SURVEY OF VOLUME 51  NUMBER 6  NOVEMBER–DECEMBER 2006

MAJOR REVIEW

Current Concepts of Ocular Manifestations in Arie Y. Nemet, MD,1 Ehud I. Assia, MD,1 David J. Apple, MD,2 and Irina S. Barequet, MD3

1Department of Ophthalmology, Sapir Medical Center, Kfar Sava, Sackler Faculty of Medicine, Tel Aviv University, Israel; 2Laboratories for Ophthalmic Devices Research, Moran Center, University of Utah, Salt Lake City, Utah, USA; and 3Godschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel

Abstract. Marfan syndrome is a widespread disorder of . It is characterized by systemic and ocular features due to mutations in the fibrillin gene. Awareness and prompt recognition of the ocular complications of Marfan syndrome may enable improvement and preservation of sight. Studies have been performed in the last few years that enable a better understanding of the genetics of the syndrome, earlier diagnosis, and improvement in the surgical techniques and options. (Surv Ophthalmol 51:561--575, 2006. Ó 2006 Elsevier Inc. All rights reserved.)

Key words. cardiovascular disease   genetics  Marfan syndrome  microfibrils  musculoskeletal abnormalities

I. Introduction ocular complications of MFS, enable significant 23 Marfan syndrome (MFS) was first described by progression in preservation of sight. a French pediatrician, Antoine Marfan, in 1896, The estimated incidence is between 1/5,000 and 1/20,000 and about 25--30% of cases represent new who reported the case of a 5-year-old girl whose 39,44,69,81 arms, legs, fingers, and toes were disproportionately mutations. It affects both sexes equally, is found in all races, and is common enough to be long and thin, whose muscle development was poor, 80 and whose spine curved abnormally. A more seen several times a year in a busy clinic setting. complete description of this condition was given earlier by the ophthalmologist Whilliams in 1876.2 It is the second most common inherited connective II. Genetics tissue disorder, after .70 It is Transmission is autosomal dominant with high characterized by musculoskeletal abnormalities, penetrance, although approximately 25--30% of cardiovascular disease, and ocular abnormalities, cases are sporadic.44,113 Although abnormalities and it can affect many structures of the eye.2,33,59 with fibrillin 1 (FBN1) are responsible for the The developments and knowledge of genetics and Marfan phenotype in approximately 80% of pa- pathogenesis in the last decade, as well as the tients, MFS can also be caused by inactivation advances in the surgical options for treatment of the mutations in TGF-b receptor 2 (TGFBR2).125 FBN1

561 Ó 2006 by Elsevier Inc. 0039-6257/06/$--see front matter All rights reserved. doi:10.1016/j.survophthal.2006.08.008 562 Surv Ophthalmol 51 (6) November--December 2006 NEMET ET AL is a main component of extracellular microfibrils two different areas as well as involvement of a third found in a wide range of tissues. FBN1 is coded for area are required. on chromosome 15 in the q21.1 locus,28,52,60,74,115 The major ocular criteria is ectopia lentis (Fig. 1), and TGFBR2 is located at 3p24.2--p25.25,28,52,60, and the minor ocular criteria includes abnormally 72,100,126 Recent studies have suggested that abnor- flat ,increased axial length of , and malities in the TGF-b signaling pathway may hypoplastic or hypoplastic ciliary muscle causing represent a final common pathway for the de- decreased .7,22,84 In their revised criteria, De- velopment of the Marfan phenotype.72,74 The gene Paepe and colleagues suggested the inclusion of defect ultimately leads to decreased and disordered molecular characteristics to the diagnostic criteria of incorporation of fibrillin into the connective tissue MFS.22 They suggested also more stringent require- matrix.47,86,98 ments for diagnosis of the MFS in relatives of an The size of the FBN1 gene is estimated to be 200 unequivocally affected individual and delineation of kb and a wide variety of mutations in FBN1 have initial criteria for diagnosis of other heritable been shown to cause MFS. Currently, more than 500 conditions with partially overlapping phenotypes. mutations have been identified and almost all are unique to an affected individual or family.8,69 However, even with the same mutation there is clinical heterogeneity among individuals.22,26 Not IV. Systemic Manifestations all patients with MFS are tall and thin with long An interdisciplinary health care team at a central fingers and pectus excavatum. Patients may appear Virginia medical center evaluated the histories of phenotypically normal with only ocular signs, such 112 persons with MFS-related traits from 15 differ- as dislocated lenses, to suggest the diagnosis. ent families;109 57.3% of them demonstrated signif- FBN1 has also been shown to harbor mutations icant cardiovascular lesions, 41.3% were initially related to a spectrum of conditions phenotypically seen with significant ocular lesions, and 50.7% related to MFS, called type-1 fibrillinopathies,3,15,93 such displayed orthopedic deformities. A total of 18% as autosomal dominant ectopia lentis, familial aortic underwent cardiac surgery. aneurysm, and Marfan-like skeletal abnormalities. The most striking physical features of patients The FBN2 locus on chromosome 5 has been linked to with MFS are the musculoskeletal defects. As a rule, congenital contractural arachnodactyly, a disorder patients are tall with long extremities; and their arm similar in some respect to the MFS, but lacking span is greater than their total height (dolichoste- cardiovascular and ocular involvement.28,115,126 nomelia). Fingers are disproportionately long and

