Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

Figure 15.10 Exfoliative material on the anterior hyaloid face.

Not all patients with the exfoliation syndrome develop glaucoma, and reports vary considerably regarding the frequency of glaucoma in eyes with this condition. In one study of patients with the exfoliation syndrome but without glaucoma on the initial examination, one third developed glaucoma during a 1.5-year follow-up (51). Some patients with bilateral exfoliation syndrome have glaucoma in both eyes, but others have a pressure rise in only one of the eyes with exfoliation. Less commonly, a patient with unilateral exfoliation may have openangle glaucoma in both eyes (20).

Figure 15.11 Value of ultrasonographic biomicroscopy in detecting exfoliation syndrome material and zonular weakness and breakage. A: Normal zonules.

exfoliation syndrome. Acta Ophthalmol Scand. 2007;85(5):495-499, with permission.) Open-Angle Glaucoma

Most eyes with exfoliative glaucoma have an open-angle mechanism, although acute angle-closure glaucoma also occurs in a small number of cases (24, 29, 52, 53). It is not uncommon for patients with the exfoliation syndrome to have an acute onset of high intraocular pressure (IOP) in the presence of open angles.

The observation that glaucoma does not develop in all eyes with the exfoliation syndrome but may develop in both eyes of a patient with unilateral exfoliation has led to the theory that exfoliative glaucoma and chronic open-angle glaucoma (COAG) may share similar mechanisms of aqueous outflow obstruction (24, 29, 54, 55). However, the much greater incidence of glaucoma in eyes with exfoliation syndrome is thought to indicate a causal relationship between the abnormal material and the elevated IOP (56). Patients with exfoliation syndrome do not have the same response to topical corticosteroids as patients with COAG do (57, 58). Furthermore, although some lysyl oxidase-like 1 gene (LOXL1) variants predispose to exfoliative glaucoma, they do not appear to be associated with COAG (59). It therefore appears that exfoliative glaucoma represents a distinct form of glaucoma, but it may be superimposed on COAG in some patients. Mechanisms of IOP elevation in exfoliative glaucomaassociated open angles may include local production of exfoliative material, endothelial cell damage of the trabecular meshwork, and passive deposition of exfoliative material and pigment originating from elsewhere in the anterior segment.

Once open-angle glaucoma has developed in an eye with exfoliation, the IOP tends to run higher and may be more

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difficult to control than in cases of COAG (60, 61 and 62). It has also been observed that the probability of developing glaucomatous optic neuropathy is higher in eyes with exfoliative glaucoma than in other forms of glaucoma at similar IOP levels (53), suggesting an intrinsic vulnerability in the optic nerve in the former group. Although disc area and other morphometric features of the optic nerve head do not differ between nonglaucomatous eyes with and without exfoliation (63), glaucomatous neuroretinal rim damage tends to be more diffuse with exfoliative glaucoma, as opposed to the sectorial preference in COAG (64). Immunoelectron microscopic studies of the lamina cribrosa have shown elastosis, suggesting abnormal regulation of elastin synthesis or degradation, or both, in the optic nerve head of patients with the exfoliation syndrome, consistent with the role of LOXL1 (65).

Acute Increases in Intraocular Pressure

Patients with exfoliation syndrome and open angles may present with acute glaucoma mimicking angleclosure glaucoma (i.e. a red eye, corneal edema, and IOP often >50 mm Hg) (52, 55, 66). In a study of 139 cases of “acute” glaucoma, comprising 25% of a series of patients with exfoliation syndrome and glaucoma, 86 had open-angle glaucoma, 21 had neovascular glaucoma, and 18 had acute angle-closure glaucoma (53). In all the latter eyes, the anterior chamber depth was less than 2.2 mm.

