摘要
The point mutation in mitochondrial DNA (mtDNA) 3243A→G is associated with many clinical disorders such as MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes) and MIDD (maternally inherited diabetes and deafness).1Sproule D.M. Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome.Ann N Y Acad Sci. 2008; 1142: 133-158Crossref PubMed Scopus (246) Google Scholar MELAS is characterized by strokelike episodes with headache, episodic nausea and vomiting, and lactic acidosis. Other findings include renal failure, neurosensory hearing loss, diabetes mellitus, and short stature.1Sproule D.M. Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome.Ann N Y Acad Sci. 2008; 1142: 133-158Crossref PubMed Scopus (246) Google Scholar Ocular findings include pigmentary retinopathy, retinal pigment epithelial (RPE) atrophy, posterior subcapsular cataract, external ophthalmoplegia, and ptosis.2Daruich A. Matet A. Borruat F.X. Macular dystrophy associated with the mitochondrial DNA A3243G mutation: pericentral pigment deposits or atrophy? Report of two cases and review of the literature.BMC Ophthalmol. 2014; 14: 77Crossref PubMed Scopus (42) Google Scholar, 3Rath P.P. Jenkins S. Michaelides M. et al.Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence.Br J Ophthalmol. 2008; 92: 623-629Crossref PubMed Scopus (38) Google Scholar In this study, we describe spectral-domain optical coherence tomography (SD-OCT) findings seen in MELAS. A 40-year-old female was referred for evaluation of progressive visual loss and pigmentary retinopathy. Medical history was significant for insulin-dependent diabetes mellitus, neurosensory deafness, short stature, and kidney transplant. Laboratory work-up revealed elevated lactic acid and mutation A>G 3243 mtDNA with 19% heteroplasmy in peripheral blood. A diagnosis of MELAS was made. Best corrected visual acuity was counting fingers OD and 6/21 OS. Funduscopy of both eyes revealed RPE atrophy around the optic nerve (ON) and in the macular area, and pigmentary retinopathy temporal to the macula, outside the vascular arcades and nasal to the ON (Figs. 1A and 2A). Hypoautofluorescence corresponding to areas of RPE atrophy was seen in both eyes. In the normal-looking retina, flecks of hyperautofluorescence and hypoautofluorescence were seen (Figs. 1B, 1C, and 2B). Full-field electroretinogram and electroculogram were normal in both eyes. In areas of RPE atrophy, SD-OCT revealed circular and ovoid structures with hyperreflective borders surrounding a central lumen compatible with outer retinal tubulations (ORTs). A hyperreflective content was seen in the ORTs lumen (Figs. 1D, 1E, and 2D). In addition, a hyperreflective cloud was identified just temporal to the fovea of the right eye (Fig. 1E). SD-OCT of the macular area outside the zone of RPE atrophy revealed loss of outer nuclear layer (ONL), attenuation of the ellipsoid zone (EZ) (Figs. 1D, 2D, and 2E), and hyperreflective material at the level of the RPE (Fig. 2C). SD-OCT of more peripheral areas revealed relative preservation of ONL and EZ (Fig. 2E).Fig. 2Colour fundus photo showing retinal pigment epithelial (RPE) atrophy around the optic nerve and extending into the macular area (A). Fundus autofluorescence showing decreased autofluorescence in areas of RPE atrophy. Punctate increased autofluorescence seen within areas of RPE atrophy may represent residual islands of RPE. Flecks of increased and decreased autofluorescence are seen in the relatively normal-looking retina outside the RPE atrophy (B). Vertical spectral-domain optical coherence tomography (SD-OCT) scan temporal to the macula showing dome-shaped hyperreflective lesions at the level of the RPE (yellow arrows) (C). Horizontal SD-OCT scan in the macular area showing outer retinal tubulations with outer hyperreflective band delimiting lumen with heterogeneous hyperreflective content (white arrows). Loss of outer nuclear layer (ONL) (red arrow) and ellipsoid zone (EZ) attenuation (blue arrow) are seen in the normal-looking retina outside the RPE atrophy (D). Horizontal SD-OCT scan close to the inferotemporal arcade showing a transition from areas of ONL loss (red arrow) and EZ attenuation (blue arrow) to areas of more preserved ONL (orange arrow) and EZ (green arrow) (E).View Large Image Figure ViewerDownload (PPT) Histopathologic studies in patients with MELAS have shown hyperpigmentation and atrophy of the retinal pigment epithelium.4Chang T.S. Johns D.R. Walker D. de la Cruz Z. Maumence I.H. Green W.R. Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.Arch Ophthalmol. 