III. Diagnosis MFS remains a clinical diagnosis and is estab- lished when sufficient features are present. How- ever, it is now possible to diagnose the patients genetically. Molecular diagnosis in families with MFS can be undertaken by using intragenic FBN1 gene markers to identify and track the disease al- lele.25,28,52,60,101,126 However, in sporadic cases, DNA-based diagnosis cannot be performed using linked markers but rather requires the identification of the specific FBN1 gene mutation.113 The first diagnostic criteria were defined in 1956 and were revised in 1979. The Berlin criteria, which were composed by a group of international genet- icists, were established in 1986.7 In 1996 the criteria were revised again to the Ghent criteria, and these are the ones that we utilize today.22 The Ghent criteria are divided in seven areas: cardiovascular Fig. 1. Subluxation of the crystalline in Marfan system, ocular system, skeletal system, dura mater, syndrome. Note the smooth contour of the lens equator pulmonary system, skin and integument, and family indicating a long standing reduced zonular traction. A or genetic history. For a diagnosis, a major criteria in single nasal zonular bundle is still intact. OCULAR MANIFESTATIONS IN MARFAN SYNDROME 563 thin (arachnodactyly). Prognathism and a high morphological observations in vivo and in cell arched palate occur more commonly,21 and a long, culture.29,129 FBN1 mutations have been therefore thin face is characteristic. Kyphoscoliosis, pectus thought to influence negatively microfibrillar as- excavatum, or pectus carinatum are common. A sembly, thus preventing normal elastogenesis and generalized muscular hypotony, laxity, and ultimately weakening the mechanical properties of joint contracture may occur. Rocker bottom feet and the tunica media.27,87 This popular view was recently genu recurvatum are the results of joint hyper- challenged by the results of homologous gene- extensibility with subsequent contracture.21,33,59,81,84 targeting experiment in the mouse.78 Those studies Cardiovascular manifestations of MFS include suggested the existence of a critical threshold of aortic and pulmonary artery dilatation, as well as functional microfibrils for tissue biomechanics, and mitral and tricuspid valve prolapse with or without FBN1 is predominantly involved in the function regurgitation. Dilatation of the sinus of Valsalva is rather than the assembly of elastic microfibrils.88,89 found in 60--80% of adults with MFS,82 and mitral Reduced FBN1 expression in the aorta may result in valve prolapse (MVP) is present in 80% of more activated TFG-b, and at a later-stage inflam- patients.75,120,125 TGF-b dysregulation in the con- mation-mediated elastolysis may also participate in nective tissue plays an important role in the the mechanical collapse of the aortic wall.102 This development of MVP in MFS.75,125 Death in patients finding is consistent with the recent finding of with MFS is usually due to heart disease. During altered immunoreactivity for MMPs and tissue childhood and adolescence in MFS, mitral valve inhibitors of MMPs (TIMPs) in vascular specimens dysfunction as well as aortic abnormalities develop from MFS patients.79,103 and progress gradually, often without symptoms, but Relatively little is known about the pathogenesis may cause considerable morbidity and mortality by of the ocular abnormalities of MFS, and there have the end of the second decade.120 Early diagnosis is been limited studies of the distribution of fibrillin in important because preventive measures significantly normal or diseased ocular tissues.19,53,55,93,116,117,124 increase life expectancy and prevent the occurrence Clumps of beaded microfibrils with a "string of of impairments and disabilities. Beta-blockers are beads" configuration were observed in the chicken the primary treatment used to delay aortic growth and human vitreous126,127 and in human and bovine and prophylactic aortic surgery.69 zonular fibrils. This distribution indicated that the beaded fibril is the microfibril, the basic unit of the elastic system.124 The involvement of the ciliary process in lens V. Pathogenesis of Ocular Abnormalities support is important in the pathogenesis of lens Elastic fibers are extracellular macro aggregates in luxation. Normal human exhibited fibrillin tissues that are normally subjected to stretching and localized to the ciliary epithelial surface, where expansile forces.129 Elastic fibers are made of an zonules attach, as well as the ciliary muscle of the elastin core surrounded by microfibrils. Those .126 MFS patients tend to have fewer and microfibrils are thought to play a role in tropoelas- abnormal ciliary processes than normal,91 and those tin deposition and elastic fiber formation in abnormities other than defective zonular fiber addition to possessing an anchoring function in production were suggested to contribute to lens some tissues. FBN1 is the major structural compo- dislocation in MFS.11,32,126 However, proteolytic nent of the microfibrils and the main defective gene damage to zonular microfibrils potentially contrib- product in MFS.8,15,29,93 However, an increasing utes to the pathogenesis of zonular dysfunction.4 number of other proteins have been identified There is wide distribution of fibrillin in other containing microfibrils in addition to FBN1 and ocular connective tissues, including the lens capsule FBN2.8,93,125 and zonules, iris, corneal epithelium, Bowman’s Some manifestations of MFS, such as lens membrane, and the . It was found also in dislocation, could plausibly be caused by a structural the , , Bruch’s membrane, and lamina deficiency of FBN1. However, others, including AV cribrosa. This distribution might explain some of valve disease, are less easily reconciled by simple loss the ocular pathology of MFS.126 of mechanical tissue integrity and more likely manifest perturbation of cell number and perfor- mance.75 The contribution of FBN1 mutations to dissecting aortic aneurysms has been traditionally VI. Animal Studies explained on the basis of histopathological findings The establishment of animal models of MFS of fragmentation of the elastic fibers with reduced enabled the testing of the pathogenesis of MFS. A elastin content in the media in MFS patients and of mouse model of MFS was used to examine 564 Surv Ophthalmol 51 (6) November--December 2006 NEMET ET AL phenotypic alteration of vascular smooth muscle 1. Blurred vision and monocular caused cells. Mice homozygous for a targeted allele of FBN1 by progressive lens subluxation and resulting revealed a predictable sequence of abnormalities in severe the vessel wall, including elastic fiber calcification, 2. Headache, dizziness, and blurred vision, caused excessive deposition of matrix elements, elastolysis, by complete anterior lens dislocation, and may and intimal hyperplasia.10 FBN1-deficient mice have result in damage to the corneal endothelium the capacity to form normal elastic fibers during and secondary embryonic development that gradually deteriorate 3. Eye pain and visual loss are caused by posterior throughout life after birth. The earliest event seen lens luxation to the vitreous that may induce was abnormal behavior of the cells surrounding phacolytic and elastic fibers. Most importantly, they showed abnor- Signs include refractive instability and distur- mal proteases, including elastic fibers proteases. bances caused by lens movements, iridodonesis, Early damage induced by these cells stimulated an phacodonesis, and recessed angle. The zonules and inflammatory response and activation of additional the lens equator may be seen in the papillary matrix-degrading enzymes. This destructive cascade aperture. The cornea may be edematous, the culminates in structural collapse of the vessel wall, intraocular pressure high, and in case of phacolytic leading to aneurysm and aortic tear.41,79 uveitis cells and flare may be seen in the anterior or Cattle affected by bovine MFS demonstrate most posterior chamber. Retinal detachment may be of the clinical features associated with the human found. disease. Immunohistochemical and metabolic label- ing studies in affected cattle have demonstrated abnormalities in fibrillin metabolism and decreased A. LENS ABNORMALITIES fibrillin immunoreactivity when compared with Marfan syndrome is often associated with lentic- 80 a normal control. Clinically identified ocular ular abnormalities,70,124 the most frequent of which features are ectopia lentis, microspherophakia, and are ectopia lentis and microspherophakia. . Histological findings included moderately hypoplastic ciliary bodies; compact filtration angles; and long, thin irises with decreased fibrous stroma. 1. Ectopia lentis Scanning electron microscopy showed wavy and Ectopia lentis (i.e., lens subluxation) (Fig. 1), is loosely arranged zonular fibers, abnormal sites of usually bilateral, symmetric, and stable from early insertion on the lens capsule, and flattened or childhood. These patients may complain of de- smooth surfaces ciliary processes.80 creased or fluctuating vision and monocular diplo- Recently, animal studies were established to pia. Findings include iridodonesis (tremulous iris) determine if other features of MFS also manifest and irregular astigmatism. Lens dislocation is an excessive activity of TGF-ß or other growth factors. important feature of several heredofamilial syn- Preliminary evidence suggests that excessive TGF-ß dromes that also include skeletal dysplasias. MFS is may cause abnormal development of the mitral valve the most prevalent of these. Bilateral lens disloca- leaflets. A genetically engineered murine model of tion occurs in 60--87% of patients.43,66 More recent myxomatous changes of the mitral valve identified observations cite a figure closer to 50%.22,81,110,123 increased expression of numerous TGF-b--related The direction of dislocation is typically super- genes that regulate cell proliferation and survival, otemporal but other directions do occur. In a series thus providing critical insight into the pathogenetic of 280 eyes, 67% had superior lens subluxation, mechanism of such changes in MFS.75,125 whereas dislocation into the vitreous cavity or anterior chamber occurred in 2--3% of eyes, and 8%17 developed glaucoma.51 In a Danish national study, the cause of congenital ectopia lentis could be established in 69% of 396 cases.40 Of the identifiable causes, 68% of cases were VII. Ocular Features of Marfan due to