- Email: [email protected]
Beyond what the eye can see
Accepted Manuscript Beyond what the eye can see Kate E. Ahmad, FRACP, Clare L. Fraser, FRANZCO, Carolyn M. Sue, FRACP, Jason J.S. Barton, MD PhD FRCPC PII:
S0039-6257(15)30055-2
DOI:
10.1016/j.survophthal.2016.02.003
Reference:
SOP 6621
To appear in:
Survey of Ophthalmology
Received Date: 30 October 2015 Revised Date:
15 February 2016
Accepted Date: 18 February 2016
Please cite this article as: Ahmad KE, Fraser CL, Sue CM, Barton JJS, Beyond what the eye can see, Survey of Ophthalmology (2016), doi: 10.1016/j.survophthal.2016.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title: Beyond what the eye can see Kate E Ahmad FRACP1 Clare L Fraser FRANZCO2 Carolyn M Sue FRACP3
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Jason J S Barton MD PhD FRCPC4 Department of Neurology, Royal North Shore Hospital, Sydney, Australia.
2
Save Sight Institute, University of Sydney, Australia
3
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Department of Neurogenetics, Kolling Institute for Medical Research, Sydney, Australia.
4
Departments of Medicine (Neurology), Ophthalmology and Visual Sciences, Psychology, University
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of British Columbia, Vancouver, Canada
Corresponding author: Kate Ahmad, Department of Neurology, Clinical Area 3E, Royal North Shore Hospital, St Leonards, NSW 2065.
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Email: [email protected]
ACCEPTED MANUSCRIPT (In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
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A 45-year-old woman woman presented with a 4-week history of visual loss. She described an initial central scotoma and color desaturation in her left eye. Over several days her peripheral vision became involved. Two weeks after onset, she noted similar symptoms in her right eye, which also progressed to severe visual loss. There was no associated eye pain, headache, or systemic symptoms.
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She had a history of chronic kidney disease, diabetes mellitus, hearing loss, and preeclampsia. Pre-eclampsia had developed during all three of her pregnancies and resulted in one stillborn child and two premature deliveries. The pre-eclampsia was presumed to have resulted in chronic kidney disease. Diabetes had been diagnosed 8 years prior to presentation and the patient had moderate to poor blood sugar control with oral hypoglycemics. Sensorineural hearing loss occurred suddenly and simultaneously 7 years ago, with no recovery. Investigations at the time failed to reveal an underlying cause. Social history was unremarkable; she did not drink alcohol or smoke cigarettes. She denied illicit drug use or recent vaccination. She was a stay at home mother to her two teenage children.
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Family history was relevant for late onset diabetes mellitus in her mother and maternal grandmother. Her mother had congenital hypoplasia of the left side of the body, which had included left sided hearing loss. This was attributed to an intrauterine injury.
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Initial examination revealed best corrected visual acuities of 6/60, N24 in the right eye, and count fingers at 1 meter in the left eye. There was a left relative afferent pupillary defect. There was no evidence of ocular inflammation. Funduscopy revealed widespread granularity of the retina. There were no abnormalities of the optic disks. Fluorescein angiography was unremarkable (Fig.1).
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What is the differential diagnosis of the visual loss, and how would you proceed? Comments Comments by Jason J S Barton, MD, PhD, FRCPC Acute bilateral visual loss has a fairly long list of possibilities, ranging all the way from the retina to striate cortex. The fact that this was sequential, with one eye affected before the other, is helpful: it excludes retrochiasmal lesions, which if sequential would affect one hemifield before the other instead. Hence the main possibilities are bilateral retinopathy or optic neuropathy. Could this be bilateral inflammatory retinopathy? Young women in particular are vulnerable to an array of retinal disorders known by their acronyms: AZOOR, PIC, ARPE, AMPPE, MEWDS and so on. These generally present in similar subacute fashion, can affect visual acuity, and some have a tendency to bilateral involvement. However, most have characteristic white spots or other lesions on funduscopy and abnormalities on fluorescein
ACCEPTED MANUSCRIPT angiography. Acute idiopathic blind spot enlargement syndrome and MEWDS (multiple evanescent white dot syndrome) can have ‘granularity’, though usually limited to the macula and evolving in later stages.10,33 The widespread nature of the granular changes mentioned here sounds different.
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Bilateral sequential optic neuritis is a possibility. Somewhat atypical is the lack of pain. In the Optic Neuritis Treatment Trial, 92% of patients had pain, and in 87% it was worse or only present with eye movement.1 Nevertheless, common things being common, this has to be a leading candidate. While bilateral sequential involvement can occur with multiple sclerosis, this should always raise suspicion for neuromyelitis optica, especially if the patient is Asian.
