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Show Journal of Clinical Neuro- ophlhalm% xy 12( 2): 89- 93, 1992. Distended Optic Nerve Sheaths in Leber's Hereditary Optic Neuropathy Philippe de Gottrau, M. D., Ernst R. Biichi, M. D., and Basil Daicker, M. D. I\:! 1992 Raven Press, Ltd., New York Distension of the optic nerve sheaths is a feature of Leber's hereditary optic neuropathy ( LHON) that has attracted attention only recently. We followed a patient with LHON for 23 years and obtained his eyes for pathological examination after death. We report the first histologic description of distension of the optic nerve sheaths, together with typical histopathological findings of LHON. Distension of the optic nerve sheaths could not be accounted for by any etiology other than LHON, although the precise pathogenic mechanisms remain enigmatic. Key Words: Leber's hereditary optic neuropathy- Optic nerve sheath distension. From the University Eye Clinic, Basel, Switzerland ( p. d. G., E. R. B., B. D.) and the CIinique d'Ophtalmologie, H6pital Cantonal, Geneva, Switzerland ( P. d. G.). This work was presented at the 1990 Meeting of the European Ophthalmic Pathology Society ( EOPS) in Coimbra, Portugal. Address correspondence and reprint requests to Prof. Dr. B. Daicker, UniversitiHs- Augenklinik, Mittlere Strasse 91, CH4056 Basel, Switzerland. 89 Since 1871, many authors have described the various characteristics of Leber's hereditary optic neuropathy ( LHON; 1- 8) and its transmission by the mitochondrial genome ( 9- 15). One apparently rare feature, however, has been revealed only recently by computed tomography ( CT) and magnetic resonance imaging ( MRI); namely, dilation of the optic nerve sheaths ( 16). We obtained the eyes of a patient aged 62 with Leber's hereditary optic neuropathy for postmortem pathological examination and discovered marked distension of the optic nerve sheaths that was unrecognized during the lifetime of the patient. In this report, we describe the typical histopathological findings of this patient with particular emphasis on the optic nerve sheaths. CASE REPORT A 39- year- old healthy man was seen in our outpatient department in 1965 suffering from a sudden painless loss of vision for about 1 month. On initial examination, visual acuity was finger counting at 1.5 m in both eyes, The discs were pale and well delimited, without any discernible microvascular abnormalities ( Fig. 1). The visual fields were constricted, with centrocecal scotomata extending nasally. The neurological examination was normal. Electroretinogram ( ERG), skull x- ray, encephalography, electroencephalogram ( EEG), and cerebrospinal fluid ( CSF) examinations were also normal. The VORL was negative. The patient had no history of tobacco or alcohol abuse, nor of exposure to toxic agents. There was no history of eye disease in the family ( parents, four sisters, one brother, one daughter). Abstinence from alcohol and smoking associated with vitaminotherapy for several weeks did not significantly improve the patient's condition. At follow- up examinations in 1970 and 1978 90 P. de GOTTRAU ET AI. FIG. 1. Fundus photograph of the left eye 8 years before death. The disc was atrophic, but not notably cupped. the situation was stable. In 1980 the patient's visual acuity was 6/ 60 in both eyes. The visual fields were further constricted, and the centrocecal scotomata were unchanged. A red- green dyschromatopsia ( Farnsworth 15 hue) was present. The amplitudes of the visual evoked potentials ( VEPs) were reduced, but the latency was normal. The patient died in 1988 from heart failure after surgery and irradiation of a carcinoma of the larynx. An autopsy was performed, and both globes were obtained for histopathological examination. PATHOLOGICAL FINDINGS The external aspect of the globes and the anterior segments were unremarkable. The discs were pale and atrophic, particularly temporally, but not notably cupped ( Figs. 1 and 2). The retina exhibited pronounced atrophy of the gangli~ n cell layer ( Gel) and nerve fiber layer ( NF~; FIg. 3) .. The outer retinal layers, the retinal pIgment epIthelium and the choroid were unremarkable. There wer: nonspecific degenerative retinal changes ~ n the periphery. The dura mater and. the arach~ Old of the optic nerve were markedly dIstended ( FIgs. 2, 4, and 5). The subdural and particularly the subarachnoid space were widened. Arachnoidal trabecula stretched across the dilated subarachnoid space ( Figs. 2, 4, and 5). There was no other histological abnormality in the optic nerve sheath~. The nerve fiber bundles in the retrobulbar optic nerve exhibited variable atrophy and gliosis, predominantly in the temporal sector ( maculopapillar bundle; Figs. 2, 5, and 6). No signs of active or previous inflammation were observed ( Fig. 6). The brain and its meninges showed no metastases, no signs of elevated intracranial pressure, and no sequelae of inflammation. There was, however, marked atrophy of the chiasma ( thickness 1 mm), the optical tracts, and the lateral geniculate bodies, mainly in the portions corresponding to the macular fibers. The systemic autopsy revealed ( a) a recurrence of the carcinoma in the larynx with infiltration of the esophagus and the trachea, ( b) metastases in the skeleton and in the kidneys, and ( c) carcinomatous Iymphangiosis of the lungs. There were no signs of chronic tobacco abuse in the lungs or of alcohol abuse in the liver. DISCUSSION LHON usually results in acute bilateral visual loss. The disorder predominantly affects young FIG. 2. Disc and proximal optic nerve in LHON. There was no cupping. Distension of the