MFS. Syndrome Fibrillin abnormalities may alter the lens de- Most people with the MFS are myopic and have velopment and its mechanism, and take part in astigmatism and dislocated lenses. However, most of the pathogenesis of ectopia lentis or other lenticular them are asymptomatic; either eye pain or visual loss abnormalities in MFS.114 Histologically, in the are rare. normal human eyes, the zonules and superficial The main ocular symptoms of MFS are the capsule, where zonules attached to the lens, are rich following: in fibrillin. Staining of fibrillin within the capsule OCULAR MANIFESTATIONS IN MARFAN SYNDROME 565 gradually decreased toward the center of the lens, should be pursued to rule out MFS (Schlote T, and the anterior and posterior central capsule is Volker M, Knorr M, Thiel HJ: Lens , lens entire free of fibrillin.126 In capsules that were dislocation in Stickler [Marshall] syndrome [ab- dissected from lenses extracted intracapsularly from stract]. Klin Monatsbl Augenheilkd 210:227--8, MFS patients, ABC immunoperoxidase staining with 1997)49,68,108 and was found in 3/115 of MFS monoclonal anti-fibrillin antibody showed fine patients.17 disorganized fibrillin-positive fragments dispersed in the anterior capsule. There was only light staining B. ANTERIOR SEGMENT for fibrillin encircling the equator, which serves as insertion platform for most zonular fibers.114 Their The anterior segment structures exhibit both zonules were few and often attenuated and broken, subtle and gross changes, some of which (especially and electron microscopy5 showed the zonule fibrils in combination) are extremely suggestive of MFS. to be finer and lacking the normal parallel Histologically, in normal human eyes, only patchy alignment with haphazardly arranged.42,73 trace fibrillin staining is detected in the corneal As explained above, abnormal ciliary processes stroma, localized to spaces between lamel- and zonules contribute to lens dislocation in lae. There is no staining of Descemet’s membrane MFS.11,32,91,126 For the same reason, coloboma of or the corneal endothelium, and the epithelial the lens may occasionally be found. Anterior basement membrane region exhibit fibrillin stain- subluxation may occur, but less commonly than in ing. The iris staining reveals diffusely fibrin locali- 126 and Weill-Marchesani syndrome.17,66 zation within the loose stromal tissue. Dislocation of the lens was found to be positively In patients with MFS, anterior chamber angle- correlated with increased axial length, which is one related findings are immature ciliary body with of the minor criteria of the Ghent diagnostic hypoplasia of the muscular elements, a very broad criteria.22 trabecular meshwork, displacement of Schlemm’s canal,11,32,126 and an inconspicuous Schwalbe’s line. 2. Microspherophakia Clinically, the anterior chamber is deep with a recessed angle, or secondary to the subluxated In this familial and typically bilateral condition lens, and the angle is usually grade 4 open.66 The the crystalline lens is small and relatively spherical iris tends to show no circumferential ridges, few with increased antero-posterior thickness. The crypts, and, occasionally, iris root cysts, and irido- cortical fibers are approximately 20% of their donesis occurs when the lens is subluxated.32,66,122 normal thickness, which suggests atypical rather than arrested fibergenesis.20,35 Recent genetic stud- ies suggested that AD Weill-Marchesani syndrome C. CORNEA (WMS)—a connective tissue disorder in which 1. Flattened and Astigmatism characteristic eye anomalies, including microspher- ophakia, ectopia of the lenses, severe myopia, and Flattened corneas in MFS patients have been reported for many years,66 and were included in the glaucoma—is associated with MFS. Both are allelic 7,22 conditions at the FBN1 locus as part of the clinical Ghent criteria, as a minor sign. Corneas should heterogeneity of type I fibrillinopathies.34 be measured with keratometry. In autorefractometer mean A data, Maume- 66,67 3. Lens Opacities nee reported a mean A of 1.47 Æ 1.51 D in MFS patients, but 33.4% of the eyes had a cylinder Premature , posterior capsular opacities, of less than 0.5 D. Recently, Sultan’s control group as well as localized opacities of the lens, which may mean A in the 3.0-mm central zone (0.78 Æ 1.4 D) be globular or small cortical opacities, may also be was not significantly different from that of the MFS present, and they tend to present at a younger age 110 10,81 group (1.09 Æ 0.87 D). (30s to 50s) than the general population. However, when corneal thickness in MFS was measured with the aid of the Orbscan Corneal 4. Ocular and Lens Coloboma Topography System,110 a significant decrease in A lens coloboma represents incomplete lens mean simulated keratometry was measured in the formation due to failure of the fetal fissure to close MFS group (sim K, 40.8 Æ 1.4 D), as compared with completely. It is often accompanied by other ocular the control group (42.9 Æ 1.1 D). A significant of the , iris, lens, , or optic decrease was found also in pachymetry measure- disk. In MFS it may represent secondary changes of ments of MFS patients as compared with the filamentary degeneration of zonular fibers. Systemic controlled group, in the center (502 Æ 41.9 microns evaluation of coloboma of the crystalline lens and 552 Æ 23.6 microns, respectively) and the eight 566 Surv Ophthalmol 51 (6) November--December 2006 NEMET ET AL midperipheral locations. Ectopia lentis was highly in an opaque stromal matrix, but morphology and linked with pachymetry and mean keratometry.110 density were normal.110 The reason for the flattened cornea is not known. It may be secondary to the increased dimensions of 2. the globe in MFS patients, the scleral thinning and Megalocornea is a nonprogressive enlargement of the associated decreased (flattened) curvature of the cornea to 13 mm or greater. An enlarged ciliary the cornea, or the pathology is primarily corneal ring causes zonular stretching leading to phacodo- due to fibrillin gene mutations and associated 66,110,126 nesis, ectopia lentis, iridodonesis, iris stromal corneal misdevelopment. FBN-1 is a possible hypoplasia, and transillumination defects. Megalo- part of anchoring function in the cornea, as the cornea can occur as part of a multisystemic disorder microfibrils may act as a flexible mechanical anchor or as an isolated anomaly, typically inherited in an X- at epithelial--mesenchymal basement membrane linked recessive manner,107 although autosomal interface. Morphologic abnormalities of elastic dominant inheritance has been reported.50,57,94 As components contribute to centrifugal stretching of a nonspecific finding it has been reported in MFS,17 the cornea and sclera, and may generate ocular and associated with congenital MFS with contrac- 110 enlargement. tures.71 As was explained above, abnormalities of Endothelial abnormalities have been reported, elastic components in MFS contribute to centrifugal such as corneal endothelium guttata formation, stretching of the cornea and sclera. The more considerable cell pleomorphism, non-reflecting stretched the eye, the thinner and more flattened endothelial black spots, and in some cases abnor- the sclera and cornea, and a final stage described as mal-looking endothelial cells. The primary defect megalocornea or cornea plana may form.110 seems to exist in the endothelial cells. The guttata formation in MFS patients is probably real corneal guttata with focal thickening of Descemet’s mem- 3. brane, because the stressed endothelial cells pro- Although there is a traditional belief that MFS is duce excess collagen posterior to Descemet’s a risk factor for keratoconus, just like collagen 58 membrane. Patients with and without lens luxa- vascular disease, ocular trauma, , tion had considerable pleomorphism, but the more and others,13 it was shown that this association does prominent the lens subluxation, the more remark- not exist. Maumnee did not observe any keratoco- able the endothelial changes. Special care must be nus in her series of 160 patients with MFS,66 and taken to protect the endothelium during surgery from 60 MFS patients detected by Orbscan posterior 104 and contact lens insertion. elevation and topograghy, neither keratoconus nor Observation of decreasing thickness of the epi- corneal ecstasias was found.110 thelial basement membrane toward the central region, was related to an increasing hemidesmo- some content of the epithelial basement membrane D. GLAUCOMA zone dynamics.126 However, in Sultan’s group, Glaucoma is more prevalent in patients with MFS epithelial and endothelial cells appeared to be than in the general white population.51,61 Primary regular in shape, and the sub-basal nerves were open-angle glaucoma is found most commonly, but visible and looked like those of normal cornea.110 glaucoma-complicating MFS may arise via any one of Histologically, fibrillin has been observed in several mechanisms. human and bovine cornea with variable patterns of Histopathologic studies reveal displacement of location.110 Normal fibrillin is localized primarily in Schlemm’s canal, or unusual prominence of the the basement membrane zone of the corneal canal and aqueous veins.2,11 This may explain the epithelium particularly in the peripheral cornea, mechanism of elevated intraocular pressure in MFS but faintly in the central cornea, and between the patients with no definite other explanation. collagenous lamella of the corneal stroma.126 No Primary angle-closure glaucoma has not been staining of the Descemet’s membrane or the corneal described in MFS. In patients with MFS, the corneas endothelium was detected.85,126 This pattern could are flat, and the anterior chambers are usually grade be related to an increased hemidesmosome content 4 open, in contrast to the angle-closure configura- in the epithelial basement membrane zone when tion.51,66 Secondary angle closure may be associated moving from limbus to central cornea. In addition, with congenital abnormalities of the anterior fibrillin was detected in pathologic corneas, such as chamber angle.51 Dense iris processes may bridge in bullous keratopathy,63 after refractive surgery,62,65 the angle recess, inserting anterior to the scleral and in keratoconus.54 In vivo confocal microscopy spur and this iris tissue sweeping across the recess showed that MFS keratocyte nuclei were embedded may have a concave configuration.77 OCULAR MANIFESTATIONS IN MARFAN SYNDROME 567

