Fundus Autofluorescence Patterns in Best Vitelliform Macular Dystrophy

Fundus Autofluorescence Patterns in Best VitelliformMacular Dystrophy

MAURIZIO BATTAGLIA PARODI, PIERLUIGI IACONO, CLAUDIO CAMPA, CLAUDIA DEL TURCO, ANDFRANCESCO BANDELLO

� PURPOSE: To provide a systematic classification offundus autofluorescence (FAF) patterns in patientsaffected by Best vitelliform macular dystrophy.� DESIGN: Cross-sectional prospective study.� METHODS: Patients affected by Best vitelliformmaculardystrophy at different stages of the disease were prospec-tively enrolled from January 2012 to July 2013. Eightyeyes of 40 patients were included in the study. All patientsunderwent a complete ophthalmologic examination,including genetic characterization, short-wavelengthFAF, and near-infrared FAF. Main outcome measureswere the recognition of the FAF patterns in the differentstages and the identification of a relationship betweenFAF patterns and best-corrected visual acuity (BCVA).� RESULTS: Six FAF patterns for both short-wavelengthand near-infrared FAF were identified, including normal,hyper-autofluorescent, hypo-autofluorescent, patchy,multifocal, and spoke-like patterns. ApplyingGass’s classi-fication for defining consecutive stages of Best vitelliformmacular dystrophy (namely vitelliform, pseudohypopyon,vitelliruptive, atrophic, and cicatricial) identified nopattern as stage-specific. Patchy patterns had the highestprevalence. A statistically significant difference (Krus-kal-Wallis ANOVA) was found among hyper-autofluorescent, patchy, and hypo-autofluorescentpatterns, both in short-wavelength (P [ .001) and near-infrared FAF (P [ .001). Hyper-autofluorescent andhypo-autofluorescent patterns were associated with betterand worse BCVA, respectively.� CONCLUSIONS: Six main patterns on both short-wavelength and near-infrared FAF were identified in Bestvitelliformmaculardystrophy.NoFAFpatterncanbeconsid-ered stage-specific. Although a difference in the BCVAamong the FAF patterns was registered, only a longitudinalstudy designed to evaluate the clinical and FAFmodificationsover the follow-up will help clarify the prognostic implica-tions of each FAF pattern. (Am J Ophthalmol 2014;-:-–-.� 2014 by Elsevier Inc. All rights reserved.)

Accepted for publication Jul 17, 2014.From the Department of Ophthalmology, University Vita-Salute,

Scientific Institute San Raffaele, Milan, Italy (M.B.P., C.D.T., F.B.);Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero eCura a Carattere Scientifico), Rome, Italy (P.I.); and Eye Clinic,Arcispedale Sant’Anna – Ferrara University Hospital, Ferrara, Italy (C.C.).

Inquiries to Pierluigi Iacono, FondazioneG. B. Bietti per l’Oftalmologia,IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Via Livenza3, Rome, Italy; e-mail: [email protected]

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2014.07.026

� 2014 BY ELSEVIER INC.

BEST VITELLIFORM MACULAR DYSTROPHY IS AN

autosomal dominant disease with variable pene-trance and expressivity, caused by mutations in the

BEST1 gene.1–4 In its classical description, Best vitelliformmacular dystrophy is clinically characterized by a bilateralyellow lesion in the macula, which tends to alter overtime. Gass’s classification identifies several stages of thelesion; namely, vitelliform, pseudohypopyon, vitelliruptive(scrambled egg), atrophic, and cicatricial.2 Histopathologicstudies have demonstrated that patients affected by Bestvitelliform macular dystrophy have an abnormal accumula-tion of lipofuscin within the retinal pigment epithelium(RPE) cells and in the sub-RPE space.5–10 Fundusautofluorescence (FAF) can significantly contribute to theclinical characterization of the disease. In particular, short-wavelength FAF, enabling the visualization of A2E andother bisretinoid pigments of lipofuscin in the RPE, providesa reliable, noninvasive tool for monitoring the progressivechanges of Best vitelliformmacular dystrophy. An autofluor-escence signal from the retina can also be acquired usingnear-infrared light, similar to the wavelengths used forindocyanine green angiography. Near-infrared FAF appearsto correspond to melanin (present in the RPE as well as thechoroid) rather than lipofuscin. As such, it provides adifferent type of information, which may be complementaryto short-wavelength FAF.11–15 Previous investigations haveshown variable patterns of short-wavelength FAF in Bestvitelliform macular dystrophy, varying from an increasedsignal, especially visible in the early stages, to a decreasedresponse toward the later stages.16–21

