Autofluorescence Findings in Acute Exudative Polymorphous Vitelliform

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only, with pale featureless optic tant insights into the underlying 3 patients and to characterize macu- discs. A computed tomographic pathogenesis that leads to optic lar, retinal, and RPE function using scan of the brain and orbits atrophy. International Society for Clinical excluded mass lesions or intraor- Electrophysiology of Vision– bital abnormalities, and magnetic Neroli Porter, MBBS, FRANZCO standard electrophysiology.5-7 resonance imaging revealed severe Susan M. Downes, MD, FRCOphth atrophy of the optic nerves, optic Carl Fratter, MPhil, DipRCPath Report of Cases. Case 1. A healthy chiasm, and optic tract. Philip Anslow, MA, MBBChir, 49-year-old man noticed a gradual de- Genetic analysis revealed com- FRCR crease in both distance and near vi- pound heterozygosity, with a GAA Andrea H. Ne´meth, MBBS, MRCP, sion, worse in his left eye, preceded expansion on one allele and a DPhil (Oxon) by a flulike illness. There was no other G-to-T base substitution in exon 4 Correspondence: Dr Ne´meth, De- relevant medical, ophthalmic, or fam- (Gly130Val) on the other. The mi- partment of Clinical Genetics, ily history. On first examination sev- tochondrial point mutations asso- Churchill Hospital, Churchill Drive, eral months later, his best-corrected ciated with MELAS (mitochondrial Oxford OX37LJ, England (andrea visual acuity (VA) was 20/30 OD and myopathy, encephalopathy, lactic [email protected]). 20/60 OS. Anterior segments, optic acidosis, and strokelike episodes) or Financial Disclosure: None re- discs, and the peripheral retina were MIDD (maternally inherited diabe- ported. within normal limits. Posterior seg- tes and deafness), MERRF (myo- ment examination showed bilateral clonic epilepsy with ragged-red fi- 1. Oppenheimer DR. Brain lesions in Friedreich’s yellow-white confluent macular de- bers), NARP (neuropathy, ataxia, ataxia. Can J Neurol Sci. 1979;6:173-176. posits (Figure 1A and B). Autofluo- 2. Cossee M, Durr A, Schmitt M, et al. Friedreich’s and retinitis pigmentosa), and Leber ataxia: point mutations and clinical presenta- rescence imaging using a confocal hereditary optic neuropathy were tion of compound heterozygotes. Ann Neurol. scanning laser ophthalmoscope 1999;45:200-206. not identified. 3. David G, Durr A, Stevanin G, et al. Molecular showed that the lesions were hyper- and clinical correlations in autosomal domi- fluorescent (Figure 1C and D), con- Comment. This patient with FRDA nant cerebellar ataxia with progressive macular sistent with lipofuscin deposits. Pat- dystrophy (SCA7). Hum Mol Genet. 1998;7: 5,6 had visual loss of a rapidity and se- 165-170. tern and full-field electroretinogram verity not previously described in 4. Francis PJ, Schultz DW, Gregory AM, et al. (ERG) and electro-oculogram7 re- FRDA. She was also noted to have a Genetic and phenotypic heterogeneity in pat- sults were normal, the latter suggest- tern dystrophy. Br J Ophthalmol. 2005;89: pattern dystrophy but had normal 1115-1119. ing normal generalized RPE func- electroretinographic results and pat- 5. Bernstein PS, Tammur J, Singh N, et al. Diverse tion that would not be in keeping with macular dystrophy phenotype caused by a novel tern electroretinographic results, complex mutation in the ELOVL4 gene. Invest Best disease. Six months later, the pa- suggesting that it is the optic nerve Ophthalmol Vis Sci. 2001;42:3331-3336. tient’s VA improved to 20/30 OU. The or optic tract disease that is causing macular deposits had diminished the visual loss rather than the pat- (Figure 1E and F), with a correspond- tern dystrophy. Macular abnormali- ing reduction in autofluorescence ties have been described in autoso- Autofluorescence Findings (Figure 1G and H). mal dominant spinocerebellar ataxia in Acute Exudative Case 2. A previously well 33-year- type 7 but not previously in FRDA; Polymorphous Vitelliform old woman had sudden onset of bi- thus, this may be a coincidental find- Maculopathy lateral ring scotomas and distortion ing in our patient.3 It is possible that in the right eye following a flulike ill- the pattern dystrophy observed in Acute exudative polymorphous vi- ness and headaches. On first exami- this case could be associated telliform maculopathy is a rare acute nation elsewhere, bilateral RPE de- with a mutation in peripherin/RDS disorder characterized by multifo- tachments were noted. These settled gene,4 the ELOVL4 gene,5 or as-yet- cal, curvilinear or oval, yellow- spontaneously over a month. When unknown genes. white, posterior pole lesions with vi- referred to our service 9 months later, The cause of optic atrophy in sion loss and preceding headaches.1 she had photophobia and difficulty FRDA is unknown, but it occurs more These retinal pigment epithelial adapting to dark. Her VA was 20/16 frequently in patients with larger GAA (RPE) lesions are associated with bi- OU. A pale white curvilinear lesion repeats and also more frequently in lateral serous detachments and appeared at each macula, with mul- compound heterozygotes than ho- evolve into deposits resembling tiple yellow circular lesions around mozygotes.2 Furthermore, optic neu- those of Best disease. During subse- the posterior pole that were brightly ropathy emerges late in the course of quent weeks, patients experience autofluorescent (Figure 2A and B). disease and may be more frequent in gradual recovery of vision.1 Optical The pattern ERG results were nor- compound heterozygotes who tend to coherence tomography2,3 and in- mal, in keeping with normal macu- survive longer. Optic atrophy is a het- docyanine green angiography4 find- lar function. The full-field ERG and erogeneous disorder often caused by ings have been described. To date, electro-oculogram results were nor- inherited or acquired abnormalities of 7 cases have been reported in the lit- mal bilaterally. There was partial reso- mitochondrial function. Further in- erature. The main aim of the cur- lution of the lesions on color photo- vestigation of the molecular mecha- rent study was to ascertain the na- graphs and confocal scanning laser nisms causing FRDA in compound ture of the posterior pole lesions ophthalmoscopy over 2 years heterozygotes may provide impor- using autofluorescence imaging in (Figure 2C and D).