Pupillary block glaucoma mechanism is rare and white-without-pressure, chorioretinal pigment pro- can be produced by an anterior lens dislocation, the liferation, and vitreous traction syndromes in the viteous or both.17,77 Lens dislocation into the peripheral , and retinal breaks. Choroidal anterior chamber can occur spontaneously,17 upon thinning and scleral crescents are commonly seen in pharmacologic dilatation of the ,66 or second- these patients. Posterior staphyloma has been ary to trauma,51 resulting in crowding of the observed, but is not a common finding. Retinal anterior chamber angle by mechanical movement detachment is the most serious complica- of the iris. Iridectomy may be effective or the tion.2,17,66,92 glaucoma can be controlled with dilation. A chronic form of glaucoma, possibly relating to an abnormal insertion of the ciliary musculature 2. Retinal Tears into the trabecular meshwork, may be also seen,11 as Fibrillin is normally present in the retina only in well as lens-position-dependent intraocular pres- the walls of retinal vessels.126 Several factors pre- sure, which should be treated by the removal of dispose patients with MFS to develop retinal de- the lens (Schlote T, Volker M, Thanos S, Thiel HJ: tachment. The majority of those patients have Glaucoma in Marfan syndrome: position-dependent ectopia lentis. The instability of subluxed or measurement of intraocular pressure as a diagnostic dislocated lenses exerts traction on the vitreous criterium [abstract]. Klin Monatsbl Augenheilkd base, leading to small tears or holes in the retinal 207:386--8, 1995). periphery resulting in retinal detachment. In Secondary open-angle glaucoma may occur fol- addition, vitreous liquefaction and posterior vitre- lowing retinal detachment, surgery, or ous detachment with no concomitant dehiscence at chronic iritis.11 In pseudophakic patients, excessive the vitreoretinal interface and abnormal vitreoreti- movement of anterior or posterior chamber in- nal adhesions at the equator predispose patients to traocular lenses leads to inflammation and pigment multiple large or even giant retinal dispression; therefore, routine scleral fixation of breaks.1,30,31,37,46,92,105 In a study involving 321 PCIOL implants is recommended.51 non-traumatic giant retinal tears, MFS was present The recommended glaucoma surgery for elevated in 2.8% of patients,37 which is about 600 times their intraocular pressure and luxated lens is either non- prevalence. penetrating deep sclerotomy to achieve pressure Retinal breaks or early retinal detachment in control without entering the anterior chamber, or these patients can be missed on routine examina- trabeclectomy with the use of antifibrotic agents. tions, owing to poor visualization secondary to small Examination of the vitreous and vitreoretinal face as and lens abnormalities.92,112 Additional risk is well as prophylactic therapy for prevention of retinal the surgery for the removal of the lens; in detachment should be done first; and, when the Maumenee’s series retinal detachment occurred in lens is luxated, it should be removed.58 four of 18 eyes cases, and vitreous loss has been attributed as a major risk.66 E. IRIS COLOBOMA Observations have shown that MFS patients with epilepsy have angioid streaks in the retina or 3. Retinal Detachment coloboma of the iris, but these may also accompany The incidence of retinal detachment in patients primary central nervous system disorders or be with MFS ranges from 5% to 25.6%.31,46,92,112 This secondary to connective tissue disorders.14,77 complication is more common in the younger age group, in the presence of ectopia lentis, in cases of F. VITREOUS increased axial length, and in aphakic eyes.1,17,35,66,92 In one study it occurred in 9% of patients with ectopic The anterior vitreous gel usually is intact but 17 extensive liquefaction involving the central and lenses and in 19% of aphakic eyes. In patients posterior is commonly seen in MFS with MFS, eyes with retinal detachment had a mean 112 axial length of 28 mm, whereas in eyes without retinal patients. Distinctly abnormal vitreous attach- 66 ments along the anterior and posterior edges of detachment, it was 24 mm on average. Retinal lattice degenerations have been reported.2 detachment was complete in 75% of eyes; more than half had a retinal break only in the temporal half of G. RETINAL ABNORMALITIES the retina, and 83% had, at least a break in the temporal half of the retina.105 Retinal detachment is 1. Retinal Degeneration bilateral in 30--42% of MFS cases,1,30 which causes one The peripheral retinal changes include myopic to consider the role of prophylactic treatment of the degeneration, lattice degeneration, atrophic holes, fellow aphakic eye in MFS. 568 Surv Ophthalmol 51 (6) November--December 2006 NEMET ET AL

