrospective controls when eval-
`uating the potential merits of a new therapeutic approach, because the
`observed difference may reflect the presence of the coexistent variable
`and not a therapeutic effect. Furthermore, when evaluating the results of
`a prospective, randomized, double—masked therapeutic trial, one must
`confirm that these variables are present in both the treatment and control
`groups in similar numbers at the conclusion of the study to prevent misin-
`terpretation of the results.
`Insofar as the factors that influence the incidence of CME are relevant
`
`to therapeutic trials concerning this syndrome, a review of these variables
`is of great practical value. Factors that investigators have considered
`potentially capable of influencing the incidence of CME following cataract
`surgery include:
`1. The thoroughness of thesearch for this syndrome, including the
`performance and examination of multiple angiograms”
`2. Whether the investigators report a retrospective study designed to
`assess patients with poor vision or a prospective study including flu-
`orescein angiograms”
`3. The introduction of new instrumentation or technology permitting
`more careful or complete diagnostic examinations”
`. A changing definition of CME following cataract surgery”
`. Whether the investigators are reporting clinical CME (angiograph—
`ic CME associated with a decrease in visual acuity) or only angio-
`C M E151"/,l9,W,22.28
`6. How long after surgery the patient is exarnined2°‘°°"°"5'”"‘38
`7. Patient characteristics, including age,‘°-3"‘"""73'77"’3'°‘ presence of vascu-
`lar disease,”°’”-““°9"5’5°-3°-89-9°-95-9° race and eye color,”-9’ and a history of
`
`CJ'l)J>
`
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`Flach
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`alcoholsim“
`
`8. A history of CME following surgery in the contralateral eye“-2°33-5“-99
`9. Comparisons of results following intracapsular cataract extraction
`(ICCE) and extracapsular cataract extraction (ECCE) with or with-
`out the presence of an intraocular lens17-2‘-’5~"”""“"“’-“"53-55'57'59-52'“-72-3‘-37-‘°°
`10. The administration of retrobulbar hyaluronidase‘°“°2
`11. The presence of intraoperative complications, including vitreous
`1oSS9,Il,52,54.63.64,72,34,87.103.104
`
`12. The presence of vitreous to the wound”°"°“‘°
`13. The presence of a peaked pupil in the postoperative period‘”7-W1"
`113
`
`14. The influence of coexistent drug use or other ocular irri-
`17,26,51,58,75,83,101,l02.1l4«l I9
`
`absence of
`15. The presence or
`Suleiil,52,54,59,80,65,69,70,78,98,I20~I23
`
`an intact posterior
`
`cap-
`
`16. The presence of specific intraocular lens qualities such as a
`polyvinlypyrrolidone coating)“ metal loops,"-5 and UV blockers,9"°*‘
`lens defects)” iris clip and rigid anterior chamber (AC) lens’7v"°v"‘
`17. Exposure
`to
`excessive
`intraoperative
`or
`postoperative
`hght79,91.98,l22.l27-131
`18. The performance of a postoperative yttrium—aluminum—garnet
`(YAG) capsulotomym-132
`19. The lapse of time between cataract extraction and secondary
`intraocular lens implantm
`20. Secondary lens implantation compared with primary lens implan-
`tationl”
`
`There is agreement that the incidence of CME is greatest in prospec-
`tive studies reporting angiographic CME including multiple angiograms
`performed 1 to 3 months following an ICCE with implantation of an iris
`clip lens in an older population of patients with systemic vascular disease.
`Furthermore, the incidence can vary with how, when, and why an investi-
`gator looks for this syndrome. However, investigators have not been in
`agreement concerning the importance of several of the potential variables
`listed previously. Therefore, the evidence suggesting that these factors
`may or may not influence the development of angiographic or clinical
`CME following cataract surgery is summarized in Table 1.
