Exfoliation syndrome occurs worldwide, although reported prevalence rates vary extensively.18-59 Reasons for this variation reflect a combination of true differences in prevalence on the basis of racial, ethnic, or other as-yet-unknown reasons, the age and sex distribution of the patient cohort or population group examined, the clinical criteria used for making a diagnosis of exfoliation syndrome, the ability of the examiner to detect early stages and/or more subtle manifestations of the disorder, and the thoroughness of examination. In particular, many cases go undetected because of failure to dilate the pupil or to examine the lens with the slit-lamp after dilation, and because of a low index of suspicion on the part of the examiner.60,61 Reports dealing with the prevalence of exfoliation syndrome in glaucoma patients and the prevalence of glaucoma in persons with exfoliation suffer from these drawbacks and also from variability in the definition of glaucoma, especially for papers published prior to 1980. This makes it often difficult to compare different series even when age-specific rates are available.
Studies on exfoliation syndrome have been conducted on diverse populations, which have included the general population, persons over age 40, persons over age 60, general medical clinic patients, ophthalmic clinic patients, patients with cataracts, glaucoma patients, hospitalized glaucoma patients, and glaucoma patients undergoing surgery. These differences have led to a great deal of confusion in the literature and should be taken into account when comparing one series to another.
For reviews of the epidemiologic literature pertaining to exfoliation syndrome, the reader is referred to previous publications.18,42,46 What stands out is that, from one examiner to another, the prevalence rates in a single country often vary threefold or more. In Scandinavia, the highest prevalence rates (in studies of persons over age 60) have been reported from Iceland (about 25%),28,33 and Finland (over 20%)26,33,52 Rates in Norway and Sweden average about one-third of those in Iceland and Finland, and those in Denmark are significantly less. In the past few years, an increasing number of reports has come from countries in which exfoliation syndrome had been previously thought rare, reversing those opinions.
The most significant comparisons are those made among different populations by the same observer. Aasved32 examined persons over age 60 in nursing homes in Norway, England, and Germany and found prevalences of 6.3%, 4.0%, and 4.7% respectively. Forsius33 looked at a wide variety of ethnic groups, including Lapps, Eskimos, Icelanders, Peruvian Indians, and Tunisians. The prevalence of exfoliation syndrome in persons over age 60 ranged from 0% in Greenland Eskimos to 21% in Icelanders. He proposed that genetic isolation may be responsible for the high incidences of disease in countries such as Iceland and Finland. In a study in Siberia, Latukh62 found a low prevalence in the native Tchutchee, but a much higher rate among immigrants to the area.
The prevalence in the United States has generally been reported to be similar to that in Western Europe. In the Framingham Eye Study, prevalence rates for persons not specifically identified as having glaucoma rose from 0.6% for ages 52 to 64 to 5.0% for ages 75 to 85.36,37 Cashwell and Shields49,53 have found lower figures in Caucasian populations in the southern United States. In a screening of 2121 people, exfoliation syndrome was present in only 1.6% of non-glaucomatous persons over age 60.49,53 American blacks have a much lower prevalence of than do whites.48,49,53,56
The prevalence of exfoliation syndrome may also vary within countries in similar environments and over short distances. In France, the overall prevalence in persons over age 70 is about 5.5%, ranging from 20.6% in Brest, to 3.6% in Toulon.43,47 Ringvold et al44,47 found prevalence rates of10.2%, 19.6%, and 21.0% in three closely situated municipalities in central Norway.
The reasons underlying true variation in prevalence rates both from one population to another and within more-or-less homogeneous populations remain to be explained. Some authors have suggested a correlation between the prevalence of exfoliation syndrome and exposure to sunlight. For example, among Australian aborigines, Taylor63 found exfoliation syndrome to be more common among those living farther north, which correlated positively with the annual total global radiation level. Exfoliation syndrome was associated positively with the occurrence of cataract and with climatic droplet keratopathy. Taylor suggested that senile cataracts are related to the amount of ultraviolet radiation and exfoliation syndrome is related to global radiation. However, Heriot et al39 screened 986 Polynesian Maori in Raratonga, which has the same latitude and climate, and found exfoliation syndrome in only 3 persons. The authors speculated about the scattering effect of the atmosphere perhaps being dependent on water vapor content and ultraviolet light. Mohammed and Kazmi64 found a much greater prevalence of exfoliation syndrome in tribes living in mountainous regions of Pakistan than among those living in lowland valleys. Forsius,33 however, found relatively little in Peruvian Indians living at an altitude of 4000 meters.
