Clinical manifestations of cuticular drusen in Korean patients

Cuticular drusen show some similarities to and differences from soft drusen in age-related macular degeneration (AMD) and might thus be a unique AMD subtype. Previous studies on cuticular drusen were performed mainly in white ethnic groups, but AMD shows ethnic differences. We investigated clinical manifestations of cuticular drusen in Korean patients to evaluate possible ethnic differences. Clinical records of Korean patients with cuticular drusen were retrospectively reviewed. Fundus distribution pattern, imaging features, and presence of large drusen, drusenoid pigment epithelial detachment (PED), and macular complications, including geographic atrophy (GA), choroidal neovascularization (CNV), and acquired vitelliform lesion (AVL), were assessed via multimodal imaging in 162 eyes with cuticular drusen (n = 81 patients; 67 females; mean age: 66.6 ± 9.1 years). Diffuse distribution was found in 61.7% and peripapillary involvement in 75.3% of eyes. Large drusen, drusenoid PED, GA, CNV, and AVL were observed in 59.3%, 26.5%, 18.5%, 3.7%, and 1.2% of eyes, respectively. The macular complication prevalence was similar between patients ≤ 60 and those > 60 years old. In Korean patients, cuticular drusen were less frequently associated with macular complications than in white patients, and the proportion of macular complications differed significantly, with AVL representing an uncommon complication.

. All patients were Koreans, and 67 patients were female (82.7%). Eleven (13.4%) patients had various types of kidney disease, including renal cyst, polycystic kidney disease, renal stone, and acute kidney injury associated with the ingestion of herbs. However, no patients had membranoproliferative glomerulonephritis type II, which was previously reported to be associated with cuticular drusen 11 . Multimodal imaging. All study subjects underwent color fundus photography (CFP), spectral-domain optical coherence tomography (SD-OCT), and FA. All individual imaging results met the diagnostic criteria. Red-free (RF), near-infrared reflectance (NIR), and fundus autofluorescence (FAF) imaging were performed in 50.6%, 97.5%, and 96.3% of patients, respectively. Ultrawide-field photographic images were acquired in 48.1% of patients. Imaging characteristics are summarized in Table 2. A macular-type distribution pattern was seen in 62 eyes (38.3%) and a diffuse-type in 100 eyes (61.7%).The average age of patients with each type of distribution pattern was 65.8 ± 8.4 and 67.1 ± 9.6 years, respectively, which was not statistically significantly different (P = 0.522, Student's t test). Peripapillary involvement and occupation of the total retinal area by cuticular drusen in more than five disc-areas were observed in 122 eyes (75.3%) and in 134 eyes (82.7%), respectively.
Multimodal imaging features of cuticular drusen in Korean patients were similar to those reported in patients of white ethnicities. Cuticular drusen were seen as hyperchromic dots on RF images in all eyes. NIR imaging of cuticular drusen showed hyporeflective centers with a surrounding hyperreflective margin (63.3%), diffuse   Figure 1 shows the multimodal imaging characteristics of cuticular drusen. In some eyes, large drusen (59.3%, Fig. 2A) were scattered among cuticular drusen, and drusenoid pigment epithelial detachment (PED, 26.5%, Fig. 2C) accompanied the cuticular drusen. Some eyes were complicated by geographic atrophy (GA, 18.5%, Fig. 2A), choroidal neovascularization (CNV, 3.7%, Fig. 2B), and acquired vitelliform lesion (AVL, 1.2%, Fig. 2C). Six eyes with CNV were classified as follows: 1 eye (0.6%) with type 1, 2 eyes (1.2%) with type 2, 2 eyes (1.2%) with a mixture of type 1 and type 2, and 1 eye (0.6%) with type 3. There was no PCV. The previously reported prevalence rates of GA, CNV, and AVL in cuticular drusen in the white ethnic groups and Japanese patients are summarized in Table 3. Statistical analysis of the relationship between age and the prevalence macular complications revealed no statistically significant differences between patients ≤ 60 years and those > 60 years old (Table 4).
Peripheral reticular pigmentary degeneration was observed in 68 eyes of 34 patients (42.0%), and all patients had a symmetric degeneration pattern in both eyes. Peripheral reticular pigmentary degeneration was present in 6 of 31 patients (19.4%) with the macular-type and 28 of 50 patients (56.0%) with the diffuse-type distribution pattern. The diffuse-type distribution of cuticular drusen was more strongly associated with the presence of peripheral reticular pigmentary degeneration than the macular-type (P = 0.001; Chi-square test).

Discussion
There have been only a limited number of reports on cuticular drusen in Asian ethnic groups, and one recent study reported on about 12 Japanese patients 13 . In the present study, we report on a sizeable number of Korean patients (81) with cuticular drusen.