However, only limited information regarding a thoroughdescription of the FAF patterns in the various stages of thedisorder is available.The aim of the present study is to provide a systematic

classification of FAF patterns on both short-wavelengthFAF and near-infrared FAF characteristic of the differentstages of Best vitelliform macular dystrophy.

METHODS

A CONSECUTIVE SERIES OF PATIENTS AFFECTED BY BEST

vitelliform macular dystrophy were prospectively recruitedfor the study. All the details of the purpose of the currentstudy were discussed with each subject, who provided a writ-ten specific informed consent. The protocol was approved by

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http://dx.doi.org/10.1016/j.ajo.2014.07.026

the institutional review board of the University Vita-Salute, Scientific Institute San Raffaele, and the proce-dures adhered to the tenets of the Declaration of Helsinki.All patients provided blood samples for genetic testingand underwent a complete ophthalmic examination,including best-corrected visual acuity (BCVA), biomicros-copy, applanation tonometry, biomicroscopic examination,short-wavelength FAF, and near-infrared FAF.

Patients were excluded from the study if they had signifi-cant cataracts or other media opacities, and/or if they hadother concomitant ocular diseases that could affect the results.

The diagnosis of Best vitelliform macular dystrophy wasmade based on the clinical appearance and was confirmedby identification of the mutation in the BEST1 gene.Patients were placed into 5 stages according to the charac-teristic of the lesion: stage 1 (subclinical, with no vitelliformalteration), stage 2 (vitelliform), stage 3 (pseudohypopyon),stage 4 (vitelliruptive/scrambled egg), and stage 5 (atrophic/cicatricial). FAF was obtained using a confocal scanninglaser ophthalmoscope (Heidelberg Retinal Angiograph 2;Heidelberg Engineering, Heidelberg, Germany). Near-infrared FAF imaging was carried out using a diode laser at787 nm wavelength for excitation and a barrier filter fordetection of emitted light above 810 nm. Short-wavelength FAF images of ocular fundi were obtained at488 nm excitation wavelength and a barrier filter with wave-length of 500 nm was used for the detection of emitted light.For both short-wavelength FAF and near-infrared FAF, 100single images (30 3 30 degree view mode, 768*768 pixels)were averaged to obtain a high-quality image.

BCVA was recorded on ETDRS charts at 4 meters by amasked examiner and converted to logMAR. FAF imagesof each patient were independently analyzed by 2 maskedexaminers after identifying 6 well-defined FAF patternsfor both short-wavelength FAF and near-infrared FAF(see below). In the absence of a unanimous consensus, athird examiner was recruited for the analysis.

The primary outcome of the study was the identificationof the FAF patterns in the different stages of Best vitelli-form macular dystrophy. The secondary outcome was thecorrelation of FAF patterns with BCVA.

Results were expressed as mean 6 standard deviation forcontinuous variables and as frequency and percentages forcategorical variables. Analysis of variance for nonparametricdata distribution (ANOVA, Kruskal-Wallis test) was usedto study the differences in the BCVA between groups ofpatients based on the FAF pattern. The x2 test was appliedto evaluate the association between the different mutationsin the BEST1 gene and the FAF pattern distribution. A Pvalue of <.05 was considered statistically significant.

