Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

The next “I” refers to “involve.” I recommend that RP sufferers involve themselves in the scientific and other activities of the Retinal Association in their country. Involve the people around you: friends, family, and business associates in your condition and in ways to assist you in coping with your condition.

The next “I” involves the word “initiate.” With a retinal degenerative condition, you should continually ensure that you are initiating situations that test your ability to cope with the condition. Exposing yourself to new challenges and finding new ways of coping with those challenges helps you cope with the retinal condition in general and assists others in realizing how they can help you with the condition.

The final “I” refers to the word “inhibit.” Do not, in any way, inhibit yourself from taking on any challenges, experiences, and new situations because of your retinal condition. The more you are able to treat this condition as simply a fact of life that you need to deal with rather than a restrictive condition that will stop you from reaching your goals and dreams, the better you are able to cope with the condition. Coping is all in the head!

II

DEGENERATIVE DISEASES OF THE RETINA

modifications) to grade retinal photographs, or the International Classification System (29) by investigators of the most recent large population-based studies (30–40) has not only enhanced the comparability of findings across studies, but also has permitted data pooling (41–43) and meta-analysis (44). As a result, data obtained from such recent population-based studies have been extrapolated to other similar populations (44).

Various AMD severity scales based on the Wisconsin AMD Grading and Classification System (28) have been proposed and used in the Beaver Dam Eye Study (45,46), the Age-Related Eye Disease Study (AREDS) system (47,48) and the Rotterdam Study team (49,50).

With the advance of imaging technology, the replacement of stereoscopic retinal photography by digital imaging is inevitable and already now underway. The detection of late AMD lesions (geographic atrophy and apparent neovascular lesions) from either stereoscopic or nonstereoscopic digital images has been found to be reasonably comparable to detection using stereoscopic slides (51,52). Agreement on the detection of early AMD lesions, drusen, or pigmentary changes (hyperand hypopigmentation), however, has been found to vary substantially (51,52) depending on grader experience and lesion appearance. The detection of retinal hyperpigmentation associated with AMD from digital images has been found to have the lowest agreement compared with assessment from stereoscopic photographic film-based grading (52). This would be expected as stereoscopic photography provides multiple fields (enabling viewing from different angles) that can enhance the detection sensitivity for this lesion.

PREVALENCE OF AMD

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Prior to the mid 1980s, a number of studies were conducted to assess the prevalence of AMD, most with relatively small sample sizes (17,53–57). As a result of the wide variations in the methods, criteria, and different observers used in ascertaining AMD phenotype by these studies, comparison of findings between these early studies is limited (17). Since the mid 1980s, a growing number of large population-based studies have been conducted, including the Baltimore Eye Survey (30), the Beaver Dam Eye Study (BDES) (31), and the Salisbury Eye Evaluation (SEE) project (58,59) in the United States, the Rotterdam Study (RS) (33) in the Netherlands, and the Blue Mountains Eye Study (BMES) (34) and Visual Impairment Project (VIP) (36) in Australia. All of these studies uniformly employed the “gold standard” of retinal photographic documentation with subsequent masked grading to ascertain AMD phenotypes and have provided robust estimates of the prevalence of AMD for white populations aged 40 yr or older. The metaanalysis conducted by the Eye Disease Prevalence Research Group (44) showed relatively high consistency in the age-specific prevalence of late AMD (Fig. 1) and large soft drusen (≥125 m in diameter) (Fig. 2) for whites across these different populations (44). In all of these studies, the prevalence of late AMD (geographic atrophy and neovascular AMD) increased exponentially with increasing age, rising from approximately less than 0.5% at age 60 yr to around 10% at more than age 80 yr (44) (Fig. 1). The prevalence of large drusen shows a similar age-related increasing trend but the rising curve associated with increasing age is more linear than exponential (44) (Fig. 2). Possible misclassification

Fig. 1. Prevalence of late AMD by age in whites (reproduced from the Eye Disease Prevalence Research Group report [44]).

Fig. 2. Prevalence of large drusen (≥125 m in diameter) by age in whites (reproduced from the Eye Disease Prevalence Research Group report [44]).

in the detection of drusen, together with the age-related natural course of AMD (involving the disappearance of large drusen associated with the progression to a more advanced AMD stage with aging (60), could explain the observed age-related linear pattern, rather than an exponential pattern, in the prevalence of large drusen.