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C D

E F D

Figure 2. From the first examination of case 2, fundus photograph (A) and autofluorescence image (B) of the right eye. From 2 years later, fundus photograph (C) and autofluorescence image (D) of the right eye. G H optical coherence tomography. Fluo- rescein angiography (Figure 3A) showed early hyperfluorescence. In- vestigations were directed toward posterior scleritis, and results of a workup for systemic immune- mediated diseases were unremark- able other than a borderline-raised C-reactive protein level (11 mg/L). The patient was treated conserva- tively. On review in our service 15 Figure 1. From the first examination of case 1, fundus photographs of the right (A) and left (B) eyes and months later, he reported fluctuat- autofluorescence images of the right (C) and left (D) eyes. From 6 months later, fundus photographs of ing central vision, photophobia, and the right (E) and left (F) eyes showing reduction of the yellow-white deposits. Autofluorescence images of slow dark adaptation. His VA was the right (G) and left (H) eyes show a corresponding reduction. 20/40 OD and 20/60 OS. Multilobu- Case 3. A previously well 38-year- drome. His VA was 20/80 OD and lar white-yellow lesions involving old man awoke one morning with a 20/125 OS when first seen else- each macula appeared and ex- sudden decrease in central vision in where. Some macular subretinal tended beyond temporal arcades both eyes and no recollected pro- fluid was noted and confirmed by (Figure 4A and B). Fluorescein an-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 giography (Figure 3B) showed com- A B plete resolution of all of the hyper- fluorescent lesions. The yellow deposits were nonfluorescent. Four months later, his VA was 20/20 OU with gravitation of the lesions infe- riorly (Figure 4C and D). All of the lesions were brightly autofluorescent (Figure 4E and F). Optical coherence tomography of the right eye showed anterior displacement of the RPE and photoreceptors overlying Figure 3. For case 3, early-phase fluorescein angiogram images of the right eye at the first examination a hyporeflective space adjacent to the (A) and 14 months later (B). hyperreflective deposit (Figure 4G). Pattern and full-field ERG revealed A B no abnormality; the electro- oculogram light rise was borderline on the right (170%) and normal on the left (185%).

Comment. The pathogenesis of acute exudative polymorphous vitelliform maculopathy is still unclear, but an inflammatory and immune- mediated cause has been proposed on the basis of associations with preceding viral illness and apparent ste- roid responsiveness.1 Dysfunction of C D the RPE initiated by different stimuli might explain the overload in lipofuscin. It has also been suggested that an inflammatory involvement of the inner choroid and RPE might result in leakage, causing the exudative detachments.4 Indocyanine green angiography findings in the acute phase have demonstrated choriocapillaris involvement and an affinity for the dye within the lesions thought to consist of inflammatory exudates.4

