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Exfoliation syndrome: More than meets the eye

2002; Wiley; Volume: 80; Issue: 5 Linguagem: Inglês

10.1034/j.1600-0420.2002.800502.x

1600-0420

Robert Ritch,

Retinal Imaging and Analysis

Exfoliation syndrome (XFS) has been recognized as a cause of glaucoma for nearly a century (Lindberg 1917). What is still only beginning to be commonly recognized is its widespread distribution, its frequency and its potential association with other diseases. It leads not only to severe, chronic open-angle glaucoma, but also to lens subluxation, angle-closure, blood–aqueous barrier impairment and serious complications at the time of cataract extraction, such as zonular dialysis, capsular rupture and vitreous loss. There is increasing evidence of an aetiological association between XFS and cataract formation and retinal vein occlusion. These associations have been reviewed (Ritch & Schlötzer-Schrehardt 2001). Exfoliation syndrome is a generalized disorder of the extracellular matrix. Aggregates of exfoliation material were identified by electron microscopy in autopsy specimens of heart, lung, liver, kidney, gall bladder and cerebral meninges in two patients with ocular XFS (Schlötzer-Schrehardt et al. 1992; Streeten et al. 1992). However, for the most part, systemic associations have yet to be proven and their significance understood. In patients with a history of transient ischaemic attacks, Repo et al. (1993) found twice the frequency of XFS as in the age-matched general population. Repo et al. (1995) also found greater resistivity indices for the ophthalmic arteries of patients with XFS, although Yuksel et al. (2001) did not. Patients with exfoliative glaucoma have been reported to have lower baseline fingertip cutaneous capillary perfusion than those with primary open-angle glaucoma or controls, take longer time to maximal cold-induced flow reduction, and need longer recovery time (Holló et al. 1998). In the Blue Mountains Eye Study, XFS correlated positively with a chart history of hypertension, angina, myocardial infarction or stroke (Mitchell et al. 1997), but a study of Icelandic families found no correlation with cardiovascular or cerebrovascular disease (Allingham et al. 2001), and others have found no increase in mortality rates in persons with XFS compared to those without (Ringvold et al. 1997; Shrüm et al. 2000). Some studies have found an association between XFS and aneurysms of the abdominal aorta (Schumacher et al. 2001) and others have not (Hietanen et al 2000; Ringvold 2001). A few small studies have found a correlation between Alzheimer's disease and XFS (Hagadus et al. 1989; Janciauskiene & Krakau 2001; Linnér et al. 2001). Importantly, XFS, as a systemic disorder, should not be considered as being a 'form' or a 'type' of glaucoma, even if its most important known manifestation is glaucoma. It is also, among all of the glaucomas, one which is potentially curable, yet, largely because of lack of interest in XFS and low awareness of its importance outside of Scandinavia until relatively recently, we have only just begun to scratch the surface of understanding the many facets of this disorder. Once thought to be peculiar to Scandinavia, XFS is now understood to be the most common identifiable cause of open-angle glaucoma worldwide (Ritch 1994). In some countries, it accounts for the majority of glaucoma cases. Reported prevalence rates have varied widely. In general, more recent studies have reported higher rates than earlier ones in the same geographic areas, presumably due to better recognition, particularly of the earlier stages. It has been found in every population in which it has been looked for except in Eskimos. Nevertheless, there are differences both between and within races and ethnic groups. The most significant comparisons are those made among different populations by the same observer. In this respect, Henrik Forsius was a pioneer. Examining persons over the age of 60 years in varied groups, including Lapps, Eskimos,Icelanders, Peruvian Indians and Tunisians, he found prevalence rates ranging from 0% in Greenland Eskimos to 21% in Icelanders (Forsius 1979). Others have found a much lower prevalence rate among African Americans than among white people of European origin (Ball 1988; Cashwell & Shields 1988a; Cashwell & Shields 1988b; Ball et al. 1989), among Siberian Tchutchee compared to immigrants to the area (Lantukh & Pyatin 1982), and among non-Hispanic Americans compared to Hispanic Americans in New Mexico (Jones et al. 1992). Within populations, variability over short distances has been found in France (Colin et al. 1985; Colin et al. 1988), Crete (Kozobolis et al. 1997), and Norway (Ringvold et al. 1988a). In Australia, persons originating from Greece, the Baltic states and India were most likely to have XFS (Gillies & West 1977). In this issue of Acta, Forsius and colleagues have re-examined data gathered earlier in order to elucidate gender distribution and association of XFS with pterygium, pinguecula and climatic droplet keratopathy in 11 samples from eight countries (Arctic, temperate and tropical) comprising 2206 persons over 50 years of age. No consistent associations were found. Associations with climatic droplet keratopathy have been noted previously and are thought to be possibly environmental (Taylor 1980; Resnikoff et al. 1991). The classification of the climates in which these studies were performed is slightly curious. Oulu, Iceland and Novosibirsk hardly seem temperate to those who live in California, France or Greece. In India and Peru, two tropical countries, the populations examined lived in the foothills of the Himalayas and high in the Andes, while Tunisia, although hot, is still in the temperate zone. The lack of association with these climate-related disorders of