In the past, results of surgeries to correct retinal However, in a prospective series of 60 patients with detachments in Marfan patients were worse rela- MFS, the ocular refractive power (--1.1 Æ 2.2 D), was tively as compared to non-MFS patients, and not statistically different from the control group especially when the eye was aphakic.92,112 Modern (--0.25 Æ 1.5 D), but this was attributed to the myopic surgical techniques and surgical instrumentation trend of that specific control group.110 have dramatically decreased the incidence of post- operative retinal detachment.46 The results of surgical repair of retinal detachment are compara- L. ble with those in normal population, and result in There is significantly elevated prevalence of successful reattachment of the retina is 75--89% of strabismus in patients with MFS, ranging from uncomplicated cases.1,31,105 The better prognosis for 19% to 39%.17,50 In a study of 573 patients with successful retinal detachment repair is good regard- MFS, occurred in 11.7%, in less of whether the eye was phakic or aphakic.64 The 2.1%, vertical deviations in 1.4%, and primary major cause of failure is proliferative vitreoretinop- inferior oblique muscle overaction in 0.5%; 3% athy and inadequate visualization of the retinal had and 7.5% had . periphery owing to small nondilating pupils.1,31,46 Abnormal afferent visual inputs to cortical centers caused by ectopia lentis, craniofacial abnormalities, H. SCLERA and genetic factors may all contribute to the higher prevalence of strabismus in this disease.50 One The sclera of MFS patients is unusually thin.2,32 explanation is that since fibrillin is abundant in Another common finding is overall enlargement of the pulley suspensions, the deviations are due to the globe, which could be a pathological expression abnormal connective tissue laxity (Demer, JL, of the stretched abnormal fibrillin,2,66,126 normally Poukens, V: Fibrillin (FBN), elastin, and smooth located between collagen lamellae of the sclera. muscle in the extraocular muscle pulleys in Marfan Blue sclera was found in four of 115 MFS patients.17 syndrome [abstract]. Invest Ophthalmol Vis Sci 39:S1102, 1998) I. CHOROID Pulley instability, resulting in extraocular muscle No clinical finding in MFS seems to show sideslip during ductions, was found in MFS patients. correlation with abnormalities of Bruch’s mem- This absence of adequate structural support for brane, which normally stains positively to fibrillin pulleys plausibly leads to gaze-related pulley shifts or in its innermost and outermost layers, and in the globe translation, as observed in MFS patients.76 basement membrane of the retinal pigment epithe- lium and the choriocapillaries. However, just like the sclera, a thin choroid has been reported in M. PUPIL patients with MFS.2,17,32 The iris sphincter and dilator muscles in MFS patients are poorly developed, resulting in often 66 J. eccentric and poorly pharmacology dilated pupils. The crypts of the anterior iris surface are frequently Fibrillin is located in the fibrovascular pial septa, absent.2,32,90,122 These changes are secondary to pia mater, arachnoid mater, dura mater, and the hypoplasia of the iris stroma and dilator mus- lamina cribrosa, but not within the nerve tissue cle.90,122 itself.126 The connective tissue changes in the lamina cribrosa that might occur in patients with MFS may theoretically influence the optic nerve N. AMBLYOPIA damage, which is related to intraocular pressure. Children with the MFS require routine eye care for screening of amblyopia. Possible reasons are K. MYOPIA axial myopia, anisometropia, astigmatism, sublux- The second most common ocular manifestation in ated lens, or microspherophakia. In a clinical study MFS is myopia, which is found in 34--44% of patients of genetic ectopia lentis, 50% had significant with MFS, as compared to 4.8% in the general permanent ametropic functional amblyopia despite population in one study.66,84 Maumenee reported good conservative management, and this figure that only 16.3% had myopia of --7.00 D or more, and approached to 100% if the lens dislocation was about 50% had myopia of --3.00 D or more.66 The approaching the center of the pupil. The worst mean average axial length is 24.9 mm in patients amblyopia was noted when the lens was still covering with MFS, being greater (25.96 mm) in those with the visual axis and the lens edge was 1.3 mm from ectopia lentis than those without (23.39 mm).77 the center of the pupil.95 OCULAR MANIFESTATIONS IN MARFAN SYNDROME 569

