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Show © 1986 Raven Press, New York Leber's Optic Neuropathy New Observations Pedro F. Lopez, M.D. and]. Lawton Smith, M.D. Leber's disease is a hereditary optic neuropathy characterized by a triad of ocular fundus changes, including circumpapillary telangiectatic microangiopathy, pseudoedema of the nerve fiber layer around the disc, and absence of peripapillary staining on fluorescein angiography. We report two families in which the first afflicted member had insufficient fundus changes to enable a diagnosis of Leber's disease. However, the presence of telangiectatic microangiopathy in either a symptomatic or asymptomatic family member established the diagnosis of Leber's optic nerve disease under these circumstances. These observations suggest that circumpapilJary telangiectatic microangiopathy is a genetic marker and may not always be a pathogenetic predeterminant of Leber's optic neuropathy. In view of our findings, we propose the term "typical Leber's disease" for patients demonstrating the characteristic fundus triad and the term "atypical Leber's disease" for patients who lack diagnostic fundus changes but who have a family member with classic telangiectatic microangiopathy. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida. Address correspondence and reprint requests to J. L. Smith, MD, Bascom Palmer Eye Institute, PO Box 016009, Miami, FL 33101, U.S.A. 144 The pathognomonic ophthalmoscopic triad of acute Leber's optic neuropathy consists of (a) circumpapillary telangiectatic microangiopathy, (b) swelling of the nerve fiber layer around the disc (pseudoedema), and (c) absence of disc or peripapillary staining on fluorescein angiography (1). The importance of circumpapillary microvascular changes and their presence in asymptomatic family members have been well documented (1-6). We report two families in which the first afflicted member lacked sufficient telangiectatic microangiopathy to enable a diagnosis of Leber's disease. In both instances, it was the presence of unequivocal telangiectatic microangiopathy in a family member (either symptomatic or asymptomatic) that established the diagnosis of Leber's optic neuropathy. CASE REPORTS Family 1 Case 1 A 45-year-old, right-handed white woman was first seen at the Bascom Palmer Eye Institute in June 1968 for painless decrease in right eye vision. She had seen an ophthalmologist 10 months earlier, at which time her corrected vision was 20/20 in both eyes. In May 1968 she happened to close her left eye while driving and noted poor vision in her right eye. She denied pain on eye movement, headaches, or any other neurologic complaints and said she had always enjoyed excellent health. There was no family history of visual loss. She was started on prednisone 40 mg/day for retrobulbar optic neuritis but experienced no significant visual improvement. Neuro-ophthalmologic examination on July 12, 1968 revealed a corrected visual acuity of 8/200 in LEBER'S lWT/C NLUI?OPATHY 145 the right eye and 20/20 + 1 in the left eye. Findings from external and motility examinations were normal. An afferent pupillary defect was present on the right. Perinlt'tric examination revealed a caecocentral scotoma in the right eye and a small paracentral scotoma in the left t've. Findings from slit-lamp examination were within normal limits. Ophthalmoscop~' rt'vealed segmental atrophy of the papillomacular bundle in the right t'yt' (Fig. 1) with some narrowing of the arterioles in the area. A small "pigtail" vessel was described coming into the low~margin of the fovea in till' right eye, but the macula~ was normal. In the left eye, the optic disc was mildIv hyperemic in appearance but was sharp in outline (Fig. 2). The fovea in the left eye was within normal limits. Fluorescein angiography of the hyperemic appearing left disc revealed no abnormal staining (Fig. 3). The patient was placed on prednisone 100 mg/ every other day and experienced slight subjective visual improvement during the first week. However, during the second week, she experienced a profound loss of central vision in her left eye. Examination on July 30, 1968 revealed the right eye vision to be 16/200 and the left eye vision to be 20/100. The visual field of the left eye at that time demonstrated extension of the paracentral scotoma into a frank caecocentral defect. The patient was given parenteral hydroxycobalamin 1000 J..lg weekly and her vision stabilized at about 15/200 in both eyes by December 1968. Follow-up fundus FIG. 1. Right eye of case 1 on July 12. 