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Show , t, 1992 Raven Press. Ltd .. New York Visual Recovery in Patients with Leber's Hereditary Optic Neuropathy and the 11778 Mutation Edwin M. Stone, M. D., Ph. D., Nancy J. Newman, M. D., Neil R. Miller, M. D., Donald R. Johns, M. D., Marie T. Lott, M. A., and Douglas C. Wallace, ph. D. Five patients with Leber's hereditary optic neuropathy ( LHON) and the 11778 mitochondrial mutation spontaneously recovered 20/ 40 or better visual acuity in at least one eye after months to years of legal blindness. The patients ranged in age from 9 to 45 years, and the duration of visual loss before recovery ranged from several months to 5.9 years. These patients constitute only about 4% of the 136 affected LHON patients we have studied who also had the 11778 mutation in their mitochondrial DNA. Thus, even though the visual prognosis for most patients with LHON and the 11778 mutation is poor, a few individuals do recover near- normal vision in at least one eye even years after the initial visual loss. Key Words: Leber's hereditary optic neuropathy- 11778 Mitochondrial mutation. From the Department of Ophthalmology ( E. M. S.), The University of Iowa College of Medicine; the Departments of Ophthalmology ( N. j. N.), Neurology ( N. j. N., D. C. W.) and the Center for Genetics and Molecular Medicine ( N. j. N., M. T. L.. D. C. W.), Emory University School of Medicine; and the Departments of Ophthalmology ( N. R. M.) Neurology ( N. R. M., D. R. j.), and Neurosurgery ( N. R. M.), The johns Hopkins College of Medicine, Baltimore, Maryland, U. S. A. Address correspondence and reprint requests to Dr. Edwin M. Stone, Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA 52242, U. S. A. This work was supported in part by unrestricted grants from Research to Prevent Blindness, Inc., to the Departments of Ophthalmology of the University of Iowa and Emory University; National Institutes of Health grants EY08426 ( Dr. Stone). and N~ 21328 ( Dr. W~ lIace); < md. a Muscular Dvstrophy Clinical RI'''~ Mo: h L', r. 1nt ( fIr h. JiL". · ). 10 Most cases of Leber's hereditary optic neuropathy ( LHON) are associated with a mutation in the circular mitochondrial DNA ( mtDNA) at position 11778 ( 1,2). This mutation causes a substitution of histidine for arginine at amino acid 340 of a subunit of the respiratory enzyme NADH dehydrogenase. Some patients who have the clinical symptoms and signs of LHON, including an extensive family history of maternal inheritance of the disease, lack the 11778 mutation. It has recently been shown that a subset of these individuals have other mitochondrial mutations ( 3). The visual prognosiS for patients with LHON is poor ( 4). Most patients with the disorder have permanently decreased visual acuity in both eyes associated with large central or cecocentral scotomas and decreased color perception. There are, however, patients with clinical symptoms and signs of LHON whose visual function spontaneously improved years after the onset of the disorder (~ 9). It has been suggested that the presence of the 11778 mutation is incompatible with visual recovery and that the few patients with LHON who do eventually recover visual function are those who have a normal 11778 locus and presumably some other mtDNA mutation ( 10). We report five patients with LHON associated with the 11778 mutation who experienced spontaneous visual improvement up to 6 years after their visual loss. CASE REPORTS ( Table 1) Case 1 A 45- year- old man noticed a sudden, painless loss of vision in his right eye in December 1969 as he tried to focus a camera. He consulted his oph- VISUAL RECOVERY IN LEBER'S OPTIC NEUROPATHY 11 TABLE 1. Summary of visual acuity Worst vision After recovery Duration of Case Age 00. 0.5 00. 0.5 binocular loss 1 45 CF 20/ 200 20/ 20 20/ 200 · 5.9 years 2 14 20/ 400 16/ 400 20/ 30 20/ 400 4 years 3 12 1/ 200b 5/ 200 1/ 200b 20/ 25 2.5 years 4 9 20/ 200 20/ 200 20/ 40 20/ 40 Several months 5 15 20/ 400 20/ 400 20/ 30 CF 4' 1 year CF, count fingers. • Surgical injury of left optic nerve during craniotomy. b Persistent hyperplastic primary vitreous and cataract present at birth. thalmologist 12 days later complaining of poor visual acuity and was found to have 20/ 300 vision 0.0., 20/ 30 0.5. There was no family history of visual loss. The patient's ocular history was significant only for a visit to the same ophthalmologist 6 years earlier at which time his examination was normal. The patient smoked 30 cigarettes per day and consumed 8 cocktails per week. The