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with spontaneous visual recovery. Clin Exp ... mtDNA 14484 mutation, optic neuritis papilloedema, visual recovery ... giectasia, pseudo-oedema of the disc and.

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Leber’s hereditary optic neuropathy masquerading as optic neuritis with spontaneous visual recovery Clin Exp Optom 2014; 97: 84–86 Tsui-Kang Hsu* MD An-Guor Wang†§ MD PhD May-Yung Yen†§ MD Jorn-Hon Liu* § MD * Department of Ophthalmology, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China † Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China § Department of Ophthalmology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China E-mail: [email protected]

Submitted: 26 November 2011 Revised: 5 February 2013 Accepted for publication: 22 February 2013

DOI:10.1111/cxo.12100 We report a case of Leber’s hereditary optic neuropathy (LHON) masquerading as optic neuritis with late visual recovery. A 28-year-old man had gradual visual loss in both eyes for two weeks. Visual acuity was 0.4 in the right eye and 0.7 in the left. Fundus examination revealed hyperaemic discs in each eye. Fluorescein angiography revealed dye leakage at both optic discs in the late phase. Static perimetry (Humphrey 30-2) revealed bilateral relative central scotomata. Magnetic resonance imaging of the optic nerves was normal and his lumbar puncture showed normal opening pressure. He received steroid pulse therapy for three days. Nevertheless, vision in his right eye deteriorated to 0.1 one month later and left vision worsened to 0.05 six months later. Fifteen months after onset, his vision began to improve. At 21 months, his vision recovered to 0.9 R and 1.0 L. Peripheral blood DNA sequencing revealed 14484 mutation of mitochondrial DNA (mtDNA). Visual recovery can occur in patients with Leber’s hereditary optic neuropathy with mtDNA 14484 mutation. LHON could be misdiagnosed as optic neuritis in some cases. Molecular examination of mtDNA mutation can confirm the diagnosis of LHON in clinically controversial patients. We should keep in mind the diagnosis of LHON when optic neuritis shows poor response to pulse therapy.

Key words: Leber’s hereditary optic neuropathy, mtDNA 14484 mutation, optic neuritis papilloedema, visual recovery

INTRODUCTION

CASE REPORT

Leber’s hereditary optic neuropathy (LHON), a maternally inherited (mitochondrial) disease, is characterised by acute or subacute bilateral loss of central vision and central or caecocentral scotoma in otherwise healthy patients (usually males) in their second to fourth decade of life.1 Clinically, this disorder presents as peripapillary telangiectasia, pseudo-oedema of the disc and absence of fluorescein staining.2 Pallor of the entire disc indistinguishable from primary atrophy generally develops within a few weeks after onset of the visual disturbance. Final visual acuity is rarely better than 0.1. The fellow eye is almost always involved within one year from the onset of the disease in the first eye.2 We report on a man with LHON with mitochondrial (mt) DNA 14484 mutation masquerading as optic neuritis who had bilateral involvement and a gradual recovery of vision after 21 months.

A 28-year-old man presented with gradual bilateral visual loss for two weeks in May 2008. He was diagnosed with optic neuritis and was referred to us on June 2, 2008. He was healthy in the past except that he had chickenpox during childhood. He was a non-smoker and consumed alcohol only occasionally. He had no history of head trauma, drug administration or hormonal disorder. No family history of eye disease was found. His visual acuity (VA) at presentation was 0.4 R and 0.7 L. There was no relative afferent pupillary defect. He denied pain on eye movement and external ocular motility was normal. Fundus examination showed that the optic discs were small and hyperaemic with indistinct margins (Figures 1A, B). Fluorescein angiography (FAG) showed bilateral staining of the optic discs in the late phase (Figures 1C,D). Perimetry (Humphrey 30-2) revealed bilateral relative central scotomata (Figures 2A,B).

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Routine blood examinations, such as complete and differential cell counts were normal. His blood biochemistry (renal and liver function) and autoimmune profile (antinuclear antibody, rheumatic factor and erythrocyte sedimentation rate) was within the normal range. Serological studies including Treponem palladim haemagglutination and fluorescent treponemal antibody absorption were negative. He did not have any skin lesions or arthritic conditions. Neurological and magnetic resonance imaging examinations were normal. Cerebrospinal fluid was clear of blood cells, glucose and protein content were normal and there was no sign of raised intracranial pressure. After serial examinations, we did not find a definite diagnosis for the bilateral persistent disc oedema. We treated the patient according to protocols for a provisional diagnosis of bilateral optic neuritis. Steroid pulse therapy with methylprednisolone one gram per day intravenously was given for © 2013 The Authors

Clinical and Experimental Optometry © 2013 Optometrists Association Australia

Leber’s hereditary optic neuritis masquerading as optic neuritis Hsu, Wang, Yen and Liu

