vitelliform lesions ( vls ) correspond to an accumulation of yellowish material in the subretinal space .
[ 1 , 2 ] . these lesions may evolve over time and may be classified in the following stages : stage i ( previtelliform ) : normal or only subtle rpe changes ( tiny , central honeycomb structure centrally ) , normal vision.stage ii ( vitelliform ) : classic  egg - yolk  lesion , normal vision or mild vision loss.stage iii ( pseudohypopyon ) : layering of lipofuscin , normal vision or mild vision loss.stage iv ( vitelleruptive ) : breakup of material gives  scrambled egg  appearance ; vision may be mildly decreased.stage v ( atrophic ) : central rpe and retinal atrophy ; vision may range from 20/30 to 20/200.stage vi ( choroidal neovascularization , cnv ) : in about 20% of patients ; vision often decreased to 20/200 or worse [ 1 , 2 ] .
stage i ( previtelliform ) : normal or only subtle rpe changes ( tiny , central honeycomb structure centrally ) , normal vision .
stage ii ( vitelliform ) : classic  egg - yolk  lesion , normal vision or mild vision loss .
stage iii ( pseudohypopyon ) : layering of lipofuscin , normal vision or mild vision loss .
stage iv ( vitelleruptive ) : breakup of material gives  scrambled egg  appearance ; vision may be mildly decreased .
stage v ( atrophic ) : central rpe and retinal atrophy ; vision may range from 20/30 to 20/200 .
stage vi ( choroidal neovascularization , cnv ) : in about 20% of patients ; vision often decreased to 20/200 or worse [ 1 , 2 ] . when detected in younger patients ,
vls usually occur in the setting of best macular dystrophy ( best disease ) , an autosomal dominant disease associated with a mutation in bestrophin 1 ( best1 ) [ 3 , 4 ] .
adult - onset foveomacular vitelliform dystrophy ( aofvd ) is a subtype of macular pattern dystrophies , being associated with mutations in the peripherin 2 ( prph2 ) gene , either sporadic or inherited in an autosomal dominant manner [ 5 , 6 ] .
the age of onset is typically between 30 and 50 years , and it is recognized as a pleomorphic disease , with great variability in size , shape , and distribution of the vitelliform material [ 1 , 5 ] . acquired vitelliform lesions ( avl ) are a different type of vl associated with multiple retinal diseases such as age - related macular degeneration ( amd ) , cuticular drusen , tractional maculopathies , pseudoxanthoma elasticum , and central serous chorioretinopathy [ 1 , 7 ] .
all the aforementioned diseases share the lack of direct apposition between the photoreceptor outer segments and the retinal pigment epithelium ( rpe ) , which could delay the phagocytosis of shed outer segment photoreceptor tips , and lead to the accumulation of yellowish subretinal vitelliform material [ 2 , 69 ] .
whereas best disease may be easily distinguished from other vls by the age of diagnosis or electrophysiological study , the differential diagnosis between aofvd and avl may be difficult in patients without familial history of disease or with simultaneous macular diseases . in this study
we characterize the vl in aofvd and avl patients using multimodal imaging analysis , exposing similarities and differences that could help in differential diagnosis between the two entities in clinical practice .
this is a retrospective study of patients diagnosed with avl or aofvd , who were evaluated in the department of ophthalmology of hospital so joo , a tertiary health care center , at porto , between june 2011 and december 2013 .
the tenets of the declaration of helsinki were followed and local ethics committee approval was obtained . only eyes having previously undergone multimodal imaging analyses ( color fundus photographs , fundus autofluorescence ( faf ) , fluorescein angiography ( fa ) , and spectral - domain optical coherence tomography ( sd - oct ) ) were included .
color fundus photographs were obtained with trc-50ex mydriatic camera ( topcon medical systems , tokyo , japan ) .
spectral - domain optical coherence tomography , faf , and fa were performed using spectralis hra + oct system ( heidelberg engineering , heidelberg , germany ) . for each patient we recorded age , type and laterality of vl , associated macular lesions , baseline and final best - corrected visual acuity ( va ) using etdrs charts , and follow - up period .
vitelliform lesions were evaluated for their stage , integrity of external limiting membrane and the assumed inner segment / outer segment junction ( classified as present , absent , or disrupted ) , intraretinal fluid , and hyporeflective area in the subretinal space both at the baseline and at the final consult .
the shape of vl was classified as round or irregular and the location was determined by the foveal topographic relationship and symmetry , being categorized as central or eccentric to the fovea .
quantitative measurements of anatomical features ( greatest linear dimension ( gld ) and lesion height ( lh ) ) were recorded using the calipers provided by the review software of the spectralis hra + oct , similar to the method used by freund et al . .
patients were divided into two groups , aofvd and avl , according to familial history and the absence of other previous retinal diseases in the former . in both groups ,
no patient has received any treatment , such as cataract surgery or cnv intravitreal injections .