Recent reports of the third National Health and Nutrition Examination Survey (NHANES III) (61,62), the Atherosclerosis Risk in Communities (ARIC) study (35), the Cardiovascular Health Study (CHS) (38), and the Reykjavik Eye Study (39) have provided further AMD prevalence data from different populations. The NHANES III

(61,62) (conducted in a multiracial US population aged >40 yr), the ARIC study (35) (conducted in persons aged 45–64 yr), and the CHS (38) (conducted in persons aged 69–97 yr) took photographs from only one eye of each subject. This could explain, in part, the lower overall late AMD prevalence in non-Hispanic whites (0.5%) (62) found in the NHANES III compared to the BDES (1.6%) (31), BMES (1.9%) (34), and RS (1.7%) (33) studies in which two eyes were photographed then graded for AMD and defined from the worse eye. The same reasons may apply for the finding of lower AMD prevalence in the ARIC study (35) compared to studies in which both eyes were photographed and graded (31,33,34). On the other hand, the CHS found similar ageand gender-specific AMD prevalence in white participants compared to these three aforementioned studies (BDES, RS, and BMES) (31,33,34). The relatively older age range of the CHS population may partly explain the similarity in findings between the CHS and the earlier studies, as AMD is a bilateral condition (63,64) and bilateral involvement increases with age (64). The Reykjavik Eye Study (39) found a higher prevalence of geographic atrophy in Iceland than that found in other white populations (31,34,44), including another European population (the Netherlands) (33). A genetic influence for all these geographic atrophy cases has been suggested (39).

Other Ethnicities

Ethnic differences in AMD prevalence have been shown in the NHANES III (61,62) and the Colorado-Wisconsin Study of ARM (65). Non-Hispanic blacks were found to have a lower AMD prevalence than non-Hispanic whites. The Baltimore Eye Survey (30), the SEE project (58,59), and particularly the Barbados Eye Study (32), which examined a more racially pure sample, have provided AMD prevalence data for black populations. Consistent findings suggest that the prevalence of AMD is lower in blacks than in whites (30,32,35,38,44,59,61,62,66), although possible selection bias may have occurred in black participants because of the low participation rate (35), a high proportion with ungradable retinal photographs (30,35,38), or poor survival in the eldest old group (30). However, the possibility that protection against AMD, particularly against late-stage AMD, from increased ocular pigmentation or gene variation in black populations is also a likely explanation of such differences, warranting further investigation (30).

Mexican Americans (Hispanic whites) were also found to have a relatively lower prevalence of late but not early AMD than non-Hispanic whites in previous studies (10,61,62,65), now confirmed by the recently completed Los Angeles Latino Eye Study (LALES) (40) with a much larger population-based sample. Survival bias could partly account for this finding in Hispanic populations, as they have much higher proportions of younger (aged <60 yr) than older (aged >70 yr) participants, seen in both the Proyecto Vision Evaluation and Research (VER) (10) and the LALES (40), compared to other white populations such as the BMES (7). The observed ethnic differences in AMD prevalence rates (30,32,61,62) could also be related to differences in the prevalence of many other risk factors, including genetic influences.

Relatively well-conducted population-based studies of AMD prevalence in Asian countries are currently emerging (37).

INCIDENCE AND PROGRESSION OF AMD

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Incidence

Prior to 1997, when the BDES study team published the first population-based finding on the 5-yr cumulative incidence of AMD (67), there were no population-based data available. The Chesapeake Bay Waterman Study (68) conducted in a small sample of watermen aged 30 or more years provided some information on the incidence of early AMD lesions. Late AMD incidence was previously estimated either using prevalence data (69) or blindness registry data (3,4).

After the turn of this century, a number of population-based studies, following the BDES (67), have provided AMD incidence in older white populations (50,60,70–72) or from Medicare claims databases (73). The cumulative 5-yr, person-specific incidence of early and late AMD is very similar between the BDES (8.2 and 0.9%) (67), the RS (7.9 and 0.9%) (50), and the BMES (8.7 and 1.1%) (60), all of which used similar study protocols in AMD phenotype ascertainment (41), although the baseline age range is slightly younger in the BDES (43–86 yr) (31) and slightly older in the RS (55–98 yr) (74) than the BMES population (49–97 yr) (41). The VIP (71) reported slightly lower person-specific incident rates of early (5.4%, using the BMES definition) and late AMD (0.5%) over a 5-yr period, partially reflecting the younger age group included in this study population (aged 40–102 yr) (36). In the Reykjavik Eye Study population (72), the 5-yr person-specific incidence of geographic atrophy was 0.85% (7 out of 846), which was higher than the incidence reported by the RS (0.4%) (50), but similar to the incidence found in the BMES (0.8%) (60). An overall high 5-yr incidence of early AMD (14.8%) found in this Icelandic population could perhaps have been because of a different definition used to classify early AMD (intermediate drusen were included in the early AMD category) (39,72), but the low reported incidence of neovascular AMD (0%) (72) is difficult to interpret, apart from an effect of the relatively small sample size.