RESULTS

EIGHTY EYES (40 PATIENTS) WERE INCLUDED IN THE STUDY.

Mean age was 44 6 12 years, with 21 male patients. Mean

2 AMERICAN JOURNAL OF

BCVA was 0.41 6 0.38 logMAR (range: 1.30–0). Allthe patients showed clear media, allowing good-qualityFAF images to be obtained. Ten eyes (12.5%) were in stage1, 37 eyes (46%) in stage 2, 8 eyes (10%) in stage 3, 19 eyes(24%) in stage 4, and 6 eyes (7.5%) in stage 5.Overall, 6 FAF patterns for both short-wavelength FAF

and near-infrared FAF were identified: normal pattern (nodifference in FAF appearance compared to a normal sub-ject), hyper-autofluorescent pattern (increased FAFsignal), hypo-autofluorescent pattern (decreased FAFsignal), patchy pattern (combined reduced and increasedFAF signal), multifocal pattern (multiple, isolatedincreased FAF signals), and spoke-like pattern (increasedFAF signals with a spoke-like configuration) (Figures 1and 2).When considering the eyes in stage 1, 8 eyes had a

normal pattern at short-wavelength FAF and a hypo-autofluorescent pattern at near-infrared FAF, whereas in2 eyes both short-wavelength FAF and near-infrared FAFrevealed a multifocal pattern (Table 1). The 2 FAF tech-niques showed a pattern concordance in 2 eyes (20%).Mean BCVA was 0.0 6 0.0 logMAR.On short-wavelength FAF, eyes in stage 2 showed a

hyper-autofluorescent pattern in 15 cases, a patchy patternin 18 cases, and a hypo-autofluorescent pattern and aspoke-like pattern in 2 cases. On near-infrared FAF, themost frequent pattern was the patchy pattern, detectablein 27 eyes, whereas a hyper-autofluorescent pattern wasvisible in 7 eyes, a hypo-autofluorescent pattern in 1 eye,and a spoke-like pattern in 2 eyes (Table 2). A patternconcordance between the 2 FAF techniques was registeredin 27 eyes (73%). Mean BCVA was 0.29 6 0.29 logMAR.Short-wavelength FAF in stage 3 revealed a patchy and a

hyper-autofluorescent pattern in 7 and 1 eyes, respectively,whereas near-infrared FAF showed a patchy pattern in allthe eyes (Table 3). Seven eyes (87.5%) revealed a patternconcordance on short-wavelength FAF and near-infraredFAF. Mean BCVA was 0.65 6 0.32 logMAR.The analysis of the 19 eyes in stage 4 disclosed that 16

and 3 eyes had a patchy and a hypo-autofluorescent patternon short-wavelength FAF, respectively. On the other hand,near-infrared FAF identified a patchy pattern in 14 eyes, ahypo-autofluorescent pattern in 4 eyes, and a hyper-autofluorescent pattern in 1 eye (Table 4). A patternconcordance for the 2 FAF techniques was found in 17eyes (89%). Mean BCVA was 0.56 6 0.31 logMAR.The examination of the eyes in stage 5 revealed that 5

and 1 eyes revealed a hypo-autofluorescent and a patchypattern, respectively, on short-wavelength FAF, whereasnear-infrared FAF identified 3 patchy and 3 hypo-autofluorescent patterns (Table 5). The 2 FAF techniquesshowed a pattern concordance in 4 eyes (66%). MeanBCVA was 1.05 6 0.12 logMAR.Overall, on short-wavelength FAF the patchy pattern

was the most frequent, being detectable in 42 eyes(52.5%), followed by the hyper-autofluorescent pattern

--- 2014OPHTHALMOLOGY

FIGURE 1. Patterns of short-wavelength fundus autofluorescence in Best vitelliform macular dystrophy. Six main patterns wereidentified according to a qualitative classification: normal (Top left), hyper-autofluorescent (Top center), hypo-autofluorescent(Top right), patchy (Bottom left), spoke-like (Bottom center), and multifocal (Bottom right).

