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Show J. Clin. Neuro-ophthalmol. 3: 211-220, 1983. Clinicopathological Study of the Visual Pathways, Eyes, and Cerebral Hemispheres in 32 Cases of Disseminated Sclerosis D. TOUSSAINT O. PERIER A. VERSTAPPEN S. BERVOETS Abstract The pathological study of the cerebral hemispheres and visual pathways in 32 cases of disseminated sclerosis, including 15 cases in which the retinal structures were investigated, lead us to point out: 1) the high frequency of histological lesions of the optic nerves, tracts and radiations; 2) the lack of correlation between the extent of demyelination of the optic nerves and the impairment of visual acuity that is mainly related to axonal lesions; 3) the relative high frequency of pathological sheathing of retinal veins; and 4) the high proportion of shadow plaques in the cerebral hemispheres in cases with clear-cut relapses and remissions. Introduction Clinical Ocular Signs According to Bradley et al.,'" acute optic neuritis of the retrobulbar type, with significant impairment of vision and central scotoma, is the first manifestation in 15-20% of patients and develops during the course of the disease in approximately 30% of patients. In several cases of disseminated sclerosis without ocular symptoms or reduction of visual acuity, degeneration of some axons in the retinal nerve fiber layer could be detected by redfree light ophthalmoscopy and abnormal-evoked potentials. These patients also frequently showed a Pulfrich phenomenon. This degeneration of retinal axons in patients without clinical ocular history or disc discoloration was observed by Feinsod et al.)() in 60% of the patients. Korol et al. 14 reported From the Universite Libre de Bruxelles, C1inique Ophtalmologique (DT, AV); Laboratoire de Neuroanatomie (OP); and Centre National de la Sclerose en Plaques, Melsbroek (5B), Bruxelles, Belgique. Portions of this article appeared originally in Toussaint, D.: Alterations du fund d'oeil dans Ja sclerose en plaques. Bu/l. Soc. Beige aphtha/mol. 199-200; 235-236, 1982, and are reprinted here through their courtesy. September 1983 that this degeneration occurred with variable frequency according to the duration of the disease: in 68% of the patients with the disease for more than 1 year and in only 32% of the patients with disseminated sclerosis for less than 1 year. Delay of the pattern visual-evoked potentials in patients without impairment of visual acuity was described in all patients by Feinsod et al. lO and in 87% by Korol et al. 14 Halliday et al. 1:3 reported this change in all patients having discolored optic discs and in 91% of the cases with normal optic discs. Rucker1ll • 19 reported retinal venous sheathing in 10% of patients. Subsequently, these lesions were described by several authors varying from 0.4% for Lossner et al. 15 to 33% for De Laee and Ardouin et al.l. ~ Bamford et al. 3 noted these retinal lesions in 11% of 127 patients in a more recent work. These authors emphasized the higher frequency of retinal venous sheathing in patients in whom the evolution of the disease and the aggravation of the neurological signs are slowly progressive. Conversely, Bamford et al.:3 reported the rare occurrence of retinal venous sheathing in patients without increasing neurological disability or with acute impairment of nervous functions. Based on a statistical analysis of 3,021 previously published cases analyzing the frequency of periphlebitis retinae in disseminated sclerosis, Tine et al.~1 were of the opinion that this retinal periphlebitis probably occurred even if not clinically reported, since many reports were limited to small numbers of patients examined under uncontrolled conditions. The authors concluded that a patient with disseminated sclerosis of average duration would get periphlebitis retinae 3.6 times during the course of the disease. Brain Pathology Greenfield et al. 11 reported that, in addition to demyelination, axonal breakdown is marked in 10% of cases and moderate in 45%. These axonal 211 Disseminated Sclerosis lesions result in a wallerian degeneration responsible for the pallor frequently observed around the plaques in myelin-stained sections. Other lesions are the so-called "shadow plaques," similar to the well-known demyelinated lesions as far as their outline and shape are concerned, but not entirely deprived of myelin. Several authors, including McAlpine et aI. I6 and Perier et aI.,17 interpreted these shadow plaques as remyeIination. Pathology of Ocular Structures and Visual Pathways With the exception of the retro-orbital visual pathways studied by neuropathologists, it is surprising that so far, there are few pathological reports concerning the eyes and the intraorbital portions of