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• W2080445150 abstract "Purpose: To determine the mutation in a Swedish family with Best disease (vitelliform macular dystrophy; VMD) and to investigate the short- and long-term effects of photodynamic treatment (PDT) on subretinal neovascularization in a young boy. Methods: The five members of three generations of a family with VMD underwent a thorough ophthalmological examination, including best-corrected visual acuity (VA), visual field, colour vision, biomicroscopy of the posterior segment (dilated), fundus photography and electro-oculography (EOG). For the proband, an eleven-year-old boy, his father and grandfather, dark adaptation test, angiography and electroretinography (ERG) were also performed. After PCR amplification, the genotype was determined by cleavage with restriction enzyme, specific for the W93C allele. Results: Four family members had an abnormal EOG response. All showed the W93C mutation in the VMD2 gene. Visual acuity ranged from 20/20 to 20/250. The fundus manifestations varied from minor pigmentary changes over egg yolk-like lesions to chorioretinal atrophy, and fluorescein angiography showed corresponding pathology. In the proband, VA decreased during follow-up from 0.5 (20/40) to 0.08 (20/250) due to a subfoveal neovascularization with haemorrhage, and PDT with visudyne was begun. The haemorrhage resolved within 2 months, and after three treatments, VA had increased to 0.25 (20/80). One year later, acuity had improved to 0.5 (20/40), and this result was stable throughout the 7 years of the follow-up. Conclusion: The mutation was determined to be W93C, the most common mutation in VMD in Sweden. In an eleven-year-old boy with subretinal neovascularization, PDT seemed to be beneficial also in a long-term follow-up. Best vitelliform macular dystrophy (VMD) is a dominantly inherited, early onset macular dystrophy, caused by mutations in the VMD2 gene (Petrukhin et al. 1998). The gene product, bestrophin, which localizes to the basolateral plasma membrane of the retinal pigment epithelium (RPE) (Marmorstein et al. 2000), is altered by the mutation, in turn resulting in accumulation of large quantities of lipofuscin in and behind the RPE and in macrophages in the subretinal space (Weingeist et al. 1982). Reduction in visual acuity (VA) and chorioretinal atrophy will follow later. Bestrophin expression is higher in the macula than peripherally, which may explain the fact that the disease lesion is to a large extent localized to the macula (Mullins et al. 2007). Choroidal neovascularization (CNV), which is common in age-related macular degeneration (AMD), may also develop in VMD. This is uncommon, however, particularly in children. CNV in AMD in elderly patients was shown to be treatable with verteporfin photodynamic treatment (PDT) in 1999 (Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 1999), long before the introduction of anti-VEGF treatment. Having examined and genetically analysed a family with VMD, including an 11-year-old boy with a vitelliform lesion and a haemorrhage (CNV) in the right eye, we asked ourselves whether PDT may also be beneficial in such a case. To our knowledge, there were no reports on PDT for Best disease with CNV and very little experience of PDT in children at that time (February, 2003). However, one report, made available to us prior to publication by one of the authors (N. Bressler), showed that such treatment had been performed safely in three children with idiopathic CNV (Mimouni et al. 2003). We therefore treated our young patient with PDT. A 1-year follow-up, showing an improvement, has been presented earlier (Frennesson et al. 2004). Today, many patients with Best disease and CNV are being treated with ranibizumab, resulting in stabilized or improved acuity (Querques et al. 2008; Caillaux et al. 2012). It has been shown that the outcome without treatment is very poor if the initial acuity is low (<0.1; <20/200) (Chung et al. 2001), and Iannaccone et al. (2011) propose that treatment (anti-VEGF) is appropriate when two of three of the following features are seen: angiographic evidence of CNV and/or presence of new blood, rapid decline in VA and reduced vision in the other eye. Here, we report on the genetic analysis of the family and the long-term results of PDT in the eleven-year-old boy, who demonstrated both CNV/new blood and rapid and pronounced decline in VA. An eleven-year-old boy with VMD-like changes (the proband) and three generations of his family (grandfather, father, mother and a sister) underwent molecular genetic analysis, and the VMD gene was searched for the mutation W93C. This mutation introduces a new restriction site for the enzyme Fnu4HI, so that affected individuals will show not only the full