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Infectious causes of inflammatory optic neuropathy are more unusual, but can present bilaterally in a subacute fashion as well. Aspergillus and mucormycosis are fungal infections that involve the sinuses: these occur more frequently in patients with diabetes or other conditions that compromise the immune system. Syphilis, lyme disease and bartonella are also important to consider, particularly if there are retinal exudates – the so-called macula star. Tuberculosis can cause a granulomatous basal meningitis that can affect both optic nerves. Bilateral acute sequential visual loss can occur with anterior ischemic optic neuropathy, for which diabetes and hypertension are risk factors3; however, disk edema should be evident and only in a minority does visual loss progress over the days after onset. Posterior ischemic optic neuropathy is far less common and occurs primarily in the setting of giant cell arteritis, for which she is too young, or severe prolonged hypotension, often in the perioperative state.3,12
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We are not told her medications, but we can infer from her past history that she is probably not taking ethambutol or amiodarone. Methanol is a cause of acute bilateral optic neuropathy, but usually with disk edema, other features including vomiting, abdominal pain and drowsiness, and probably not a delay of 2 weeks between the first and the second eye.27
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She has no history of craniofacial trauma. Compression by tumors tends to be unilateral, and would present more gradually unless there was hemorrhage into the tumour. Pituitary apoplexy is one mechanism of sudden visual loss that could be bilateral. Often there are severe headaches and ocular motility defects, though.32 Infiltration of the nerves by meningeal metastases can cause this picture also. Does her past history give us any clues? She has diabetes, as does her mother and maternal grandmother. She and her mother also have deafness. This could point to the maternally inherited diabetes and deafness (MIDD) syndrome, which is associated with the mitochondrial mutation usually associated with MELAS21; however, MIDD is associated with a characteristic macular pattern dystrophy rather than retinal granularity or optic neuropathy.19,22 Macular pattern dystrophy is easily seen on funduscopy and visual loss is usually minimal or slowly progressive, which is not the clinical picture here. Wolfram syndrome is an autosomal recessive condition that also groups some of her diverse problems. It is also known by the acronym DIDMOAD, for diabetes insipidus, juvenile-onset diabetes mellitus, optic atrophy, and deafness.9 It can also be associated with renal abnormalities; however, it usually manifests earlier in life, and visual dysfunction is gradual rather than sudden.
ACCEPTED MANUSCRIPT Sudden bilateral deafness is itself an interesting problem. It is a recognized complication of diabetes, and the risk doubles if there is renal insufficiency.6,17 This is usually attributed to microvascular ischemia. If so, this would increase her risk for similar ischemia to the optic nerves. Again, though, this should have created disk edema. Finally, as stated above, diabetes also increases the risk of mucormycosis.
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Our first step in investigation has to be neuroimaging, preferably MRI orbit and sella, with and without contrast. I would also consider adding MRI of the spine while she is in the machine, given the possibility of neuromyelitis optica: however, a neurologic examination for signs of myelopathy would be an even better idea first. On review of the imaging I would look for sinus disease that might have spread to the orbit, and consult otolaryngology if this were found. If imaging is negative, a cerebrospinal fluid analysis looking for inflammation, infection and neoplasia should follow, keeping in mind that cytology has a sensitivity of only 50%.
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Case Report (Continued) The presentation was thought to be representative of a bilateral, sequential optic neuropathy. An inflammatory cause was initially suspected and the patient was admitted for investigation and management. MRI brain and orbits showed increased signal in both the intraconal and intracanicular portions of the optic nerves. These changes extended back to the optic chiasm and tracts (Fig.2). There were no other MRI abnormalities. CSF analysis showed normal cell count, glucose, cytology and no oligoclonal bands. Protein was mildly elevated at 0.64g/L. Testing for syphilis and HIV was negative, and autoimmune serology including NMO-IgG and antiphospholipid antibodies, was negative. During the investigative phase, she was empirically treated with 5 days of intravenous methylprednisolone, but her vision continued to deteriorate. Are there any other further investigations that may be useful? Would you consider any further treatment options? Comments (Continued)
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Comments by Dr Barton
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The MRI at least confirms that this is optic neuropathy and not a retinopathy. The fairly extensive signal change is impressive. Older and recent studies show that 20 to 50 mm of signal change is considered a ‘long’ lesion for the optic neuritis associated with multiple sclerosis2,14; the changes here are well beyond that. We are not told if she had gadolinium with her MRI. It would be of interest to know if there is any enhancement, not so much of the optic nerves, but of the basal meninges. Such enhancement would point to granulomatous inflammation such as sarcoidosis or tuberculosis. A chest X-ray, serum ACE, and gallium scan could then be considered; however, failure to respond to steroids is against inflammation, although one might question if five days is enough of a trial for granulomatous disease.
Not all patients with the clinical syndrome of neuromyelitis optica are positive for antiaquaporin-4 antibodies-- the incidence of seronegativity is estimated at 9%20--however, if there is no clinical evidence of myelopathy and the antibody test is negative, the utility of an MRI of her spine would likely be marginal.
ACCEPTED MANUSCRIPT The lack of other abnormalities on MRI is reassuring about some other life-threatening possibilities. MR of the orbits and sella is 91% sensitive for pituitary apoplexy.28 If the orbits and sinuses appear normal on MR, the likelihood of mucormycosis is reduced. Nevertheless, examination of her nasopharynx by an otologist may help definitively exclude this dangerous condition.
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Case Report (Continued) The patient was discharged from hospital with no light perception vision in both eyes, but experienced some minor recovery over the subsequent months, allowing her to see some movement and contrast in the left peripheral field. 18 months later, she sought a second opinion in a tertiary neuro-ophthalmology clinic. At this time, her examination was little changed, but her optic disks now appeared pale with a normal cup to disk ratio. Optical coherence tomography (OCT) confirmed marked thinning of the peripapillary retinal nerve fibre layer. Neurological examination revealed evidence of a length dependent sensorimotor neuropathy.