the optic nerves in disseminated sclerosis. Cases which have been studied have frequently shown plaques in the optic nerves, chiasm, tracts, and radiations. In some instances they are perivenous. Perivascular round cell infiltration is often present. Gartner9 found changes in the eyes and optic nerves in all 14 eyes from 10 patients. He reported atrophy of the ganglion cells in the macula and "newly formed connective tissue about the central retinal vessels, the blood vessels, on and near the disc, presenting thickened sclerosed walls." FoglO described briefly the sheathing of a retinal vein with lymphocytes and plasmacytes and early organization of the vitreous body in adjacent parts of the lesion. Present Clinicopathological Study Material and Methods A complete pathological investigation of the central nervous system was performed in 32 cases of disseminated sclerosis and of 27 eyes from 15 of these patients. The age of the patients at death varied from 20 to 77 years (mean = 41.5). The diagnosis of disseminated sclerosis was confirmed in all cases by the pathological study of the central nervous system. The optic nerves were studied on frontal sections posterior to the optic canal in 30 cases (60 optic nerves) and on frontal sections within the intraorbital portion of the nerve,S mm behind the eye, in nine cases (13 optic nerves). Myelin was stained by the WoeIcke-Heindehain technique and cells by cresyl violet. In 30 cases the axons were impregnated by the Bodian method. Most eyes were cut in three parts: two calottes, the retinal tissues of which were used for trypsindigested preparations, and the medial horizontal portion, 3-mm thick, embedded in paraffin or in gelatin. Some eyes were cut vertically in two equal fragments. The retinal tissues of the posterior fragment were divided into four pieces used for flat mount sections after embedding in paraffin or gelatin. The paraffin block sections were stained with hematoxylin-eosin, Masson's trichrome, PAS-Weigert's hematoxylin, and Bodian method. In the specimens embedded in gelatin, myelin was impregnated by sudan red, sudan black, and oil red 0, and cells were stained with toluidin blue or with Weigert's hematoxylin. Ocular Signs and Symptoms Clinical symptoms and signs were available in 23 cases (46 eyes). Visual acuity tested by the Snellen method at 5 meters was reduced by more than 9 units; by 7-9 units; by 3-6 units; and by 12 units, respectively in 22, seven, nine, and two eyes. Visual acuity was normal in six eyes of four patients. Two patients had 20/20 in both eyes, and two other patients each had 20/20 in one eye. However, one had 20/50 in the affected eye and the other 20/30 in the affected eye. In the majority of patients, reduction of visual acuity was symmetrical in both eyes. The discs were obviously pale on the whole surface in 18 eyes and in the temporal portion in six eyes. The discs were of normal color in 20 eyes. The color of the disc was symmetrical in both eyes in 20 patients. In one patient, visual acuity was 20/ 70 in the discolored side and 20/60 in the normally colored side. Another patient had visual acuity of 20/400 in the discolored side and 20/25 in the normally colored side. Retinal venous sheathing was obviously present in six patients and doubtful in two. Pathology Optic Nerves The lesions observed on frontal sections of the prechiasmatic portions of the optic nerves can be classified as follows, according to their aspect on myelin stained preparations: A = Plaque with complete demyelination involving more than half the section. B = Plaque with complete demyelination involving less than half the section. C = Shadow plaque appearing as a well-delimited area of incomplete demyelination D = Area with undefined limits containing weakly stained myelin. E = Disseminated circular areas, about 50 microns in size, limited to one optic fascicle, containing some lipid and no axons. Fifty-three optic nerves were abnormal (88.3%); 18 (34%) with lesion A, 16 (30.2%) with lesion B, 8 (15%) with lesion C, and 11 (20.8%) with lesion D. Alterations of type E were noticed in the intraorbital portion of three optic nerves having central diffuse demyelination in their posterior intracranial Journal of Clinical Neuro-ophthalmology Toussaint, Perier, Verstappen, Bervoets _. '-:.... , .. -, ---...... .. • Figure 1. Case 2. Central region of cerebral hemisphere. Woelcke-Heidenhain myelin stain. There are several completely demyelinated lesions typical of disseminated sclerosis. One of these is located mostly in the white matter (Wj. but largely impinges upon the cortex (c). Others are located entirely within the cortex (arrows). About one-half of the lesions are of the shadow-type like that marked by letter 5 (X2.4). portion