(16 eyes; 20%), the hypo-autofluorescent pattern (10 eyes;12.5%), the normal pattern (8 eyes; 10%), and lastly thespoke-like and multifocal patterns (2 eyes per each sub-group; 2.5%, respectively).

On near-infrared FAF, the most frequent pattern was thepatchy pattern, which could be found in 52 eyes (65%),followed by the hypo-autofluorescent pattern (16 eyes;20%), the hyper-autofluorescent pattern (8 eyes; 10%),and the spoke-like and multifocal patterns (2 eyes pereach subgroup; 2.5%, respectively). On the whole, apattern concordance between the 2 FAF techniques wasobserved in 57 eyes (71%), being more common in the in-termediate stages and less frequent in the subclinical stage.

The correlation with BCVA was investigated, consid-ering the 3 most represented FAF subtypes (hyper-auto-fluorescent, hypo-autofluorescent, and patchy patterns),but excluding the 3 patterns with low samples (specifically,normal, spoke-like, and multifocal patterns). The Shapiro-Wilk test was used to evaluate the data distribution. At0.05 level the data were not significantly drawn from anormally distributed population; hence Kruskal-WallisANOVA was used. A statistically significant difference

VOL. -, NO. - FUNDUS AUTOFLUORESCENCE IN B

was found among hyper-autofluorescent, patchy, andhypo-autofluorescent patterns both in short-wavelengthFAF (P ¼ .001) and near-infrared FAF (P ¼ .001).To test the difference between the 3 above-mentioned

patterns of near-infrared FAF and short-wavelength FAF(hyper vs hypo, hyper vs patchy, and hypo vs patchy), aMann-Whitney test was used, followed by Holm’s sequen-tial Bonferroni correction (with .05 as the threshold Pvalue [alpha level]). Both in the near-infrared FAF group(hyper vs hypo [P ¼ .05], hyper vs patchy [P ¼ .04], andhypo vs patchy [P ¼ .006]) and in the short-wavelengthFAF (hyper vs hypo [P ¼ .001], hyper vs patchy [P ¼.003], and hypo vs patchy [P ¼ .02]), a statistically signifi-cant difference in BCVA was found in each comparisonconsidering the BCVA.Overall, as regards short-wavelength autoflueorescence,

BCVA was higher in the hyper-autofluorescent pattern(mean BCVA: 0.21), followed by the patchy pattern (meanBCVA: 0.50), and worse in the hypo-autofluorescent pattern(mean BCVA: 0.80). A similar trend was registered with re-gard to near-infrared FAF subgroup analysis, with higherBCVA in the hyper-autofluorescent pattern (mean

3EST VITELLIFORM DYSTROPHY

FIGURE 2. Patterns of near-infrared fundus autofluorescence in Best vitelliformmacular dystrophy. Six main patterns were detectedon near-infrared fundus autofluorescence: normal (Top left), hyper-autofluorescent (Top center), hypo-autofluorescent (Top right),patchy (Bottom left), spoke-like (Bottom center), and multifocal (Bottom right).

TABLE 1. Fundus Autofluorescence Pattern Distribution and

Mean Best-Corrected Visual Acuity Values in the 10 Eyes

With Stage 1 Best Vitelliform Macular Dystrophy

Normal

Fundus

Autofluorescence

Multifocal

Fundus

Autofluorescence

Hypo-Fundus

Autofluorescence

SW-FAF

(no. eyes/%)

8 (80%) 2 (20%) 0

Mean

BCVA (6SD)

0.0 6 0.0 0.0 6 0.0 -

NIR-FAF

(no. eyes/%)

0 2 (20%) 8 (80%)

Mean

BCVA (6SD)

- 0.0 6 0.0 0.0 6 0.0

BCVA¼ best-corrected visual acuity; NIR-FAF¼ near-infrared

autofluorescence; SD ¼ standard deviation; SW-FAF ¼ short-

wavelength fundus autofluorescence.