O. VASCULAR MALFORMATIONS AND EVENTS cataract surgery may develop with greater frequency Dural ectasia is an important extraocular manifesta- in these patients than in the general population. tion of MFS patients.6 On the basis of findings in three Vitreous loss and incarceration in the wound, iris large studies,36,83,121 dural ectasia has been observed in prolapse, corneal edema, postoperative , 63--92% of patients with MFS. In these patients, the and persistent postoperative iritis are frequent. dilation of the dural sac is almost always at the level of Although intraocular lenses implanted either via the lumbar region. Dural ectasia is a sensitive and iris- or scleral-fixation method or by pars plana specific marker that can assist in confirmation of vitreolensectomy are options, with contact a diagnosis of MFS in young patients.36 lens correction is still favored by many surgeons. Although several investigators have either stated Large posterior chamber intraocular lenses are or implied that patients with MFS have an increased recommended for people with MFS. These lenses prevalence of intracranial aneurysms, based on should always be sutured in place by iris and/or 106 clinical, pathology, and an autopsy series,101 this scleral fixation. The use of anterior chamber association remains questionable.16,119 lenses is not recommended because patients with A case of retinal artery occlusion in a patient with MFS tend to have eyes that are larger than normal MFS was described, assumed to be secondary to and have abnormally deep anterior chambers with a possible thromboembolism from prolapsed mitral a recessed angle (standard anterior chamber lenses valve.12 tend to be too small). Complications from anterior chamber lenses include excess movement of the lenses, corneal decompensation, inflammation of the iris, glaucoma, pain, and the need for corneal VIII. Treatment transplantation (Maumenee I: Management of Interventions vary from simple optical correction Dislocated Lenses and Other Eye Concerns by spectacles or contact lenses to medical manipu- [www.marfan.org]). lations of the iris diaphragm to surgical removal of Pars plana vitreolensectomy was found to be a safe the lens.23 and effective treatment for subluxated lenses in The presence of a subluxated lens is often a series of 40 eyes of MFS patients. All patients compatible with reasonable visual acuity. If the demonstrated stable or improved visual acuity follow- subluxation is mild, the patient views through the ing surgery with low incidence of complications.48 phakic portion of the pupil, whereas with a large Intraocular lenses have been implanted in chil- subluxation, he views through the aphakic portion dren affected by ectopia lentis using the scleral of the pupil. The aphakic correction can be fixation and functional success was obtained in all achieved sometimes by pupillary dilatation, or rarely eyes. Postoperative visual acuity was 20/20 to 20/ by using argon laser to the iris, thus opening the 40.48,116,130 Similar results were achieved in another pupil in the direction of the laser application. In the series, which concluded that scleral-fixated intraoc- third case, where the edge of the lens splits the ular lenses are the first choice in MFS patients pupil, there is often an indication for surgery. First, because they reduce the complications of lens the best phakic and aphakic optical correction decentration. In another long follow-up in eyes of should be tried, and often it is necessary to try children who were implanted intraocular lenses in many different lenses before the optimum vision is which the holes in the haptics were sutured in the obtained.118 However, in some cases, surgical sulcus, with the knots buried in the scleral bed, therapy should not be delayed, as irreversible without capsular support, the results suggested that amblyopia may develop.95,128 sulcus fixation is a good option to correct aphakia in The main surgical ophthalmic procedure per- children.48 formed in MFS is lens extraction. The indications Breakage of the 10-0 prolene suture, often used to for this procedure are the following: suture the posterior chamber intraocular lenses to the scleral wall, may occur 3--10 years after surgery. A 1. Lens malpositioning where the lens edge combined scleral and iris posterior chamber in- bisects the pupil and optical correction is traocular lens fixation (Fig. 2) provides a four-point impossible fixation with a higher chance for long-term stability 2. Lens dislocation into the vitreous cavity (Fig. 3). This is especially important in children in 3. Anterior displacement of the lens and second- whom a sutured lens may require stable fixation for ary glaucoma 70 years or more. Also, intraocular lenses should 4. Cataract formation preferably be sutured using a 9-0 prolene suture, The procedure is, however, quite complicated in which has a 60% more tensile strength than a these patients. Virtually all the complications of 10-0 suture. 570 Surv Ophthalmol 51 (6) November--December 2006 NEMET ET AL

