best dystrophy is known to be related to an autosomal dominant inheritance caused by mutation in the best1 gene . however , there is another entity called autosomal recessive bestrophinopathy ( arb ) , described by burgess et al .   in 2008 as an autosomal recessive condition associated with biallelic mutations in the best1 gene , with either homozygous or compound heterozygous sequence variants . in both best dystrophy and arb , yellow epithelial retinal and deep retinal pigment deposits are present , and arb can also be associated with choroidal neovascularization ( cnv ) early in its course . this report describes a challenging case with long - term follow - up of bestrophinopathy and innovative , multimodal management . in december 2000 , an 8-year - old caucasian girl presented with a sudden loss of vision in her right eye . visual acuity was 20/200 in the right eye and 20/20 in the left . fundus examination revealed a pale , dot - like , subretinal lesion inferior to the foveola with subretinal fluid and subretinal hemorrhage along the inferior arcade ( fig . fluorescein angiography showed an area of hyperfluorescence with leakage at the center of the macula of the right eye , indicating the presence of a subretinal neovascular membrane ( fig . the left eye showed an area of hyperfluorescence without leakage , indicating staining of the retinal pigment epithelium ( rpe ) both around and inferior to the foveal center ( fig . 1d ) . a stratus optical coherence tomography ( oct ) ( carl zeiss , germany ) performed at that time demonstrated intra- and subretinal fluid in the macula of the right eye . electrophysiological tests were performed , demonstrating a full - field electroretinogram with normal cone pathway responses but reduced rod responses . electrooculogram was clearly abnormal , with an arden ratio of 1 : 1 in the right eye and 1 : 2 in the left ( online suppl . figure , see www.karger.com/doi/10.1159/000473696 ) . at that time , best dystrophy was the differential diagnosis . the relevant family history was negative and family screening was unremarkable . in the absence of current - day options , i.e. , photodynamic therapy ( pdt ) and anti - vascular endothelial growth factor ( vegf ) agents , in december 2000 , the therapeutic procedure of choice for such a case ( type 2 subretinal membrane ) was the removal of the submacular membrane through a 20-g pars plana vitrectomy ( ppv ) . a successful removal was performed , and 3 months after surgery , she had 20/25 vision in the right eye . postoperative fluorescein angiography revealed an area of staining fluorescence around the fovea , with no leakage . in july 2004 she returned showing an excellent result in the right eye , maintaining her postoperative 20/25 vision ( fig . the left eye had undergone a sudden decrease in vision , with a clinical picture resembling that of the right eye noticed 4 years earlier . fluorescein angiography revealed the presence of a submacular neovascular membrane with hyperfluorescence and leakage at the foveal center ( fig . 2d ) , and stratus oct examination clearly revealed a type 2 membrane ( fig . one month later , the subretinal membrane had grown , showing more subretinal hemorrhage . as her vision continued to deteriorate three months later , her vison was 20/30 in the left eye , showing no signs of subretinal membrane . ten years later she returned , complaining of central vision deterioration in both eyes over the previous 12 months . 3a , b ) and autofluorescence retinography were performed on both eyes , showing an area of hypoautofluorescence covering most of the posterior pole in both eyes . spectral domain oct revealed large amounts of fluid with many cystic spaces and appearance of retinoschisis in both eyes ( fig . a multifocal electroretinogram was performed showing decreased b waves in both eyes , being worse in the right eye . in the beginning of 2014 , she had tried 4 bevacizumab injections in each eye and dorzolamide eye drops for the last 6 months , both without success . after discussion with the patient ( then aged 22 ) and her parents , a decision was made on an experimental , multimodal approach : another ppv with removal of the internal limiting membrane ( ilm ) plus c3f8 gas injection in the left eye . four weeks after surgery , all retinal fluid had disappeared and her vision was 20/60 . 