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The family history of maternally inherited diabetes, combined with the personal history of diabetes, deafness and renal failure raised the possibility of mitochondrial disease. The bilateral sequential optic neuropathy was thought to be in keeping with a Leber hereditary optic neuropathy (LHON) phenotype. The patient went on to be tested for the three primary LHON mutations. None were detected. Would any further genetic testing be appropriate at this point? Comments (Continued) Comments by Dr Barton
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Mutations have been associated with the LHON phenotype, but the commercially available tests only cover the three most frequently found mutations.34 Also, even though the classic presentation is acute bilateral central scotomata in a young man, the advent of genetic testing has shown that women can present similarly, as well as older patients with more progressive bilateral visual loss in the setting of nutritional deficiency and alcohol use - what used to be known as tobacco-alcohol amblyopia.7,16 Optic neuropathy can occur as part of an overlap with other mitochondrial syndromes, so testing for some of those mutations may be of interest also, even if she does not have those other features yet: the m.3376G>A and m.3697G>A mutations are associated with an LHON/MELAS overlap, for example.4,30 The value of this additional testing can be debated – the efficacy of current therapy for mitochondrial disorders remains modest at best.24 Her teen-aged children may have some stake in the results, though, since mitochondrial mutations are inherited from the mother. Her story is not typical of other hereditary optic neuropathies. Kjer autosomal dominant optic atrophy is associated with OPA1 mutations, but the visual loss is rarely if ever this acute or this severe. 29 Wolfram syndrome is due to a mutation in either the WFS1 gene on chromosome 4, which encodes wolframin, a protein involved in endoplasmic reticulum function, or the CISD2 gene for the protein ERIS, also on chromosome 4 and also localized to the endoplasmic reticulum.25 Again, though, this is not the typical clinical picture of Wolfram syndrome. Does the finding of polyneuropathy suggest any specific genetic tests? Hereditary sensorimotor neuropathy (HMSN, also known as Charcot-Marie-Tooth) can be associated with optic neuropathy, particularly HMSN type VI, though the optic neuropathy begins in the
ACCEPTED MANUSCRIPT teens and progresses slowly to blindness.13 Recent work has shown that this is associated with mutations in genes for mitofusin 2 or C12orf65.23,31 There is only one intriguing older case of a patient with Charcot-Marie Tooth disease and sudden unilateral visual loss with a central scotoma and hyperemic optic disk, resembling the typical scenario of LHON.18 It is highly unlikely that our patient has Riley-Day syndrome, a more severe early-onset disorder that can be associated with optic atrophy.
Case Report (Continued)
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In the end, most hereditary optic neuropathies would not fit her clinical scenario of abrupt bilateral visual loss. If one would chase anything, it would be other unusual mitochondrial mutations associated with LHON.
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A referral was made for consideration of further genetic testing. While the three primary LHON mutations account for >90% of cases of LHON, there remain cases where an alternative mitochondrial DNA point mutation is the culprit. In addition, the presence of diabetes and hearing loss is unusual for an uncomplicated LHON case, and it was thought that more extensive testing for mtDNA mutations was warranted. A panel testing for a further 19 mtDNA mutations was ordered. This was positive for the presence of m.13513G>A mutation in both urine and blood.
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Discussion Mutations in mitochondrial DNA are well known for resulting in bilateral, sequential optic neuropathy, usually in the context of LHON. In >90% of LHON cases, 1 of 3 primary mutations is detected (m.11778G>A, m.3460G>A, m.14484T>C). There are multiple other mutations associated with a LHON phenotype, but these are most often described in individuals or single families, and pathogenicity is not always proven.34 The m.13513G>A (p.D393N, ND5) mutation seen in this case is recognized as a disease causing mtDNA mutation. It has a clinically heterogenous phenotype, usually manifesting as Leigh Syndrome or mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS).5 There are two cases reported of LHON/MELAS overlap. In both these cases, optic neuropathy developed in the second decade and was followed by stroke like episodes within 2 years. There are no reported cases of isolated LHON, or of LHON in combination with maternally inherited diabetes, deafness and renal failure such as in this case. It has been noted, that severe optic atrophy is seen in some children with this mutation.26 This has been suggested to be a progressive optic atrophy, though in young children the tempo would be harder to confirm. Hearing loss is often noted.
The MT-ND5 gene is located in mitochondrial DNA from base pair 12,337 to 14,148. The MTND5 gene produces a 67 kDa protein composed of 603 amino acids. MT-ND5 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes.A There have been multiple mutations of MT-ND5 described which result in LHON, either in isolation or more usually in overlap phenotypes with MELAS, Leigh syndrome and/or myoclonic epilepsy with ragged red fibers (MERRF). Some MT-ND5 mutations also seem to act as secondary mutations, potentially modifying the effect of primary LHON mutations.B
ACCEPTED MANUSCRIPT In cases of LHON with a primary mutation, there is evidence that early treatment with idebenone (a ubiquinone analogue) results in better visual outcomes, hence the diagnosis is important to consider early.15 In unusual LHON cases such as the described patient, the benefits of idebenone have not been studied, but treatment may be considered given its high tolerability and the devastating nature of the visual loss.