BCVA: 0.18), followed by the patchy pattern (meanBCVA: 0.44) and the hypo-autofluorescent pattern(mean BCVA: 0.83).


The comparison analysis between the BEST1 gene mu-tations and the phenotypic expression of the disease onthe FAF patterns did not reveal a specific distribution forthe FAF changes.

DISCUSSION

BEST VITELLIFORMMACULAR DYSTROPHY IS ANAUTOSOMAL

dominant disorder with variable penetrance. Genetic link-age has mapped the disease to the long arm of chromosome11 (11q12–q13), particularly to the BEST1 gene, whichencodes a protein called bestrophin-1.1–4 The complexmetabolic changes induced by the mutations in theBEST1 gene ultimately lead to an extensive accumulationof lipofuscin within the RPE cells, clinically resulting inthe yellow subretinal lesion visible at the posteriorpole, characteristic of the classic ‘‘vitelliform’’ phenotype.Histopathologic studies have confirmed the abnormalincrease of lipofuscin within the RPE cells in thesepatients.5–10 Best vitelliform macular dystrophy can revealvariable FAF patterns, according to the stage of the


TABLE 2. Fundus Autofluorescence Pattern Distribution and Mean Best-Corrected Visual Acuity Values in 37 Eyes With Stage 2 BestVitelliform Macular Dystrophy

Hyper-Fundus Autofluorescence Patchy Spoke-like Hypo-Fundus Autofluorescence

SW-FAF (no. eyes/%) 15 (40%) 18 (49%) 2 (5%) 2 (5%)

Mean BCVA (6SD) 0.20 6 0.19 0.35 6 0.32 0.2 6 0.0 0.5 6 0.7

NIR-FAF (no. eyes/%) 7 (19%) 27 (73%) 2 (5%) 1 (3%)

Mean BCVA (6SD) 0.1 6 0.1 0.32 6 0.29 0.2 6 0.0 1

BCVA ¼ best-corrected visual acuity; NIR-FAF ¼ near-infrared autofluorescence; SD ¼ standard deviation; SW-FAF ¼ short-wavelength

fundus autofluorescence.

TABLE 3. Fundus Autofluorescence Pattern Distribution andMean Best-Corrected Visual Acuity Values in 8 Eyes With

Stage 3 Best Vitelliform Macular Dystrophy

Hyper-Fundus Autofluorescence Patchy

SW-FAF (no. eyes/%) 1 (12.5%) 7 (87.5%)

Mean BCVA (6SD) 0.4 0.70 6 0.32

NIR-FAF (no. eyes/%) 0 8 (100%)

Mean BCVA (6SD) - 0.66 6 0.32






Hyper-Fundus

Autofluorescence Patchy

Hypo-Fundus

Autofluorescence

SW-FAF

(no. eyes/%)

0 16 (84%) 3 (16%)

Mean

BCVA (6SD)

- 0.56 6 0.33 0.6 6 0.17

NIR-FAF

(no. eyes/%)

1 (5%) 14 (74%) 4 (21%)

Mean

BCVA (6SD)

0.8 0.55 6 0.34 0.57 6 0.15




disease and to the specific FAF technique employed. Short-wavelength FAF enables the visualization of A2E and otherbisretinoid components of lipofuscin in the RPE, andis currently considered the best noninvasive technique inorder to achieve a comprehensive visualization of theabnormal lipofuscin accumulation. Several authors havedescribed the short-wavelength FAF abnormalities of Bestvitelliform macular dystrophy, characterized by anincreased signal, especially visible in the early stages, anda trend toward a decreased response in the later stages.11–16 In addition to short-wavelength FAF, near-infraredFAF is a relatively new imaging modality that is gainingan increasing role in monitoring retinal disease. In partic-ular, the near-infrared FAF signal is mainly generated bythe melanin granule accumulation within the RPEcells,17–19 and alterations in its pattern can reflect thechanges in the RPE content or in the melanin distribution.