PCR product of 126 bp but also two smaller fragments of 84 and 42 bp (Petrukhin et al. 1998). After polymerase chain reaction (PCR) amplification, the genotype was determined by cleavage of the PCR product with a restriction enzyme, specific for the W93C allele, and the fragments were separated on an agarose gel. All family members underwent a thorough ophthalmological examination, including VA (Snellen chart and, in addition, ETDRS for the proband), slit lamp examination of the anterior segment, biomicroscopy of the posterior segment (dilated), fundus photography and electrooculography (EOG), according to the standard by the International Society for Clinical Electrophysiology of Vision (ISCEV). In the grandfather, the father and the proband, visual fields (Goldmann perimetry), colour vision (Standard Pseudochromatic Plates), dark adaptation (Goldmann–Weeker) and fluorescein angiography were also performed as well as scotopic and photopic 30 Hz flicker electroretinography (ERG; ISCEV standard). In addition, the boy was subjected to indocyanine green angiography (ICG-A). The grandfather, a 67-year-old man (a foster child of unknown ancestry) had a VA of 0.6 (20/35) in the right eye and strabismic amblyopia in the left eye [VA 0.08 (20/250)] but without any visual complaints. He showed chorioretinal atrophy and degenerative changes in both maculae with atrophy and pigment clumping in the periphery, consistent with VMD. Fluorescein angiography showed corresponding pathology. EOG was abnormal (Arden ratio 1.2) but ERG was normal. The father, a 40-year-old man, was diagnosed with VMD at the age of 34. Visual acuity was 0.32 (20/60) in the right eye and 0.2 (20/100) in the left eye. He showed stage IIId lesions (Fishman et al. 1993) in both maculae with chorioretinal atrophy and corresponding pathology in fluorescein angiography. EOG was severely pathologic with an Arden ratio of 1.1. Further examinations, including ERG, were normal. The boy’s 14-year-old sister’s VA was normal (1.0; 20/20) in both eyes. Fundus examinations showed only minor pigmentary changes in the maculae. As a sign of VMD, the EOG was abnormal: Arden ratio 1.1. The mother did not have any visual problems, and VA, fundus biomicroscopy, fundus photography and EOG (Arden ratio 2.1) were all normal. The proband was given glasses for hyperopia and astigmatism at the age of 4, resulting in a VA of 1.0 (20/20) in both eyes. In 2001, at the age of 9, his optician referred him to our department because of a recent decrease in vision in the left eye to 0.3 (20/70). Visual acuity in the right eye was still 1.0 (20/20). Funduscopy revealed Best disease lesions in both eyes, pseudohypopyon in the right eye and an egg yolk lesion surrounded by a fairly thin subretinal haemorrhage in the left eye (Fig. 1A). No treatment was given, but the haemorrhage resolved over a period of 3.5 months, and VA increased to 0.7 (20/30) in the left eye. The fairly good initial acuity and the rapid recovery seem to indicate a limited CNV. Fourteen months later, VA had increased to 1.0 (20/20) and remained approximately the same (85–83 letters) through the last follow-up in October 2010. There were no signs of haemorrhage in the fundus photograph (Fig. 1B). At this stage, it was also possible to perform a fluorescein angiography, showing a hyperfluorescent lesion without signs of leakage (Fig. 1C). In an SD-OCT in 2010, when this equipment became available, a fairly steep lesion is seen. The overlaying retina seems to have retained its photoreceptor layer to a large extent (Fig. 1D). The boy, left eye. (A) Fundus photograph at the age of 9 years, showing a fairly thin haemorrhage surrounding a vitelliform lesion. Visual acuity 0.3 (20/66). (B) Fourteen months later: The haemorrhage has been resorbed spontaneously with some pigment remaining. Visual acuity 1.0 (20/20). (C) A fluorescein angiogram (8 min) on the same day does not show any leakage. (D) In an SD-OCT, 8 years later, a fairly steep lesion is seen. The overlaying retina seems to have retained its photoreceptor outer and inner segments to a large extent. In April 2002, the right eye showed a reduced acuity to 0.5 (20/40), and a thin haemorrhage, surrounding a vitelliform lesion, was observed in the macula (Fig. 2A). EOG was abnormal with an Arden ratio of 1.3. The photopic ERG was slightly subnormal. Perimetry showed a central scotoma. Other examinations including scotopic ERG, dark adaptation and colour vision were normal. The following year, VA in this eye varied between 0.2 (20/100) and 0.5 (20/40). At this stage, fluorescein angiography did not show an unequivocal CNV with leakage. At a scheduled visit in January 2003, however, VA in the right eye had decreased substantially to 0.08 (20/250), indicating a more severe lesion, without