We report several similarities in demographic characteristics and clinical findings associated with cuticular drusen between Koreans and white ethnic groups. There was a trend toward female sex being a risk factor for cuticular drusen in white ethnic groups, with a female preponderance of proportion of 60.0-92.1% 4,6,9,10,[12][13][14]19 . A similar female preponderance was observed in our Korean patients (82.7%) as well as in the recent Japanese study (66.6%) 13 . There were also similarities in the fundus distribution pattern between the white ethnic groups Most multimodal imaging features of cuticular drusen in Korean patients revealed no significant differences from those reported in patients of white ethnicities. For example, types 1, 2, and 3 OCT patterns were seen in 37.0%, 43.2%, and 19.8% of Korean patients, and in 33%, 49%, and 18% of patients of white ethnicities 4 . The FAF and ICGA findings were also similar between these ethnic groups.
Peripheral cuticular drusen were reported to be associated with senile reticular pigmentary degeneration in white ethnic groups 10,12 . In Korean patients, peripheral reticular pigmentary degeneration was present in 42% of patients, and the diffuse distribution-type was more strongly associated with peripheral reticular pigmentary degeneration than the macular-type (56% vs 19.4%). However, we could not compare the finding in Korean patients to those in white ethnic groups, because previous studies in white ethnic groups used different diagnostic criteria and classification methods.
However, the current data also revealed several noticeable differences in the clinical manifestation of cuticular drusen between Koreans and white ethnic groups (Table 3). According to the present study, Korean patients have GA far more frequently than CNV (18.5% vs 3.7%). One recent, small study reported similar findings in a white ethnic group; however, most previous studies on patients of white ethnicity reported smaller differences between the prevalence of GA and CNV. These studies reported that CNV could develop in 3.6-56% of patients in white ethnic groups 4,6,10,12,14 . In Korean patients, CNV was observed in only 6 eyes (3.7%) of 5 patients (6.2%); thus, the frequency of CNV in Koreans appeared to be relatively lower than the frequencies reported in white ethnic groups. www.nature.com/scientificreports/ A similar ethnic difference was reported for exudative AMD. A previous study reported that Asian Americans had a lower risk of exudative AMD than in white Americans 15 . Interestingly, none of the eyes with CNV had PCV lesions, which is the preponderant neovascularization subtype in Asians 20 . A single hospital-based study reported that the prevalence of PCV in Korean exudative AMD patients was 24.6% 21 .
Around one-quarter (24.2-26.7%) of eyes with cuticular drusen in white ethnic groups reportedly develop vitelliform lesions 4,10 . However, only 1.2% of eyes among our Korean patients had vitelliform lesions. A recent Japanese study found no AVL in 12 patients, supporting the finding of a low frequency of AVL in Korean patients 13 . Thus, it appears that Korean patients might have AVL less frequently than white ethnic groups; however, prospective, longitudinal studies are needed to verify these findings.
In our analysis of the relationship between aging and the prevalence of macular complications, we found that, unlike in patients of white ethnicities, there were no statistically significant differences in macular complications between patients ≤ 60 years and those > 60 years old 4 . We found a similar result when we changed the age cut-off to 65 or 70 years (data not shown).
Recently, Sakurada et al. reported that drusenoid PED was the most frequent AMD-associated macular pathology in eyes of Japanese patients (33.3%) 13 . In Korean patients, drusenoid PED was seen in 26.5% of eyes. The frequency of drusenoid PED in white ethnic groups has not been reported. Further studies are therefore needed to compare drusenoid PED between Asians and white ethnic groups.
Previous studies of cuticular drusen have used various diagnostic criteria (Table 3). Cohen et al. used the simple criteria based on the characteristic FA finding, while Van de Ven et al. used more complex criteria based on size, location, symmetry, and number of drusen, in addition to the characteristic FA finding 9,14 . In a recent large observational cohort study by Balaratnasingam et al., cuticular drusen were diagnosed by a combination of multiple imaging modalities, and FA was not mandatory 4 . In the present study, strict diagnostic criteria were used with multimodal imaging. CFP, OCT, and FA were used in the diagnosis of all patients, and NIR and FAF images were also assessed in more than 96% of patients.
A previous study suggested that cuticular drusen might initially develop in the peripheral fundus during the early phase of the disease 8,10,12 . Of 210 eyes in 105 Korean patients previously diagnosed with cuticular drusen, 22 eyes had drusen distributed only in the peripheral retina. However, they were excluded from analysis in this study, because we consider that there is currently insufficient evidence that these lesions are the same as the cuticular drusen observed at the posterior fundus. Further studies including longitudinal studies are needed to understand the nature of peripheral drusen showing hyperfluorescence in FA. www.nature.com/scientificreports/ The current study had several limitations. The study was retrospective and cross-sectional. The results from Korean patients were indirectly compared to those from white ethnic groups reported in previous studies, which used slightly different diagnostic criteria and assessment methods. Eyes having only peripheral lesions were excluded from analysis in this study; further studies are needed to verify the nature of these peripheral lesions. The number of patients ≤ 60 years old was markedly smaller than the number of patients > 60 years old, which may have affected statistical analyses.