Figure 1. Fundus photographs at first presentation. (A and B) Right and left optic discs were small and hyperaemic with indistinct margins. (C and D) Fluorescein angiography revealed staining of the optic discs in the late phase.

three days and then tapered with oral prednisolone over two weeks. The patient’s vision did not improve but dropped to 0.1 R and remained at 0.7 L one month later. His left vision deteriorated gradually to 0.5 in August and then to 0.1 in September 2008. Fundus examination revealed persistent hyperaemic discs in both eyes. A genetic study of mtDNA 11778 mutation was negative. Six months later, his VA was 0.1 R and 0.05 L. Electroretinography (standard full field) was normal. Fifteen months after onset, his vision began to improve to 0.4 R and 0.7 L. At 21 months, his vision recovered to 0.9 R and 1.0 L with a normal visual field in the right eye (Figure 2D) and mild depression in the left (Figure 2C). Peripheral blood mtDNA analysis revealed 14484 mutation.

DISCUSSION At first presentation, LHON has distinct clinical characteristics but may overlap with optic neuritis in many aspects. Riordan-Eva and colleagues3 investigated 107 patients from 79 families having LHON by the presence of mtDNA mutations at positions 11778 (60 families), 3460 (seven families) or 14484 (12 families). Most patients had the tendency of bilateral presentation with a median inter-eye delay of eight weeks.3 In this study, 19 patients had pain in an affected eye or on eye movements and four patients experienced Uhthoff’s phenomenon.3 A multiple sclerosis-like illness was observed in 45 per cent of females with the 11778 mutation.3 In another study, Lai and colleagues4 compared the clinical

© 2013 The Authors Clinical and Experimental Optometry © 2013 Optometrists Association Australia

characteristics of LHON (55 patients) with optic neuritis (48 patients) and found that LHON was more common in male patients (46 of 55 versus 21 of 48) with onset at a younger age (median 16 years versus 30 years). A family history of maternal relatives affected (25 of 50 versus 2 of 48) was more common in LHON. Moreover, LHON seems to have a more severe effect than optic neuritis, in that it presents more frequently with reduced visual acuity, it has a greater tendency to last more than two weeks (42 of 49 versus 10 of 48) and is often associated with a central scotoma (26 of 39 versus 12 of 35).4 Bilateral acute optic neuritis is rare in adults in Western countries, but is relatively common in Asian populations. The proportion of bilateral acute optic neuritis is 11 per cent (30 of 285) of patients with acute optic neuritis in Denmark,5 6.4 per cent (15 of 220) in the USA,6 25 per cent in India7 and 29 to 33 per cent in China.8 The underlying cause of the higher prevalence of bilateral acute optic neuritis in the Asian region remains unknown. One possible reason is that the prevalence of neuromyelitis optica (Devic’s disease) which usually affects the optic nerves bilaterally is much higher in Asia than in Western countries. Besides, the percentage of males with bilateral acute optic neuritis in previous studies was 53 per cent in Denmark,5 73 per cent in the USA6 and 56 per cent in China.8 Nevertheless, without DNA analysis, it is difficult to differentiate between these two disease entities at first presentation. The visual recovery time in LHON varies. Acaroglu, Kansu and Gogulu9 described three patients with LHON with counting fingers acuity at presentation. One male with 11778 mutation had improved to 0.3 in both eyes after 10 months. A girl with 3460 mutation also had her VA recover to 0.3 in both eyes after 20 months. The third patient did not have a genetic diagnosis.9 Momtchilova and colleagues10 described a boy with 11778 mutation, who developed recurrent bilateral optic neuropathy, with final VA improving to 0.9 R and 0.8 L. Leo-Kottler and colleagues11 reported a man with 11253 mutation suffering from progressive bilateral blurred vision which recovered to 0.6 in both eyes after three years. Spruijt and colleagues12 described partial improvement in 87 cases of LHON and it usually occurred after more than a year. Nevertheless, there is no documentation for the degree of improvement in these 87 patients. Clinical and Experimental Optometry 97.1 January 2014

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Leber’s hereditary optic neuritis masquerading as optic neuritis Hsu, Wang, Yen and Liu

REFERENCES

Figure 2. Visual field (Humphrey 30-2) plots (A right eye, B left eye), revealed bilateral relative central scotomas (A and B) at presentation. After 21 months, there was no central scotoma in the right eye (D) and mild depression in the left (C).