Angle-Closure Glaucoma

A less-common mechanism of glaucoma in patients with the exfoliation syndrome is acute or chronic angle-closure glaucoma (24, 29, 42, 52, 53). A number of mechanisms may create a tendency toward pupillary block and angle closure, including zonular weakness, causing anterior movement of the lens; lens thickening from cataract formation; increased adhesiveness of the iris to the lens (occasionally with posterior synechiae) due to exfoliative material, sphincter muscle degeneration, and uveitis; and iris rigidity from hypoxia. Patients with exfoliation syndrome predisposed to angle closure may have a relatively small anterior segment despite normal axial length. Naumann coined the term relative anterior microphthalmos to describe eyes with normal axial lengths but disproportionately smaller anterior segment, as defined by a horizontal corneal diameter of 11 mm or less (67). Such patients tend to have a shallower central anterior chamber depth and a greater-than-average lens thickness.

ETIOLOGY AND PATHOGENESIS

The ultrastructural appearance of exfoliation syndrome is that of random 10 to 12 nm fibrils, arranged in a fibrillogranular matrix and occasionally coiled as spirals (68, 69). Evidence supports the concept that exfoliation is an inherited microfibrillopathy involving transforming growth factor-1, oxidative stress, and impaired cellular protection mechanisms as key pathogenetic factors (Fig. 15.12). In a landmark study in the Icelandic and Swedish populations, a common genetic variant was identified as a major risk factor for exfoliation syndrome and glaucoma (70). Polymorphisms in the coding region of LOXL1 located on chromosome 15q24 are associated with exfoliation syndrome and exfoliative glaucoma in these and other populations. The disease-associated polymorphisms are found in virtually all individuals with exfoliation syndrome in the studied populations. LOXL1 is one of many enzymes essential for the formation of elastin fibers: It plays a role in modifying tropoelastin, the basic building block of elastin, and catalyzes the process for monomers to cross-link and form elastin (Fig.15.13). Mice lacking LOXL1 protein have diffuse elastic tissue changes associated with tropoelastin accumulation, including pelvic organ prolapse, enlarged airspaces of the lung, loose skin, and vascular abnormalities (71).

Figure 15.12 Summary of current understanding of exfoliation syndrome pathogenesis. TIMP, tissue inhibitor of matrix metalloproteinase (MMP); TGF-ß1 , transforming growth factor beta 1. (Courtesy of

Ursula Schlötzer -Schrehardt, PhD.)

Although LOXL1 is a major risk factor for exfoliation syndrome and exfoliative glaucoma, strong evidence suggests that additional genetic or environmental factors will be identified that influence disease expression and severity. For example, despite similar prevalences of LOXL1 risk variants, the clinical prevalence of exfoliation syndrome is ninefold lower in a white population from Australia compared with whites in Iceland (72). Nevertheless, the finding of LOXL1 involvement will provide critical insights into the pathophysiology of exfoliation syndrome, providing an opportunity for novel treatment approaches. Since the disease-associated LOXL1 variant is commonly found in both affected and unaffected individuals, genetic testing is of limited clinical value at this time (73).

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Figure 15.13 LOXL1 is one of a family of lysyl oxidase enzymes essential for the formation of elastin fibers. It has an important role in modifying tropoelastin, the basic building block of elastin, and catalyzing process for monomers to cross-link and form elastin. TE, tropoelastin. (Reproduced from Liu X, Zhao Y, Gao J. Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet. 2004;36 (2):178-182, with permission.)

Ocular and Systemic Sources

Exfoliative material is produced by many cell types in the anterior segment, including lens capsule epithelium, iris epithelium, vascular endothelium, corneal endothelium, and Schlemm canal endothelium. The material has also been found in extrabulbar tissue, including the conjunctiva (67, 74, 75), which appears to be another independent source of the material. This has been demonstrated in conjunctival biopsies of eyes that did not have the typical clinical appearance of exfoliative material on the anterior lens capsule but were suspected on the basis of other signs, such as pigment dispersion and iris transillumination defects (76). Other extrabulbar sites where exfoliative material has been identified include extraocular muscles, orbital septa, posterior ciliary arteries, vortex veins, and central retinal vessels passing through the optic nerve sheaths (75).

The exfoliative material has also been demonstrated in tissues throughout the body of patients with the exfoliation syndrome, including lung, heart, liver, gallbladder, skin, kidney, and cerebral meninges (77,

78), suggesting a systemic process involving generalized abnormal elastin metabolism. DIFFERENTIAL DIAGNOSIS

The exfoliation syndrome must be distinguished from other forms of lens exfoliation and from other causes of pigment dispersion.