1968. Note minimal nature of neurovascular changes around the disc. FIG. 2. Left eye of case 1 on July 12,1968. This photograph was slightly blurred. photographs on December 18, 1968 (Figs. 4-6) revealed bilateral papillomacular bundle atrophy. Case 2 In 1985, the 23-year-old, right-handed son of case 1 was referred to the Bascom Palmer Eve Institute for evaluation of visual loss of 9 months' duration. Prior to this he had always had good vision; a routine eye examination in school when he was 12 years old had revealed 20/20 acuity in both eyes. Nine months prior to referral, when working FIG. 3. Fluorescein angiogram of left eye of case 1 in July 1968 showed no staining. , Clill NCIl1'(1-ol'hthallllol. Vol. 6. No.3. 1986 I'. I. LOPLZ AND f. LAWTON SMITH \~'~~•. " .. I"~-.~ ~_I.i. . ~.....~... • , • I~)J.-. FIG. 4. Right eye of case 1 on December 18, 1968. in a print shop, the patient began to have trouble reading and painless blurring of vision in the left eye. Within 3 months, his right eye became involved. An ophthalmologist in October 1985 had found the right eye vision to be 20/40 and the left eye vision to be 20/400. The patient identified 12/13 color plates with the right eye and 9/13 with the left eye. Visual fields showed a paracentral scotoma in the right eye and a caecocentral scotoma in the left eye. The fundi demonstrated blurred disc margins and telangiectatic vessels in both eyes. A fluorescein angiogram was considered to be normal. In November 1985 another consultant noted that the patient's vision was down to 20/400 FIG. 5. Enlarged (2 x ) photo of right disc of case 1 on December 18, 1968. Note papillomacular bundle atrophy. FIG. 6. Enlarged (2 x) photo of left disc of case 1 on December 18. 1968. Note papillomacular bundle atrophy. in both eyes and made a diagnosis of Leber's optic nerve disease. The patient had no other neurological complaints. The patient's family history was particularly important for two reasons: his mother (case 1) suffered a similar visual loss 17 years ago with no sl:'bsequent improvement, and he is the youngest ot seven siblings-three brothers aged 29-35 and four sisters aged 24-36-all with excellent vision. A 42-year-old deceased brother was also reported to have had good vision. Neuro-ophthalmologic examination of case 2 on December 16, 1985 revealed a visual acuity of 2?/2~0 in ~he right eye and 20/500 in the left eye. Findings trom external and motility examinations ~ere normal. The pupils reacted to light. Visual held examination revealed full peripheral fields to 3/330 white in both eyes, but absolute central sco~ omas approximately 60° in diameter were plotted In both eyes. Findings from slit-lamp examination were .no~mal. Ophthalmoscopy and Hruby lens examl~atIon. revealed textbook fundus changes of L~ber s optic neuropathy (Figs. 7-8). The right diSC was hyperemic in general but this stood in stark contrast to focal papillomacular bundle pallor b~tween 8 and 10 o'clock (Fig. 9). A profound loss ot nerve fiber pattern was noted between the upper a~d lower temporal arcades. Striking circumpapillary telangiectatic microangiopathy was obse~ved, with some of the vessels actually extending over the surface of the disc. The macula a~d peripheral fundus were normal. In the left eye (Fig. 10) there was pseudoedema of the nerve fiber layer, best seen nasally, with focal papillomacular LEBER'S OPTIC NEUROPATHY /47 FIG. 7. Right eye of case 2 on December 16, 1985. Shows changes of acute Leber's optic nerve disease. bundle atrophy, and classic circumpapillary telangiectatic microangiopathy. Three sisters of case 2 were subsequently examined, all of whom had 20/20 vision with correction. These sisters, aged 24, 26, and 36, were found to have absent, mild and moderate telangiectatic microangiopathy, respectively. The 5-year-old son of the youngest sister had 20/30 vision in both eyes and minimal telangiectatic microangiopathy. The referring ophthalmologist (Dr. Sedwick) subsequently provided fundus photographs of case 2 made on October 2, 1985 (2 months before our examination) (Figs. 11-12) and again on June 6, 1986 (6 months after our examination) (Figs. 13-14). These showed the classic sequential fundus changes of Leber's optic neuropathy. FIG. 8. Left eye of case 2 on December 16, 1985. Shows changes of acute Leber's optic nerve disease. FIG. 9. Enlarged (2 x) photo of right disc of case 2 on December 16, 1985. Abnormal vessel of microangiopathy marked with arrow. Comment The diagnosis of Leber's optic neuropathy in the 45-year-old woman (case 1) was virtually impossible to make when she presented in view of her sex, age, negative family history, and the lack of diagnostic fundus changes. Indeed, the initial impressions of retrobulbar optic neuritis or toxic amblyopia did not yield to the true etiologic diagnosis until 17 years later, when her son (case 2) presented with classic Leber's optic neuropathy replete with striking circumpapillary telangiectatic microangiopathy. It should be emphasized that the presence of fundoscopic neovascular abnor- FIG. 10. Enlarged (2 x) photo of left disc of case 2 on December 16, 1985. Abnormal vessel marked with arrow. I C1ill Nl'lIro-ol"llh"llIIol. Vol. 6, No.3, 1986 1-18 I'. I /( l/'LL AND f. LAWTON SMITH FIG. 11. Right eye of case 2-photo made October 4. 