right optic disc was hyperemic, and a central field defect was noted on Amsler grid. Optic neuritis was diagnosed and steroid treatment was begun. There was no improvement after 4 months of treatment. The patient was referred to another ophthalmologist who noted count fingers vision at 6 feet 0.0. He was admitted to the hospital for evaluation, but the only abnormality that was found was 80 mg% protein in the cerebrospinal fluid ( CSF) ( normal 40-- 45 mg%). In October 1970, 10 months after his initial visual loss, the visual acuity in the left eye began to change and dropped steadily to 20170 over the next eight months. Central scotomas were present in both eyes. Retrobulbar neuritis was diagnosed, and the patient was treated with a brief course of Vasodilan ( isoxuprine hydrochloride) without benefit. One year later, the patient underwent an exploratory craniotomy, which failed to reveal any pathology. Intraoperative damage to the left optic nerve caused the visual acuity in the left eye to drop to 20/ 200 where it has remained. The patient was treated with weekly vitamin B12 injections for the next 3 years for a possible nutritional amblyopia. In November 1975, almost 6 years after his initial visual loss, the patient regained 20/ 20 vision in his right eye over a period of days to weeks. The vision in the right eye has remained stable for 15 years. The diagnosis of Leber's hereditary optic neuropathy was not suspected until a 40- year- old nephew lost vision bilaterally in 1990 and was found to have the 11778 mutation in his mitochondrial DNA. An investigation of the nephew's family was the impetus to test our patient, who was also found to be homoplasmic for the 11778 mutation. Case 2 A 14- year- old boy with a negative family history for any eye disease was thought to be perfectly healthy until March 1986, when he experienced painless loss of vision in the left eye. Within several weeks, the vision in the right eye began to decrease. He underwent a computed tomography ( CT) scan of the brain and orbits that showed no abnormalities. By May 1986, visual acuity had dropped to 20/ 400 O. U., there were bilateral central scotomas, and both optic discs were noted to be hyperemic and slightly swollen. The results of an evaluation that included magnetic resonance imaging ( MRI), serologic studies, and lumbar puncture were normal. The patient was referred to a neuro- ophthalmologist who diagnosed possible LHON. In July, the patient had visual acuity of 20/ 400 0.0. and 16/ 400 0.5. Color vision using HardyRand- Rittler ( HRR) pseudoisochromatic plates was 1 of 10 0.0. and 0 of 10 0.5. Visual field testing demonstrated bilateral central scotomas with some constriction of the peripheral fields. There was a mild left relative afferent pupillary defect. Ophthalmoscopy revealed mild swelling and hyperemia of the nasal portion of the right optic disc with some mild temporal pallor. The left optic disc was diffusely pale. The patient was examined at regular intervals over the next 3 years, during which time his vision initially worsened and then stabilized. In August 1989, the visual acuity was still 6/ 200 O. U., color vision was markedly diminished in each eye, and there were large central scotomas. Both optic discs were diffusely pale. The patient's blood was found to be homoplasmic for the 11778 mutation. During the summer of 1990, the patient began to experience improvement in visual func- I Clill Neuro- ophthalmol. Vol. 12. No. 1. 1992 12 E. M. STONE ET AL. tion in both eyes. He was seen in October 1990, 4.5 years after th~ initial onset of visual symptoms, at which time his visual acuity had improved to 20/ 30 0.0., and 20/ 400 0.5. The central scotomas had decreased markedly in size. Both optic discs remained pale. Case 3 A 12- year- old boy born with persistent hyperplastic primary vitreous ( PHPV) and cataract O. O. experienced blurred vision 0.5. This progressively worsened over the next 3 months to an acuity of 5/ 200. Absent color vision, a large central scotoma ( Fig. 1, panel A) and optic atrophy were documented. The results of an extensive evaluation including a brain CT scan with and without cisternography, brain MRI, ( ERG) and electrocardiogram ( EKG) were normal. Visually evoked responses were absent. The patient's medical history was also notable for mild growth retardation and sexual immaturity. Family history was negative for visual loss. Thirty months later, the patient had the sudden onset of a " flash" in his left eye, followed 1 hour later by the ability to see well with