with blurred limits in one and complete demyelination in the other two. Seven optic nerves were normal histologically. In two patients, both optic nerves were normal. In the first one, both discs were normal, but visual acuity could not be measured due to mental disturbances. In the second one, both discs were discolored and visual acuity was 20/80 in both eyes. In the three optic nerves which were normal histologically in their posterior intracranial portions, the optic discs were normally colored, and visual acuity was 20/20 in one, 20/50 in another, and 20/80 in the last one. Lesions also were observed frequently in the optic chiasm and tracts, but these were not studied systematically in all cases, so no quantitative data on their frequency were available. Brain In the cerebral hemispheres (Fig. 1), shadow plaques scattered among other lesion, or in some cases being part of a completely demyelinated lesion, were observed in 26 patients. Shadow plaques were particularly numerous in cases with clear-cut relapses and remissions, whereas they were usually absent in cases with slow progressive evolution. Periventricular demyelinated lesions were observed in 30 patients and a portion of the optic radiations in 25 patients. The lateral geniculate bodies were often involved by demyelinated September 1983 lesions, but were not always present in the brain sections studied. Eyes In six of 15 patients (Table 1) from which the retinal tissues were investigated, we found an abnormal fibrillar material along the veins. There was no correlation between the presence of this material and the duration of the disease (mean duration of 7.9 years in the group of patients with retinal venous sheathing and of 10 years in the group without these alterations). The trypsin-digested retinal preparations (Fig. 2), as well as the histologic flat mount sections from tissues embedded in paraffin (Fig. 3), showed that this regularly thickened material was uniformly distributed around all of the retinal veins from their peripapillary portions up to the equator. This material was green with Masson's trichrome and unstained with the fibrillar acidic protein (GFAP) immunologic reaction for glia. In one case with retinal venous sheathing, perivascular infiltrates were observed in the posterior intracranial portion of the optic nerve of the same eye. In two specimens with retinal venous sheathing, we observed nodular lymphoplasmatocytoid infiltrates surrounding some retinal vessels and invading the vitreous in one (Figs. 4 and 5). In most of the eyes, we noticed an obvious rarefaction of 213 Disseminated Sclerosis .-. M-N-o- Cl ..., Cl W :> ::E :> 3 "" <t: E ..... E ..... ..... ..... E ..... E E E E .... N.. ..M o M oM 'N" ..M o N 00 ..'" 00 N OM 00 o "'N 00 00 NN 00 00 00 o o + o + o o ++ ++ + o o o o o o o + +t o ..,... + ...I.. + + o o o o + ++ +++ o o o + o o o o o o + o o N o c: ., ''U"" :l: <t: :> Lo.. ..... E E .>,< '" ..... N o M ....... ., ''"" 00 "'''' 00 0"''0'' 00 ~"''..". :::l'~ '" :::l .~ U > '" + o + .<'": U.,Q. ..,..-..>. 0.. Q..,'" o c: '" o o o o o o o U", .~ ........ "'''' I u" ~i~ Q.\A .... _""'''~c''. ....c...:.. the ganglion cells in the macular area and of the axons of the nerve fiber layer in the intermaculopapillary area (Figs. 6 and 7). Comments The axonal degeneration of the retinal nerve fiber layer detected by red-free light ophthalmoscopy seems to be due to the rarefaction of the intermaculopapillary nerve fibers. Our observations confirm those of Gartner~ in most caSes of disseminated sclerosis. These axonal and neuronal lesions might be the result of a retrograde retinal optic nerve degeneration from a focus of demyelination somewhere in the retro-ocular visual pathways. The occurrence of lesions in the optic nerve in disseminated sclerosis is certainly not restricted to patients with a past history of optic neuritis. The finding of pale discs, abnormal visual-evoked potentials, and retinal axonal degenerations in patients with no history of previous visual impairment support this statement. Abnormal visualevoked potentials in these patients could be related Journal of Clinical Neuro-ophthalmology Toussaint, Perier, Verstappen, Bervoets 100pm Figure 2. Case 5. Trypsinic-digested retinal preparation. PAS-Hematoxylin stain. Venous sheathing (arrow). 100lim -' Figure 3. Case 2. Section of flat mount retinal tissues embedded in paraffin. Masson's trichrome stain. Venous sheathing (arrow). September 1983 215 Disseminated Sclerosis 50J,J Figure 4. Case 6. Cross section of the retina showing lymphoplasmatocytoid retinal infiltrate. Hematoxylin-eosin stain. 