1993; 111: 1254-1262Crossref PubMed Scopus (67) Google Scholar, 5Rummelt V. Folberg R. Ionasescu V. Yi H. Moore K.C. Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation.Ophthalmology. 1993; 100: 1757-1766Abstract Full Text PDF PubMed Scopus (61) Google Scholar In this study, we described hyperreflective lesions at the level of the RPE that corresponded clinically to pigment deposits (Fig. 2C). In addition, RPE atrophy was seen around the ON and extending to the macular area (Figs. 1A–C, 2A, and 2B). No obvious choroidal atrophy was seen. A previous study in patients with MELAS showed hyperreflective dome-shaped lesions in areas of pigment deposits, in addition to areas of chorioretinal atrophy.2Daruich A. Matet A. Borruat F.X. Macular dystrophy associated with the mitochondrial DNA A3243G mutation: pericentral pigment deposits or atrophy? Report of two cases and review of the literature.BMC Ophthalmol. 2014; 14: 77Crossref PubMed Scopus (42) Google Scholar In our study using SD-OCT, ORTs were seen within areas of outer retina and RPE atrophy close to residual islands of surviving photoreceptors/RPE and at the edge of preserved and disrupted retina (Figs. 1D, 1E, and 2D). ORTs have been described in many retinal degenerative diseases including 2 patients with MIDD.6Goldberg N.R. Greenberg J.P. Laud K. Tsang S. Freund K.B. Outer retinal tubulation in degenerative retinal disorders.Retina. 2013; 33: 1871-1876Crossref PubMed Scopus (83) Google Scholar Histopathologic studies of MELAS have shown that photoreceptor layer loss occurs in the macula, with photoreceptor preservation toward the retinal periphery.4Chang T.S. Johns D.R. Walker D. de la Cruz Z. Maumence I.H. Green W.R. Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.Arch Ophthalmol. 1993; 111: 1254-1262Crossref PubMed Scopus (67) Google Scholar In this study, SD-OCT of macular areas outside the zone of RPE atrophy showed ONL loss and EZ attenuation (Figs. 1D, 2D, and 2E). Away from the macula, a transition zone was observed from areas of ONL loss and EZ attenuation to areas of relative ONL and EZ preservation (Fig. 2E). This corroborates the histopathology findings. Histologic studies of patients with advanced age-related macular degeneration characterized ORTs by circular or ovoid tubes formed by degenerated photoreceptors and enveloping Muller cells in areas of severely disrupted or absent RPE.7Schaal K.B. Freund K.B. Litts K.M. Zhang Y. Messinger J.D. Curcio C.A. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology.Retina. 2015; 35: 1339-1350Crossref PubMed Scopus (92) Google Scholar Immunohistochemistry and transmission electron microscopy studies have shown that cones are the main photoreceptor of macular ORTs.7Schaal K.B. Freund K.B. Litts K.M. Zhang Y. Messinger J.D. Curcio C.A. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology.Retina. 2015; 35: 1339-1350Crossref PubMed Scopus (92) Google Scholar, 8Curcio C.A. Medeiros N.E. Millican C.L. Photoreceptor loss in age-related macular degeneration.Invest Ophthalmol Vis Sci. 1996; 37: 1236-1249PubMed Google Scholar The ORT lumen is delimited by external limiting membrane (ELM) and may contain degenerated RPE and non-RPE cells.7Schaal K.B. Freund K.B. Litts K.M. Zhang Y. Messinger J.D. Curcio C.A. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology.Retina. 2015; 35: 1339-1350Crossref PubMed Scopus (92) Google Scholar In SD-OCT, this may, at least in part, explain the heterogeneous hyperreflective content seen in ORTs (Figs. 1D, 1E, and 2D). The outer hyperreflective band around the lumen may correspond to ELM and inner segment ellipsoid mitochondria.7Schaal K.B. Freund K.B. Litts K.M. Zhang Y. Messinger J.D. Curcio C.A. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology.Retina. 2015; 35: 1339-1350Crossref PubMed Scopus (92) Google Scholar The hyperreflective cloud (Fig. 1E) may represent spheroid cones at the edge of an ORT.7Schaal K.B. Freund K.B. Litts K.M. Zhang Y. Messinger J.D. Curcio C.A. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology.Retina. 2015; 35: 1339-1350Crossref PubMed Scopus (92) Google Scholar In summary, SD-OCT demonstrated ORTs within areas of RPE atrophy in patients with MELAS. This finding is seen in other degenerative diseases with significant RPE and outer retinal damage.6Goldberg N.R. Greenberg J.P. Laud K. Tsang S. Freund K.B. Outer retinal tubulation in degenerative retinal disorders.Retina. 2013; 33: 1871-1876Crossref PubMed Scopus (83) Google Scholar ONL loss and EZ attenuation present in normal-looking retinal areas may precede RPE loss and ORT formation.