his left eye. An examination revealed visual acuity of 20/ 25 0.5. and normal color vision. The Goldmann visual field 0.5. continued to show a large dense central scotoma, but within the center was an approximately 2- degree area of intact visual field and acuity ( Fig. 1, panel B). The optic disc was profoundly atrophic. The blood of the patient and several maternally related family members was found to be homoplasmic for the 11778 mitochondrial DNA mutation. Case 4 A 9- year- old girl presented with bilateral visual loss that progressively deteriorated over 1 month to 20/ 200 O. U. Errors in color vision and central visual field defects were noted. Ophthalmoscopic examination was remarkable for optic disc pallor. An evaluation included a normal brain MRI and CSF analysis, and an " inconclusive" muscle biopsy. She was found to have previously unrecognized insulin- dependent diabetes mellitus and was treated accordingly. Family history was notable for several maternal relatives with permanent bilateral visual loss that occurred in their 30s secondary to LHON. Blood samples from the patient and maternally related family members were homoplasmic for the 11778 mutation. Several months later, the patient noted gradual improvement in visual acuitv in first the left. then the right, eye. At FIG. 1. Goldmann visual fields from Case 3 before and after recovery. Areas between isopters are shaded: white denotes an area more sensitive than the 12e isopter, while the darkest gray indicates an area that cannot see the V4e target. Panel A is the field obtained 5 months after the onset of symptoms at which time the visual acuity was 5/ 200. Panel B is the field obtained 2 years later when the central acuity had improved to 20/ 25. Notice the small fenestration in the central scotoma. the most recent examination, she was 20/ 40 O. U. Her optic discs remain profoundly atrophic. Case 5 A I5- year- old boy experienced decreased vision in his left eye, which progressively deteriorated over months. An ophthalmologic examination was normal, and the patient was diagnosed as having ( A) ( B) VISUAL RECOVERY IN LEBER'S OPTIC NEUROPATHY 13 factitious visual loss. After 8 months of psychotherapy, the vision in the right eye began to fail. Six months later, his visual acuity was 20/ 400 O. U., and optic atrophy was noted. Visual evoked responses revealed increased latency. A brain MRI and brainstem- evoked potentials were normal. The patient's medical history was negative, and his family history was unremarkable for visual loss except for his maternal grandmother, who had cataracts and glaucoma. An examination of the patient's blood revealed it to be homoplasmic for the 11778 mutation. Approximately 1 year after the onset of visual loss in the right eye, the patient noticed gradual improvement in the central acuity of the right eye over several weeks. An examination revealed visual acuities of 20/ 30 0.0. and count fingers at 4 feet 0.5. There was no relative afferent pupillary defect. Goldmann visual fields showed bilateral central scotomas to approximately 20 degrees O. U., but within the scotoma 0.0., there was central sparing of vision of about 5 degrees. His optic discs showed optic atrophy temporally, and there was loss of nerve fiber layer in the papillomacular bundles of both eyes. DISCUSSION It has long been recognized that a small subset of patients with LHON eventually recover a substantial amount of central visual acuity ( 6- 9). However, before the identification of a specific, assayable causative mutation, the diagnosis of LHON was rarely certain, and visual recovery in patients initially thought to have LHON raised the possibility of an incorrect diagnosis. With the identification of the 11778 mutation came the ability to make a firm diagnosis of LHON. The great majority of patients who lose their central vision as the result of the 11778 mutation do not recover it. In fact, the five cases described in this report represent only about 4% of the 136 11778 LHON patients who have been studied in our three institutions. Holt et al. ( 10) suggested that the 11778 mutation is incompatible with visual recovery. Our five cases demonstrate conclusively that patients with the 11778 mutation can recover vision. The documentation of spontaneous visual recovery in patients with the 11778 mutation is important for several reasons. First, it allows us to discuss the small, but real, possibility of visual recovery with our patients in whom we identify the 11778 mutation. Second, it allows us to be certain that this