`
`CLINICAL CHARACTERISTICS
`
`CME following cataract surgery consists of a maldistribution of the retinal
`intravascular fluid within the macula. The leakage of the intravascular con-
`tents from dilated perifoveal capillaries initially causes thickening of the
`macula, which may progress to cystoid expansions within the outer plexi—
`form (Henle’s) layer and inner nuclear layer of the retina. These cystoid
`
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`Cystoid Macular
`
`Following Surgery
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`TABLE I: FAcroRs INFLUENCING THE INCIDENCE or CME
`FoLLowINc CATARACI‘ SURGERY
`
`RESULTS or
`COMPARISON
`
`ANCIocRAI>IIIc
`CME
`
`CLINICAL
`CME
`
`ICCE>ECCE
`
`Increased
`
`Increased
`
`Iris clip>AC>PC°
`
`Increased
`
`Increased
`
`Absent > present‘
`
`Increased
`
`Same
`
`REFERENCES
`
`35,50,51,53,56,
`57,59,60,62,65,
`69,71,72
`27,28,30,56,94,
`125,134
`78
`
`Same
`
`Same
`
`Increased
`
`Same
`
`Same
`
`Same
`
`102
`
`79
`
`91,98
`
`VARIABLE
`
`Type of
`surgery
`
`Placement
`of IOL
`
`Integrity
`of posterior
`capsule
`Hyaluronidase
`in retrobulbar
`
`Operating
`microscope light
`Environmental
`
`light
`
`Contralateral
`CME
`VVhen examined
`
`Age
`
`Systemic vascular
`disease (diabetes,
`hypertension)
`Vitreous loss
`
`Vitreous to
`wound
`
`Abnormal
`
`Present > absent
`
`Increased
`
`Increased
`
`pupil shape
`Iris incarceration
`in wound
`Race
`
`Epinephrine
`
`Present > absent
`
`Increased
`
`Increased
`
`1 13
`
`White > black
`Present > absent“
`
`Increased
`Increased
`
`Increased
`Increased
`
`83,97
`114,115,116,
`117,118,119
`
`AC, anterior chamber; CME, cystoid macular edema; angiographic CME, visual acuity nor-
`mal; clinical CME, visual acuity abnormal; ECCE, extracapsular cataract extraction; ICCE,
`intracapsular cataract extraction; IOL, intraocular lens; PC, posterior chamber; UV, ultravio-
`let.
`
`"
`
`Initially investigators observed no difIerence.5”’-°’>7’~‘°5 Subsequently good evidence for AC
`> PC,”“°‘ iris-supported lenses poorer prognosis,” iris clip lenses particularly
`
`PAGE 5 OF 78
`
`Absent =
`Present ‘
`UV filter =
`no filter‘
`IOL without
`UV filter >
`IOL with UV
`filter
`Present>absent
`
`1-3 mo greatest
`incidence
`
`Older > younger“
`
`Increased
`
`Increased
`
`Increased
`
`Increased
`
`Increased
`
`Increased
`
`Present > absent‘
`
`Increased
`
`Increased
`
`Present > absent“
`
`Increased
`
`Increased
`
`Present > absent
`
`Increased
`
`Increased
`
`8,20,56,
`98,99
`20,39,40,45
`
`20,68,73,77,
`93,94
`7,20,29,34,
`39, 45,50,
`95,96
`9,11,52,54,
`63,64,72,84,
`87,103,135
`120,104,105,
`106,107,109,
`110
`19,27,112,113
`
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`TABLE I (CONTINUED): FACTORS INFLUENCING THE INCIDENCE or CME
`FOLLOWING Carzuucr SUnCEnr
`
`‘
`
`In addition, defects in IOU” and
`Copeland and metal loop and rigid AC lenses.”*°°-9‘-'1‘
`polyvinylpyrrolidone-coated lensesm all increased angiographic and clinical CME.
`Many investigators observed disrupting posterior capsule increases CME.5’~5"5°"“-6°-‘W’-"*‘ In
`addition, a secondary capsulotomy increased CME,5“‘>’“~53 including YAG capsulotomy.”°
`However, a well-controlled, prospective, randomized study shows an increase in angio-
`graphic CME, but no signifiant difference in vision.” In addition, a YAG capsulotomy
`does not appear to increase clinical CME?”
`Initially, small study suggested presence of hyaluronidase increases CME,“" but these
`investigators agreed that a larger study was needed. Subsequently, a larger well-con-
`trolled study showed no difference.“
`’ Although microscopic light can cause retinal damage”‘ and investigators wondered if this
`light might predispose to CME,"“’° there is no evidence of a relationship. Furthermore,
`a well-designed study shows no effect on CME."
`Most agree that increased age is associated with increased CME, but an increased inci-
`dence has been reported in younger adults.“ Furthermore, a limbal approach to cataract
`surgery in pediatric patients appears to be associated with more CME” as compared with
`a pars plana approach using vitrectomy instrumentation.”
`‘ The reported association of systemic disease (systemic hypertension, diabetes mellitus)
`and increased CME has prompted some to recommend treatment prior to surgery to
`reduce CME.“ This is a good idea, but no evidence exists that will decrease CME."