Genetic factors predisposing to susceptibility have barely begun to be explored. This very intriguing possibility requires further investigation and meaningful interpretation awaits elucidation of the underlying etiology of the disorder.
The prevalence of exfoliation syndrome increases markedly with age. =46or instance, in the general population in Norway, it ranges from 1% at age 40 to 7.8% over age 80.65 Forsius46 found its incidence to double every decade after age 50. In a Finnish population, exfoliation syndrome was found in 10% of patients aged 60 to 69, 21% of those aged 70 to 79, and 33% of those aged 80 to 89.26 In a Finnish screening, Rouhiainen and Ter=E4svirta66 found exfoliation syndrome in either eye of 8.5% of 65-year-olds and 13.2% of 75-year-olds. In Japan, Iizuka et al58 found prevalence rates of 0.7% in persons from ages 50 to 60 and 7.3% in persons over age 80.
The reported prevalence of exfoliation syndrome in older individuals ranges from 0% among Eskimos to as high as 38% in Navaho Indians.23,33 Taylor et al30 found a prevalence of 1.3% to 16% in Australian aborigines, depending on age.
Early onset of exfoliation syndrome has been found in certain population subgroups. In an examination of the earliest signs of exfoliation syndrome, Bartholomew found the onset of what he termed the pregranular stage at about the age of 40 in South African Bantu, with 6.4% of the population being affected in the 30-39 age group.67 Other groups with early onset include Skolt Lapps, Icelanders at Husquik, and Australian aborigines.18 The youngest reported patient was 22 years of age.68
Women have predominated in some series of exfoliation syndrome without glaucoma.18,22,58,69-72 Others have found equal numbers.73 =46orsius46 reported that exfoliation syndrome was more common in men in populations with high ultraviolet exposure, including Yugoslavs, Australian aborigines, Peruvian Indians, and Asian Indians. Yalaz59 also found a greater prevalence among men in Turkey.
In some studies, men with exfoliation syndrome appear more likely to develop glaucoma.58,74-76 Of 100 consecutive patients with exfoliation syndrome, Kozart and Yanoff76 found a 3:1 ratio of women to men, while 10 of 25 men and 17 of 75 women had elevated intraocular pressure (IOP). Moreno Monta=F1=E9s et al77 found glaucoma in exfoliation syndrome to appear earlier in men and with a higher mean IOP, while more men developed visual field defects than women. However many studies have found no sex predilection in patients with glaucoma.18,22,28,47,50,66,69,78-82
Although familial occurrence of exfoliation syndrome has been described by a number of authors, no clear hereditary pattern has been discerned.18,83-91 Aasved91 studied 203 relatives over age 40 in families of 25 probands and found exfoliation syndrome in 19 persons (9.4%), as opposed to finding it in 1% of persons over 40 in the general population. He suggested that exfoliation syndrome may occur as a dominant trait. Ringvold et al45 found two homozygous twin pairs discordant for exfoliation syndrome, while Teikari et al92 found two pairs concordant and 3 discordant. Exfoliation syndrome is so common that it is difficult to draw conclusions and, because it develops in older patients, multiple affected family members are difficult to find. The possibility of both exfoliation and primary open-angle glaucoma occurring in the same pedigree further confuses the issue.
Two intriguing observations should be mentioned here. In the Middle Norway eye-screening study, Ringvold et al45 found the prevalence of exfoliation syndrome in both members of 343 married couples to be significantly higher (P=3D0.022) than one would expect assuming independent occurrence of the disorder. K=FCchle and Naumann93 reported exfoliation syndrome developing in three eyes of two patients at ages 37 and 42 after penetrating keratoplasty from elderly donors. Both groups speculated as to the potential transmissibility of the syndrome. Further work in this area is necessary.
Although not well described, there appears to be an association between exfoliation syndrome and cataract formation.18,34,50,59-61,63, 93,116,136,147,174-179 There is an increased prevalence of exfoliation syndrome in eyes coming to cataract surgery and an increased prevalence of cataracts in eyes with exfoliation syndrome. Histopathologic examination of lenses after cataract extraction supports the idea that exfoliation syndrome is underdiagnosed. Krause and Tarkkanen180 examined 100 lenses of 98 patients and found exfoliation syndrome in 33%. Preoperatively, only one-half of these patients had been diagnosed as having the disease.