Capsular Delamination

Another group of disorders that involve exfoliation of the anterior lens capsule has been referred to as true exfoliation of the lens capsule or capsular delamination (8, 9, 10 and 11). These cases differ from the exfoliation syndrome in that an underlying precipitating factor, such as trauma, exposure to intense heat, or severe uveitis, is often, but not always, present (5, 6, 7, 8, 9 and 10). The nature of the lens exfoliation also differs, with thin, clear membrane-like material separating from the anterior lens capsule and often curling at the margins (8, 9 and 10). Glaucoma occurs infrequently with capsular delamination.

Primary Amyloidosis

This generalized, systemic disease, which may be familial or nonfamilial (79, 80), has numerous ocular manifestations, including glaucoma. The amyloid may be deposited as a white, flaky substance throughout the eye, including the pupillary margin of the iris, the anterior lens capsule, and the anterior chamber angle, creating a clinical picture that resembles the exfoliation syndrome (79, 80). In the autosomal-dominant condition, familial amyloidotic polyneuropathy, glaucoma is the most common ocular manifestation, and an ultrastructural study revealed accumulations of amyloid fibrils and multilayered plaques of basement membrane-like material in the intertrabecular spaces (81).

Pigment Dispersion

Many conditions in addition to the exfoliation syndrome are characterized by increased pigmentation of the trabecular meshwork. They include the pigment dispersion syndrome and pigmentary glaucoma (see Chapter 17); some forms of anterior uveitis (see Chapter 22), melanosis and melanomas (see Chapter 21), and COAG; and otherwise normal eyes with unusually heavy pigment dispersion. These conditions can usually be distinguished from the exfoliation syndrome by observing the characteristic appearance of the anterior lens capsule and iris in the latter disorder. However, the exfoliation syndrome has developed in patients with the pigmentary dispersion syndrome (82).

MANAGEMENT Glaucoma

Glaucoma associated with exfoliation syndrome can be particularly challenging to manage (61, 62). IOP can fluctuate considerably, and care should be taken when setting the target pressure range. Because of higher IOP fluctuation, some choose to set a lower target IOP and follow up these patients more closely. Patients with exfoliative glaucoma typically have an excellent

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response to prostaglandin analogues and laser trabeculoplasty, particularly argon laser trabeculopexy (83, 84 and 85). When incisional surgical intervention becomes necessary, filtering surgery is generally advocated. One study suggested that exfoliative glaucoma has a poorer response to medical therapy than COAG but that it has a better response to trabeculectomy (86). Cataract surgery may also decrease the IOP in patients with exfoliation syndrome and exfoliative glaucoma and open angles (87).

Cataract

Although lens extraction is not advocated for the management of exfoliative glaucoma, cataract extraction for improvement of visual acuity is frequently indicated and requires special consideration in these patients. With traditional extracapsular cataract surgery and with phacoemulsification, patients with the exfoliation syndrome have a higher-than-average risk of zonular and capsular breaks (88). This is most likely caused by degeneration of the zonular fibrils (33), but it may also be associated with a thin posterior lens capsule (89). Other factors that may complicate cataract surgery in these patients are poor pupillary dilatation and occasional synechiae between the iris pigment epithelium and the peripheral anterior lens capsule (90). Preoperatively, the surgeon should look for evidence of zonular dialysis, such as phacodonesis and asymmetric anterior chamber depth (33); the corneal endothelium should also be

evaluated carefully for compromise. Ultrasonographic biomicroscopy can be very helpful when trying to decide if significant zonular dialysis is present, and also to detect the presence of stretched zonules. Helpful tips for cataract surgery are to make the capsulorrhexis large so as to enable the nucleus or pieces of the nucleus to prolapse into the anterior chamber, thus minimizing zonular stress; a large capsulorrhexis also helps prevent capsular phimosis, which is common in eyes with exfoliation syndrome. During hydrodissection, care should be taken to tap on the center of the nucleus from time to time to decompress fluid pressure on a weak posterior capsule. If zonular weakness is evident intraoperatively, a capsule tension ring or capsule tension segments can be helpful. In addition to taking special care to minimize zonular stress during nucleus manipulation and removal of the cortex, if the pupil size is small, the surgeon should consider mechanically dilating and maintaining pupil dilatation. The use of a posterior chamber intraocular lenses is well tolerated in patients with the exfoliation syndrome, although there may be a greater risk for fibrinoid reaction in these patients (91).