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Mitochondrial disease often provides a diagnostic challenge given the phenotypic variability, the range of potential inheritance patterns and presentations that may mimic other more common conditions. Certain symptom clusters may assist in pointing towards a mitochondrial etiology, and in this patient the combination of diabetes and deafness with an unexplained optic neuropathy prompted testing. Where genetic testing for mitochondrial disease is available, a broad approach may be useful. Testing for LHON mutations alone would not have detected this patient’s mutation, and in the future sequencing the entire mitochondrial genome may provide the most accurate diagnostic tool. In this case, the patient has a unique phenotype which had not yet been described in association with this mutation. In cases of bilateral, sequential optic neuropathy; vascular, inflammatory and toxic causes are often excluded before mitochondrial disease is considered. With evidence that early treatment of LHON with idebenone may lead to better long term visual outcomes, this delay should be avoided where possible.
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Abstract: A 45 year old woman presented with acute sequential optic neuropathy resulting in bilateral complete blindness. No significant visual recovery occurred. Past medical history was relevant for severe pre-eclampsia with resultant renal failure, diabetes mellitus, and sudden bilateral hearing loss when she was. There was a family history of diabetes mellitus in her mother. Testing for common causes of bilateral optic neuropathy did not reveal a diagnosis for her illness. The maternal history of diabetes, and personal history of diabetes and deafness prompted testing for mitochondrial disease. The three primary mitochondrial DNA mutations responsible for Leber Hereditary Optic Neuropathy (LHON), but the patient was subsequently found to have a disease causing mitochondrial DNA mutation, m.13513G>A. The case illustrates the importance of early testing for mitochondrial disease, and demonstrates that LHON like presentations may be missed if testing is limited to the three primary mutations.
Key words: Optic neuropathy, genetic visual loss, mitochondrial disease, Leber hereditary
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References
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optic neuropathy, deafness and diabetes.
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1. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol. 1991;109(12):1673-8. 2. Berg S, Kaschka I, Utz KS, Huhn K, Lammer A, Lammer R, et al. Baseline magnetic resonance imaging of the optic nerve provides limited predictive information on short-term recovery after acute optic neuritis. PLoS One. 2015;10(1):e0113961. 3. Biousse V, Newman NJ. Ischemic Optic Neuropathies. N Engl J Med. 2015;372(25):2428-36. 4. Blakely EL, de Silva R, King A, Schwarzer V, Harrower T, Dawidek G, et al. LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. Eur J Hum Genet. 2005;13(5):623-7. 5. Brautbar A, Wang J, Abdenur JE, et al. The mitochondrial 13513G>A mutation is associated with Leigh disease phenotypes independent of complex I deficiency in muscle. Molecular Genetics and Metabolism. 2008.; 8: 484-490
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6. Chien CY, Tai SY, Wang LF, Hsi E, Chang NC, Wu MT, et al. Metabolic Syndrome Increases the Risk of Sudden Sensorineural Hearing Loss in Taiwan: A Case-Control Study. Otolaryngol Head Neck Surg. 2015;153(1):105-11. 7. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber's hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Ophthalmol. 1993;111(11):1482-5. 8. Funalot B, Reynier P, Vighetto A, Ranoux D, Bonnefont JP, Godinot C, et al. Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy. Ann Neurol. 2002;52(3):374-7. 9. Ganie MA, Bhat D. Current developments in Wolfram syndrome. J Pediatr Endocrinol Metab. 2009;22(1):3-10. 10. Gross NE, Yannuzzi LA, Freund KB, Spaide RF, Amato GP, Sigal R. Multiple evanescent white dot syndrome. Arch Ophthalmol. 2006;124(4):493-500. 11. Han J, Lee YM, Kim SM, Han SY, Lee JB, Han SH. Ophthalmological manifestations in patients with Leigh syndrome. Br J Ophthalmol. 2015;99(4):528-35. 12. Hayreh SS. Posterior ischaemic optic neuropathy: clinical features, pathogenesis, and management. Eye (Lond). 2004;18(11):1188-206. 13. Ippel EF, Wittebol-Post D, Jennekens FG, Bijlsma JB. Genetic heterogeneity of hereditary motor and sensory neuropathy type VI. J Child Neurol. 1995;10(6):459-63. 14. Kapoor R, Miller DH, Jones SJ, Plant GT, Brusa A, Gass A, et al. Effects of intravenous methylprednisolone on outcome in MRI-based prognostic subgroups in acute optic neuritis. Neurology. 1998;50(1):230-7. 15. Klopstock T, Yu-Wai-Man P, Dimitradis K et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 2011. 16. Korkiamaki P, Kervinen M, Karjalainen K, Majamaa K, Uusimaa J, Remes AM. Prevalence of the primary LHON mutations in Northern Finland associated with bilateral optic atrophy and tobacco-alcohol amblyopia. Acta Ophthalmol. 2013;91(7):630-4. 17. Lin SW, Lin YS, Weng SF, Chou CW. Risk of developing sudden sensorineural hearing loss in diabetic patients: a population-based cohort study. Otol Neurotol. 2012;33(9):1482-8. 18. McCluskey DJ, O'Connor PS, Sheehy JT. Leber's optic neuropathy and Charcot-MarieTooth disease. Report of a case. J Clin Neuroophthalmol. 1986;6(2):76-81. 19. Michaelides M, Jenkins SA, Bamiou DE, Sweeney MG, Davis MB, Luxon L, et al. Macular dystrophy associated with the A3243G mitochondrial DNA mutation. Distinct retinal and associated features, disease variability, and characterization of asymptomatic family members. Arch Ophthalmol. 2008;126(3):320-8. 20. Misu T, Fujihara K, Itoyama Y. [Neuromyelitis optica and anti-aquaporin 4 antibody-an overview]. Brain Nerve. 2008;60(5):527-37. 21. Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008;25(4):383-99. 22. Ogun O, Sheldon C, Barton JJ. Pearls & oy-sters: maternally inherited diabetes and deafness presenting with ptosis and macular pattern dystrophy. Neurology. 2012;79(6):e546.
