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Show Original Contribution Retinal Neuronal Loss in Visually Asymptomatic Patients With Myoclonic Epilepsy With Ragged-Red Fibers Raymond P. Najjar, PhD, Pascal Reynier, MD, PhD, Angélique Caignard, MD, Vincent Procaccio, MD, PhD, Patrizia Amati-Bonneau, MD, Heather Mack, MD, Dan Milea, MD, PhD Background: Myoclonic epilepsy with ragged-red fibers (MERRF, OMIM, #545000) is a rare neurological condition mostly caused by the m.8344A.G mitochondrial DNA pathogenic variant, which can variably affect multiple tissues, including the retina and optic nerve. We report detection of visually asymptomatic neuroretinal loss in 3 patients with genetically confirmed MERRF, using spectral domain optical coherence tomography (SD-OCT). Methods: All patients underwent a complete ophthalmic examination including assessments of visual acuity, color vision, pupillary reactions, extraocular movements, applanation tonometry, slit-lamp, and dilated fundus examinations. Standard automated perimetry or Goldmann kinetic perimetry was performed, as well as fundus photographs and SD-OCT of the optic nerve head and macula. Results: Despite the absence of visual symptoms in all patients, and normal visual acuity and visual fields in 1 patient, the 3 genetically confirmed patients (point mutations m.8344A.G; age range: 18-62 years) with MERRFrelated neurological manifestations, displayed thinning of the retinal nerve fiber layer and variable alterations of the macular ganglion cell complex. Conclusions: Visually asymptomatic patients with genetically confirmed MERRF can display features of structural neuroretinal loss, quantifiable with SD-OCT. Further inves- Department of Visual Neurosciences (RPN, DM), Singapore Eye Research Institute, The Academia, Singapore; Ophthalmology and Visual Sciences Program (RPN, DM), Duke-NUS Medical School, Singapore; Departments of Ophthalmology, Biochemistry and Genetics (PR, AC, VP, PA-B and DM), Angers University Hospital, Angers, France; Department of Neuro-Ophthalmology (DM), Singapore National Eye Centre, Singapore; and Department of Surgery (Ophthalmology) (HM), Melbourne Medical School, University of Melbourne, Melbourne, Australia. tigations are needed to establish whether OCT can assess early neurodegeneration in MERRF. Journal of Neuro-Ophthalmology 2019;39:18-22 doi: 10.1097/WNO.0000000000000690 © 2018 by North American Neuro-Ophthalmology Society M yoclonic epilepsy with ragged-red fibers (MERRF, OMIM, #545000) is a rare neurological and multisystem disorder, associated with mitochondrial DNA pathogenic variants, the most common being the m.8344A.G change in the MTTK gene encoding the transfer RNA for lysine (1). Patients with MERRF typically present during adolescence or early adulthood with myoclonus, epilepsy, and ataxia, often associated with other manifestations, such as myopathy, cognitive impairment, heart conduction deficit, diabetes, myalgia, hearing loss, and ragged-red fibers on muscle biopsy reflecting mitochondrial damage (1). Various degrees of penetrance and severity of the condition have been reported, ranging from asymptomatic to severe, life-threatening deficits. Sensory impairment including hearing loss, peripheral neuropathy, and visual loss due to optic atrophy and/or retinal dystrophy may occur in MERRF (2), yet ophthalmic involvement in the disease has not yet been thoroughly evaluated using modern retinal imaging techniques. This scarce information is surprising, given the high propensity of mitochondrial conditions to affect the visual system (3) and the increasing efficiency of retinal imaging to assess such neurodegenerative changes (4). The aim of our study was to evaluate occurrence of structural neuroretinal abnormalities in visually asymptomatic patients with genetically confirmed MERRF. The authors report no conflicts of interest. METHODS Address correspondence to Dan Milea, MD, PhD, Visual Neuroscience Group, Singapore Eye Research Institute, The Academia, 20 College Road Discovery Tower Level 6, 169856, Singapore; E-mail: dan.milea@snec.com.sg This study included patients with genetically confirmed MERRF and typical neurological manifestations in the absence of any visual symptoms. Patients were referred to 2 academic 18 Najjar et al: J Neuro-Ophthalmol 2019; 39: 18-22 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution neuro-ophthalmology institutions between September 2009 and November 2016. All patients with MERRF who had symptomatic optic neuropathies or retinopathies, or other causes of visual loss, were excluded. All patients underwent a comprehensive ophthalmic examination, including refraction and assessment of best-corrected visual acuity (VA) (LogMAR chart; Lighthouse Int, NY), color vision (Ishihara plates; Kanechara & Co, Tokyo, Japan), pupillary reactions, extraocular movements, intraocular pressure (Goldmann applanation tonometry), and slit-lamp and fundus examinations. Standard automated perimetry (Car Zeiss Meditec, Dublin, CA) or Goldmann kinetic perimetry was performed in each patient; fundus photographs and spectral domain optical coherence tomography (SD-OCT) (Cirrus HD-OCT; Carl Zeiss Meditec) of the optic nerve and macula were obtained. The study received the local ethical committee approval and was conducted in agreement with the tenants of Helsinki convention. RESULTS Patient 1 An 18-year-old man of Chinese origin with a family history compatible with MERRF was referred for ophthalmic examination. The patient's medical history disclosed epilepsy for the past 4 years, treated with levetiracetam and ubidecarenone. Molecular diagnosis of MERRF was confirmed by the identification of the m.8344A.G pathogenic variant with a mutation rate of 65% in blood. The patient had no visual complaints, and his neurological examination was unremarkable. VA was 20/25 in the right eye and 20/20 in the left eye. Color vision testing was normal, whereas automated visual fields showed mild depression bilaterally (Fig. 1A). Both optic discs appeared pale (Fig. 1B) and SD-OCT disclosed bilateral peripapillary retinal nerve fiber layer (RNFL) thinning (Fig. 1C), associated with diffuse thinning of the macular ganglion cell-inner plexiform layer (GC-IPL) (Fig. 2). An extensive workup could not identify any glaucomatous, compressive, inflammatory, or nutritional/toxic cause of optic neuropathy. Patient 2 A 62-year-old white woman with a personal and family history of genetically confirmed MERRF (point mutation m.8344A.G identified on muscle biopsy) was referred for ophthalmic evaluation. Her neurological symptoms included myoclonus and severe ataxia for the past 2 decades, treated with levocarnitine and levetiracetam. No other systemic involvement was noted. The patient was visually FIG. 1. Patient 1. A. Automated visual fields show mild field loss in both eyes. Bilateral optic disc pallor is present (B) along with global thinning of the peripapillary RNFL (C). OD, right eye; OS, left eye; RNFL, retinal nerve fiber layer. Najjar et al: J Neuro-Ophthalmol 2019; 39: 18-22 19 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Patient 1. Fovea-centered OCT of the macular cube (512 · 128) with automatic segmentation and color-coded thickness and deviation maps of the combined ganglion cell-inner plexiform layers (GC-IPLs). The scans showed a bilateral diffuse thinning of the GC-IPL. GCL, ganglion cell layer; IPL, inner plexiform layer; OCT, optical coherence tomography; OD, right eye; OS, left eye. FIG. 3. Patient 2. A. Kinetic visual fields demonstrate mild constriction of central isopter. Both optic discs are pale, especially temporally (B), and OCT reveals bilateral thinning of the peripapillary RNFL (C). OCT, optical coherence tomography; OD, right eye; OS, left eye; RNFL, retinal nerve fiber layer. 20 Najjar et al: J Neuro-Ophthalmol 2019; 39: 18-22 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Patient 3. A. Automated visual fields are normal. There is mild bilateral temporal optic disc pallor (B) and matching bilateral thinning of the temporal RNFL (C). OD, right eye; OS, left eye; RNFL, retinal nerve fiber layer. FIG. 5. Patient 3. Fovea-centered OCT of the macular cube (512 · 128) with automatic segmentation and color-coded thickness and deviation maps of the ganglion cell layer (GCL). Macular GCL thickness was minimally reduced in the nasal sectors of the left eye and within normal limits in the right eye. OCT, optical coherence tomography; OD, right eye; OS, left eye. Najjar et al: J Neuro-Ophthalmol 2019; 39: 18-22 21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution asymptomatic, and her VA was 20/25 in both eyes, with normal color vision, full extraocular movements, and no ptosis. Examination of the other