Response to treatment with intravitreal anti-vascular endothelial growth factors in bilateral exudative cuticular drusen



To present the response to treatment with anti-vascular endothelial growth factor (VEGF) agents of exudative cuticular drusen (CD) in a patient who developed temporary suspended scattering particles in motion (SSPiM) after injection in the symptomatic eye and full recovery of subretinal hyperreflective exudation (SHE) in the fellow eye by multimodal imaging modalities.


A 46-year-old patient was diagnosed with exudative CD associated with type I and II (mixed type) macular neovascularization (MNV) in the right eye, and quiescent type I MNV was detected in the left eye by en face optical coherence tomography angiography (OCTA). Bilateral flat irregular pigment epithelial detachments were found in both eyes by optical coherence tomography (OCT). A week after injection of intravitreal aflibercept (IVA), oval shaped hypersignals developed at Henle’s fiber layer with a petaloid appearance and at the subfoveal space as detected by en face OCTA in the right eye. These oval hypersignals were considered as SSPiM. They disappeared 4 weeks later and did not recur. During follow-up of the patient, juxtafoveal SHE and disruption of the ellipsoid zone (EZ) were noticed in her left asymptomatic eye by OCT. Fluorescein angiography disclosed leakage at the location of the SHE. Choriocapillaris flow analyzed by cross-sectional OCTA disclosed time-dependent local alterations before and after the development of SHE. SHE recurred twice, and juxtafoveal type I MNV subsequently developed at the same location. Intravitreal ranibizumab (IVR) treatment was initiated because of distorted vision accompanied by the development of SHE and persistent subfoveal fluid accumulation, as documented by OCT during IVA treatment. Complete recovery of the EZ took place consistently in both eyes with stable vision over three years of follow-up.

Conclusions and Importance

Temporary SSPiM could be seen in the early period after IVA injection once but has not recurred up to three years’ follow-up in the right eye of our patient with exudative CD. Prompt and appropriate treatment of SHE by intravitreal anti-VEGF agents (IVA and IVR) prevented the permanent deterioration of visual acuity in the left eye with type I MNV at her thirty-months follow-up.


Cuticular drusen (CD), also known as basal laminar drusen (BLD), is considered as a unique subgroup of age-related macular degeneration (AMD). Gass in 1977, speculated that uniformly small round drusen might be caused by the nodular thickening of the basement membrane of the retinal pigment epithelium (RPE). However, various studies have shown that CD appears as numerous, uniform, round, yellow-white punctate accumulations under the RPE. , , Drusen may be closely arranged in a tightly knit pattern giving the orange-peel display through the entire macular/paramacular area by fundus examination. Drusen are more easily visualized during the early arteriovenous phase exhibiting the fundus a “stars-in-the-sky” or “milky-way” image by fluorescein angiography (FA). Optical coherence tomography (OCT) analysis of the CD patients disclosed the region of the drusen between the Bruch’s (BM) and the RPE. , Henceforth, CD is located external to the RPE, small with steep sides, and contain dense hyalinized contents as revealed by light microscopy, whereas electron microscopy shows that the CD contents are homogenous and electron dense, with small vacuoles attributed to extracted lipids distributed throughout.

The heterogeneity of fundus features in CD patients points to a need for classification of the disease. Recently, Sakurada et al. classified eyes with CD into three phenotypes and longitudinally analyzed the risk of geographic atrophy (GA) and macular neovascularization (MNV). Phenotype 1, the classical form of CD, includes bilateral, symmetrical, concentrated cluster of translucent and yellowish, small (25–75 μm) sub-RPE elevations. Phenotype 2 shows a scattered distribution of similar but less densely populated drusen in the posterior pole infrequently extending into the peripheral fundus. Phenotype 3 involves a mix of CD and large drusen (above 200 μm) presenting as colloidal/hyalinized in nature. A strong association was found between CD (especially phenotypes 2 and 3) and GA/MNV, providing evidence that CD is likely to be a part of age-related macular degeneration (AMD). It has been reported that throughout the five-year follow-up of CD patients, the estimated cumulative incidences of advanced AMD were 12.9% for phenotype 1 and 50.5% for phenotype 2, 53% for phenotype 3, respectively. Thus, CD is a dependent risk factor for AMD progression leading to visual impairment.

Case report

In September 2017, a 46-year-old woman was referred for decreased vision and metamorphopsia in her right eye which developed in the previous three months. She had no previous remarkable systemic or ophthalmic history. Her best corrected visual acuities were 6/20 in the right eye, and 20/20 in the left eye. The results of her biomicroscopic examination and tonometry recordings were normal.