`# Although most CME occurs without surgical complications, vitreous loss increases CME
`and vitreous to the wound prolongs CME and can be associated with a poorer progno-
`siSv27.30.3s
`
`°° Topically applied epinephrine and dipivalyl epinephrine can induce CME in eyes follow-
`ing cataract surgery. This is reversible if treatment is discontinued in a timely fashion.
`
`spaces tend to be smaller peripherally and larger centrally and often cul-
`minate in a typical petaloid or stellate appearance. This accumulation of
`transudate may or may not be associated with a measureable decrease in
`visual acuity.”-*4‘
`A patient with CME may be asymptomatic or may complain of
`decreased vision, a positive central scotoma, and metamorphopsia.“
`Direct or indirect ophthalmoscopy may reveal only the absence of the
`foveal light reflex or a vague irregularity within the macular region. During
`ophthalmoscopy, red—free light can be used to help demonstrate cystoid
`spaces.” However, most of the time, CME is best detected with slit—lamp
`biomicroscopy using a Goldmann fundus Contact lens or a Hruby lens.”
`Initially, there is a loss of the foveal light reflex, which is associated with
`the loss of the foveal depression and the appearance of a yellowish spot
`deep in the foveal area. The thickened, yellowish macular changes can
`progress to the formation of cystoid spaces that are best appreciated using
`retroillumination and red—free light, which makes the inner walls of the
`cystic cavities more visible. These can appear in a rosette pattern. Splinter
`hemorrhages can layer blood in the cystoid spaces.“‘2 Coalescence of the
`
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`Cystoid Macular Edema Following Surgery
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`cystoid spaces can form a foveal cyst or even inner lamellar holes as the
`surface of the cyst elevates and peels away.” A shallow sensory retinal
`detachment can develop owing to diffusion of excess transudate beneath
`the photoreceptors.‘ The subretinal fluid can stimulate the retinal pigment
`epithelium with hypotrophic or hyperpigmentary changes and, less com-
`monly, disciforrn scar formation.“ A grayish membrane with glinting
`reflexes from the inner surface of the retina can indicate the presence of
`an epiretinal membrane. This has been described in up to 10% of the eyes
`that have developed CME.““"‘1"“3-““ In addition to these retinal findings,
`many eyes with CME have a coexistent circumcomeal flush, mild iritis,
`vitritis, and a low—grade papillitis sometimes associated with peripapillary
`hemorrhages.
`Most of the time, CME follows an uncomplicated cataract surgery, and
`it is diagnosed in an eye with a relatively normal gross anatomy. However,
`patients may demonstrate an associated ocular anatomic derangement
`such as vitreous and/or iris incarceration in the surgical incision, vitreous
`adherence to the iris, poor pupillary dilation, an abnormally shaped or
`updrawn pupil, secondary glaucoma, or corneal decompensation. A clini-
`cal examinafion will not confirm the diagnosis of CME in 5% to 10% of the
`eyes with CME.“ Even a retinal detachment can mimic CME.”
`Fluorescein angiography is the diagnostic procedure of choice for patients
`with a questionable diagnosis of CME.“~‘5'”9
`Following the systemic administration of sodium fluorescein to a
`patient with CME, the involved eye demonstrates early perifoveal capil-
`lary dilation and leakage with pooling of fluorescein in the macular cystoid
`spaces and late staining of the optic nerve associated with leaking of cap-
`illaries of the optic nerve head.7 A highly resolved, stereoscopic analysis of
`negatives from eyes with CME is the best way to identify characteristic
`angiographic features of this syndrome.“-139 During the early stages of the
`angiogram, the macula appears dark as the dye perfuses choroidal and reti-
`nal vascular systems. Early in the retinal venous filling phase, the presence
`of CME becomes apparent as dilated perifoveal vessels that become
`prominent and leak the dye—stained transudate. In later stages of the
`angiogram, lea.kage from the deep retinal capillary circulation fills the larg-
`er cystic spaces in a stellate, or rosette, perifoveal pattern. This dye—stained
`fluid accumulates in the outer plexiform and inner nuclear layers of the
`retina. Photographs are best taken at 10 minutes postinjection to enhance
`the appearance of macular cyst or hole formation, which provides a com-
`plete and sensitive angiographic analysis?“ Dye leakage from the retinal
`vessels, optic nerve, and anterior uvea into the anterior and posterior
`chambers and into the vitreous cavity during the very late stages of the
`angiogram create an anterior and posterior haze that reduces the resolu-
`tion of the macular changes. The dye leakage from the iris and optic disc
`
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`may persist even after the CME has resolved.
