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Show Journal of Neuro- Ophtlmlmolox!/ 16( 3): 178- 181, 1996. © 1996 Uppincott- Raven Publishers, Philadelphia Peripapillary Fluorescein Leakage in 11778 Leber's Optic Neuropathy May- Yung Yen, M. D., Yau- Huei Wei, Ph. D., and Jorn- Hon Liu, M. D. A 17- year- old young man presented with a 2- month sequential visual loss in both eyes. Vision was 20/ 200 in the right eye and 20/ 400 in the left eye. Both discs were hyperemic with circumpapillary telangiectasia and nerve fiber swelling. Fluorescein angiography revealed a fuzzy hyperfluorescence due to leakage from dilated capillaries on both discs in the late transit. Molecular mitochondrial DNA study confirmed a homoplasmic 11778 Leber's optic neuropathy. Key Words: Leber's optic neuropathy- Peripapillary fluorescein leakage- Mitochondrial DNA mutation. Leber's hereditary optic neuropathy ( LHON) is a maternally inherited disease characterized by acute or subacute loss of central vision, usually in young men. The ophthalmoscopic triad of the acute disease are circumpapillary telangiectatic microangiopathy, pseudoedema of the optic discs, and absence of fluorescein staining ( 1). Optic atrophy is apparent within 2 months. A Leber's patient is presented in this study who had the 11778 point m u t a t i o n . However, fluorescein angiography showed dye leakage of both discs. Manuscript received November 17, 1994; accepted September 26, 1995. From the Department of Ophthalmology, Taipei Veterans General Hospital ( M. Y. Y., J. H. L.), and the Department of Biochemistry, National Yang- Ming University ( Y. H. W.), Taipei, Taiwan, Republic of China. Address correspondence and reprint request to Dr. May- Yung Yen, Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC, 11217. CASE REPORT A 17- year- old boy noticed a rapid, painless loss of vision in his left eye in March, 1985. Two months later, he noticed visual decrease in his right eye. He was referred to us in May, 1985 after no improvement with medications. No prodromal common cold, headache, or orbital pain ensued. He did not smoke or drink. There was no family history of visual disturbance. Also, his medical history was unremarkable. Eye examination revealed the best corrected visual acuity of 20/ 200 OD and 20/ 400 OS. The right eye read 11/ 15 of Ishihara color plates but the left eye read no color plates. There were large central scotomas on Goldmann perimetry. Both discs were hyperemic with circumpapillary telangiectasia and nerve fiber swelling incurred ( Fig. 1). The arteriovenous phase of the fluorescein angiogram revealed dilated capillaries at the optic discs. A fuzzy hyperfluorescence due to leakage from dilated capillaries was found at the discs in late tran-sit ( Fig. 2). A complete blood cell count, erythrocyte sedimentation rate ( ESR), blood chemistry study, urinalysis, serological test for syphilis, immunological assays for antinuclear antibody titer, rheumatoid 278 FLUORESCEIN LEAKAGE IN LHON FfG. T. Both discs were hyperemic with circumpapillary telangiectasia and had nerve fiber swelling. factor, C- reactive protein, immunoglobulin, cerebrospinal fluid examination, and computed tomography ( CT) of the brain and orbit were all found to be normal. Despite the fundoscopic findings and no family history, on the bases of the characteristic clinical course and patient age, hereditary LON was diagnosed. The patient was rechecked in August, 1990. Best corrected vision was 20/ 200 OU. He could read 15/ 15 of Ishihara color plates from each eye. Fundos-copy revealed temporal pallor of both discs. A molecular genetic study of blood mitochondrial DNA ( mtDNA) revealed that the patient, his mother, and his younger brother all had homoplasmic 11778 point mutations. This result had been reported previously ( 2). The patient was subsequently followed annually. In 1993, he could see 20/ 60 OU and read 15/ 15 of Ishihara color plates. Fundoscopic findings remained unchanged. Vision has remained stable ever since. COMMENT In 1988, Wallace et al. ( 3) reported a G to A mutation at nucleotide position 11778 of mtDNA isolated from patients with LHON. The 11778 muta- FiG. 2. Fluorescein angiography revealed dilated capillaries on the optic discs in the arteriovenous phase and leakage of dye from both discs in the late phase. J Neuiv- Oplttlmlmol, Vol. 76, No. 3, 1996 180 M- Y YEN ET AL. tion accounts for - 50- 70% of Caucasian cases and > 80% of Japanese cases ( 4). The presence of the 11778 point mutation was verified with 100% sensitivity and 100% specificity by the use of SfaNI and Mae III enzymes ( 5). Thus far, 15 transition mutations located in different genes for the mito-chondrially encoded subunits of respiratory chain complexes have been associated with this disease ( 6- 15). Among them, 11778, 3460, and 14484 point mutations have never been detected in normal controls, and are classified as primary LHON mutations. Since LHON mutations affect different respiratory complexes, it has been suggested that LHON results from a nonspecific decrease in mitochondrial energy production ( 10). Since the Wallace mutation ( 11778 point mutation) was reported, molecular analysis has become a simple