Fundus examination (Kowa VX-20; Kowa Company Ltd, Japan) disclosed features of CD in both eyes and severe macular edema in the right eye ( Fig. 1 A). Fluorescein angiography (FA; Kowa VX-20; Kowa Company Ltd, Japan) clearly outlined late leakage from the MNV and macular edema in the right eye ( Fig. 1 B). The stars-in-the-sky (milky way) appearance caused by CD on FA was prominent ( Fig. 1 B). OCT (RTVue XR Avanti; Optovue, Inc, Fremont, CA) disclosed subfoveal hyperreflective material corresponding to mixed type (types 1 and 2) MNV with intrafoveal hyporeflective cysts ( Fig. 1 C). Flat irregular retinal pigment epithelial detachment (FIRPED) was located at the temporal macula seen as double-layer sign ( Fig. 1 C). A 6-mm en face optical coherence tomography angiography (OCTA) choriocapillaris slab (AngioVue RTVue XR Avanti; Optovue, Inc, Fremont, CA) disclosed mixed type subfoveal MNV in the right eye ( Fig. 1 D). Intravitreal aflibercept (IVA) injection (2 mg in 0.05 mL) was administered via pars plana into the right eye. We observed perifoveal weak hypersignals at the deep capillary plexus at Henle’s fiber layer (HFL) in the right eye on 2-mm en face OCTA slabs ( Fig. 1 E). A week after the first injection of IVA into the right eye, en face OCTA revealed several ovoid hypersignals with a flower petal arrangement perifoveally at the deep capillary plexus slab at HFL and at the subfoveal location ( Fig. 1 F). Four weeks after injection of IVA, the hypersignals located at HFL and the subfoveal space disappeared and did not recur (not shown). A total of three repetitive injections of IVA were administered into the right eye four weeks apart, and her visual acuity in the right eye increased to 20/20, however metamorphopsia was not resolved.

Fig. 1

Red-free fundus photograph ( A ) discloses macular edema (blue star), tiny hard exudates (blue arrow), and SDD (red arrow) in the right eye. Fluorescein angiography ( B ) shows late (11min 20sec) fluorescein leakage, indicating macular edema associated with subfoveal CNV (blue arrow) and a milky way appearance, particularly around the paramacular region. OCT ( C ) demonstrates hyperreflectivity of mixed type MNV (types I and II; six-point red star), an intrafoveal hyporeflective cyst (four-point black star), and subfoveal hyporeflective fluid (four-point blue star) and flat irregular retinal pigment epithelial detachment (red arrow). A 6-mm en face OCTA choriocapillaris slab ( D ) reveals subfoveal hypersignals, indicating mixed type MNV (blue arrows) and type I MNV (red star). En face OCTA of a 2-mm deep capillary plexus slab before injection of IVA ( E ) illustrates a distorted vortex pattern and two weak perifoveal hypersignals (blue arrows) as SSPiM. One week after IVA ( F ), en face OCTA of the deep capillary plexus discloses a restored vortex pattern, and several perifoveal SSPiM hypersignals (blue arrows) appear as flower petals. The red triangle at the umbo indicates a subfoveal SSPiM hypersignal ( E ). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

At a follow-up examination in January 2018, her visual acuity was stable in the right eye. The macular edema was resolved, but there was minor subfoveal fluid accumulation in the right eye by OCT (not shown). Her left eye was asymptomatic; however, fundus examination of the left eye revealed cream-colored circular juxtafoveal exudation ( Fig. 2 A). The margin of the exudation was sharp ( Fig. 2 A). During FA, leakage was observed at the late phase in the left eye ( Fig. 2 B). Subretinal hyperreflective exudation (SHE) was noticed on OCT ( Fig. 2 C). The external limiting membrane (ELM) was intact ( Fig. 2 C). IVA injection was administered on the same day because of juxtafoveal SHE in the left eye. The patient was monitored by fundus photos (not shown), OCT, and OCTA at one week ( Fig. 2 D) and four weeks ( Fig. 2 E). Two more consecutive injections of IVA were administered to the left eye four weeks apart. The results at her one-year follow-up after the first IVA injection are shown in Fig. 2 F.

Jul 10, 2021 | Posted by in OPHTHALMOLOGY | Comments Off on Response to treatment with intravitreal anti-vascular endothelial growth factors in bilateral exudative cuticular drusen
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