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Show II) 1986 Raven Press, New York Leber's Optic Neuropathy and Charcot-Marie-Tooth Disease Report of a Case DruAnn J. McCluskey, M.D., Patrick S, O'Connor, M.D., and James Timothy Sheehy, M.D. The case of a patient with Charcot-Marie-Tooth disease who developed the acute fundus findings of Leber's optic neuropathy is described. Previous reports have proposed a genetic interrelationship between the two diseases. This relationship has been speculative, however, because the acute fundus findings of Leber's have never been observed in a case of Charcot-MarieTooth disease. This case adds support for a suggested genetic relationship between the two diseases. It is also possible that the optic atrophy previously described in Charcot-Marie-Tooth may represent the late findings of Leber's optic neuropathy. From the Department of Ophthalmology, University of Texas Health Science Center (D.-A.J.M., P.S.O'c.) and The Neurology Clinic of San Antonio (J.T.S.), San Antonio, Texas. Address correspondence and reprint requests to Patrick S. O'Connor, M.D., 12709 Toepperwein Rd., Suite 206, San Antonio, TX 78233, U.S.A. 76 Optic atrophy has been reported in association with Charcot-Marie-Tooth (CMn disease (1-9); however, such cases are relatively rare. Although the nature of the optic atrophy seen in these patients has been described as similar to that occurring in the hereditary optic atrophies (4), in the majority of cases reported the description of the clinical course of visual loss, appearance of the disc, and visual fields has been fragmentary or omitted. Hereditary and sporadic neurologic disorders commonly are associated with Leber's optic neuropathy (10-16); however, only one family has been described with Charcot-Marie-Tooth and concurrent Leber's disease (9). In this report, the two conditions were feIt to be inherited independently and none of the patients with optic atrophy were observed during the acute phase. We describe the clinical course of a patient with Charcot-Marie-Tooth disease who presented with acute visual loss and the classic fundus findings of Leber's optic neuropathy (19). To our knowledge, this is the first such case reported. CASE REPORT History The patient was a 47-year-old white male, wheelchair-bound secondary to the progressive atrophy of Charcot-Marie-Tooth disease. He had no visual complaints until apprOximately 3 months prior to examination. At that time, when momentarily occluding his right eye, he noticed livery blurry" vision out of the left eye, "like butter over a lens." The patient was seen by an ophthalmologist at that time, but no abnormality was noted. The vision on the left remained poor over the next LEBER'S AND CHARCOT-MARIE-TOOTH DISEASE 77 2 months, and he began experiencing intermittent episodes of blurred vision on the right. The patient had had Charcot-Marie-Tooth disease for many years and had been started recently on Diabinese for type II diabetes. There was no history of toxin exposure, dietary irregularities, or alcohol ingestion, but the patient occasionally chewed tobacco. Family history was positive for dominantly inherited Charcot-Marie-Tooth disease, with no history of visual loss on the maternal or paternal side. On examination, the patient's best corrected vision was 20/30·1 on the right and count fingers at 2 ft on the left. There was no ptosis and his motility examination was normal. No Ishihara color plates were missed on the right, but none could be identified on the left. Goldmann visual field testing was normal on the right, but showed a large cecocentral scotoma to the 1I-4E isopter on the left (Fig. 1). A 2 + Marcus-Gunn pupil was present on the left. Slit-lamp examination was normal. Funduscopic exam revealed a hyperemic, slightly congested disc on the right with peripapillary telangiectasia, most pronounced along the superior and inferior temporal arcades (Fig. 2a). No hemorrhages were noted. The macula and periphery were normal. Mild peripapillary congestion, a few telangiectatic vessels, and early temporal pallor were evident on the left (Fig. 2b), but the macula and periphery were normal. Fluorescein angiography revealed no leakage from the disc or peripapillary region during either the early or late phases (Fig. 3). The patient had a slight facial diplegia and ataxia of speech. There was marked distal wasting of aU four extremities (Fig. 4) and a pes cavus deformity. Motor testing was 4/5 proximally and 2/5 distally in the upper extremities, with 3/5 proximal strength and 0/5 distal strength in the lower extremities. Sensation was mildly diminished and distal deep tendon reflexes were absent. Oinical Course An FTA-ABS, complete blood cell count with differential, Serum B12, and folate were normal. A high-resolution computerized tomography scan with and without contrast was also normal. The