50.um Figure 5. Case 13. Cross section of the retina showing Iymphl)plasmatocytoid retinal infiltrate invading the vitreous body in adjacent p<lrt, llf the le,jon. Hematoxylin-eosin stain. Journal of Clinical Neuro-ophthalmology Toussaint, Perier, Verstappen, Bervoets ,iii' Figure 6. Case 3. Section of flat mount retinal intermaculopapillary area. Rare ganglion cells and increased number of glial cells. Hematoxylin-eosin stain. to the presence of some axonal alterations somewhere in the visual pathways with preservation of the fibers for central vision. In some patients, these slight alterations of the optic nerve are sufficient to induce a retrograde degeneration resulting in pallor of the disc and in retinal axonal alterations. The incompletely demyelinated lesions in the optic nerve may be due to several mechanisms, either wallerian degeneration (ascending) ofaxons from demyelinated lesions in more anterior portions of the nerve, or retrograde (descending) degeneration from demyelinated foci situated in more posterior portions of the optic pathways. Other changes are shadow plaques resulting from partial remyelination around intact axons. The only way to differentiate wallerian degeneration from shadow plaques is the blurred limits of the former lesion contrasting with the sharp outline of the latter. If the whole surface of the optic nerve is affected by a shadow plaque, this distinction cannot be achieved. In some of our cases with visual acuity reduced to 20/200 or 20/400, the optic nerves were completely (or nearly completely) demyelinated, whereas in others they showed only a partial (more or less pronounced) demyelination. Conversely, September 1983 visual acuity was sometimes only slightly reduced when demyelination of the optic nerve was prominent. Therefore, in disseminated sclerosis, there is no obvious correlation between the extent of demyelination of the optic nerve and the reduction of visual acuity. Conversely, the extent of axonal breakdown in the optic nerves does correspond with the deterioration of the visual acuity. This discrepancy is well-illustrated in the following cases. The visual acuity of patient 2 was 20/50 in both eyes, and the patient was able to read his newspaper easily up to the last days of his life. The posterior intracranial sections of one optic nerve were completely demyelinated, and the section at the same level of the other showed the preservation of only three peripheric fascicules (Fig. 8). We may rule out the possibility of acute premortem lesions in the absence of any myelinic debris. Absence of rarefaction of the normal structure of the axons in the optic nerve account for the preservation of good visual acuity in this patient (Fig. 9). In patient 5, visual acuity was 20/200 in the right eye and 20/80 in the left. Demyelination was not as extensive as in case 2, although affecting a large portion of the prechiasmatic frontal sections of 217 Disseminated Sclerosis Figure 7. Case 2. Section of flat mount retinal intermaculopapillary area showing rarefied axons in the nerve fiber layer. Bodian silver stain. ... Figure 8. Case 2. Right optic nerve, posterior intracranial segment. Subtotal demyelination of the section, only small peripheral fasides remaining myelinated in the top right part of the section (X30). Woelcke-Heidenhain myelin stain. Journal of Clinical Neuro-ophthalmology Toussaint, Perier, Verstappen, Bervoets Figure 9. Case 2. Section of right optic nerve immediately following that of Fig. 8. Large magnification of typical field in the completely demyelinated central area. The axons are not reduced in number and have a normal appearance. Bodian silver stain. Figure 10. Case 5. Right optic nerve, same magnification as Fig. 9. There is a conspicuous reduction in the number of axons, several of which are pathologically swollen. Bodian silver stain. September 1983 219 Disseminated Sclerosis both optic nerves. In this patient, the rarefied and sometimes swollen appearance ofaxons (Fig. 10) accounts for the reduction of visual acuity. In patient 7, visual acuity was reduced to 20/400 in the right eye and 10/500 in the left. The only changes were a discrete myelin pallor with undefined limits in small peripheric areas of both optic nerves. These changes seemed to result from axonal remyelination without restoration of nerve conduction. In addition to the rarefaction of the axons and ganglion cells of retina in disseminated sclerosis, two kinds of lesions involving the walls of the retinal vessels were present. The first is a venous sheathing observed by ophthalmoscopy at the posterior pole, appearing as white bands of uniform thlLkness on one or both sides of the vein 3 or 4 disc diameters long. This change was considered by Gartner9 to be newly formed connective tissues. In fact, our histological observations in six cases suggest that this venous sheathing is formed by a fibrillar material. The