statistical calculations were performed using statistical package for social sciences ( version 20.0 ; spss , inc . ,
categoric variables were compared using the chi - square test , and differences for quantitative variables were analyzed by mann - whitney u or kruskal - wallis test .
the association between va and quantitative measures of lesion was analyzed by kendall 's tau test .
thirteen patients were diagnosed with avl ( 16 eyes ) and six with aofvd ( 12 eyes ) .
the median follow - up was 10 months , being the 25th75th percentiles [ 529 ] .
the groups were followed up by a similar median ( p = 0.782)the avl group was followed up by a median of 9 [ 7 ; 22 ] months and aofvd by 11 [ 5 ; 28 ] months . a summary of patient characteristics in each group is presented in table 1 . in our case series ,
vls were more frequent in patients in their eighth decade and a slight female predominance was observed .
we found no statistical differences in the demographic characteristics between the two groups . at presentation , the majority of lesions were stage ii , with the classic egg - yolk pattern being present in 8 eyes ( 50% ) of avl patients and in 7 eyes ( 58.33% ) of aofvd group .
pseudohypopyon was observed in 5 patients ( 31.25% ) in avl group , compared with 2 cases ( 16.7% ) in aofvd , which also represented a nonsignificant difference between groups ( p = 0.662 ) .
the presence of vitelleruptive stage was also evenly distributed between groups ( 3 eyes versus 2 eyes , p = 0.662 ) .
bilateral vls were found in 3 avl patients ( 23.1% ) and in 6 aofvd patients ( 100% ) , being significantly associated with the adult - onset disease ( p = 0.013 ) .
regular and centered lesions were associated with adult - onset type ( p = 0.004 and p = 0.016 , resp . ) , whereas irregular and eccentric lesions were more frequent in acquired disease ( figures 1 and 2 ) .
vitelliform lesions observed in the fundoscopic examination were topographically correspondent to hyperreflective material localized between rpe and ellipsoid zone or elm in sd - oct ( figures 1 and 2 ) .
a disrupted ellipsoid zone was statistically associated with adult - onset type of disease both at first and at last clinical evaluation ( p = 0.020 and p = 0.049 ) . in acquired form , either the integrity or the absence of this line was more common than a disruption .
there was no relation between the integrity of ellipsoid zone and the initial or final va ( p = 0.131 and p = 0.384 , resp . ) .
initial median lh was 142.5  m in avl patients and 118.5  m in aofvd cases .
this intergroup difference did not achieve statistical significance ( p = 0.452 ) . at the last follow - up visit ,
however , in avl group , when comparing the initial and final measurement of lh , there was significative shrinkage ( 142.5 versus 125.5 , p = 0.009 ) , which was not the case in aofvd group ( 118.5 versus 189 , p = 0.348 ) .
greatest linear dimension of vl was also similar when we compare the two groups , at both the initial and the last follow - up visit ( p = 0.336 and p = 0.213 ) .
once again , in the avl group there was shrinkage , with initial and final measurements being statistically different ( 864 versus 761.5 , p = 0.001 ) , while in aofvd group growing was not significant ( 736 versus 1355 , p = 0.188 ) .
we were not able to measure vl of 10 eyes in the final observation : 4 patients lost follow - up ( 6 eyes ) , 1 developed cnv ( 1 eye ) , 2 evolved to vitelli - disruptive - like stage of the disease ( 2 eyes ) , and 1 aofvd case presented an atrophic - like stage of the disease in one eye .
vitelliform lesions were hyperautofluorescent in faf exams ( figures 1 and 2 ) . in some cases with pseudohypopyon , faf revealed a hypoautofluorescent superior half and a hyperautofluorescent bottom half .
some cases evolved to vitelli - disruptive stage and one aofvd case presented the atrophic stage of the disease . in either case , residual macular lesions were hypoautofluorescent , revealing damage to the rpe . in each patient , fa showed early hypofluorescence of the yellowish subretinal vl ( figure 1 ) , occasionally with a halo of hyperfluorescence ( figure 2 ) .
a progressive late staining of vl was observed during the angiogram ( figures 1 and 2 ) .
concerning avl group , early amd was the most frequent concurrent disease , being found in 7 cases .
we found a correlation between loss of va and increasing gld ( p = 0.034 ) and a tendency to an increase in thickness ( p = 0.058 ) .
this study exposed both similarities and differences between avl and aofvd patients in a multimodal assessment .
bilateral vls with regular shape , central location , disrupted ellipsoid zone , and the absence of other fundoscopic findings were significantly associated with aofvd . on the other hand , va , lh , and gld did not appear to be distinctive features between these two different clinical entities .
regard , sd - oct was determinant to localize vitelliform material in the subretinal space , between rpe and ellipsoid zone [ 3 , 8 ] .
fundus autofluorescence also proved to be useful in the controversial theme regarding the composition of vitelliform material , since typical hyperautofluorescence of vl was consistent with previous histopathological findings of outer segment material , melanin granules , and 
fluorescein angiography is a keystone in the diagnosis of retinal disease , and it has been fundamental to identify several distinct entities associated with vl , particularly in avl patients .