Our results indicate that overall 6 main FAF patterns canbe identified in the different stages of Best vitelliform mac-ular dystrophy: normal, multifocal, hyper-autofluorescent,hypo-autofluorescent, patchy, and spoke-like patterns.The most frequent FAF pattern, as visualized on bothFAF techniques, is the patchy pattern, followed by thehyper-autofluorescent pattern on short-wavelength FAFand the hypo-autofluorescent pattern on near-infraredFAF. It is noteworthy that no specific FAF pattern couldbe considered typical of a definite Best vitelliform macular


dystrophy stage. In particular, the most frequent pattern,the patchy pattern, could be identified across all thedifferent intermediate clinical stages of the disease. Simi-larly, the hyper-autofluorescent pattern was found mainlyin the vitelliform stage, especially on short-wavelengthFAF, but it was also identified in patients classified in stages3 and 4. We noted a trend toward a more frequent appear-ance of a patchy pattern in pseudohypopyon and vitellirup-tive stages, while the hypo-autofluorescent pattern wasmore typical of subclinical and atrophic/cicatricial stages.It is of interest that near-infrared FAF showed a hypo-autofluorescent pattern in the majority of eyes with sub-clinical Best vitelliform macular dystrophy. This FAFresponse may reflect either a reduced amount of melaninor an irregular melanin distribution within RPE cells inthe subclinical stage of the BEST1 gene defect. Interest-ingly, in this stage the near-infrared FAF signal is altered,but the short-wavelength FAF signal is almost normal,suggesting that near-infrared FAF may be more sensitivein the early phases of the disease. The comparison withFAF responses in age-related macular degeneration(AMD) may be interesting. Whereas short-wavelengthFAF in early and late stages of AMD has been analyzed,




Hypo-Fundus Autofluorescence Patchy

SW-FAF (no. eyes/%) 5 (83%) 1 (17%)

Mean BCVA (6SD) 1.06 6 0.13 1

NIR-FAF (no. eyes/%) 3 (50%) 3 (50%)

Mean BCVA (6SD) 1 6 1.1 1 6 0




scant information is currently available for near-infraredFAF. Early AMD as imaged on near-infrared FAF canshow focal hyper-autofluorescence, focal hypo-autofluo-rescence, and linear hyper-autofluorescence, whereaslate AMD frequently discloses a hypo-autofluorescentresponse.22 Thus, the FAF pattern on near-infrared turnsout to be dissimilar especially in the early stage of Best vitel-liform macular dystrophy, often characterized by hyper-autofluorescent or patchy patterns.

As expected, BCVA varied even within the same FAFpatterns across the different Best vitelliform macular dys-trophy stages. In fact, it is well known that visual acuitydeterioration usually develops only with the breakup ofthe vitelliform stage and the development of geographicRPE atrophy. In our case series BCVA was generally lowerin the hypo-autofluorescent pattern, with the exception ofthe eyes in the subclinical stage, characterized by fully pre-served visual acuity.

The interpretation of the complex FAF patterns can be amatter of speculation. In particular, the amount of melaninwithin the RPE cells may have an indirect effect on lipofus-cin accumulation and/or the photo-oxidation of lipofuscin-related compounds.23–25 The altered near-infrared FAFpatterns detectable since the subclinical stage may suggestthat the effects of mutations of the BEST1 gene mayinfluence the RPE homeostasis. Even though the role of