1985 malities per se does not invariably portend the occurrence of Leber's disease (5). However, their absence in case I indicates that.a paucity of fundus findings in a patient neither prognosticallv precludes nor diagnostically excludes Leber's optic neuropathy if circumpapillar~' telangiectatic microangiopathy is present in a family member. Family 2 Case 3 A 19-year-old, right-handed vvhite man first consulted an ophthalmologist in January 1985 for sudden painless loss of vision in both eyes. His vision had been normal until the previo~s week when he began to note slight blurring of \'isil)l1 FIG. 12. Left eye of case 2-photo made October 4, 1985. FIG. 13. Right eye of case 2-photo made June 6. 1986 and difficult~, reading. The symptoms had apparentlv resolved by the weekend. However, on , , Monda~', whl>n dri\'ing home from schooL he ex-perienced an abrupt and profound visual loss in both eyes. After barely being able to finish driving home he was rushed to an ophthalmologist. Because of suspected optic neuritis, he was started on prednisone 60 mgda~'. However, no significant visual improvement occurred. He was subsequently seen b~' a neurologist and two neuro-ophthalmologists. Neurologic examination, cerebrospinal tluid studies. computed tomography and radionuclide brain scan re\'ealed no abnormalities, The impression was of idiopathic optic neuritis, G. 14. left eye of case 2-pnoto made June 6, 1986. Note dramatic decrease in pseudoedema and microvascular changes over the previous eight months. Compare the sequential changes as seen in Figures 9-14. LEREWS OPTIC NEUI~OPATHY /49 One year later, the patient was rl'fl'rred to the Bascom Palmer Eye Institutt' for persistent poor vision. Past history revealed that Iw had had two rather severe flu-likl' episodes prior to the onsl't of visual loss. However, his tempt'ratllre did not exceed 99°F. He had receivl'd no injections, drugs, or immunizations before tht' onset of the present illness. He denied Uhthoif's symptom, L'lwrmitte's symptom, pain on motilln of tht' globe, or any other neurologic abnormality. He had been subject to migraine headaches bl'ginning at age 13 but these had cleared spontaneously by age 15. The family history was neg"tiw for similar visual loss; however, there had bet'n no maternal uncles in three preceding generations. Neuro-ophthalmologic examination on Januarv 17, 1986 revealed a visual acuity of 10/350 in both eyes. Findings from external a~d motility examinations were normal. The pupils were rather large and reacted to light. No afferent pupillary defect was noted. Perimetric examination revealed intact peripheral fields but large absolute central scotomas in both eyes. Findings from slit-lamp examination were normal. Ophthalmoscopy revealed clear media in both eyes. Definite diffuse pallor was noted in both discs. The right eye showed mild circumpapillary vascular tortuosity along the lower temporal arcade (Fig. 15). The left eye showed similar but lesser changes (Fig. 16). Applanation tension was 15 in both eyes and blood pressure was 150/80. The patient's immediate family was examined. The 49-year-old father's vision was 20/25-3 in right FIG. 15. Right eye of case 3 on January 17, 1986. Note unimpressive microvascular changes. FIG. 16. Left eye of case 3 on January 17,1986. eye and 20/20-2 in left eye. His blood pressure was 120/68. Results of ophthalmoscopy were within normal limits. Small vessels in the circumpapillary retina were slightly prominent. However, these were the same all the way around and did not resemble the prolongated abnormal vessels characteristic of the microangiopathy of Leber's optic neuropathy. The 45-year-old mother had 20/15-2 acuitv in both eyes. Ophthalmoscopy revealed a congei-,ital conus in the right eye. Modest telangiectatic vessels were noted along the lower temporal region of the left eye, but were not distinctive enough to make a definite diagnostic call. However, the patient's 17-year-old brother, who had 20/15-1 vision in both eyes and was totally asymptomatic, showed on ophthalmoscopy classic and profuse circumpapillary telangiectatic changes in both eyes (Figs. 17-19). COllllllellt The clinical presentation of this 19-year-old man was very suggestive of Leber's optic neuropathy. Indeed, this diagnosis had been considered by the other consultants who had seen the patient. However, the apparent simultaneous onset of symptoms in both eyes, together with subtle fundus changes and a negative family history made them initially suspect an idiopathic optic neuritis. The key to the diagnosis was ophthalmoscopic examination of the 17-year-old asymptomatic brother which demonstrated striking circumpapillary telangiectatic microangiopathy. 