Similar to AMD prevalence, the incidence of this condition is strongly age-related (50,60,67,71), showing an exponential curve with increasing age (see Fig. 2 of the RS report [50]).

A substantially higher incidence of neovascular AMD (varying from 12 to 26% over 5 yr) has been observed in the second eye of clinic patients with unilateral neovascular AMD (75–82). In a population-based case sample (BMES) (60), a similar incidence of second eye unilateral late-AMD cases was observed over 5 yr: 19% of second eyes developed either of the two late-AMD lesions (neovascular AMD or geographic atrophy with or without involvement of the fovea) in subjects with either late lesion in the first eye; 29% of second eyes developed end-stage AMD (either neovascular AMD or geographic atrophy involving the fovea) in subjects with unilateral end-stage AMD (60).

To date, only the BDES (45) has reported 10-yr cumulative incidence and progression of AMD data. The person-specific incidence was 12.1% for early and 2.1% for late AMD over 10 yr (45), including 1.4% for incident neovascular AMD and 0.8% for incident geographic atrophy. In addition to age, the incidence of late AMD was also strongly related to the severity of early-AMD lesions at baseline (45).

Progression

Progression of AMD from soft or reticular drusen, or retinal pigmentary abnormalities to geographic atrophy, or neovascular AMD has been well documented in a number of clinical case series (81,83–86). In the BDES and the BMES, early ARM lesion characteristics have been studied in detail in terms of the distribution, location, size, lesion type, and area involved in relation to the risk of subsequent development of late AMD (45,87–89). Large soft drusen (≥125 m in diameter), soft drusen with indistinct margins (indistinct soft or reticular drusen), or pigmentary changes involving large macular areas plus close proximity to the fovea indicate a much higher risk of subsequent late AMD development (45,88).

Late AMD lesions do not usually regress, apart from retinal pigment epithelial (RPE) detachment (45). Although large soft drusen may disappear without signs of progression, such disappearance is often associated with progression of the disease to a more advanced stage (60).

Other Ethnicities

Currently, there are no AMD incidence data available for other ethnicities except blacks. The Barbados Eye Study recently reported the 4-yr incidence of macular changes in a black population aged 40 to 84 yr at baseline (90). Incident neovascular AMD was observed in 1 of the 2362 persons at risk (0.04%) and incident geographic atrophy in none of the 2419 at risk (0%) over the 4-yr period. The incidence of early AMD lesions, including intermediate-sized drusen, was also relatively low (5.2%, 60 out of 1160) (90). The proportion of participants in this study with ungradable retinal photographs, however, was relatively high (19.3%, 616 out of 3193) (90).

RISK FACTORS ASSOCIATED WITH AMD

PREVALENCE OR INCIDENCE

Genetic Influences

All observational studies, including clinic-based case-control studies (91) and popu- lation-based surveys (92–95), have shown that family history is a consistent, strong risk factor for AMD with a risk ratio around 3 or higher for subjects with an AMD family history compared to those without. Familial aggregation in AMD prevalence (93,96–100) and incidence (94) has been confirmed in different study populations. Studies in twins (101–104) have provided further evidence supporting a genetic basis for AMD by showing that the concordance of AMD phenotypes is much higher in monozygotic twins than in dizygotic twins (103,104), spouses (102), or in the general population (101). A strong genetic component in the etiology of AMD is thus beyond doubt

(19,24,103,105).

The search for AMD-related genes, however, has been far from conclusive (24,106). Much research effort has been put into the search for AMD genes (24,46,106–142). To date, inconsistent findings from this research suggest that multiple genes are likely to be responsible for the AMD susceptibility of affected individuals (24,105,138,143). Although inconsistent findings have been reported from different study populations (110), particularly with respect to exact gene loci (24), two AMD-related chromosome