the patient noticing. A haemorrhage surrounded most of the vitelliform lesion. It was thicker nasally with oedema and prominent striae. In addition, there was a large haemorrhage below the lesion (Fig. 2B). Together, this indicated a possible CNV. Indocyanine (ICG) (Fig. 2C) and fluorescein angiography (Fig. 2D) seemed to confirm a CNV with leakage at the nasal side of the lesion. Because a dramatic decrease in acuity had occurred, and because PDT had been safely used to treat idiopathic CNV in children, resulting in cessation of leakage and a certain increase in VA (Mimouni et al. 2003), we considered using PDT in this case. We also consulted two internationally recognized experts in the field, Drs. Neil and Susan Bressler, Baltimore, who after seeing the images recommended PDT. This was begun in late February, 2003, following the standard procedure according to the TAP study (Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 1999): verteporfin (6 mg/ m2 BS) infused intravenously and followed by laser application for 83 seconds, using a diode laser (Coherent Opal) of 689 nm, 600 mW/cm2 and 50 J/cm2. The boy, right eye. (A) Age 10 years. Fundus photograph of the first haemorrhage, fairly thin and surrounding the vitelliform lesion. Visual acuity 0.5 (20/40). (B) Fundus photograph showing an egg yolk (vitelliform) lesion surrounded by haemorrhages, oedema and prominent retinal striae, in particular nasally. A large haemorrhage below the lesion. Visual acuity 0.08 (20/250). (C) ICG angiogram, late phase (3 weeks after the fundus photo), which seems to show a plaque with leakage in the upper nasal part. (D) Fluorescein angiogram (FA), early and late phases (3 weeks after the fundus photo), showing a possible CNV with leakage in the upper nasal part. The proband, his grandfather, father and sister all showed the mutation W93C in Bestrophin, the most common mutation in VMD in Sweden, whereas his mother had a normal VMD2 gene (Fig. 3). This mutation creates a restriction site for the enzyme Fnu4HI, which cuts the 126 bp PCR product in two fragments, 84 and 42 bp long. As the affected individuals have one normal and one mutated gene, one large band is seen for the normal gene, and two smaller fragments are present derived from the mutated variant (Fig. 2). Bestrophin was analysed for the mutation W93C. The mutation creates a restriction site for the enzyme Fnu4HI which cleaves the PCR 126 base pair (bp) product into two smaller fragments, 84 and 42 bp in length. As only the PCR product from the mutated gene is cleaved, three fragments are seen in affected individuals. In the boy, PDT with verteporfin was performed three times at 12-week intervals. Already 2 months after the first treatment, almost all haemorrhages had disappeared (Fig. 4A), but some leakage and oedema were still present. Three months after the third treatment, no uneqivocal leakage could be detected in the fundus photograph or in the fluorescein angiogram (Fig. 4B,C), and treatment was terminated. At 14 months after the third treatment, no intraretinal oedema was seen in the OCT (Fig. 4D). The spaces at the sides of the lesion are not necessarily caused by leakage. Visual acuity improved from 0.08 (20/250) to 0.25 (20/80). One year later, acuity had increased to 0.5 (20/40) (69 letters). During 2006, 2007 and 2008, acuity was stable at 0.5 (70-72 letters). At the latest follow-up in October 2010, 7 years after treatment, acuity was still 0.5 (70 letters). The fundus photograph showed a vitelliform lesion, most likely with fibrosis, but with no signs of haemorrhage or leakage (Fig. 5A). 3-D images from the Heidelberg Spectralis SD-OCT showed a massive lesion with a prominent retinal elevation. There are no signs of retinal oedema in the horizontal cross section (Fig. 5B,C). However, in spite of a fairly good acuity, the photoreceptor outer and inner segments seem somewhat disrupted. (A) Fundus photograph of the boy, only 2 months after the first photodynamic treatment (PDT). The haemorrhages have almost entirely disappeared. (B) Three months after the third PDT. No signs of haemorrhage but striae radiating from the lesion. (C) Three months after the third PDT. Fluorescein angiogram, late phase. Fluorescein is accumulated in the vitelliform lesion, but there is no unequivocal leakage. Visual acuity 0.25 (20/80). (D) Fourteen months after the third PDT. OCT, showing the vitelliform lesion. No sign of intraretinal oedema. The space between the retina and the RPE seen at the edge of the lesion is not necessarily caused by leakage. Visual acuity 0.5 (20/40). The patient at the latest follow-up in October 2010, 7 years after treatment with an acuity of 0.5 (70 letters). (A) The vitelliform lesion seems to show fibrosis and some pigment, but there are no signs