`Fluorescein angiograms are of great diagnostic value. However, even
`experienced clinicians are unable to read up to 15% of these angiograms
`owing to factors associated with the postoperative eye. These factors
`include the presence of an intraocular lens and/or an intact posterior cap-
`sule, which create bothersome reflections; anterior synechiae or poorly
`dilated pupils, which limit sufficient light from entering the eye; vitreous
`haze, which obscures detail; and inadequate patient cooperation.“‘°
`Fluorescein angiographic grading systems have been developed to
`monitor patients with CME.“‘““7 However, highly skilled investigators
`have reported an improvement in vision without change in the degree of
`edema, a reduction in edema without a corresponding improvement in
`vision, and a deterioration in vision associated with gradual disappearance
`of CME on angiogram.“ Published photographs of 4 angiograms, each
`taken from a patient with 20/50 visual acuity, depict severity of grade 1
`through grade 4.“‘ Therefore, there is agreement that angiograms are of
`great value to confirm the presence or absence of CME, but the degree of
`leakage does not always correlate with the visual acuity. ‘5'“"27'5”'3“*3-““‘~“*’*‘5°
`There are several reasons why the correlation between visual acuity
`and angiogram grade may be poor in patients with CME following cataract
`surgery. An angiogram documents fluid in cystoid spaces in the outer plex-
`iform layer, but decreased vision may be associated with edema in the pho-
`toreceptor area or elsewhere. A coexistent anatomic change such as a pre-
`retinal membrane, a macular cyst or hole, the presence of perifoveal reti-
`nal pigment epithelium atrophy, disciform scarring, or a papillitis may
`limit an increase in visual acuity.‘5-“9 Finally, the presence of ocular dis-
`eases other than CME, such as glaucoma and corneal edema, may be
`responsible for the reduced vision.
`The potentially poor correlation between a fluorescein angiogram
`grade and visual acuity has important clinical implications for the use of
`angiograms during studies designed to evaluate the effectiveness of a
`treatment for CME following cataract surgery. A fluorescien angiogram is
`useful for confirming the diagnosis of CME during clinical studies, but the
`visual acuity should be the primary efficacy parameter in therapeutic tri-
`als. Furthermore, clinical data collected from patients with angiographi—
`cally proven CME should not be excluded from analysis simply because
`the corresponding angiogram is unreadable or unavailable. Although the
`measurement of visual acuity in patients with CME is somewhat subjec-
`tive, its determination yields the most clinically relevant information at our
`disposal at present, provided it is obtained using proper technique and
`precautions."‘9"5‘ However, it must be recognized that the improvement in
`vision may reflect an ameliorating effect of treatment, which is not syn-
`onymous with the elimination of the edema.“ Investigators may develop
`
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`Cystoid Macular Edema Following Surgery
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`565
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`methods to measure retinal thickening that are inexpensive and easy to
`incorporate into ophthalmic practice in the future. New methods may pro-
`vide a more objective method for following changes in the retinal edema
`present in eyes with CME that is more consistent with changes in visual
`l48,l50.l52,l53
`
`HISTOPATHOLOGY
`
`Histopathologic specimens from patients with CME following cataract
`surgery show retinal capillary dilation and serous fluid in the outer plexi-
`form and inner nuclear layers and inflammatory cells in the iris, ciliary
`body, and around blood vessels.”5~‘5“57 Sometimes there are associated iri-
`dovitreous adhesions. The eosinophilic transudate displaces rod and cone
`nuclei and receptor cell axons. Severe CME involves most of the retinal
`layers. Perifoveal cysts can become confluent, forming larger cysts or
`lamellar holes. Shallow serous detachments occur in some eyes with
`CME.‘ In addition to retinal changes, swollen mitochondria are present in
`ganglion cell axons in the prelaminar area, and degeneration of fibrous
`astrocytes between axons and occlusion of laminar blood vessels by ede-
`matous endothelial cells and pericytes can be present.