KEY POINTS

Exfoliation syndrome is an inherited microfibrillopathy associated with polymorphisms in LOXL1. It is generally recognized by the typical appearance of exfoliative material on the anterior lens capsule and is a relatively common disorder in older individuals among many populations worldwide. It is characterized by a protein-like material on the lens, iris, and various other ocular and extraocular structures.

It is a major risk factor for development of open-angle glaucoma and, in some cases, angle-closure glaucoma. The condition may be unilateral or bilateral, and about 40% of patients with exfoliation syndrome may have associated glaucoma.

Early recognition and appropriate management are essential to good outcomes. Early signs of exfoliation syndrome include a light frosting of material on the lens capsule best seen with a dilated pupil, heavy (often irregular) pigment in the trabecular meshwork, and visualization of exfoliative material on the zonules or ciliary body. Ocular manifestations associated with exfoliation syndrome include glaucoma, cataract, zonular and lens capsule weakness, poor pupillary dilatation, blood-aqueous barrier breakdown, corneal endothelial decompensation, and retinal vein occlusion.

Any patient with exfoliation and a shallow peripheral and central anterior chamber depth should have gonioscopy and be evaluated for a prophylactic peripheral iridotomy.

When contemplating cataract surgery in a patient with exfoliation syndrome, check the status of the lens zonules (i.e., examine for presence of phacodonesis or lens subluxation).

Glaucoma is especially challenging to control in patients with exfoliation syndrome. Care should be taken to set the target pressure range and follow carefully, because there is greater diurnal IOP fluctuation in exfoliative glaucoma patients, and IOP can spike out of control in a short period.

Patients may require aggressive treatment and frequent, close follow-up.

REFERENCES

1.Ritch R. Exfoliation syndrome: the most common identifiable cause of open-angle glaucoma. J Glaucoma. 1994;3(2):176-177.

2.Schlotzer-Schrehardt U, Naumann GOH. Ocular and systemic exfoliation syndrome. Am J Ophthalmol. 2006;141(5):921-937.

3.Mitchell P, Wang JJ, Smith W. Association of exfoliation syndrome with increased vascular risk. Am J Ophthalmol. 1997;124(5):685-687.

4.Lindberg JG. Clinical investigations on depigmentation of the pupillary border and translucency of the iris in cases of senile cataract and in normal eyes in elderly persons. Acta Ophthalmol Suppl. 1989;190:1-96.

5.Elschnig A. Detachment of the zonular lamellae in glass blowers [in German]. Klin Monastsbl Augenheilkd. 1922;69:732-734.

6.Kraupa E. Linsenkapselrisse ohne Wundstar [in German]. Z Augenheilkd. 1922;48:93.

7.Butler TH. Capsular glaucoma. Trans Ophthalmol Soc U K. 1938;68:575-589.

8.Radda TM, Klemen UM. True idiopathic exfoliation [in German]. Klin Monbl Augenheilkd. 1982;181(4):276-277.

9.Brodrick JD, Tate GW Jr. Capsular delamination (true exfoliation) of the lens. Report of a case. Arch Ophthalmol. 1979;97(9):1693-1698.

10.Cashwell LF Jr, Holleman IL, Weaver RG, et al. Idiopathic true exfoliation of the lens capsule. Ophthalmology. 1989;96(3):348-351.

11.Dvorak-Theobald G. Pseudo-exfoliation of the lens capsule: relation to true exfoliation of the lens capsule as reported in the literature and role in the production of glaucoma capsulocuticulare. Am J Ophthalmol. 1954;37(1):1-12.