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23. Ouvrier R, Grew S. Mechanisms of disease and clinical features of mutations of the gene for mitofusin 2: an important cause of hereditary peripheral neuropathy with striking clinical variability in children and adults. Dev Med Child Neurol. 2010;52(4):328-30. 24. Peragallo JH, Newman NJ. Is there treatment for Leber hereditary optic neuropathy? Curr Opin Ophthalmol. 2015;26(6):450-7. 25. Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. 2012;24(4):512-7. 26. Ruiter EM, Siers MH, van den Elzen C, et al. The mitochondrial 13513G > A mutation is most frequent in Leigh syndrome combined with reduced complex I activity, optic atrophy and/or Wolff-Parkinson-White. Eur J Hum Genet. 2007 Feb;15(2):155-61 27. Sharpe JA, Hostovsky M, Bilbao JM, Rewcastle NB. Methanol optic neuropathy: a histopathological study. Neurology. 1982;32(10):1093-100. 28. Sibal L, Ball SG, Connolly V, James RA, Kane P, Kelly WF, et al. Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases. Pituitary. 2004;7(3):157-63. 29. Skidd PM, Lessell S, Cestari DM. Autosomal dominant hereditary optic neuropathy (ADOA): a review of the genetics and clinical manifestations of ADOA and ADOA+. Semin Ophthalmol. 2013;28(5-6):422-6. 30. Spruijt L, Smeets HJ, Hendrickx A, Bettink-Remeijer MW, Maat-Kievit A, Schoonderwoerd KC, et al. A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia. Arch Neurol. 2007;64(6):890-3. 31. Tucci A, Liu YT, Preza E, Pitceathly RD, Chalasani A, Plagnol V, et al. Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. J Neurol Neurosurg Psychiatry. 2014;85(5):486-92. 32. Vella A, Young WF. Pituitary apoplexy. The Endocrinologist. 2001;11:282-8. 33. Volpe NJ, Rizzo JF, 3rd, Lessell S. Acute idiopathic blind spot enlargement syndrome: a review of 27 new cases. Arch Ophthalmol. 2001;119(1):59-63. 34. Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy, in Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al (eds): GeneReviews(R). Seattle (WA) 1993.
Other Sources of Cited Information A. "MT-ND5". Genetics Home Reference. US National Library of Medicine. http://ghr.nlm.nih.gov/gene/MT-ND5 Retrieved 13 October 2015 B. “Complex 1, Subunit ND5; MTND5”. Online Mendelian Inheritance in Man. John’s Hopkins University. http://www.omim.org/entry/516005 Retrieved October 13 2015.
ACCEPTED MANUSCRIPT Legends: Figure 1 - a) Color fundus photos right and left eye (b) Normal arterial
phase fluorescein angiogram
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Figure 2 – T2 weighted MRI (axial and coronal views) demonstrating increased signal in the optic nerves, the optic chiasm and optic tracts.
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S0039-6257(15)30055-2
DOI:
10.1016/j.survophthal.2016.02.003
Reference:
SOP 6621
To appear in:
Survey of Ophthalmology
Received Date: 30 October 2015 Revised Date:
15 February 2016
Accepted Date: 18 February 2016
Please cite this article as: Ahmad KE, Fraser CL, Sue CM, Barton JJS, Beyond what the eye can see, Survey of Ophthalmology (2016), doi: 10.1016/j.survophthal.2016.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title: Beyond what the eye can see Kate E Ahmad FRACP1 Clare L Fraser FRANZCO2 Carolyn M Sue FRACP3
1
RI PT
Jason J S Barton MD PhD FRCPC4 Department of Neurology, Royal North Shore Hospital, Sydney, Australia.
2
Save Sight Institute, University of Sydney, Australia
3
SC
Department of Neurogenetics, Kolling Institute for Medical Research, Sydney, Australia.
4
Departments of Medicine (Neurology), Ophthalmology and Visual Sciences, Psychology, University
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of British Columbia, Vancouver, Canada
Corresponding author: Kate Ahmad, Department of Neurology, Clinical Area 3E, Royal North Shore Hospital, St Leonards, NSW 2065.
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Email: [email protected]
ACCEPTED MANUSCRIPT (In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
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A 45-year-old woman woman presented with a 4-week history of visual loss. She described an initial central scotoma and color desaturation in her left eye. Over several days her peripheral vision became involved. Two weeks after onset, she noted similar symptoms in her right eye, which also progressed to severe visual loss. There was no associated eye pain, headache, or systemic symptoms.
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She had a history of chronic kidney disease, diabetes mellitus, hearing loss, and preeclampsia. Pre-eclampsia had developed during all three of her pregnancies and resulted in one stillborn child and two premature deliveries. The pre-eclampsia was presumed to have resulted in chronic kidney disease. Diabetes had been diagnosed 8 years prior to presentation and the patient had moderate to poor blood sugar control with oral hypoglycemics. Sensorineural hearing loss occurred suddenly and simultaneously 7 years ago, with no recovery. Investigations at the time failed to reveal an underlying cause. Social history was unremarkable; she did not drink alcohol or smoke cigarettes. She denied illicit drug use or recent vaccination. She was a stay at home mother to her two teenage children.