cranial nerves was normal. Kinetic perimetry revealed mild constriction of the central isopter (Fig. 3A) and funduscopy showed bilateral optic disc pallor (Fig. 3B). There was global thinning of the peripapillary RNFL (Fig. 3C). No other causes of optic neuropathy could be identified on subsequent workup. Patient 3 A 40-year-old white man with genetically confirmed MERRF (m.8344A.G pathogenic variant with a mutation rate of 55% in blood and 63% in urine) had a complete ophthalmic examination. His medical history included epilepsy, myoclonus, and ataxia for more than a decade, being treated with levocarnitine and ubidecarenone. The patient had no visual symptoms. VA was 20/20 in each eye, color vision and eye movements were normal. Automated perimetry was unremarkable (Fig. 4A), yet funduscopy disclosed bilateral temporal optic disc pallor (Fig. 4B) that matched a bilateral temporal thinning of the peripapillary RNFL on SD-OCT (Fig. 4C). The macular ganglion cell layer (GCL) thickness was minimally affected in the nasal region of the left eye (Fig. 5). No other causes of optic neuropathy could be identified. DISCUSSION In our study, we found that 3 visually asymptomatic patients with genetically confirmed MERRF had neuroretinal abnormalities affecting the RNFL and the macular ganglion cell complex. Previous reports of patients with MERRF have included optic neuropathy or retinopathy as a cause of visual loss (1-3,5-7). The prevalence of MERRF-associated optic neuropathy is variable, ranging from 10% (8) to 39% (3). However, the ophthalmic details in these case series are limited (6). Gronlund et al (6) found partial or total "optic atrophy" in 6 of 7 patients with MERRF, but interestingly, severe visual loss was reported only in 2 of them. By contrast, another study did not mention the presence of optic neuropathy among 34 patients with MERRF (1). To the best of our knowledge, neuroretinal involvement using OCT has not yet been quantitatively evaluated in patients with MERRF. None of our 3 patients had visual symptoms, yet 2 patients exhibited mild VA and field loss. However, on OCT, all 3 displayed RNFL and ganglion cell loss consistent with subclinical optic neuropathy. In Patient 1, there was GC-IPL loss associated with RNFL thinning, whereas in Patient 3, there was relative sparing of the 22 macular GCL, especially in the right eye, despite bilateral temporal thinning of the peripapillary RNFL. In conclusion, MERRF can be associated with retinal abnormalities detectable with OCT in visually asymptomatic patients. Further studies are needed to understand whether these abnormalities represent potential biomarkers of neuroretinal degeneration, or early subclinical signs of an optic neuropathy. Meanwhile, we suggest that a thorough ophthalmic examination, including OCT, may be indicated in patients with suspected or confirmed MERRF. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: D. Milea and P. Reynier; b. Acquisition of data: D. Milea, P. Reynier, A. Caignard, V. Procaccio, and H. Mack; c. Analysis and interpretation of data: R. P. Najjar, D. Milea, P. Reynier, H. Mack, P. Amati-Bonneau, and V. Procaccio. Category 2: a. Drafting the manuscript: R. P. Najjar and D. Milea; b. Revising it for intellectual content: R. P. Najjar, D. Milea, P. Reynier, H. Mack, A. Caignard, V. Procaccio, and P. Amati-Bonneau. Category 3: a. Final approval of the completed manuscript: R. P. Najjar, D. Milea, P. Reynier, H. Mack, A. Caignard, V. Procaccio, and P. AmatiBonneau. REFERENCES 1. Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, et al. Phenotypic heterogeneity of the 8344A.G mtDNA "MERRF" mutation. 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Ophthalmological findings in children and young adults with genetically verified mitochondrial disease. Br J Ophthalmol. 2010;94:121-127. 7. Zhu CC, Traboulsi EI, Parikh S. Ophthalmological findings in 74 patients with mitochondrial disease. Ophthalmic Genet. 2017;38:67-69. 8. Altmann J, Buchner B, Nadaj-Pakleza A, Schafer J, Jackson S, Lehmann D, Deschauer M, Kopajtich R, Lautenschlager R, Kuhn KA, Karle K, Schols L, Schulz JB, Weis J, Prokisch H. Expanded phenotypic spectrum of the m.8344A.G "MERRF" mutation: data from the German mitoNET registry. J Neurol. 2016;263:1452-1453. Najjar et al: J Neuro-Ophthalmol 2019; 39: 18-22 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