The etiologic relationship between the two disorders remains unclear. However, further elucidation of a possible common etiology is is particularly important clinically in view of the increased risk of complications at the time of cataract surgery in these patients and to further our understanding of pathophysiologic events at the cellular level.
Patients with exfoliation syndrome are much more prone than patients without to have complications at the time of cataract extraction.133,135,142,178,181-187 Patients with exfoliation syndrome dilate less well, there are greater incidences of capsular rupture and vitreous loss. Guzek et al135 found pupil size to be the most important risk factor for vitreous loss. Zonular damage accounts for much of the increased complication rate. Zonular fragility increases the risk of lens dislocation or zonular dialysis up to ten times.143,184,187-190
Despite the involvement of the lens capsule in exfoliation syndrome, one study found no significant differences in mean capsular thickness between exfoliation syndrome and normals.191 Capsular elasticity is also normal and exfoliation syndrome does not preclude nucleus extraction through a capsulorhexis.192,193
There are a number of characteristics of eyes with exfoliation syndrome which could predispose to the development of angle-closure. Pupillary block may be caused by a combination of posterior synechiae, increased iris thickness or rigidity, or anterior lens movement secondary to zonular weakness or dialysis.
Posterior Synechiae. The tendency of eyes with exfoliation to form posterior synechiae enhances the frequency and severity of relative pupillary block.
Exfoliation material appears to be produced by the equatorial lens epithelium, iris pigment epithelium, and non-pigmented ciliary epithelium.11,13,139,202,207,212,304-309 At these locations, it is commonly found within epithelial cells in association with abnormal basement membrane.310 The lens capsule itself appears normal, although it may contain amorphous material. The exfoliation material on the surface of the lens is believed to result partially from deposition of material produced by the iris and ciliary body and partially from material produced by the lens epithelium which passively diffuses through the anterior lens capsule.
Cell adhesion is a major function of the extracellular matrix. There is extensive support for the hypothesis that exfoliation syndrome represents a disorder of the extracellular matrix characterized by overproduction or abnormal breakdown of cell surface-associated material. Davanger311 reported that the exfoliation fibril is a proteoglycosaminoglycan consisting of a protein core surrounded by polysaccharide side chains. There are histochemical and antigenic similarities between zonular elastic microfibrils and exfoliation material.312-317 The production of exfoliation material may be related to disordered basement membrane metabolism.12,125,318-321
These characteristics of exfoliation material can explain its tendency toward "stickiness". It accounts for the differences in pigment particle appearance and distribution (eg., diffusely over the peripheral iris surface) from that in pigment dispersion syndrome (eg., concentrated in circumferential iris furrows). The iris pigment epithelium and the lens surface, both coated with exfoliation material, tend to adhere, resulting in posterior synechiae, particularly when pupillary movement is inhibited by miotic therapy. Bartholomew268 coined the term "iridocapsular block" for this phenomenon. Perhaps the best analogy would be Velcro.
Because of the strength of these adhesions, the attachment of the pupillary ruff to the lens may be stronger than its attachment to the iris stroma (Fig 47). The vascular abnormalities affecting the iris stroma can also affect the synechiae (Fig 46). However, we have never seen neovascular twigs extending onto the lens surface. This suggests that these vessels are tiny collaterals rather than actual rubeosis.
The development of posterior synechiae predisposes to secondary miotic-induced angle-closure glaucoma. We have seen chronic angle-closure develop after several years of miotic therapy in eyes that initially had wide open angles. It has generally been thought that prolonged miotic treatment caused relative pupillary block through extreme miosis, but perhaps it is actually more likely due to formation of posterior synechiae. This needs to be investigated. The development of secondary miotic-induced angle-closure glaucoma could also be stimulated by zonular weakness.
Increased Iris Rigidity. The iris in eyes with exfoliation appears to be more rigid than in eyes without exfoliation syndrome.133,137 Exfoliation material is deposited within the iris stroma, where it may be densely concentrated.202,203,304 Iris rigidity would also explain, at least in part, the tendency to a smaller pupil and poorer dilation in eyes with exfoliation syndrome.