`The intraretinal cysts can develop from the accumulation of fluid
`either intracellularly or extracellulaiy. Initially, extracellular serous fluid
`was thought to compress Miiller cells and receptor cell axons to form the
`walls of the cysts.’ Subsequently, histologic evidence of intracytoplasmic
`edema of Miiller cells suggested intracellular fluid accumulation as the
`origin and location of the cystic changes.‘5“5*’ However, evidence exists that
`the cysts can arise from expansion of extracellular spaces.1°° It is possible
`that the observed histologic differences relate to tissue fixation tech-
`nique.”-‘°°
`Histologic evidence shows vitreous traction producing macular holes
`with surrounding cystoid changes.“ This histopathologic observation sug-
`gests that vitreous traction may relate to the development of CME follow-
`ing cataract surgery. However, cystic macular degeneration and associated
`hole formation linked to with vitreoretinal traction occurs in both aphakic
`and phakic eyes. Therefore, these findings are believed to be related to a
`different entity.” In addition, the cystic spaces in these eyes are filled with
`a mucopolysaccharide, and these eyes lack the characteristic increased
`vascular permeability as seen in fluorescein angiograms that support this
`distinction.’°"°“‘"’3
`
`DYNAMICS OF EDEMA FORMATION
`
`CME is a nonspecific retinal sign of ocular disease that consists of an
`abnormal accumulation of intracellular and extracellular eosinophilic tran-
`sudate associated with thickening of the retina and the formation of cystic
`
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`changes within the outer plexiform layer and inner nuclear layer of the
`macula. The blood-retinal barrier (BBB) is a condition of restricted per-
`meability between blood and retina dependent on the integrity of inter-
`cellular junctional complexes (tight, nonleaky junctions) existing in both an
`epithelial (retinal pigment epithelium) and an endothelial (endothelium of
`retinal capillaries) cell layer within the retina.1““‘*“
`Our understanding of the dynamics underlying the development of the
`maldistribution of fluid in eyes with CME following cataract surgery is
`based on a recognition of Starling’s hypothesis and its relationship to the
`blood-brain barrier and the BRB.1“”“ Edema occurs in any tissue when
`the rate of capillary filtration exceeds the rate of fluid removal from
`perivascular interstitium.“ The abnormal accumulation of transudate
`within the macula is determined by an increased permeability state of the
`BRB and an imbalance between tissue forces determined by osmotic pres-
`sures in the plasma and retina (largely dependent on protein concentra-
`tion), hydrostatic pressures within the retinal capillaries and surrounding
`retinal tissue, and tissue compliance of the corresponding retina.”-“"’“°“
`Macula edema develops when the rate of capillary filtration exceeds
`the rate of fluid outflow from the retina in spite of autoregulation of blood
`flow pressure attempting to prevent increased hydrostatic pressures and
`increased permeability of retinal capillaries and in spite of the resistance
`offered by the low retinal tissue compliance. Retinal tissue compliance is
`low because the cellular elements supported by Miiller cells combined
`with minimal extracellular space resists fluid accumulation. CME will
`develop when the BBB permits intravascular fluid entry to exceed its exit
`to the point of overcoming retinal tissue compliance. Disruptions of tight
`junctions in both inner (capillary endothelial cells) and outer (retinal pig-
`ment epithelium) portions of the BBB may be involved in this process.“-17°
`As excessive transudate accumulates within the retina, the macular
`
`region is presidposed to the collection of this fluid by virtue of its anatom-
`ic structure. The horizontal course of the outer plexiform layer extends
`transversely from cone nuclei to bipolar cells, and the resultant laxity of
`this layer predisposes to the formation of a reservoir for the accumulation
`of transudate?“ Furthermore, the avascularity of the foveolar area restricts
`absorption?“ As a result of this predilecfion for the accumulation of fluid,
`the macula has been said by some experienced investigators to “act as a
`sponge” or to have an “inherent turgesability.”7'”2 In addition to these
`anatomic considerations, the foveal region has large concentrations of cells
`with a high metabolic activity. Inflammatory, metabolic, or vascular distur-
`bances can lead to increased concentrations of tissue metabolites with loss
`
`of biochemical activity. 139
`Although there is agreement about the contribution of these anatomic
`and biochemical factors to the development of CME following cataract
`
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`Cystoid Macular Edema Following Surgery
`
`567
`
`surgery, a complete understanding of the dynamics of this fluid accumula-
`tion is not within our grasp. Investigators have emphasized that the pref-
`erential leakage from perifoveal capillaries in eyes with CME observed
`during angiograms remains unexplained and may reflect an important,
`unrecognized capillary vitreous interaction.”
`
`CME ASSOCIATED WITH OTHER DISORDERS
`
`CME represents the accumulation of fluid within cells or spaces in the
`outer plexiforrn layer and the inner nuclear layer of the retina.’-15”“ This
`nonspecific intraretinal macular manifestation can be associated with
`many ocular and systemic disorders in addition to cataract surgery.”""“’ It
`is important to recognize these potential associations for at least two rea-
`sons. First, these associated conditions provide us with clues to the patho-
`genesis of this syndrome as discussed in the following section of this paper.