Fig. 3. Irido-scleral fixation of a posterior chamber IOL in another case. The scleral sutures are buried into the sclera and covered by conjunctiva (white arrows). Iris sutures are indicated by black arrows.

Recently, preservation of the capsular bag by inserting capsular tension ring and re-centering it by suturing the ring to the sclera was advised by several surgeons.56 Both the capsular tension ring and the intraocular lense haptic can be secured to the scleral wall (Fig. 5). Maintaining the posterior capsular diaphragm as a barrier between the anterior and posterior segments of the eye is considered advan- tageous by some surgeons; however, complications such as tear of the anterior and posterior capsule Fig. 2. Surgical correction of subluxated lens by com- may occur. Abundant lens epithelial proliferation bined iris and scleral fixation, surgeon’s view (upper lid over the remaining capsule, leading to secondary below). a: Superior temporal subluxation of the crystalline IOL decentration, has been reported.24 lens of an 8-year-old child. b: The lens material is aspirated by a 0.4-mm pore cannula. Fluid is provided by anterior chamber maintainer located infero-temporally. c: Anterior vitrectomy including complete removal of the capsular bag. d: A 10-0 prolene suture (Ethicon W1713) is inserted approximately 1 mm posterior to the limbus (right). A 27G needle is inserted on the opposite side (left) to guide the needle out at the desired location. e: The suture is threaded through the positioning hole at the haptic of the PMMA intraocular lens (Balance, Hanita Lenses, Israel). The suture is tied end-to-end with a second suture introduced in a similar fashion. f: Insertion of the intraocular lens behind the iris. Pulling of the sutures on both sides centers the lens and brings the intraocular lens loops into position at the ciliary sulcus. g: Fixation of the intraocular lens loops to the iris. This is done to provide additional support and minimize the risk lens subluxation in case of suture breakage or inadvertent cutting of the scleral stitch. h: Final position. The posterior chamber intraocular lens is well centered and supported by four-point fixation to the sclera and the iris.