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Family history was relevant for late onset diabetes mellitus in her mother and maternal grandmother. Her mother had congenital hypoplasia of the left side of the body, which had included left sided hearing loss. This was attributed to an intrauterine injury.
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Initial examination revealed best corrected visual acuities of 6/60, N24 in the right eye, and count fingers at 1 meter in the left eye. There was a left relative afferent pupillary defect. There was no evidence of ocular inflammation. Funduscopy revealed widespread granularity of the retina. There were no abnormalities of the optic disks. Fluorescein angiography was unremarkable (Fig.1).
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What is the differential diagnosis of the visual loss, and how would you proceed? Comments Comments by Jason J S Barton, MD, PhD, FRCPC Acute bilateral visual loss has a fairly long list of possibilities, ranging all the way from the retina to striate cortex. The fact that this was sequential, with one eye affected before the other, is helpful: it excludes retrochiasmal lesions, which if sequential would affect one hemifield before the other instead. Hence the main possibilities are bilateral retinopathy or optic neuropathy. Could this be bilateral inflammatory retinopathy? Young women in particular are vulnerable to an array of retinal disorders known by their acronyms: AZOOR, PIC, ARPE, AMPPE, MEWDS and so on. These generally present in similar subacute fashion, can affect visual acuity, and some have a tendency to bilateral involvement. However, most have characteristic white spots or other lesions on funduscopy and abnormalities on fluorescein
ACCEPTED MANUSCRIPT angiography. Acute idiopathic blind spot enlargement syndrome and MEWDS (multiple evanescent white dot syndrome) can have ‘granularity’, though usually limited to the macula and evolving in later stages.10,33 The widespread nature of the granular changes mentioned here sounds different.
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Bilateral sequential optic neuritis is a possibility. Somewhat atypical is the lack of pain. In the Optic Neuritis Treatment Trial, 92% of patients had pain, and in 87% it was worse or only present with eye movement.1 Nevertheless, common things being common, this has to be a leading candidate. While bilateral sequential involvement can occur with multiple sclerosis, this should always raise suspicion for neuromyelitis optica, especially if the patient is Asian.
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Infectious causes of inflammatory optic neuropathy are more unusual, but can present bilaterally in a subacute fashion as well. Aspergillus and mucormycosis are fungal infections that involve the sinuses: these occur more frequently in patients with diabetes or other conditions that compromise the immune system. Syphilis, lyme disease and bartonella are also important to consider, particularly if there are retinal exudates – the so-called macula star. Tuberculosis can cause a granulomatous basal meningitis that can affect both optic nerves. Bilateral acute sequential visual loss can occur with anterior ischemic optic neuropathy, for which diabetes and hypertension are risk factors3; however, disk edema should be evident and only in a minority does visual loss progress over the days after onset. Posterior ischemic optic neuropathy is far less common and occurs primarily in the setting of giant cell arteritis, for which she is too young, or severe prolonged hypotension, often in the perioperative state.3,12
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We are not told her medications, but we can infer from her past history that she is probably not taking ethambutol or amiodarone. Methanol is a cause of acute bilateral optic neuropathy, but usually with disk edema, other features including vomiting, abdominal pain and drowsiness, and probably not a delay of 2 weeks between the first and the second eye.27
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She has no history of craniofacial trauma. Compression by tumors tends to be unilateral, and would present more gradually unless there was hemorrhage into the tumour. Pituitary apoplexy is one mechanism of sudden visual loss that could be bilateral. Often there are severe headaches and ocular motility defects, though.32 Infiltration of the nerves by meningeal metastases can cause this picture also. Does her past history give us any clues? She has diabetes, as does her mother and maternal grandmother. She and her mother also have deafness. This could point to the maternally inherited diabetes and deafness (MIDD) syndrome, which is associated with the mitochondrial mutation usually associated with MELAS21; however, MIDD is associated with a characteristic macular pattern dystrophy rather than retinal granularity or optic neuropathy.19,22 Macular pattern dystrophy is easily seen on funduscopy and visual loss is usually minimal or slowly progressive, which is not the clinical picture here. Wolfram syndrome is an autosomal recessive condition that also groups some of her diverse problems. It is also known by the acronym DIDMOAD, for diabetes insipidus, juvenile-onset diabetes mellitus, optic atrophy, and deafness.9 It can also be associated with renal abnormalities; however, it usually manifests earlier in life, and visual dysfunction is gradual rather than sudden.
ACCEPTED MANUSCRIPT Sudden bilateral deafness is itself an interesting problem. It is a recognized complication of diabetes, and the risk doubles if there is renal insufficiency.6,17 This is usually attributed to microvascular ischemia. If so, this would increase her risk for similar ischemia to the optic nerves. Again, though, this should have created disk edema. Finally, as stated above, diabetes also increases the risk of mucormycosis.
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Our first step in investigation has to be neuroimaging, preferably MRI orbit and sella, with and without contrast. I would also consider adding MRI of the spine while she is in the machine, given the possibility of neuromyelitis optica: however, a neurologic examination for signs of myelopathy would be an even better idea first. On review of the imaging I would look for sinus disease that might have spread to the orbit, and consult otolaryngology if this were found. If imaging is negative, a cerebrospinal fluid analysis looking for inflammation, infection and neoplasia should follow, keeping in mind that cytology has a sensitivity of only 50%.