retrobulbar dural and arachnoidal sheaths was conspicuous ( between large arrowheads). Atrophy and gliosis were more marked on the temporal side in the proximal optic nerve ( between arrows). Heidenhain, bar = 1 mm. DISTENDED OPTIC NERVE SHEATHS IN LHON 91 FIG. 3. Retina of the posterior pole in LHON. The NFL and GeL were atrophic ( arrowheads). Hematoxylin- eosin. bar = 200 lLm. men in their second or third decade, generally with a positive family history. Early ophthalmoscopic findings include a glistening opacity of the peripapillary nerve fiber layer with irregular telangiectatic dilation of capillaries, a blurred disc, and tortuosity of the retinal vessels. Atrophy of the disc develops 2 to 4 weeks later, mostly on the temporal side and rarely involving the entire disc ( 4). The final visual acuity is usually not higher than 6/ 60. Typically, the visual fields show a relative or absolute centrocecal scotoma. Color vision is altered by defects in the protan, deutan, and tritan axes. The VEPs are reduced in amplitude and the latency is prolonged, whereas the ERG and EOG are undisturbed ( 1- 8). In 1871, Theodor Leber was the first to describe FIG. 4. Transverse section of the retrobulbar optic nerve ( gross specimen). Note the widened subarachnoid space and the thin arachnoidal trabecula. White bar = 1 mm. this clinical entity and to suspect a hereditary disorder ( 1). Confirmation that a mitochondrial DNA mutation is responsible for the inheritance of this disease was, however, provided only recently ( 815). Nevertheless, the exact physiopathological mechanisms leading to optic atrophy remain enigmatic. We believe that our patient suffered from LHON, even though we did not observe the fundus in the acute stage. The clinical picture and the functional disturbances were consistent with this disease. Multiple sclerosis was ruled out because of the absence of other neurological symptoms or alterations in the CSF; the autopsy findings did not suggest a demyelinizing disorder. Optic atrophy secondary to vitamin B deficiency (" alcoholtobacco amylopia") was considered improbable, as there were no findings suggesting alcohol or tobacco abuse or inadequate nutrition. Finally, an optico- chiasmatic arachnoiditis leading to a pressure increase in the optic nerve sheaths could not be demonstrated by gas encephalography or postmortem. The absence of a positive family history for our patient is notable, but his pedigree is rather limited. The existence of " sporadic" LHON has indeed been questioned ( 17). In such patients, the diagnosis of LHON can be confirmed, however, by the presence of peripapillary microangiopathy in siblings and maternal relatives ( 17). Unfortunately, no relatives of our patient could be examined to search for this particular feature. On the other hand, 28 out of 49 pedigrees of LHON were represented by singleton cases in a recent study ( 8). The histopathology of LHON has only rarely been reported. The first description was presented JClin Neuro- ophtiUllmol. Vol. 12. No. 2, 1992 I P. de GOTTRAU ET AL. FIG. 5. Transverse section of the retrobulbar optic nerve. The dura and arachnoid were distended, and the subdural ( arrowheads) and subarachnoid ( a) spaces were widened. Tender arachnoidal trabecula ( arrows) were bridging the subarachnoid space. There was marked atrophy and gliosis in the maculopapillar bundle ( asterisk). Luxol- Van Gieson, bar = 1 mm. by Karl Rehsteiner in 1930 ( 2). In 1958, Kwittken and Barest ( 18) published a description including the pathology of the entire intracerebral optic pathways, and a third case was published in 1966 by Adams et al. ( 19). Most of the findings in our case were similar to those previously described by these authors. Distension of the dura mater and arachnoid of the optic nerve, however, constituted a remarkable peculiarity in our patient. The histopathology of this feature in LHON has, to our knowledge, not been reported previously. Clinically it attracted attention only recently, when it was revealed by CT and MRI studies ( 16). Optic nerve scans by MRI were found to be abnormal on at least one side in all patients with LHON ( 20). The abnormality consisted of an increased signal, which was considered most likely to represent gliosis in the chronic phase and perhaps edema in the acute phase. No reliable statement was possible, however, on the dimensions of the optic nerve itself or its sheaths. Unfortunately, our findings failed to provide an explanation for the mechanisms leading to distension of the optic nerve sheaths. In particular, no signs of intracranial hypertension or arachnoiditis were revealed. The pathogenesis of distension of the optic nerve sheaths in LHON remains therefore to be elucidated. I Clin Neuro- ophthalmoi, Vol. 12, No. 2, 1992 FIG. 6. Transverse section of optic nerve. Atrophy and gliosis were pronounced in the temporal sector ( white star). Note the arachnoidal trabecula and the absence of inflammation or scarring. PAS, bar = 500 fLm. DISTENDED OPTIC NERVE SHEATHS IN LHON 93 REFERENCES 1. Leber T. Ober hereditare und congenital angelegte Sehner- 12. venJeiden. A. p. Graefes Arch OphthalnwI1871; 17: 249- 91. 2. Rehsteiner K. Die erste anatomische Untersuchung eines Falles von geschlechtsgebunden- hereditarer Sehnervena- 13. trophie ( Leber'scher Krankheit). A. p. Graefes Arch Ophtlral-mol 1930; 125: 14- 28. 14. 3. Nikoskelainen E, Hoyt WF, Nummelin K, Schatz H. Fun-dus findings in Leber's hereditary optic neuroretinopathy. 15. Arch 01' hthalmoI1984; 102: 981- 9. 4. Berninger TA, Bird AC, Arden GB. Leber's hereditary optic atrophy. 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