`Second, recognition of these associations is important during the evalua-
`tion of a potential therapeutic response. If the associated condition is pre-
`sent, treatment of this disorder can affect the presence or the severity of
`the associated CME. Furthermore, CME related to this condition may or
`may not be influenced by the treatment being evaluated. Therefore, the
`presence of an associated condition must be identified, and patients with
`the disorder must either be omitted from the study or, if included, some
`assurance that the condition is present in both treatment and control
`groups in comparable numbers must be provided.
`Therefore, it is important to remember that the following disorders
`and systemic conditions have been reported in association with CME in
`the absence of cataract surgery:
`1. Choroidal tumors”‘‘'"‘"’
`
`2. Topical epinephrine and dipivalyl epinephrine treatment““"“"~”7'”9
`3. Dominant and X—linked retinitis pigmentosa5"““5°'"““’* and probably
`even in the recessive forml" (characteristic fluorescein angiographic
`leakage variable even in the same pafient)
`4. Favre-Goldmann syndromelssm
`5. Retinal detachment surgery"'19‘”°’
`6. Penetrating keratoplasty’°”°5
`including bird-shot chorioretinitis,
`7. Ocular inflammatory diseases,
`chronic cyclitis, and idiopathic vitritis‘5-“”°“‘°
`8. Diabetes mellitis5°*“‘~‘-"°'“"“3
`9. Arteriosclerotic vascular disease5°"°5
`
`10. Systemic hypertension‘5’5°-‘°5
`11. Vascular occlusive disease”'”9*‘59'“”18
`
`12. Infants without hereditary eye disease at birth“9*’2°
`13. Vitreous surgery“
`14. Laser surgery“
`
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`568
`
`Flach
`
`15. Fundus flavimaculatusm
`
`16. Cryotherapy and segmental buckling of retinal tears without detach-
`mentsm
`
`17. Ring choroidal atrophy“
`18. Gyrate atrophy of choroid and retina“
`19. Idiopathic epiretinal membranes“
`20. Serpiginous choroidopathyz”
`21. Dominantly inherited cystoid changes of the retina”‘‘'”‘
`In addition to these conditions, several disorders have been described
`
`as associated with macular edema. However, they do not manifest the
`characteristic fluorescein angiographic findings of CME. These disorders
`include nicotinic acid treatment,23’*”5 parafoveal retinal telangiectasia,””‘5
`juvenille X—chromosome—linl<ed refinoschisis,” adult-onset cystic macular
`degeneration and “hole” formation with or without vitreomacular trac-
`tion,” and possibly ocular trauma. ”"3°”37 However, the presence of retinal
`edema following ocular trauma in clinical cases lacks solid evidence. Even
`within laboratory studies it is variable, leading some investigators to ques-
`tion if “Berlin edema” is still valid.’3w9
`
`PATHOGENESIS
`
`surgery remains
`The pathogenesis of CME following cataract
`obscure.‘5-2°-22-”°'°“»“" Clinical observations and experimental studies suggest
`that the pathophysiology of this postoperative problem may be multifacto—
`rial. Among the factors of potential clinical importance are vitreous trac-
`tion,‘*3°-‘°7*“"""°”‘”“‘ vascular instability,1'1“-33'5°"55-‘5*"‘5”‘°"‘“‘3 a relative ocular
`hypotony,3”““52 a lack of stability inside an aphalcic eye called endoph-
`inflammationI.7.8.13,520-22.28.37-39,45,5l,98,ll2,l24,l2G,l35,l54-l56,207,2I0,248,254-265
`
`prostag—
`as
`such
`chemical mediators
`endogenous
`including
`landins”“'5"""-“’°*25‘”5*”""‘2-”‘“7‘ and other autacoids,”-“‘”“”’2 a functional distur-
`bance of the blood-ocular barriers,”’-‘‘“’‘'‘‘‘‘’’”‘”7 and ultraviolet radia-
`tion.’9'9"9“*""‘3°"“ Each of these potential etiologic factors has been consid-
`ered as a rationale for the consideration of a corresponding treatment as
`discussed in the following section of this paper.
`Most investigators agree that inflammation is the major etiologic factor
`in the development of CME following cataract
`surgery.1430'”-“'27*1”*2“7~2’9
`There is clinical, histopathologic, experimental, and pharmacologic evi-
`dence to suppor