of haemorrhage or leakage. (B) 3-D SD-OCT image demonstrates a prominent retinal elevation. (C) SD-OCT cross section through the massive lesion with no sign of intra- or subretinal oedema. The photoreceptor layer seems to show some disruption. The clinical diagnosis VMD was firmly established for four members of the family and by molecular genetic analysis and excluded for one member with a normal fundus. As it was known that PDT could reduce vision loss in elderly patients with CNV in AMD (Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 1999), we asked us whether it could be used to treat CNV in Best disease. The fact that our patient was an 11-year-old boy and that PDT, at that time, had not been used in children was a problem. However, we had information from a report of its successful use in three children with idiopathic CNV (Mimouni et al. 2003) and, as mentioned above, we were also recommended by international authorities to use PDT in this case. On this basis, we treated our patient. The haemorrhages disappeared in a short time and the oedema somewhat later. Visual acuity gradually increased from 0.08 (20/250) to 0.25 (20/80) after the third treatment and to 0.5 (20/40) 1 year later. This acuity was stable all the way through the 7-year follow-up. These improvements seem to favour a beneficial result of PDT. One has to consider a spontaneous regression, however. At an earlier time, our patient’s left eye showed an egg yolk lesion surrounded by a fairly thin subretinal haemorrhage. Visual acuity did not decrease more than to 0.3 (20/70). Without treatment, the haemorrhage slowly disappeared over a period of 3.5 months, and acuity increased to 0.7 (20/30). Later, it improved to 1.0 (20/20). A similar haemorrhage developed in the right eye with an acuity reduced to 0.5 (20/40). Without treatment, the acuity did not improve during the following year. Then, VA rapidly decreased dramatically to 0.08, and the haemorrhage and oedema increased substantially. Therefore, treatment appeared more urgent for this eye. It has been shown earlier that the outcome without treatment in cases of VMD with a haemorrhage was very poor if the initial acuity was low (<0.1; <20/200) (Chung et al. 2001). Iannaccone et al. (2011) reported on a 6-year-old child with Best disease and with rapid vision loss to 20/200 due to subfoveal CNV. The child was treated with intravitreal injections of bevacizumab and VA recovered. They propose that treatment is appropriate when two of three of the following features are seen: angiographic evidence of CNV and/or presence of new blood, rapid decline in VA and reduced vision in the other eye. Our patient demonstrated both CNV/new blood and rapid and pronounced decline in VA. After PDT, there was a rapid resorption of the haemorrhage and acuity increased, which may be the result of the PDT treatment, but a spontaneous improvement cannot be fully ruled out. In Fig. 4D, spaces are seen at the sides of the vitelliform lesion. Leakage does not seem to be the most likely explanation, because there are no unequivocal signs of leakage in the fundus photo or in the fluorescein angiogram. There may be other explanations, for example, the one offered by the group at Creteil (Querques et al. 2008), that is, that they are caused by a gradual resorption of the vitelliform material. In addition to our initial report on PDT in this young boy in 2004 (Frennesson et al. 2004), there are also other publications on successful PDT treatment for CNV in VMD in children (Waheed et al. 2004; Rich et al. 2009) and in an adult patient (Andrade et al. 2003). In more recent years, ranibizumab (Querques et al. 2008; Caillaux et al. 2012; 24 eyes) and bevacizumab (Leu et al. 2007) have also been used for the same diagnosis in children with stabilization or improvement in VA. In conclusion, the present report on long-term follow-up of PDT for CNV in Best disease, together with other publications, seems to support a successful outcome of this treatment with a rapid resorption of the haemorrhage and the oedema and often with a substantial improvement in VA that can be stable over many years. A spontaneous resolution cannot be fully excluded, however. The present investigation was supported by grants from Crown Princess Margareta’s Foundation for the Visually Handicapped, the Foundation for Promotion of Vision, the Foundation for the Visually Handicapped in Östergötland, and ALF Grant County Council of Östergötland." @default.
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• W2080445150 title "Best vitelliform macular dystrophy in a Swedish family: genetic analysis and a seven-year follow-up of photodynamic treatment of a young boy with choroidal neovascularization" @default.
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