ocular connective tissue strongly suggest that we are dealing with a very different cause for XFS, in which climate might play only a permissive role, if any. There were also no consistent ratios of male to female involvement, as in the literature on this topic in general. Different studies have reported XFS to be more common in either men or women, or equally distributed. Some studies have found glaucoma more prevalent in men; others have not. If there is a crucial clue in all the data that has been gathered on this topic, it has not yet been found. No theories pertaining to climatic factors have been borne out consistently in studies of the distribution of exfoliation syndrome. Forsius & Luukka (1973) found no XFS in Eskimos but did find it in 20% of Lapps living at the same latitude. Taylor 1979 hypothesized UV irradiation as a cause for an increasing incidence of XFS in the eyes of Australian aborigines from south to north, but XFS was rare in inhabitants of the Cook Islands, located at a similar latitude (Heriot et al. 1983). It was found to be more prevalent in people living at high altitudes in two series (Mohammed & Kazmi 1986; Kozobolis et al. 1997) but not in a third (Forsius 1979). What is needed at this time are epidemiological studies designed to fill in the gaps in our knowledge and perhaps elucidate underlying genetic variability. The Navajo Indians have an extraordinarily high rate of XFS, with 38% of people over 60 years of age affected (Faulkner 1971). The climate in which they live is similar to that of Tunisia. However, comparative information on other Native American tribes, which belong to different linguistic groups, is lacking. Most smaller tribal groups have few if any full blood members any more, but larger ones are amenable to study. Those which come to mind are the Lakota (Sioux), Chippewa, Apache and Cherokee in North America and the Yanomamo of Venezuela. Information regarding sub-Saharan Africa is almost non-existent. It would also be interesting to examine populations in truly tropical regions, for instance, the inhabitants of Sri Lanka, Sulawesi, New Britain, Tonga or the Dayaks of Borneo. One way of performing comparative studies would be to create a collaboration on the Internet. Standardized photographs of various stages of development of XFS and various appearances of both exfoliation material and associated pigment signs would permit investigators worldwide to use the same criteria in detecting and grading XFS. Thewebsite would include protocols and data forms that could be completed ande-mailed to a collecting centre, saving great amounts of money in postage and fax bills. To this end, the Lindberg Society's website, established to stimulate global collaboration in the study of this disease (Tarkkanen & Kivelä 2002), might be a good place to start. So where must we now look in order to better understand the aetiological factors involved in the development of XFS? Its prevalence increases with age in all reported studies. Is it found in diseases associated with premature ageing, such as progeria or Down's syndrome? Forsius et al. (2002) suggest that the variable prevalence of XFS, independent of climatic factors, provides indirect evidence of the importance of genetic factors in the aetiology of XFS. There is a lot to be said for this possibility, but until now, finding answers has not been easy. The fact that the disease is associated with ageing eliminates the possibility of obtaining samples of large multigenerational families. A reported preponderance of maternal transmission of XFS in families has raised the possibility of mitochondrial inheritance (Allingham et al 1990; Damji 1998; Damji et al. 1999). In the near future, microarray analysis might begin to tell us which genes in people with XFS are up-regulated or down-regulated compared to people without XFS. This brings us to another interesting possibility – that of an infectious origin. It is possible that XFS represents a delayed reaction to a common infection early in life. There is increasing indirect evidence for such a possibility. Ringvold et al. (1988b) found the prevalence of XFS in both members of married couples to be significantly higher than would be expected by chance. There has been an increasing number of reports of younger patients developing XFS after penetrating keratoplasty from elderly donors (Hørven & Hutchinson 1967; Küchle & Naumann 1992; Konstas & Williamson 1993; Sampaolesi et al. 1995). Kountouras et al. (2001) reported a significantly greater proportion of patients with both primary open-angle glaucoma and exfoliative glaucoma to be positive for H. pylori on gastric biopsy than were anaemic controls. An autoimmune reaction to an infective agent might provide an explanation as to why the preponderance of patients with XFS have asymmetric involvement. Are Eskimos the only population in which XFS has not been found because they are isolated in an extremely harsh climate in which the infectious agent cannot survive? Many, if not all autoimmune disorders are believed to have an infectious origin, and genetic factors predispose to both infection and the sequelae of infection. What we do know is that we are dealing with a disease which affects millions of people and which is a leading cause of blindness. Yet there is a huge lack of awareness of its importance, particularly by major funding agencies and the public in general, which is as unaware of XFS today as it was of glaucoma a generation ago. Largely because of this, the necessary research into the nature and origin of exfoliation material and investigations into ways of treating or preventing this disease by manipulating its production or breakdown have moved slowly because of lack of manpower. It is time for the world to recognize XFS as a disease in its own right and give it greater attention.