second lesion appears on ophthalmoscopy as white-grayish dots covering the vessel walls and often more peripheral than the venous sheathing. This change could represent localized cellular infiltrates as observed histologically in two of our cases similar to those described by FoglO and considered by Haarl2 as fresh inflammatory lesions. In this respect, Haarl2 assumes that continuous venous sheathing could represent the end result of this inflammatory lesion. Two types of retinal vascular alterations were confused frequently and were reported with a frequency varying from 0.4% to 33%. These discrepancies may be explained by the use of different ophthalmoscopic conditions and by the lack of sharp criteria for evaluation of retinal changes. The clinical features varied according to several factors, including the intensity and the wave length of the light used in ophthalmoscopy. The relationship between the two types of retinal vascular lesions remains unsettled. However, owing particularly to the unknown nature of the sheathing, we may assume that both changes could be the result of an immunologic process which in the central nervous system, including the optic nerves, results in demyelination. References 1. Ardouin, M., Feuvrier, Y. M., Castros, A., and Urvoy, M.: La periphlebite retinienne de la sclerose en plaques (it propos de dix observations). Rev. OtoNeuro- Ophthalmol. 32: 3-8, 1960. 2. Ardouin, M., Urvoy, M., Clement, J., and Oger, J.: Uveite et sclerose en plaques. Mythe et realite. ]. Fr. Ophthalmol. 2: 127-130, 1979. 3. Bamford, C. R., Ganley, J. P., Sibley, W. A., and Laguna, J. F.: Uveitis, perivenous sheating and multisclerosis. Neurology 28: 119-124, 1978. 4. Bornstein, M. B., and Crain, S. M.: Functional studies of cultured brain tissues as related to "demyelinative disorders," Science 148: 1242-1244,1965. 5. Bradley, W. G., and Whitty, C. W.: Acute optic neuritis: Prognosis for development of multiple sclerosis. ]. Neurol. Neurosurg. Psychiatry 31: 10-18, 1968. 6. Cerf, J. A., and Carels, G.: Multiplesclerosis: Serum factor producing reversible alterations in bioelectric responses. Science 152: 1066-1068, 1966. 7. De Laet, H.-A.: Les raies paraveineuses dans la sclerose en plaques: Leur signification pour Ie pronostic de I'affection. Acta Neurol. Belg. 63: 384-393, 1963. 8. Feinsod, M., and Hoyt, W. F.: Subclinical optic neuropathy in multiple sclerosis. ]. Neurol. Sci. 20: 161-175, 1973. 9. Gartner, S.: Optic neuropathy in multiple sclerosis: Optic neuritis. Arch. Ophthalmol. 50: 718-726,1953. 10. Fog, T.: Pathologico-anatomicallesions in multisclerosis. Ugeskr. Loeg. 125: 1291-1293, 1963. 11. Greenfield, J. G., and King, L. S.: Observations on histopathology of cerebral lesions in disseminated sclerosis. Brain 59: 445-457, 1936. 12. Haar, M.: Changes of the retinal veins in multisclerosis. Acta Neurol. Scand. 40: 17-20, 1964. 13. Halliday, A. M., McDonald, W. I., and Mushin, ].: Visual evoked responses in diagnosis of multiple sclerosis. Br. Med.]. 4: 661-664, 1973. 14. Korol, S., and Babel, ].: Potentiels evoques visuels et ophtalmoscopie a la lumiere anerythre dans les formes subcliniques des nevrites retro-bulbaires de la sclerose en plaques.]. Fr. Ophthalmol. 2: 463-470, 1979. 15. Lossner, J., Muller, J., and Bachmann, H.: Occurence of uveitis and retinal vein periphlebitis consequent to multiple sclerosis. Psychiatr. Neurol. Med. Psychol. 20: 348-353, 1968. 16. McAlpine, D., Lumsden, C. E., and Acheson, E. D.: Multiple Sclerosis, A Reappraisal. Williams & Wilkins Co., Baltimore, 1965. 17. Perier, 0., and Vrebos, J.: Reflexions sur certains caracteres histologiques de la sclerose en plaques. Acta Neurol. Psych. Belg. 63: 443-453, 1963. 18. Rucker, C. W.: Sheating of retinal veins in multiple sclerosis. ].A.M.A. 127: 970-973, 1945. 19. Rucker, C. W.: Retinopathy of multiple sclerosis. Am. Ophthalmol. Soc. 45: 564-570, 1947. 20. Silverskiold, B. P.: Retinal periphlebitis and chronic disseminated encephalomyelitis. Acta Psychol. Neurol. Scand. 74: 55-56, 1951. 21. Tine, E., and Per Kragh Andersen: The frequency of periphlebitis retinae in multiple sclerosis. Acta Neurol. Scand. 65: 601-608, 1982. Acknowledgments The authors thank Drs. J. Ketelaer, R. E. Gonsette, and H. A De Laet of the Centre National de la Sclerose en Plaques, from whom a continuous series of postmortem examinations of patients was obtained. This investigation was supported by grants from the FRSM, Belgium (0. Perier: no. 2621962; D. Toussaint: no. 2051262), and was partly subsidized by the National Multiple Sclerosis Foundation, U.s.A. Write for reprints to: Dr. Daniel Toussaint, Hopital Universitaire Brugmann, Plave Van Gehuchten, 4, 1020 Brussels, Belgium. Journal 0f Clinical Neuro-ophthalmology |