patient was begun on Neo-Betalin 12 (1 cc i.m. weekly for 10 weeks), zinc (220 mg orally with meals), and a multivitamin preparation. A subtenons injection of Kenalog (40 mg) was given on the right. The patient was advised to abstain from aU alcohol and tobacco products, and was referred FIG. 1. Goldmann visual fields demonstrating a large cecocentral scotoma on the left at initial presentation. The visual field on the right was normal. to his internist for blood glucose control with the recommendation that Diabinese be discontinued. Despite strict adherence to the above regimen, abstinence from tobacco, and the discontinudtion of Diabinese, the vision on the right had declined to 20/200 at his 2-month follow-up visit. A trace Marcus-Gunn pupil was present on the left and only one Ishihara color plate was identified on the right. Repeat visual fields now revealed a large cecocentral scotoma on the right (Fig. 5). The right disc demonstrated increasing atrophy and loss of the peripapillary telangiectasias. The patient's vision fell to 5/200 over 4 months of follow-up. Eight months after onset he began having episodes of visual improvement lasting minutes to an hour or more, but with no sustained visual change. DISCUSSION Leber (17) considered the optic neuropathy he described in 1871 as a pure clinical entity, uncomplicated by any other morbid condition. In contrast, de Weerdt and Went (12) found that 24 of 34 patients with Leber's disease had mild or severe neurologic abnormalities and believed Leber's disease "to be an affection of the central nervous system not necessarily restricted to the optic nerves." Numerous case reports have supported this conclusion. Adams et al. (10) described the combination of Leber's disease: dementia, paraparesis, and/or posterior column disease. Dissemi- I C/i/l Nturo-ophllullmol. Vol. 6, No.2, 1986 78 D. ,. McCLUSKEY ET AL. (a) FIG. 2. Clinical appearance of the optic nerves on initial pres.entation. The right nerve <a) was hyperemic with associated peripapillary telangiectatic vessels al.ong the te~poral arcades. The left nerve (b) demonstrated early temporal pallor With mild peripapillary congestion. nated or multiple sclerosis (11,14), epilepsy (14), and various ataxias also have been associated with Leber's (15,16). In fact, Ferguson and Critchley's observations led them to conclude that Leber's optic neuropathy is definitely linked to the heredofamilial ataxias (14). Other authors (13) have considered Leber's to be related to all the heredodegenerative diseases. In contrast to the other heredodegenerative disorders, optic atrophy occurs relatively rarely in Charcot-Marie-Tooth disease. When noted, the optic atrophy seen in these cases has been described as consistent with the general category of a hereditary optic atrophy (4) or type III atrophy as described by Van Leeuwen and Van Bogaert (16) (slow concentric visual field constriction with progressive optic atrophy). The initial symptom of Leber's is blurred central vision in one eye, often described as a fog obscuring the vision. The second eye typically becomes affected within several days or a few weeks (18). In the acute stage, there is a pathognomonic funduscopic picture, including a circumpapillary telangiectatic microangiopathy (18-20), with dilatation and increased tortuosity of vessels around the disc and within the proximal arcades. The peripapillary nerve fiber layer has a thick and opaque appearance (pseudopapilledema) which may be associated with disc hyperemia (21). There is no leakage from the disc or telangiectatic vessels on fluorescein angiography (18,19). Visual fields typi-cally show large cecocentral scotomata secondary to nerve-fiber loss in the papillomacular bundle (21). Although Leber's optic neuropathy has been suggested by several authors (1,8) as a diagnostic possibility in Charcot-Marie-Tooth patients, this concept has been largely dismissed as "highly unlikely" (8) or "mere speculation" (1). Only two reports (2,9) of concomitant Charcot-Marie-Tooth disease and optic atrophy with the characteristic hereditary pattern of Leber's have been described. Although bilateral central or cecocentral scotomata were noted in some cases (1,4,8,9), only generalized constriction (1,6) or no visual field defect (7) was noted in others, findings inconsistent with the diagnosis of Leber's. A disc pallor, more marked temporally (1,4,9), has been the only fundus appearance described in these cases. In no instance were the characteristic papillary, peripapillary, and angiographic changes of Leber's disease described or documented. Only one family, reported by McLeod et aI. (9), dearly had a history consistent with concomitant Leber's and Charcot-Marie-Tooth disease. However, these authors regarded this as a coincidental occurrence of two independently inherited diseases. To our knowledge, our patient represents