12.Ringvold A. Epidemiology of the pseudo-exfoliation syndrome. Acta Ophthalmol Scand. 1999;77 (4):371-375.

13.Astrom S, Stenlund H, Linden C. Incidence and prevalence of exfoliations and open-angle glaucoma in northern Sweden: II. Results after 21 years of follow-up. Acta Ophthalmol Scand. 2007;85(8):832-

14.Ringvold A, Blika S, Elsas T, et al. The prevalence of exfoliation in three separate municipalities of Middle-Norway. A preliminary report. Acta Ophthalmol Suppl. 1987;182:17-20.

15.Luntz MH. Prevalence of pseudo-exfoliation syndrome in an urban South African clinic population. Am J Ophthalmol. 1972;74(4):581-587.

P.260

16.Ball SF, Graham S, Thompson H. The racial prevalence and biomicroscopic signs of exfoliative syndrome in the glaucoma population of southern Louisiana. Glaucoma. 1989;11:169-175.

17.Damji KF, Bains HS, Amjadi K, et al. Familial occurrence of exfoliation in Canada. Can J Ophthalmol. 1999;34(5):257-265.

18.Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001;45(4):265-315.

19.Ohrt V, Nehen JH. The incidence of glaucoma capsulare based on a Danish hospital material. Acta Ophthalmol. 1981;59:888-893.

20.Lindblom B, Thorburn W. Observed incidence of glaucoma in Halsingland, Sweden. Acta Ophthalmol. 1984;62(2):217-222.

21.Blika S, Ringvold A. The occurrence of simple and capsular glaucoma in Middle-Norway. Acta Ophthalmol Suppl. 1987;182:11-16.

22.Yalaz M, Othman I, Nas K, et al. The frequency of exfoliation syndrome in the eastern Mediterranean area of Turkey. Acta Ophthalmol. 1992;70(2):209-213.

23.Moreno-Montanes J, Alvarez Serna A, Alcolea Paredes A. Pseudoexfoliative glaucoma in patients with open-angle glaucoma in the northwest of Spain. Acta Ophthalmol. 1990;68(6):695-699.

24.Roth M, Epstein DL. Exfoliation syndrome. Am J Ophthalmol. 1980;89(4):477-481.

25.Miyake K, Matsuda M, Inaba M. Corneal endothelial changes in exfoliation syndrome. Am J Ophthalmol. 1989;108(1):49-52.

26.Schlotzer-Schrehardt UM, Dorfler S, Naumann GOH. Corneal endothelial involvement in exfoliation syndrome. Arch Ophthalmol. 1993;111(5):666-674.

27.Naumann GOH, Schlotzer-Schrehardt U. Keratopathy in exfoliation syndrome as a cause of corneal endothelial decompensation: a clinicopathologic study. Ophthalmology. 2000;107(6):1111-1124.

28.Naumann GOH, Schlotzer-Schrehardt U. Corneal endotheliopathy of exfoliation syndrome (letter). Arch Ophthalmol. 1994;112:297.

29.Layden WE, Shaffer RN. Exfoliation syndrome. Am J Ophthalmol. 1974;78(5):835-841.

30.Seland JH, Chylack LT Jr. Cataracts in the exfoliation syndrome (fibrillopathia epitheliocapsularis). Trans Ophthalmol Soc UK. 1982;102 Pt 3:375-379.

31.Arnarsson A, Jonasson F, Sasaki H, et al. Risk factors for nuclear lens opacification: the Reykjavik Eye Study. Dev Ophthalmol. 2002;35:12-20.

32.Mizuno K, Muroi S. Cycloscopy of exfoliation. Am J Ophthalmol. 1979;87(4):513-518.

33.Futa R, Furuyoshi N. Phakodonesis in capsular glaucoma: a clinical and electron microscopic study. Jpn J Ophthalmol. 1989;33(3):311-317.

34.Schlotzer-Schrehardt U, Naumann GOH. A histopathologic study of zonular instability in exfoliation syndrome. Am J Ophthalmol. 1994;118(6):730-743.