bestrophin is still controversial, this protein is thoughtto be a calcium-activated chloride channel, which inturn acts as a regulator of voltage-gated Ca2þ chan-nels.26,27 In animal models it was demonstrated thatchloride can influence calcium-dependent exocytosis indifferent cell types,28 and calcium was in turn found toexert a variable influence on melanin storage in melano-phores.29 In particular, calcium would appear to influencenot melanin aggregation, but melanin dispersion throughthe calcium-mediated pattern. We hypothesize thatbestrophin mutations cause a calcium imbalance owing toalterations in chloride conductance affecting melaninexocytosis in the early stages of the disease, contributingto lipofuscin accumulation in lysosomes and altered auto-fluorescence signals. It is notable that fluorescent melano-lipofuscin granules and fluorescent melano-lysosomes havealready been observed in human-cultured RPE cells,30,31

suggesting a link between melanin and lipofuscin-lisosomalpathways. From the clinical point of view, an intricate inter-action between lipofuscin and melanin responses on FAFhas been described in AMD and some dystrophies,14,15,22

suggesting that a dynamic inter-relationship between the 2fluorophores occurs over the course of the disorders.We acknowledge that this study has several limitations,

especially regarding the absence of a longitudinal follow-upshowing the possible FAF changes over time for each pa-tient. Moreover, FAF assessment was subjective and basedon a qualitative evaluation of the images. Furthermore, al-terations in FAF may occur owing to dynamic processes,including circadian rhythms, the level of dark adaptation,and photoreceptor bleaching.In conclusion, the present study found 6 main patterns

on both short-wavelength FAF and near-infrared FAF inBest vitelliform macular dystrophy. The most frequentpattern is the patchy pattern, although the same FAF pat-terns can be identified in different stages of the disease. Alongitudinal study designed to evaluate the clinical andFAF modifications over a follow-up period may be usefulto fully understand the course of the disease and the prog-nostic implications of each FAF pattern in view of thefuture therapeutic options.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTERESTand report the following: F. Bandello is an advisory board member for Allergan, Novartis Pharmaceuticals Corporation, Farmila-Thea, Bayer ScheringPharma, Pfizer, Alcon, Bausch And Lomb, Genentech, Alimera Sciences, Sanofi Aventis, and Thrombogenics. The other authors have no proprietary/financial interest. The authors indicate no funding support. Contributions of authors: conception and design (M.B.P.); analysis and interpretation(M.B.P., P.I., C.C., C.D., F.B.); writing of article (M.B.P., P.I., C.C., C.D., .F.B.); critical revision of article (M.B.P., P.I., C.C., F.B.); final approval ofarticle (M.B.P., P.I., C.C., C.D., F.B.); data collection (M.B.P., P.I., C.C., C.D.); supply of materials, patients, or resources (M.B.P., P.I., C.C., C.D.,F.B.); statistical expertise (P.I., M.B.P.); literature research (P.I., M.B.P.).

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28. Turner JE, Sedej S, Rupnik M. Cytosolic Cl- ions in the regu-lation of secretory and endocytotic activity in melanotrophsfrom mouse pituitary tissue slices. J Physiol 2005;566(Pt 2):443–453.

29. Gonzalez A 3rd, Crittenden EL, Garcıa DM. Activation ofmuscarinic acetylcholine receptors elicits pigment granuledispersion in retinal pigment epithelium isolated from blue-gill. BMC Neurosci 2004;13(5):23.

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Biosketch

Maurizio Battaglia Parodi received his medical degree from the University of Genoa and completed his residency in

Ophthalmology at the University of Trieste. He is a medical retina specialist and is currently working at the

Department of Ophthalmology at University Vita-Salute in Scientific Institute San Raffaele in Milan.

7.e1 --- 2014AMERICAN JOURNAL OF OPHTHALMOLOGY

Biosketch

Pierluigi Iacono achieved the medical degree from the University of Trieste and completed the residency program in

Ophthalmology at the same University. He is a medical retina specialist with special interests in age-related macular

degeneration, and myopia. Dr Iacono has currently an appointment at Fondazione GB Bietti in Rome.

VOL. -, NO. - 7.e2FUNDUS AUTOFLUORESCENCE IN BEST VITELLIFORM DYSTROPHY

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Fundus Autofluorescence Patterns in Best Vitelliform Macular Dystrophy