150 I). F. LOPEZ AND ,. LAWTON SMITH FIG. 17. Right eye of asymptomatic brother of case 3 on January 17, 1986. Through the courtesy of Dr. Slavin, we were subsequently able to obtain copies of fundus pictures made of case 3 on February 26, 1985 (Figs. 20-21). These showed not only subtle microangiopathic changes but also a disparate degree of segmental disc and papillomacular bundle atrophy. This indicated that perhaps the lesions in the two eyes occurred independently of each other rather than simultaneously. Perhaps the initial symptoms of blurring and difficulty reading experi- FIG. 18. Enlarged (2 x) disc photo of right eye of asymptomatic brother of case 3 on January 17, 1986. Circumpapillary microvascular telangiectatic changes were very dramatic on Hruby lens examination, although they are difficult to see here, even with magnification. An abnormal vessel is marked by an arrow. FIG. 19. Left eye of asymptomatic brother of case 3 on January 17, 1986. Telangiectatic changes were easily seen with Hruby lens around this disc. enced the week prior to the visual catastrophe signaled involvement of the first eye, which was not further noted until the second eve became involved when the patient was coming home from school. This may have resulted in the apparent simultaneous bilateral visual loss experienced by this patient. DISCUSSION Leber's optic neuropathy is a hereditary disorder characterized in men by a rapid loss of central vision during early adult life (6,7). According FIG. 20. Right eye of case 3 on February 26. 1985 (courtesy of Dr. Slavin). LEBER'S OPTIC NEUROPATHY /5/ FIG. 21. left eye of case 3 on February 26. 1985 (courtesy of Dr. Slavin). Note circumpapillary changes seen in retrospect that were much less apparent in Figs. 17-19 (January 17,1986). to Leber (7), the disease affects males nine times as often as females and usually strikes between the ages of 18 and 23. Classically, the disease is transmitted through uninvolved women and frequently affects the maternal uncles and brothers of the patient (1,6). Both sex-linked recessive and cytoplasmic inheritance have been proposed as explanations for these phenomena; however, the genetics of the disorder remain uncertain (6,8). When the disease first appears in a family, the diagnosis is often delayed or never made. The affected patient is subjected to extensive neurodiagnostic procedures. Recognition of the acute phase of Leber's optic neuropathy was improved by the description of a triad of pathognomonic fundus changes (1), among which is circumpapillary telangiectatic microangiopathy. Recently, Nikoskelainen et a1. (5) have demonstrated the presence of similar neurovascular changes in asymptomatic family members of patients with Leber's disease. These authors emphasized that such neurovascular abnormalities may occur in varying degrees in asymptomatic members of the family. In this study, we describe a gradation of neurovascular abnormalities in symptomatic patients with Leber's disease. In two families, the fundus changes in the propositi were inconclusive. The diagnosis of Leber's disease was made by finding the pathognomonic microangiopathy in a symptomatic or asymptomatic family member. In the first case, the nonclassical clinical presentation and absent neurovascular fundus changes postponed the diagnosis of Leber's disease until her youngest son (case 2) presented 17 years later with classic Leber's optic neuropathy including the full-blown ophthalmoscopic diagnostic triad. In case 3, although the clinical presentation was suggestive of Leber's optic nerve disease, the fundus neurovascular abnormalities were insufficient to confirm that diagnosis. However, the striking and diagnostic fundus findings in the patient's asymptomatic brother established the diagnosis. The histories of the families reported in this study suggest that there is no correlation between the severity (number, size or tortuosity) of the telangiectatic microangiopathy and the occurrence of Leber's optic neuropathy in either males or females. In family 1, the mother had nil to equivocal microangiopathy in the acute phase of her disease, whereas her symptomatic son presented, years later, with overt microangiopathy and two of her asymptomatic daughters showed subtle microvascular changes. In family 2, the symptomatic man had minimal microangiopathy when seen in consultation, although his asymptomatic brother possessed striking telangiectatic microangiopathy. The lack of correlation