35.Prince AM, Ritch R. Clinical signs of the exfoliation syndrome. Ophthalmology. 1986;93(6):803-

36.Repo LP, Terasvirta ME, Tuovinen EJ. Generalized peripheral iris transluminance in the exfoliation syndrome. Ophthalmology. 1990;97(8):1027-1029.

37.Brooks AM, Gillies WE. The development of microneovascular changes in the iris in exfoliation of the lens capsule. Ophthalmology. 1987;94(9):1090-1097.

38.Asano N, Schlotzer-Schrehardt U, Naumann GOH. A histopathologic study of iris changes in exfoliation syndrome. Ophthalmology. 1995;102(9):1279-1290.

39.Repo LP, Terasvirta ME, Koivisto KJ. Generalized transluminance of the iris and the frequency of the exfoliation syndrome in the eyes of transient ischemic attack patients. Ophthalmology. 1993;100 (3):352-355.

40.Repo LP, Suhonen MT, Terasvirta ME, et al. Color Doppler imaging of the ophthalmic artery blood flow spectra of patients who have had a transient ischemic attack. Correlations with generalized iris transluminance and exfoliation syndrome. Ophthalmology. 1995;102(8): 1199-1205.

41.Sampaolesi R. Neue Untersuchungen über das Pseu do-KapselhäutchenGlaukom (Glaucoma Capsulare) [in German]. Ber Deutsch Ophthal Ges. 1959;62:177-183.

42.Wishart PK, Spaeth GL, Poryzees EM. Anterior chamber angle in the exfoliation syndrome. Br J Ophthalmol. 1985;69(2):103-107.

43.Ritch R. Exfoliation syndrome and occludable angles. Trans Am Ophthalmol Soc. 1994;92:845-944.

44.Shah KC, Damji KF, Chialant D, et al. Why do some patients with exfoliation syndrome develop angle closure glaucoma? Invest Ophthalmol Vis Sci. 1999;40:S80.

45.Gross FJ, Tingey D, Epstein DL. Increased prevalence of occludable angles and angle-closure glaucoma in patients with exfoliation. Am J Ophthalmol. 1994;117(3):333-336.

46.Schlotzer-Schrehardt U, Naumann GOH. Trabecular meshwork in exfoliation syndrome with and without open-angle glaucoma. A morphometric, ultrastructural study. Invest Ophthalmol Vis Sci. 1995; 36(9):1750-1764.

47.Kuchle M, Nguyen NX, Horn F, et al. Quantitative assessment of aqueous flare and aqueous ‘cells’ in exfoliation syndrome. Acta Ophthalmol. 1992;70(2):201-208.

48.Ritch R, Vessani RM, Tran HV, et al. Ultrasound biomicroscopic assessment of zonular appearance in exfoliation syndrome. Acta Ophthalmol Scand. 2007;85(5):495-499.

49.Grodum K, Heijl A, Bengtsson B. Risk of glaucoma in ocular hypertension with and without exfoliation. Ophthalmology. 2005;112(3): 386-390.

50.Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56.

51.Slagsvold JE. The follow-up in patients with exfoliation of the lens capsule with and without glaucoma. 2. The development of glaucoma in persons with exfoliation. Acta Ophthalmol. 1986;64 (3):241-245.

52.Brooks AM, Gillies WE. The presentation and prognosis of glaucoma in exfoliation of the lens capsule. Ophthalmology. 1988;95(2):271-276.

53.Gillies WE, Brooks AM. The presentation of acute glaucoma in exfoliation of the lens capsule. Aust N Z J Ophthalmol. 1988; 16(2):101-106.

54.Sampaolesi R, Argento C. Scanning electron microscopy of the trabecular meshwork in normal and glucomatous eyes. Invest Ophthalmol Vis Sci. 1977;16(4):302-314.

55.Cebon L, Smith RJ. Exfoliation of lens capsule and glaucoma. Case report. Br J Ophthalmol. 1976;60(4):279-282.

56.Aasved H. Intraocular pressure in eyes with and without fibrillopathia epitheliocapsularis (so-called senile exfoliation or exfoliation). Acta Ophthalmol. 1971;49(4):601-610.