3d , f ) , although at a much lower level . at this point , a genetic examination to test her for bestrophin protein was requested , as arb was suspected . these tests , performed by the laboratory of genetics of the federal university of so paulo , brazil , confirmed a homozygous variation in the best1 gene ( splice site c.768 + 1g > a ) . the vision in the left eye remained stable and the cystic space did not enlarge , so 1 year later , the patient decided to have the same procedure in the right eye . as with the left eye , all fluid resolved and the cystic spaces disappeared for a few months . three months after surgery , fluid started to appear again , but at a much lower level than before surgery , and has remained so until the present , 1 year after surgery . the patient described here presented with cnv under the foveal area in one eye at the age of 8 , and 4 years later developed the same condition in the other eye . at that time , the only treatment available was surgical removal of the neovascular membrane through ppv . anti - vegf therapy was not available at that time , and recent studies report good results in this type of patient . arb onset usually occurs early in life , the disease presenting with decrease visual acuity . other clinical signs of this condition are diffuse rpe dysfunction , intraretinal and subretinal fluid , and atypical subfoveal vitelliform lesions associated with extramacular and extrafoveal subretinal deposits . a transmembrane protein primarily expressed in the basolateral membrane of the rpe and named bestrophin-1 the functional role of bestrophin-1 within the rpe remains uncertain , with possible functions as a ca - activated cl channel , a regulator of voltage - gated ca channels , or as a hco3 channel . it is postulated that before the photoreceptor outer segments are shed , large amounts of osmolytes are released which adversely influence the role of bestrophin in rpe cell membranes , leading to faulty phagocytosis and disrupted fluid transport across the rpe . the rate of vegf production from rpe cells is also thought to depend on the activity of voltage - dependent l - type ca channels and may be responsible for the early occurrence of cnv in arb . described elongated and thickened photoreceptor outer segments together with thin processes bridging the space between the photoreceptor and rpe layers in an 11-year - old boy with arb . .   found that bilateral intravitreal bevacizumab treatment in a 6-year - old child with arb and associated cnv in one eye did not resolve the fluid fully , although the cnv responded favorably . this is similar to our experience , where the classic cnv was no longer active on fluorescein angiography , but the intraretinal spaces persisted on spectral domain oct . these separations ( schisis ) in between many retinal layers connected by columns in both eyes are also oct features seen in juvenile x - linked retinoschisis . the same features were found in our patient . the fluid in the intraretinal space did not seem to respond to anti - vegf agents , given that there did not appear to be any benefit in the patient following 4 injections of bevacizumab . therefore , current oct - driven treatment protocols applicable to neovascular age - related macular degeneration [ 7 , 8 ] advocating treatment until complete resolution of fluid is achieved   may not be appropriate in cnv associated with causes other than age - related macular degeneration . besides anti - vegf , treatment with pdt has been reported for choroidal neovascular membrane associated with best vitelliform dystrophy . on the other hand , the good temporary response to ppv and ilm peeling plus gas was encouraging for both the treatment team and the patient . within 2 weeks , all fluid disappeared and vision improved . this case highlights the successful outcome of bilateral , consecutive ppv with subretinal neovascularization removal and subsequent ilm peeling with gas endotamponade in a case of bestrophinopathy , and emphasizes the importance of a genetic test as a diagnostic tool in patients with macular dystrophies . this appears to be the longest follow - up reported in the literature to date for a case of arb . all authors declare that have no significant competing financial , professional , or personal interests that might have influenced the performance or presentation of the work described in this paper .
herein , we report the case of an 8-year - old girl who presented in december 2000 with a submacular neovascular membrane in the right eye , with a clinical diagnosis of best disease . at that time , she underwent pars plana vitrectomy ( ppv ) with removal of the subretinal choroidal neovascularization ( cnv ) . her vision 
 improved from 20/200 to 20/25 . 
 four years later , a new cnv developed in the other eye . 
 initially , she underwent unsuccessful photodynamic therapy . 
 as her vision worsened , she underwent a second , this time successful , ppv with membrane removal in the left eye , with vision improving to 20/30 . 
 ten years later , she returned complaining of vision loss over the last year . 
 her vision was 20/200 ou , and optical coherence tomography demonstrated very large intraretinal cystoid spaces resembling bilateral macular schisis . 
 four ranibizumab injections as well as dorzolamide eye drops were tried , both without success . 
 finally , she underwent ppv with internal limiting membrane peeling and gas - fluid exchange in the left eye . 
 one month later , the macula appeared flat and vision had improved to 20/60 . 
 the same procedure was performed 1 year later for the right eye , with vision improving to 20/80 . 
 one year later , mild cystic spaces developed again in both eyes , although much smaller than previously observed . 
 her vision remained stable .