Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients

Abstract

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.10⁶) was lower in Provence-Côte d'Azur with a Mediterranean diet (1.9/1.10⁶), and higher in regions with intensive farming or industrialized activities (5 to 20/1.10⁶). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.

Figure 1

Fundus photographs of a 56-year-old woman with an EMAP disease. Visual acuity is 20/400 in both eyes. (A,B) There is a bilateral and symmetrical extensive geographic macular atrophy with a diameter larger in vertical than horizontal (beneath blue arrows) in both eyes (A right and B left-eye). Atrophic lesions are also noted in the far peripheral and temporal retina in both eyes (white arrows). The extension of the macular atrophy and the association with peripheral small patches of atrophy is not common in AMD. (C) Color-magnified photograph of the midperipheral retina that reveals the striking density of pseudodrusen.

Figure 2

Extensive macular atrophy with pseudodrusen (EMAP) compared to atrophic age-related macular disease (AMD) with pseudodrusen. In EMAP, macular atrophy is extensive with a larger vertical axis passing over the optic nerve head (white arrow) to reach the nasal part of the peripapillary retina (A). The atrophy is dark, well-delineated on autofluorescence photograph (B). In AMD, there are several patches of macular atrophy restricted to the macular zone (C) surrounded by pseudodrusen and classic AMD drusen. On FAF, the atrophic patches are dark and surrounded by mild hyperautofluorescent AMD drusen (D, white arrows).

Figure 3

SD-OCT pattern in EMAP-pseudodrusen (A) and in age-related pseudodrusen (B). The deposits are above the RPE in both cases. In EMAP (A), the deposits have a diffuse pattern (between white arrows) adjacent to the macular atrophic lesion (dotted line arrows). In AMD (B), pseudodrusen have a nodular pattern (white arrows).

Figure 4

(A) Birth date distribution of cases by year. Cases were included from 40 to 80 years old. Note the strikingly high frequency of patients born between 1947–1950. (B) Geographical French repartition of EMAP patients according to their birthplace. The disease incidence is high in regions with industrialized or farming activities (in red). Disease incidences (per 10⁶ inhabitants): White no case, Green 1 to 2, Yellow 2 to 5, Orange 5 to 10, Red > 10. The French map with permission from http://jfbradu.free.fr/cartesvect/fdcfrance.htm. This map was modified with Microsoft Paint, version 6.3 (2013, Microsoft Corporation, Redmond, Washington, USA).

Figure 5

Full-field electroretinogram in EMAP patient. Dark-adapted 0.01 ERG responses are reduced after a 20 minute-dark adaptation time (ISCEV protocol), but dramatically recover after a 120 minute prolonged dark adaptation. The rod-impairment could be induced by the pseudodrusen i.e. diffuse subretinal deposits located between the retinal pigment epithelium and the inner and outer segments of the photoreceptors. Severe decrease of Light-adapted 3.0 ERG and flicker ERG responses as noted in EMAP patients, and not in AMD, suggests that cone degeneration is part of the EMAP process.