the first case of Charcot-Marie-Tooth disease in which the classic acute fundus findings of Leber's optic neuropathy have been documented. Although his age of onset and lack of a strong family LEBER'S AND CHARCOT-MARIE-TOOTH DISEASE 79 AG.3. Fluorescein angiography of the right nerve on initial presentation. There was no leakage from the disc. peripapillary area. or telangiectatic vessels, as shown in the early (a) or mid-phase (b) photos. The late photo (c) demonstrates the absence of late staining in these areas. (b)- history of visual loss is somewhat atypical, such variations have been reported previously (22). Most convincing were our patient's visual field defects and funduscopic and fluorescein angiographic findings, which combined can be considered pathognomonic for Leber's optic neuropathy. In spite of these characteristic findings, other diagnostic possibilities were considered. A similar fundus picture has been described in malnutriIional optic neuropathy (23), but our patient had no history of poor diet, or alcohol or tobacco abuse. Additionally, the fundus picture in malnutritional optic neuropathy differs somewhat from Leber's in that the vascular abnormality seen occurs in the arcuate areas of the nerve fiber layer rather than at the optic disc and temporal peripapillary areas. Also, there was continued deterioration of the patient's visual status in the face of adequate treatment for this condition. Idiosyncratic reactions to sulfa derivatives with a resultant toxic optic neuritis (24,25) have been reported; however, vision typically recovered after withdrawal of the offending drug. No improvement was noted in our patient after withdrawal of Diabinese, and, in fact, his vision worsened off the drug. In view of the discovery of this case representing concomitant Charcot-Marie-Tooth and active I C/;I/ Nfllro-opilthallllol. Vol. 6. No.2. 1986 (a) (b) 80 D. I. Mc(LUSKJ::Y J::T AL. FIG. 4. Marked distal muscular wasting of the upper (a, b) and lower (e) extremities was present. ----- (e) Leber's optic neuropathy, it appears that the two disorders may be related actually rather than incidentally. This relationship is not surprising in view of the well-described association between Leber's disease and a broad spectrum of other heredodegenerative disorders, as well as recent re- , Om ""·"" ... ,,.11,11"'11I01. Vol. 6. No.2. /9/!6 ports linking Charcot-Marie-Tooth disease and other neuromyopathic conditions (26,27). Although x-linked recessive and autosomal recessive inheritance patterns have been described in Charcot-Marie-Tooth disease (28), the most characteristic mode of inheritance is autosomal LEBER'S AND CHARCOT-MARIE-TOOTH DISEASE 81 RG. 5. Goldmann visual fields at 2-month follow-up. demonstrating a large cecocentral scotoma on the right. The visual field on the left was unchanged. dominant (18). The transmission of Leber's disease is strictly maternal and does not follow mendelian principles (18). This transmission pattern, whereby all daughters but no sons of an affected or carrier mother pass the disease to their descendants, has suggested inheritance of a cytoplasmic "agent" which may represent mitochondrial DNA (21), The simultaneous occurrence of CharcotMarie- Tooth disease and Leber's disease could be explained easily by the transmission of DNA within the nucleus of either zygote in the case of Charcot-Marie-Tooth disease, with associated transmission of DNA contained within the maternal mitochondria in the case of Leber's. In summary, we present a case in which the acute fundus findings of Leber's were observed in a patient with Charcot-Marie-Tooth disease. This case, coupled with the prior observation of the familial occurrence of Leber's with Charcot-MarieTooth disease, may suggest that the optic atrophy reported in patients with Charcot-Marie-Tooth in the past might, in fact, have been due to Leber's. While both diseases could occur in an individual by chance alone, the actual genetic bond between the two may become more apparent as more such cases are described. Acknowledgment: This work was supported in part by a Research to Prevent Blindness Development Award and grants from Fight for Sight and the San Antonio Area Foundation. REFERENCES 1. Schneider D. E., Abeles M. M. Charcot-Marie-Tooth disease with primary optic atrophy. J NcrI' Me,,1 Dis 1937;85:541-7. 2. Sainton P. L'amyotrophic type Charcot-Marie [Thesis). Paris: G SteinheiJ, 1894. Cited by Milhorat (8). 3. Vizioli F. Del' atrof a muscolare progressiva neurotica. Bull R Acad Mcd-Chir (Napoli) 1889. Cited by Milhorat (8). 4. Hoyt W. F. Charcot-Marie Tooth disease with primary optic atrophy. Arch OphthalllloI1960;64:145-8. 5. Bah'r R. S., Upton A. R. M. Variation of phenotype in Charcot-Marie-Tooth disease. Neuropiidialrie 1979;10: 290-5. 6. Rosenberg R. N., Chutorian A. 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