In our experience, eyes with exfoliation syndrome appear to be more prone to chronic angle-closure glaucoma than to acute angle-closure glaucoma. These eyes generally have a deeper anterior chamber and flatter iris, so that the plane of the iris surface is not as high as it is in acute angle-closure glaucoma. Because the iris is more rigid than normal, aqueous pressure in the posterior chamber causes it to bulge at the weakest point, which is the iris root. This localized bombe narrows the angle, gives a pseudoplateau iris configuration on gonioscopy, and leads to chronic angle-clsoure glaucoma. After laser iridotomy, the angle opens widely, as opposed to true plateau iris, in which the ciliary processes are situated abnormally anteriorly and maintain the plateau configuration.322,323
Zonular Weakness and Phakodonesis. Exfoliation syndrome affects the zonular system early in the course of the disease. Bartholomew133 found the zonular fibers clinically to separate from their attachments to the ciliary body and produce a characteristic inferior displacement of the lens. Phakodonesis is common, yet not always associated with iridodonesis, perhaps attributable to increased iris rigidity.133
Weakening of the zonular support and subsequent laxity of the lens could allow it to move slightly more anteriorly, predisposing the eye to pupillary block, particularly in the prone position. Forward movement of the lens with bulging of the iris root secondary to pupillary block underlies the pseudoplateau configuration. This mechanism is consistent with the findings of a relatively deep central anterior chamber and plateau-like iris in contrast to the iris bombe of pupillary block or pupillary occlusion.
In extreme cases, the lens may come sufficiently forward to induce ciliary block, as described by von der Lippe et al.271 Miotic treatment may exacerbate both relative pupillary block and forward movement of the lens-iris diaphragm. Pilocarpine decreases anterior chamber depth and increases the axial length of the lens, even in elderly patients.324-330 Overtreatment with pilocarpine can severely exacerbate attacks of angle-closure glaucoma that are unresponsive to initial medical treatment.331 Pilocarpine has been reported to cause attacks of angle-closure glaucoma.332-335 One of the patients of Franks et al270 had anterior chamber shallowing caused by pilocarpine. Strong miotics, particularly in the presence of weakened zonules, should be more likely to exacerbate a tendency to angle-closure. It has been our impression that miotic-induced angle-closure is more common in eyes with exfoliation syndrome as opposed to eyes without exfoliation syndrome.
The biometric findings in the present series support the concept of zonular laxity in eyes with exfoliation syndrome. After pilocarpine, the lens thickness in the eyes with exfoliation syndrome increased by only half that observed in the clinically unaffected eyes (0.07 mm increase versus 0.14 mm increase, respectively). Pilocarpine thus accentuated the differences between the lens thickness of affected and unaffected eyes. The anterior chamber shallowing after pilocarpine was linearly related to the anterior chamber depth in both normal and exfoliation eyes, especially by optical pachymetry.
Ultrasound biomicroscopy is rapidly proving valuable in analyzing the mechanisms of various types of glaucoma.323,336-338 There are numerous potential applications to the analysis of eyes with exfoliation syndrome. Our finding of deeper anterior chambers in eyes with exfoliation syndrome is consistent with clinical and subclinical phacodonesis in affected eyes. The presence of a wider angle in the temporal quadrant suggests the possibility that zonular involvement is more pronounced temporally than nasally. This may be correlated with the finding that exfoliation material is found earliest in temporal quadrants. Temporal versus nasal angle disparity may prove to be a useful test for early exfoliation syndrome and might serve as a predictor for possible complications at the time of cataract extraction. However, further studies are necessary to compare angle widths in normals and to determine confidence intervals for accuracy of these measurements./
Another biometric method, Scheimpflug photography, is useful in analyzing iris contour in eyes with angle-closure glaucoma.339,340 It has been reported to be potentially valuable in detection of early stages of exfoliation syndrome prior to clinical involvement on slit-lamp examination.341 This technique may also be useful in measuring angle width.
Zonular laxity with anterior lens displacement may also predispose an eye with exfoliation syndrome to elevated IOP in the presence of an open angle. Rosenquist et al,342 using a reversible footplate plunger to the anterior lens capsule, found that anterior lens displacement decreased outflow facility by 36% (P<0.0001). Histologically, there was narrowing of the intertrabecular spaces and Schlemm's canal. If such a mechanism is operative in eyes with exfoliation syndrome, it might provide a partial explanation (in addition to cessation of iris pigment liberation) for the observation that eyes with glaucoma in exfoliation syndrome have a significant lowering of IOP after cataract extraction.343