between the severity of the telangiectatic microangiopathy and the occurrence of Leber's optic neuropathy indicates that the pathology of this disease is not in the ophthalmoscopically visible microvasculature. Indeed, Lessell et a1. (9) have noted that it seems unlikely that the malformed blood vessels (microangiopathy) are directly responsible for the loss of vision, as they are visible in the fundus long before vision is lost and are found in unaffected family members. The dissociation between the severity of the microangiopathy and the presence of Leber's disease in these two families supports Roger's contention that microangiopathic telangiectasias are a coincidental genetic marker for Leber's disease (3). Although we recognize that acute Leber's optic neuropathy can occur in an individual showing only minimal degrees of the characteristic fundus changes, we do not wish to minimize their diagnostic importance. Indeed, we hesitate to make the diagnosis of Leber's optic neuropathy in the absence of circumpapillary telangiectatic microangiopathy in either the patient or a family member. Many questions remain to be answered about Leber's optic neuropathy. Is the telangiectatic microangiopathy present at birth? Do the small vessels seen in children remain stable or do they increase in size, number or tortuosity? What is the overlap between normal circumpapillary microvasculature and subtle telangiectatic microangiopathy and how is the distinction between them I Gill Nl'lIrtl'Ill'lJtlwlllllll. Vol. 6. Nil. 3. 1986 /52 P. F. LOPEZ AND f. LAWTON SMITH best defined? Are there <lny predictive f<lcturs that identify subsets of <lsymptom<ltic f<lmily members who are Iikl'1y to <lcquire the dise<lse? Are the fundus findin~s lesser in dl'~rel' in affected women than in men? What accounts for the more rapid clearing of the fundus chan~es in some patients than in others? In view l)f our findin~s, we propose two designations of diagnostic utility in acute Leber's optic neuropathy. "Typical" Leber's optic neuropathy is defined as a clinical presentation compatible with the disease plus the pathognomonic ophthalmoscopic triad (1). "Atypical" Leber's optic neuropathy is defined as a clinical presentation compatible with Leber's disease but with an absence or paucity of telangiectatic microangiopathy in the patient, and the presence of diagnostic fundus changes in a family member (either symptomatic or asymptomatic). The occurrence of atypical Leber's optic neuropathy, as documented in our two families, argues strongly for careful ophthalmoscopic examination of family members when this diagnosis is contemplated. The importance of reviewing magnified high resolution colored fundus photographs of the optic discs made early in the course of the disease may also prove helpful in confirming the diagnosis. Acknowledgments: Dr. L. A. Sedwick and Dr. M. L. Slavin kindly provided fundus photographs and additional clinical details of the patients here reported, I ellll Nl'"m-"/,iltlltIl,,ItII. V"I. 6. No. .J, 198b which were of great help. The excellent photographic work of Mrs. Ditte Hess, Mrs. Erhnda Duna, and other members of the Bascom Palmer Institute section of photugraphy is greatly appreciated. Finally, the painstaking work of Mrs. Barbara French in the darkroom, as well as her enlargements and photographic printing, are gratefully acknowledged. REFERENCES 1. Smith )L. Huyt WF, Susac )0. Ocular fundus in Leber's uptic neuropathy. Arch 0I'hthalmo/1973;90:349-54. 2. NikuskeJainen E, Sogg RL, Rosenthal AR, et al. The early phase of Leber's hereditary optic atrophy. Arch Ophtha/mol J977;95:969-78. 3. Rogers)A Leber's disease. AlIst! Ophtha/mo/1977;5:111-9. 4. Carroll WM, Maslaglia FL Leber's optic neuropathy; a clinical and visual evuked potential study of affected and asymptomatic members of a six generation family. Brain 1979; 102:559-80. 5. Nikuskelainen E, Huvt WF. Nummelin K. Ophthalmoscopic findings in Leber's optic neuropathy: 1. Fundus iindings in asvmptomatic family members. Arch Ophtha/mol 1982;100 1597-1602 6. Miller NR. ~Val,;h alld HOI/I', tI II Ilea/ Ilellro-ophthil/mology. Vol. 1 Baltimore: Williams & Wilkins. 1982:311-7. 7. Leber T. Ueber hereditare und cungenitalangelegte sehnervenleiden. Gral'rt", Ardl ClIII Exl' 01'''tI1l1Imol 1871;17:24991. 8. Wallace DC A ne\\' manifestation oi Leber's disease and a ne\\' explanation ior the agency responsible for its unusual pattern oi inheritance. Bralll 1970;93: 121-32. 9. Lessell S, Gise RL Krohel GB. Bilateral optic neuropathy with remission in young men; \'ariation on a theme by Leber' Arch Xc"",1 1983AO:2-6. 10. McCluskey OJ, O'Connor PS, Sheehy )T. Leber's optic neuropath\' and Charcot-:-'Iarie-Tooth Disease. ! CIill .\["/Iro(' I'htha/Hll'! 1986;6:76-81. |