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Case Report (Continued) The presentation was thought to be representative of a bilateral, sequential optic neuropathy. An inflammatory cause was initially suspected and the patient was admitted for investigation and management. MRI brain and orbits showed increased signal in both the intraconal and intracanicular portions of the optic nerves. These changes extended back to the optic chiasm and tracts (Fig.2). There were no other MRI abnormalities. CSF analysis showed normal cell count, glucose, cytology and no oligoclonal bands. Protein was mildly elevated at 0.64g/L. Testing for syphilis and HIV was negative, and autoimmune serology including NMO-IgG and antiphospholipid antibodies, was negative. During the investigative phase, she was empirically treated with 5 days of intravenous methylprednisolone, but her vision continued to deteriorate. Are there any other further investigations that may be useful? Would you consider any further treatment options? Comments (Continued)
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Comments by Dr Barton
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The MRI at least confirms that this is optic neuropathy and not a retinopathy. The fairly extensive signal change is impressive. Older and recent studies show that 20 to 50 mm of signal change is considered a ‘long’ lesion for the optic neuritis associated with multiple sclerosis2,14; the changes here are well beyond that. We are not told if she had gadolinium with her MRI. It would be of interest to know if there is any enhancement, not so much of the optic nerves, but of the basal meninges. Such enhancement would point to granulomatous inflammation such as sarcoidosis or tuberculosis. A chest X-ray, serum ACE, and gallium scan could then be considered; however, failure to respond to steroids is against inflammation, although one might question if five days is enough of a trial for granulomatous disease.
Not all patients with the clinical syndrome of neuromyelitis optica are positive for antiaquaporin-4 antibodies-- the incidence of seronegativity is estimated at 9%20--however, if there is no clinical evidence of myelopathy and the antibody test is negative, the utility of an MRI of her spine would likely be marginal.
ACCEPTED MANUSCRIPT The lack of other abnormalities on MRI is reassuring about some other life-threatening possibilities. MR of the orbits and sella is 91% sensitive for pituitary apoplexy.28 If the orbits and sinuses appear normal on MR, the likelihood of mucormycosis is reduced. Nevertheless, examination of her nasopharynx by an otologist may help definitively exclude this dangerous condition.
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Case Report (Continued) The patient was discharged from hospital with no light perception vision in both eyes, but experienced some minor recovery over the subsequent months, allowing her to see some movement and contrast in the left peripheral field. 18 months later, she sought a second opinion in a tertiary neuro-ophthalmology clinic. At this time, her examination was little changed, but her optic disks now appeared pale with a normal cup to disk ratio. Optical coherence tomography (OCT) confirmed marked thinning of the peripapillary retinal nerve fibre layer. Neurological examination revealed evidence of a length dependent sensorimotor neuropathy.
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The family history of maternally inherited diabetes, combined with the personal history of diabetes, deafness and renal failure raised the possibility of mitochondrial disease. The bilateral sequential optic neuropathy was thought to be in keeping with a Leber hereditary optic neuropathy (LHON) phenotype. The patient went on to be tested for the three primary LHON mutations. None were detected. Would any further genetic testing be appropriate at this point? Comments (Continued) Comments by Dr Barton
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Mutations have been associated with the LHON phenotype, but the commercially available tests only cover the three most frequently found mutations.34 Also, even though the classic presentation is acute bilateral central scotomata in a young man, the advent of genetic testing has shown that women can present similarly, as well as older patients with more progressive bilateral visual loss in the setting of nutritional deficiency and alcohol use - what used to be known as tobacco-alcohol amblyopia.7,16 Optic neuropathy can occur as part of an overlap with other mitochondrial syndromes, so testing for some of those mutations may be of interest also, even if she does not have those other features yet: the m.3376G>A and m.3697G>A mutations are associated with an LHON/MELAS overlap, for example.4,30 The value of this additional testing can be debated – the efficacy of current therapy for mitochondrial disorders remains modest at best.24 Her teen-aged children may have some stake in the results, though, since mitochondrial mutations are inherited from the mother. Her story is not typical of other hereditary optic neuropathies. Kjer autosomal dominant optic atrophy is associated with OPA1 mutations, but the visual loss is rarely if ever this acute or this severe. 29 Wolfram syndrome is due to a mutation in either the WFS1 gene on chromosome 4, which encodes wolframin, a protein involved in endoplasmic reticulum function, or the CISD2 gene for the protein ERIS, also on chromosome 4 and also localized to the endoplasmic reticulum.25 Again, though, this is not the typical clinical picture of Wolfram syndrome. Does the finding of polyneuropathy suggest any specific genetic tests? Hereditary sensorimotor neuropathy (HMSN, also known as Charcot-Marie-Tooth) can be associated with optic neuropathy, particularly HMSN type VI, though the optic neuropathy begins in the
ACCEPTED MANUSCRIPT teens and progresses slowly to blindness.13 Recent work has shown that this is associated with mutations in genes for mitofusin 2 or C12orf65.23,31 There is only one intriguing older case of a patient with Charcot-Marie Tooth disease and sudden unilateral visual loss with a central scotoma and hyperemic optic disk, resembling the typical scenario of LHON.18 It is highly unlikely that our patient has Riley-Day syndrome, a more severe early-onset disorder that can be associated with optic atrophy.