very unusual pattern of visual recovery is in fact occurring in patients with bona fide LHON and not some other disease such as nutritional am-blyopia that one would more readily expect to be associated with visual recovery. The percentage of our 11778 LHON patients who recovered vision is substantially lower than the 12- 25% reported by other investigators ( 5,8,11) for groups of patients with the clinical diagnosis of LHON. This difference could be caused by a higher rate of recovery in patients with other mitochondrial mutations ( 3), but at least some of the discrepancy is probably caused by the accidental inclusion of non- leber's cases in series that were gathered according to clinical criteria alone. There are several additional noteworthy features of our five patients. In our experience, the most common incorrect diagnosis made in cases of LHON, especially during the period when only one eye is affected, is optic neuritis. Patients so diagnosed frequently receive steroids, often in large doses, without effect. The fact that large doses of steroids were given to our first patient without benefit, only to have his vision return spontaneously nearly 6 years later, strengthens our anecdotal clinical impression that steroids are of no benefit in this disease. Two of our patients recovered vision by developing small islands of normal vision within their central scotomas as depicted in Fig. 1. This phenomenon was first noted by Hancock in 1908 ( 12). In 1970, Brunette and Bernier ( 11) published tangent fields with this finding from one of their Leber's patients who had recovered vision. In our experience, such fenestrated scotomas are characteristic of recovered LHON, and this diagnosis should be entertained whenever this visual field finding is present. The visual recovery in some of our patients was rather rapid and was signaled by flashing lights within the scotoma. The mechanism of the visual recovery in these patients is, at present, wholly unknown. However, it is exciting to think that some of our patients with LHON might recover even 6 years after their visual loss. We are hopeful that further study of such patients will uncover some portion of the visual recovery mechanism that is amenable to medical intervention so that patients who have lost vision from LHON might be successfully treated. Acknowledgments: The authors wish to thank Dr. Francis C. Dunn, Jr., for providing the clinical information and blood sample from Case 1. We thank Drs. Myles Behrens, Norman J. Schatz, and Steven E. Feldon for permission to use Cases 2, 3, and 4, respectively. Cases 3, 4, and 5 are designated Cases 60.01, 44.01, and 78.01, respectively, in Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's Hereditary Optic Neuropathy with the 11778 mutation. Am JOphthalmoI1991; 111: 750- 762. J Clill Neuro-{) phtlwlmol, Vol. 12, No. I, 1992 E. M. STONE ET AI. RFFERENCES :\ · " Il.. L · t · .... , 2"".' · , h '.;, Lot! MT, et al. Mitochondrial DNA mut. ltinn JssL> ci""' d with Leber's hereditary optic neurop, lthy. Scil'llce 198/); 242: 1427- 30. 2. Singh G, Lot! MT, Wallace DC. A mitochondrial DNA mutahem as a cause of Leber's hereditary optic neuropathy. N EnSf J Med 1989; 320: 1300- 5. J. Johns DR, Berman, J. Alternative simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biodzem Biophys Res Comml/ n 1991; 174: 1324- 30. 4. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy, II: The fundus findings in the affected family members. Arch Ophthall1lo/ 1983; 101: 1059- 68. 5. Lundsgaard R. Leber's disease: a genealogic, genetic, and clinical study of 101 cases of retrobulbar optic neuritis in 20 Danish families. Acta Ophthalmo/ 1944; 21( Suppl): 1- 306. , Clin Neuro- ophthalmol, Vol. 12, No. 1, 1992 6. Bird AMD, McEachern D. Leber's hereditary optic atrophy in a Canadian family. Can Med Ass / 1949; 61: 376- 83. 7. Constantine EF. Leber's disease with recovery. Arch Ophthalmo/ 1955; 53: 608. 8. Van Senus AHC. Leber's disease in the Netherlands. Doc Ophtha/ mo/ 1963; 17: 1- 161. 9. Lessell 5, Gise RL, Krohel GB. Bilateral optic neuropathy with remission in young men: variation on a theme by Leber? Arch Nel/ ro/ 1983; 40: 2"'{). 10. Holt IJ, Miller DH, Harding AE. Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy. / Med Genet 1989; 26: 739- 43. 11. Brunette JR, Bernier, RG. Diagnostic et pronostic de la maladie de Leber: incidence de la recuperation totale spontanee. Un Med Canada 1970; 99: 643- 52. 12. Hancock. Hereditary optic atrophy ( Leber's Disease). Roy Lond Ophtha/ Hosp Rep 1908; 17: 167- 77. |