In conclusion, Korean patients with cuticular drusen showed features similar to those previously reported in white ethnic groups with regard to female preponderance, distribution pattern, and most multimodal imaging characteristics. However, the cuticular drusen were less frequently associated with macular complications in Korean patients than in white ethnic groups, and AVL was found rarely. Thus, we thought that this study provides the preliminary evidences for future prospective studies to investigate ethnic differences in cuticular drusen.

participants.
Clinical records of patients diagnosed with cuticular drusen at the retina clinic of Samsung Medical Center, Seoul, Korea, between January 2010 and July 2018 were retrospectively reviewed. Patients who had other retinal disorders that interfered with the assessment of angiography images, including diabetic retinopathy, hypertensive retinopathy, and retinal vein occlusion, were excluded. Patients who had ocular conditions that might affect the evaluation of cuticular drusen, such as severe cataract, previous trauma history, and previous vitreoretinal surgery history, were also excluded.
Definition of cuticular drusen and AMD. The current study used strict diagnostic criteria for cuticular drusen, mainly based on the definition originally proposed by Gass and the criteria proposed by Van de Ven et al. and by Balaratnasingam et al. 1,4,9 . In brief, cuticular drusen were defined as multiple, yellow or pale, small, round lesions observed in fundus examination and CFP, showing a symmetric distributed pattern between bilateral eyes. There should be at least 50 scattered, uniformly-sized, small (25-75 μm) hyperfluorescent drusen with a typical "stars-in-the-sky" appearance on FA images in each eye 4,9 . The lesions had to be located beneath the RPE, with RPE elevation on OCT images 4,24 . NIR and FAF imaging features were used to assist the diagnosis, although neither of these imaging tests were considered as mandatory for diagnosis 4,23 .
Fundus topographic distribution patterns of cuticular drusen were classified as either the macular-or the diffuse-type, based on the results of CFP and FA 4 . Briefly, a macular distribution-type was defined as drusen distributed only within the major vascular arcades, whereas the diffuse-type was defined as drusen involving the macula, but also extending beyond the vascular arcades. Involvement of the peripapillary region and the total retinal area occupied by cuticular drusen, exceeding 5 disc-areas, were also analyzed 4 .
Multimodal imaging data were assessed for RF findings, FAF findings, NIR patterns, morphologic features on OCT b-scan, and ICGA findings. NIR patterns were categorized as hyporeflective centers with a surrounding hyperreflective margin, diffuse hyperreflectivity, heterogeneous reflectivity, or a combination of these patterns 4 . Morphological features on OCT b-scans were divided into a type 1 pattern, showing shallow elevation of the RPE-basal laminar band with difficult to discern internal drusen contents; a type 2 pattern, showing a sawtooth appearance and hyporeflective internal contents; and a type 3 pattern, showing broad, mound-shaped elevations of the RPE-basal laminar band with hyporeflective internal contents 4 .
The presence of large drusen, drusenoid PED, and macular complications, including GA, CNV, and AVL, was also assessed 4,19 . Large drusen was defined as at least 3 times the greatest height or diameter of typical cuticular drusen 4 . Drusenoid PED was defined as one-half disc diameter of confluent soft drusen under the center of the macula 25 . GA was defined as unifocal or multifocal sharply demarcated hypopigmented areas with large choroidal vessels visible due to RPE atrophy, observed on CFP images and hypoautofluorescence with a diameter of at least 175 μm observed on FAF images [26][27][28] . CNV was considered to be present if subretinal hemorrhage or fluid with subretinal tissue was observed on CFP and OCT images. A disciform scar was also included as evidence of old CNV. By using OCT, FA, and ICGA, CNV was classified into types 1, 2, and 3 using the Gass-Freund classification 1,29 . AVL was considered to be present if a yellowish subretinal material was observed in CFP images and hyperautofluorescent collections within the macular area, not secondary to vitelliform macular dystrophy, were observed on FAF images. These corresponded to hyperreflective lesions between the RPE-Bruch's membrane band and the external limiting membrane seen on OCT images 30,31 .
Peripheral cuticular drusen are reported to be associated with senile reticular pigmentary degeneration 10,12 . Peripheral reticular pigmentary degeneration was defined as a reticular pattern of degenerated lesions that appeared hypofluorescent in the peripheral fundus areas on FA images 32,33 . The presence of peripheral pigmentary degeneration was evaluated and its prevalence according to the distribution pattern was compared.
Imaging features of cuticular drusen, including involvement of the peripapillary region and the total retinal area occupied by cuticular drusen exceeding 5 disc-areas, were also analyzed 4 . To investigate the relationship between aging and the prevalence of macular complications, patients were divided into age groups ≤ 60 years and > 60 years. The prevalence of macular complications was statistically compared between these two groups.