Case Report (Continued)
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In the end, most hereditary optic neuropathies would not fit her clinical scenario of abrupt bilateral visual loss. If one would chase anything, it would be other unusual mitochondrial mutations associated with LHON.
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A referral was made for consideration of further genetic testing. While the three primary LHON mutations account for >90% of cases of LHON, there remain cases where an alternative mitochondrial DNA point mutation is the culprit. In addition, the presence of diabetes and hearing loss is unusual for an uncomplicated LHON case, and it was thought that more extensive testing for mtDNA mutations was warranted. A panel testing for a further 19 mtDNA mutations was ordered. This was positive for the presence of m.13513G>A mutation in both urine and blood.
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Discussion Mutations in mitochondrial DNA are well known for resulting in bilateral, sequential optic neuropathy, usually in the context of LHON. In >90% of LHON cases, 1 of 3 primary mutations is detected (m.11778G>A, m.3460G>A, m.14484T>C). There are multiple other mutations associated with a LHON phenotype, but these are most often described in individuals or single families, and pathogenicity is not always proven.34 The m.13513G>A (p.D393N, ND5) mutation seen in this case is recognized as a disease causing mtDNA mutation. It has a clinically heterogenous phenotype, usually manifesting as Leigh Syndrome or mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS).5 There are two cases reported of LHON/MELAS overlap. In both these cases, optic neuropathy developed in the second decade and was followed by stroke like episodes within 2 years. There are no reported cases of isolated LHON, or of LHON in combination with maternally inherited diabetes, deafness and renal failure such as in this case. It has been noted, that severe optic atrophy is seen in some children with this mutation.26 This has been suggested to be a progressive optic atrophy, though in young children the tempo would be harder to confirm. Hearing loss is often noted.
The MT-ND5 gene is located in mitochondrial DNA from base pair 12,337 to 14,148. The MTND5 gene produces a 67 kDa protein composed of 603 amino acids. MT-ND5 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes.A There have been multiple mutations of MT-ND5 described which result in LHON, either in isolation or more usually in overlap phenotypes with MELAS, Leigh syndrome and/or myoclonic epilepsy with ragged red fibers (MERRF). Some MT-ND5 mutations also seem to act as secondary mutations, potentially modifying the effect of primary LHON mutations.B
ACCEPTED MANUSCRIPT In cases of LHON with a primary mutation, there is evidence that early treatment with idebenone (a ubiquinone analogue) results in better visual outcomes, hence the diagnosis is important to consider early.15 In unusual LHON cases such as the described patient, the benefits of idebenone have not been studied, but treatment may be considered given its high tolerability and the devastating nature of the visual loss.
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Mitochondrial disease often provides a diagnostic challenge given the phenotypic variability, the range of potential inheritance patterns and presentations that may mimic other more common conditions. Certain symptom clusters may assist in pointing towards a mitochondrial etiology, and in this patient the combination of diabetes and deafness with an unexplained optic neuropathy prompted testing. Where genetic testing for mitochondrial disease is available, a broad approach may be useful. Testing for LHON mutations alone would not have detected this patient’s mutation, and in the future sequencing the entire mitochondrial genome may provide the most accurate diagnostic tool. In this case, the patient has a unique phenotype which had not yet been described in association with this mutation. In cases of bilateral, sequential optic neuropathy; vascular, inflammatory and toxic causes are often excluded before mitochondrial disease is considered. With evidence that early treatment of LHON with idebenone may lead to better long term visual outcomes, this delay should be avoided where possible.
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Abstract: A 45 year old woman presented with acute sequential optic neuropathy resulting in bilateral complete blindness. No significant visual recovery occurred. Past medical history was relevant for severe pre-eclampsia with resultant renal failure, diabetes mellitus, and sudden bilateral hearing loss when she was. There was a family history of diabetes mellitus in her mother. Testing for common causes of bilateral optic neuropathy did not reveal a diagnosis for her illness. The maternal history of diabetes, and personal history of diabetes and deafness prompted testing for mitochondrial disease. The three primary mitochondrial DNA mutations responsible for Leber Hereditary Optic Neuropathy (LHON), but the patient was subsequently found to have a disease causing mitochondrial DNA mutation, m.13513G>A. The case illustrates the importance of early testing for mitochondrial disease, and demonstrates that LHON like presentations may be missed if testing is limited to the three primary mutations.
Key words: Optic neuropathy, genetic visual loss, mitochondrial disease, Leber hereditary
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References
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optic neuropathy, deafness and diabetes.
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Other Sources of Cited Information A. "MT-ND5". Genetics Home Reference. US National Library of Medicine. http://ghr.nlm.nih.gov/gene/MT-ND5 Retrieved 13 October 2015 B. “Complex 1, Subunit ND5; MTND5”. Online Mendelian Inheritance in Man. John’s Hopkins University. http://www.omim.org/entry/516005 Retrieved October 13 2015.
ACCEPTED MANUSCRIPT Legends: Figure 1 - a) Color fundus photos right and left eye (b) Normal arterial
phase fluorescein angiogram
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Figure 2 – T2 weighted MRI (axial and coronal views) demonstrating increased signal in the optic nerves, the optic chiasm and optic tracts.
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