Iris capture of the intraocular lens optic is Fig. 4. Complication of scleral or iris fixation-iris capture a common complication of scleral and iris fixation of the intraocular lens optic. Oftentimes the capture (Fig. 4). This can usually be treated by pupil resolve spontaneously or following pharmacological manipulations or it resolves spontaneously. dilation of the pupil. OCULAR MANIFESTATIONS IN MARFAN SYNDROME 571

detachment in eyes with minimal displacement of the lens and well-dilated pupils can be repaired with standard scleral buckling techniques with an encir- cling band.31 This approach can also be applied to retinal detachments in patients who have under- gone pars plana lensectomies. In cases of severe lens subluxation or dislocation, pars plana lensectomy, vitrectomy, internal drainage, chorioretinal adhesion techniques, and retinal tamponade with long-acting gases or silicone oil should be considered.31,45,92 Silicone band or buckle can help to reduce the incidence of recurrent retinal detachment from anterior vitreous traction. Re- trieval of posteriorly dislocated lenses may be done by perfluorocarbon liquids.111 Additional tech- niques, such as epiretinal and subretinal membrane peeling and retinotomy, may be necessary in cases with severe proliferative vitreoretinopathy.38 Because the incidence of bilateral retinal de- tachment is high in MFS,1 careful evaluation of fellow eyes on a regular basis is of extreme importance. Although no studies have proven the benefit of prophylactic treatment of peripheral Fig. 5. Surgical correction of subluxated crystalline lens retinal lesions in MFS, it should definitely be utilizing the natural capsular bag; surgeon’s view (upper considered in high-risk cases.92 lid below). a: Superior temporal subluxations of the Strabismus repair is indicated under the same crystalline lens. b: Capsular tension ring (ECR, Hanita Lenses, Israel) is injected into the capsular bag through circumstances that would suggest surgery in the 128 a small capsulorhexis, prior to removal of the lens general population. material. c: Lens material is aspirated using a 0.4-mm Because these patients are of normal intelligence, pore Anis cannula. The capsular tension ring prevents the and because neurologic stigmas are uncommon in collapse of the capsule in spite of the large zonular defect. MFS, any central nervous system abnormality, which d: Posterior chamber foldable intraocular lens is im- 131 planted into the capsular bag (3-piece Acrysof, Alcon, does occur, should be investigated appropriately. Fortworth, TX, USA). The IOL is still subluxated Approximately 50% of patients with MFS are superiorly. e: Securing the ring and the intraocular lens diagnosed by an ophthalmologist. This is usually loops to the scleral wall. A 10-0 prolene suture (Ethicon because myopia is not adequately corrected by W1713) is inserted 1 mm from the limbus behind the lens lenses.97 When a new patient is seen by the equator. After penetrating through the lens capsule (posterior and anterior) the needle is externalized ophthalmologist, referral for full medical and through the main incision, rotated 180, and reinserted. orthopedic evaluation is incumbent on the primary Passing in front of the lens capsule the needle is directed physician. The immediate family should also be to penetrate the scleral wall approximately 2 mm parallel examined completely, due to the potentially lethal to the insertion site. f: Tying of the suture relocates the associated systemic implications. IOL and the capsular bag into a central position. The knot is buried in the scleral wall and covered with conjunctiva. IX. Prophylaxis New modifications of capsular tension rings, such Patients with MFS need routine eye care for as the Cionni ring or capsular segments, offer optical correction of refractive errors; in children options to secure the capsular bag to the scleral suspected of having MFS, repeated refraction wall without jeopardizing the integrity of the measurements should be done to prevent ambly- capsular bag and may further enhance the safety opia. of scleral fixation. In addition, MFS patients need periodic monitor- Retinal detachment surgery should be performed ing of intraocular pressure; lens location, stability, when needed, using standard techniques. The and opacities; and fundus examination for retinal decision as to whether to perform scleral-buckling abnormalities. Any new ocular symptom, such as surgery, vitrectomy, or both depends on the com- glare, floaters, or any change of the visual field, plexity of the detachment, the status of the vitreous, should be checked immediately by an ophthalmol- and the severity of lens displacement.92 Retinal ogist. 572 Surv Ophthalmol 51 (6) November--December 2006 NEMET ET AL

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