it is well known that all vls share a yellowish appearance in fundoscopic evaluation , a subretinal location and homogeneous hyperreflectivity in sd - oct , hyperautofluorescence in faf , and a similar behavior during fa [ 2 , 4 , 6 , 9 , 10 ] .
theoretically , we can distinguish these patients by the age of diagnosis , familial history , and the presence or absence of associated diseases .
however , in clinical practice , this distinction is often difficult since we frequently consult patients for the first time in their sixth to eighth decade , with simultaneous retinal diseases and unknown familial ophthalmological history .
in fact , the age of diagnosis in our series was not significantly different between the avl and aofvd group . bilateral disease , although not exclusively , was associated with aofvd and unilateral disease was present only in the avl group .
the association found between avl and simultaneous retinal diseases , namely , early amd , was previously reported by several authors and expected according to the diagnostic criteria used for the two groups [ 2 , 6 , 9 , 11 , 12 ] .
we found no statistical difference in va , lh , and gld between groups , both at initial and at final observation .
however , during the follow - up , we recorded a significant decrease in median lh and gld in the avl group . on the other hand , aofvd lesions became larger and thicker at an apparent larger scale but failed to demonstrate a statistically significant change .
this finding could be explained by the different etiologies of these two clinical entities . in avl patients ,
vls are secondary to an underlying retinal disease and could tend to evolve earlier to atrophy .
contrarily , in aofvd patients vls occur as a result of a genetic predisposition , becoming atrophic only at later stages .
further studies are necessary to validate this different clinical course between the two entities , namely , the earlier progression to atrophy in avl patients .
nevertheless , one must add that pseudohypopyon was observed in 31% of avl patients , a finding considered to be rare in these patients .
a recent report by gonalves et al . also presented a case of avl in a patient with cuticular drusen diagnosed in pseudohypopyon stage .
this patient evolved to a stage similar to vitelli - disruptive stage described in best disease , maintaining a good va , probably due to a preserved ellipsoid zone [ 1 , 2 ] . in our series
, we did not find an association between va and the integrity of ellipsoid zone .
contrasting with previously published series , we found a statistically significant correlation between loss of va and increasing gld .
the main distinctive features we found between avl and aofvd groups in multimodal imaging were morphological , namely , the shape of vls and their topographic relationship with the fovea .
there was a strong association of centrally located and regular ovoid vl in aofvd patients , as opposed to irregular shaped and eccentrically located vl in avl cases . in 1974 , gass first described retinal findings in aofvd as  round or oval , yellow , subretinal lesions in the foveal area of each eye  . on the contrary ,
later studies reported significant variability in size and shape of vl both in aofvd and in avl patients [ 1 , 2 , 5 , 7 , 15 ] .
the size of our sample could partially explain the statistical significance of our morphological findings .
however , since acquired lesions develop from previous retinal diseases , this could define their variable location and shape , leading us to believe that in clinical practice more vls will be eccentric and irregular in avl patients when compared to aofvd .
the sample size was also small , limiting our ability to detect further statistic correlations or differences .
we included both eyes of some patients in the analysis , which may influence the results , though it is partially controlled by the statistical methods used .
we measured vl with the caliper function of sd - oct , which , despite being used in other studies , could introduce some variability in lh and gld values .
when consulting a patient presenting a vl with unknown age of onset , familial history , or previous retinal diseases , some aspects of multimodal imaging assessment may lead the ophthalmologist to a correct diagnosis of either avl or aofvd .
these features may comprise laterality , shape , vl location in relation to fovea , and its size evolution .
 
 purpose . to characterize vitelliform lesions ( vls ) in adult - onset foveomacular vitelliform dystrophy ( aofvd ) and acquired vitelliform ( avl ) patients using multimodal image analysis 
 . methods . 
 retrospective study of twenty - eight eyes from nineteen patients diagnosed with avl or aofvd . 
 they were evaluated by color fundus photographs , fundus autofluorescence ( faf ) , fluorescein angiography ( fa ) , and spectral - domain optical coherence tomography ( sd - oct ) . 
 results . 
 bilateral vls were associated with aofvd ( p = 0.013 ) . 
 regular and centered vls were associated with aofvd ( p = 0.004 and p = 0.016 ) , whereas irregular and noncentered lesions were more frequent in avl patients . 
 visual acuity , greatest linear dimension ( gld ) , lesion height ( lh ) , and pseudohypopyon were similar between groups . 
 whereas median lh and gld in avl group diminished significantly during follow - up ( p = 0.009 and p = 0.001 ) , aofvd lesions tended to become larger and thicker . conclusions . when consulting a patient presenting a vl with unknown age of onset , familial history , or previous retinal diseases , some aspects of multimodal imaging assessment may lead the ophthalmologist to a correct diagnosis . 
1. Introduction
2. Methods
3. Results
4. Discussion
5. Conclusions