E F Hyporeflective spaces overlying the RPE, possibly corresponding to serous fluid beneath the yellow deposits, have been documented with optical coherence tomography.2,3 These spaces resolve in conjunc- tion with diminution of the deposits and visual improvement3 corre- lating with the reestablishment of the normal RPE-photoreceptor complex anatomy. Autofluorescence intensity has been found to parallel the amount and distribution of lipofuscin.8 The cur- G H rent data support previous sugges- tions that the yellow deposits in acute exudative polymorphous vitelliform maculopathy contain lipofuscin.1,2 Ac- cumulation may result from im- Figure 4. For case 3, fundus photographs taken at our institution 14 months after the first examination in the right (A) and left (B) eyes, fundus photographs taken 18 months later in the right (C) and left (D) paired function of the RPE and its ini- eyes, and autofluorescence images of the right (E) and left (F) eyes and optical coherence tomographic tial failure to clear the increased images of the right (G) and left (H) eyes 16 months later. lipofuscin load or abnormally high

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 outer-segment turnover. Spontane- maculopathy and may further the un- gland, for providing his first and ous clinical resolution suggests ac- derstanding of its pathophysiology. original fluorescein angiograph. tive RPE phagocytosis. It is notable 1. Gass JDM, Chuang EL, Granek H. Acute exu- that previous articles1,4 have de- Veronika Vaclavik, MD Kenneth G.-J. Ooi, MSurg (Ophth) dative polymorphous vitelliform maculopathy. scribed more severely abnormal elec- Trans Am Ophthalmol Soc. 1988;86:354-366. tro-oculogram results, possibly at a Alan C. Bird, MD 2. Chan CK, Gass JDM, Lin SG. Acute exudative Anthony G. Robson, PhD polymorphous vitelliform maculopathy different or earlier stage of recovery; syndrome. Retina. 2003;23:453-462. we have no other explanation for the Graham E. Holder, PhD 3. Cruz-Villegas V, Villate N, Knighton RW, Rub- Andrew R. Webster, MD samen P, Davis JL. Optical coherence tomo- apparent discrepancy. Previous stud- graphic findings in acute exudative polymor- ies have failed to show mutations in phous vitelliform maculopathy. Am J Ophthalmol. Correspondence: Dr Vaclavik, 2003;136:760-763. the VMD2 or RDS genes in affected Division of Molecular Genetics, 4. Vianna RNG, Muralha A, Muralha L. Indocya- patients that can be causative of in- Institute of Ophthalmology, Uni- nine-green angiography in acute idiopathic exu- herited Best maculopathy and adult dative polymorphous vitelliform maculopathy. versity College London, 11-43 Bath Retina. 2003;23:538-541. 2,3 vitelliform macular dystrophy. This St, London EC1V 9EL, England 5. Von Ru¨ ckmann A, Fitzke FW, Bird AC. Distri- is in keeping with the absence of a bution of pigment epithelium autofluorescence ([email protected]). in retinal disease state recorded in vivo and its family history in our patients and Financial Disclosure: None re- change over time. Graefes Arch Clin Exp those previously described. In addi- ported. Ophthalmol. 1999;237:1-9. 6. Bach M, Hawlina M, Holder GE, et al. Standard tion, the normal ERG results in case Acknowledgment: We would like to for pattern electroretinography. Doc Ophthalmol. 3 precluded a diagnosis of Vogt- acknowledge the contribution of 2000;101:11-18. Koyanagi-Harada or paraneoplastic Arthur Fu, MD, to the identifica- 7. Marmor MF, Holder GE, Seeliger MW, Yama- moto S. Standard for clinical electroretinogra- syndrome. Autofluorescence imag- tion of the third case in this series, phy (2004 update). Doc Ophthalmol. 2004;108: ing is likely to be of help in the diag- and Tom R. G. Poole, FRCOphth, 107-114. 8. Marmor MF, Zrenner E. Standard for clinical nosis and monitoring of acute exu- Department of Ophthalmology, electro-oculography. Doc Ophthalmol. 1993; dative polymorphous vitelliform Frimley Park Hospital, Surrey, En- 85:115-124.

Correction

Error in Figure. In the Laboratory Sciences article by Kuiper et al titled “Association of Connective Tissue Growth Factor With Fibrosis in Vitreoretinal Disorders in the Human Eye,” published in the October issue of the ARCHIVES (2006;124: 1457-1462), some errors occurred in Figure 2. The figure is reprinted correctly as follows. We regret the error.

140

120

100

CTGF, ng/mL CTGF, 60

0123 0123 0123 0123 Macular Hole Macular Pucker Retinal Detachment PDR With or Without PVR

Primary Diagnosis and Degree of Fibrosis

Figure 2. Connective tissue growth factor (CTGF) levels in relation to primary diagnosis and degree of fibrosis. The horizontal bars represent the geometric mean CTGF levels for each category. PDR indicates proliferative diabetic retinopathy; PVR, proliferative vitreoretinopathy.

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