Some prognostically significant factors have been identified in patients with LHON, probably the most important of which is the type of mtDNA mutation.13 The 14484 mutation leads to a 37 to 71 per cent chance of visual improvement, whereas the 11778 mutation is associated with a positive visual prognosis of only four per cent.13 The 3460 mutation leads to the same chance of recovery as the 11778 mutation.13 Other factors reported to be associated with favourable prognosis are young age (onset before 20 years), small central scotoma at presentation, thicker retinal nerve fibre layer and large disc size.14 In our patient, the central scotoma was relatively small, which is a favourable factor for visual recovery. In addition, his optic disc remained hyperaemic for a long time without atrophic change, which may also represent a favourable factor for visual recovery. The common pathogenic LHON mutations at nucleotide positions 3460, 11778 and 14484, affecting ND1, ND4 and ND6 subunit genes of complex I of the respiratory chain respectively, may cause complex I dysfunction. An extensive biochemical analysis of the mitochondrial defects revealed that Clinical and Experimental Optometry 97.1 January 2014

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the 3460 mutation resulted in 79 per cent reduction in complex I activity and the 11778 mutation resulted in 20 per cent reduction, while the 14484 mutation did not affect complex I activity.15 An extended respiration study revealed that the 3460 mutation reduced the maximal respiration rate at 20 to 28 per cent, the 11778 mutation 30 to 36 per cent and 14484 mutation 10 to 15 per cent.15 These results imply that 14484 mutation caused a much milder biochemical defect and a milder decrease of respiratory function than other primary mutations of 11778 and 3460, which in turn may provide a possible reason for the higher recovery rate in 14484 mutation in LHON. Leber’s hereditary optic neuropathy could be misdiagnosed as optic neuritis or papillitis. We should keep in mind the diagnosis of LHON when optic neuritis shows poor response to pulse therapy and consider further analysis through mtDNA examination.

1. Yen MY, Wang AG, Wei YH. Leber’s hereditary optic neuropathy: A multifactorial disease. Prog Retin Eye Res 2006; 25: 381–396. 2. Newman NJ. Leber’s hereditary optic neuropathy. Ophthalmol Clin North Am 1991; 4: 431–447. 3. Riordan-Eva P, Sander MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The Clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995; 118: 319–337. 4. Lai CT, Wang Q, Li Z, Wang W, Zhu J, Lu Y, Zhang XJ, Yu HF. Leber hereditary optic neuropathy and optic neuritis: similarities and differences of clinical characteristics. [in Chinese]. Zhonghua Yan Ke Za Zhi 2007; 43: 793–797. 5. Frederiksen J. Bilateral acute optic neuritis: prospective clinical, MRI, CSF, neurophysiological and HLA findings. Neuro-Ophthalmology 1997; 17: 175– 183. 6. de la Cruz J, Kupersmith MJ. Clinical profile of simultaneous bilateral optic neuritis in adults. Br J Ophthalmol 2006; 90: 551–554. 7. Sethi HS, Menon V, Sharma P, Khokhar S, Tandon R. Visual outcome after intravenous dexamethasone therapy for idiopathic optic neuritis in an Indian population: a clinical case series. Indian J Ophthalmol 2006; 54: 177–183. 8. Du Y, Li K, Yang J, Xu X, Li JJ, Zhou RW, Zhang Y et al. Disc swelling and mild initial visual acuity loss predict a better short-term visual acuity outcome in bilateral acute optic neuritis. J Clin Neurosci 2012; 19: 1380–1382. 9. Acaroglu G, Kansu T, Dogulu CF. Visual recovery patterns in children with Leber’s hereditary optic neuropathy. Int Ophthalmol 2001; 24: 349–355. 10. Momtchilova M, Pelosse B, Saliba M, Abdiche G, Doummar D, Laroche L, Billette De Villemeur T. Recurrent visual loss in Leber hereditary optic neuropathy: a case report. J Fr Ophtalmol 2008; 31: 409–415. 11. Leo-Kottler B, Luberichs J, Besch D, Christ-Adler M, Fauser S. Leber’s hereditary optic neuropathy: clinical and molecular genetic results in a patient with a point mutation at np T11253C (isoleucine to threonine) in the ND4 gene and spontaneous recovery. Graefe’s Arch Clin Exp Ophthalmol 2002; 240: 758–764. 12. Spruijt L, Kolbach DN, de Coo RF, Plomp AS, Bauer NJ, Smeets HJ, de Die-Smulders CE. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol 2006; 141: 676–682. 13. Fraser JA, Biousse V, Newman NJ. The neuroophthalmology of mitochondrial disease. Surv Ophthalmol 2010; 55: 299–334. 14. Ramos CdoV, Bellusci C, Savini G, Carbonelli M, Berezovsky A, Tamaki C, Cinoto R et al. Association of optic disc size with development and prognosis of Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2009; 50: 1666–1674. 15. Brown MD, Trounce IA, Jun AS, Allen JC, Wallace DC. Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778 or 14484 Leber hereditary optic neuropathy mitochondrial DNA mutation. J Biol Chem 2000; 275: 39831–39836.

ACKNOWLEDGEMENT

This study was supported by the grant of Taipei Veterans General Hospital (V99C1–136). © 2013 The Authors Clinical and Experimental Optometry © 2013 Optometrists Association Australia

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