diagnostic test for LHON, especially in atypical cases. With molecular analysis, atypical cases with delayed diagnosis have been reported increasingly ( 16- 19). Before the molecular study was available, the diagnosis was usually made by family history, clinical characteristics, and fluorescein angiography. At the onset of visual loss, the optic disc is swollen and has a marked increase in small vessels giving a " vasculitis" appearance. Peripapillary microangiopathy, visible in the early stages, is an important " marker" of the condition. Since Smith, Hoyt, and Susac ( 1) first pointed out the characteristic fundus findings, namely, circumpapillary telangiectatic microangiopathy, swelling of the nerve fibers, and absence of staining in fluorescein angiography, classic changes were found in symptomatic patients, presymptomatic cases, and asymptomatic maternal relatives. Absence of circumpapillary telangiectasia, although is certainly the hallmark of LHON, does not exclude the diagnosis of LHON even during the acute stage ( 20). Most reports have indicated that no leakage of dye occurs on fluorescein angiography ( 1,21). The fluorescein angiography of our patient showed dye leakage from dilated capillaries on both discs in late transit. Obvious optic disc edema on ophthalmoscopy and fluorescein leakage from the optic nerve does not preclude a diagnosis of Leber's optic neuropathy. Walsh and Hoyt ( 22) mention that some cases of LHON may be associated with pronounced swelling of the discs, hemorrhages, and exudates. They reported on one patient with a family history of visual loss in whom 2 diopters of bilateral optic disc edema were noted ( 22). Also, Rossazza et al. ( 23) presented a patient with bilateral disc edema, and reviewed other cases of Lundsgaard et al., Guillaumat et al. and Bregeat ( see 23). However, only one case in Newman's report ( 20) demonstrated disc leakage on angiography. A review of fluorescein angiography of our 12 patients with 11778 point mutations indicated that only one patient had dye leakage on the optic discs. As compared with the other patients, this patient had a higher degree of swelling in circumpapillary nerve fibers, and this may account for the fluorescein dye leakage. Although the mechanism of the pathogenesis of the disease still remains unknown fluorescein leakage on the optic discs does not exclude a diagnosis of LHON. Acknowledgment: This work was supported by grant no. NSC 83- 0412- B- 075- 107 ( M. Y. Y.) from the National Science Council. REFERENCES 1. Smith JL, Hoyt WF, Susac JO. Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 1973; 90: 349- 54. 2. Yen MY, Yen TC, Pang CY, Liu JH, Wei YH. Mitochondrial DNA mutation in Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci 1992; 33: 2561- 6. 3. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242: 1427- 30. 4. Mashima Y, Hiida Y, Oguchi Y, Kudoh J, Shimizu N. High frequency of mutations at position 11778 in mitochondrial ND4 gene in Japanese families with Leber's hereditary optic neuropathy. Hum Genet 1993; 92: 101- 2. 5. Johns DR. Improved molecular- genetic diagnosis of Leber's hereditary optic neuropathy. N Engl } Med 1990; 323: 1488- 9. 6. Johns DR, Berman J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biochem Biophys Res Commun 1991; 174: 1324- 30. 7. Howell N, Kubacka I, Xu M, McCullough DA. Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am ] Hum Genet 1991; 48: 935- 42. 8. Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savon-taus ML. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1991; 48: 1147- 53. 9. Johns DR, Neufeld MJ. Cytochrome b mutations in Leber hereditary optic neuropathy. Biochem Biophys Res Commun 1991; 181: 1358- 64. 10. 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A mitochondrial DNA / Ncuro- Ophthalmol, Vol. 16, No. 3, 2996 FLUORESCEIN LEAKAGE IN LHON 181 mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber's hereditary optic neuropathy and dystonia. Proc Natl Acad Sci USA 1994; 91: 6206- 10. 16. Borruat FX, Green WT, Graham EM, Sweeney MG, Morgan- Hughes JA, Sander MD. Late onset Leber's optic neuropathy: a case confused with ischemic optic neuropathy. Br } Ophthalmol 1992; 76: 571- 3. 17. Weiner NC, Newman NJ, Lesscll S, et al. Atypical Leber's hereditary optic neuropathy with molecular confirmation. Arch Neurol 1993; 50: 470- 3. 18. Hotta Y, Hayakawa M, Fujiki K, et al. An atypical Leber's hereditary optic neuropathy with the 11778 mutation. Br ] Ophthalmol 1993; 77: 748- 50. 19. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber's hereditary optic neuropathy masquerading as tobacco- alcohol amblyopia. Arch Ophthalmol 1993; 111: 1482- 5. 20. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991; 111: 750- 62. 21. Nikoskelainen E, Hoyt WF, Nummelin K, Schatz H. Fundus findings in Leber's hereditary optic neuroretinopathy, III: fluorescein angiographic studies. Arch Ophthalmol 1984; 102: 981- 9. 22. Walsh FB, Hoyt WF. Clinical neuro- ophthalmology. 3rd erf, vol. 1. Baltimore: Williams & Wilkins, 1969: 914. 23. Rossazza MMC, Degiovanni E, Larmande A- M, Rouzaud M. L'oedema papillaire et la maladie de Leber. Bull Soc Ophthalmol 1973; 4: 595- 7. / Neuro- Ophthalmol, Vol. 16, No. 3, 1996 |
