Journal of the neuroloyical Sciences, 1975, 25:165 182
165
~=i,Elsevier ScientificPublishing Company, Amsterdam- Printed in The Netherlands
The Onset and Progression of the Lesion in Multiple Sclerosis* C. W. M. ADAMS
Department qf Pathology, Guy's Hospital Medical School. London. SEI 9RT (Great Britah~)
(Received 9 November, 1974)
INTRODUCTION The main theme of this paper is to consider the histopathological processes involved in the onset and enlargement of the plaque in multiple sclerosis (MS). It is proposed first to discuss the established plaque before considering what may be earlier lesions. ESTABLISHEDLESIONS Established lesions are often gross and destructive- such as those encountered around the ventricles and sometimes in the mid-brain and cord. The inert burnt-out plaque is repaired by dense isomorphic astrogliosis and shows neither hypercellularity at its edge nor lipid phagocytosis by gitter cells. Whether or not the inert lesion can be reactivated is not known, and the extent of remyelination remains problematical (P6rier and Gregoire 1965 ; Suzuki, Andrews, Waltz and Terry 1969). Active established lesions in MS can reasonably be characterized by hypercellularity, increased histochemical enzyme activity and prominent lipid-laden gitter cells near or at their edges (Fig. 1 ; see Friede 1961 ; Ibrahim and Adams 1963; Friede and Knoller 1964; Adams, Ibrahim and Leibowitz 1965). It is uncertain whether the lipid phagocytes in multiple sclerosis directly attack myelin (see Suzuki et al. 1969), in the same way as they do in experimental allergic encephalomyelitis (Lampert 1967a and b). The role of these phagocytes certainly includes that of resorbing the tissue debris and esterifying the free cholesterol of myelin to the ester form (Petrescu 1966, 1969; also see Day 1964). The hypercellularity at the rim of the active established plaque seems to be responsible for the increased enzyme activity here. Nevertheless, it is still uncertain in what proportion oligodendrocytes, astrocytes and microglia are present in this active rim: the nature of the reactive cells at this site remains unclear. Oligodendrocytes are, however, absent (Lumsden 1951) or substantially reduced in
* This paper was read at the Symposiumon MultipleSclerosis,organizedby the MedicalResearchCouncil and the MultipleSclerosis Society,held in London on 17-18 October, 1974.
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number (Ibrahim and Adams 1963 : Lumsden 1970) in the central area of established mature lesions. It is of great interest that Simpson, Tourtellotte, Kokmen, Parker and Itabashi (1969) found a rim of IgG immunofluorescence around active cellular lesions. This prompted us to examine the edge of 6 active plaques in MS: a small proportion ( ~ 2 °/o)of cells had the light-microscopic appearance of small lymphocytes, but none were recognizable as plasma cells. The occurrence of lipid phagocytosis in the plaque is not necessarily evidence of very recent onset, for myelin in the central nervous system is -at least in Wallerian degeneration--only slowly broken down over the course of a year (chemistry see McCaman and Robins 1959; ultrastructure--see Lampert and Cressman 1966; Bignami and Rolston 1969). Plaques that are apparently newly-formed show great activity, as revealed by marked cellularity and numerous lipid-laden gitter-cells throughout the lesion (Figs. 1 and 2; Ibrahim and Adams 1965). Such plaques often show an infiltration of lymphocytes and macrophages around the vein running through the centre of the lesion (Fig. 3; see THE EARLY1.ESION).
Enlargement of the establishedplaque The cellularity and myelin breakdown at the edge of active plaques indicate that they expand outwards at their circumference. In hyperactive plaques, a rim of diminished histochemical staining for basic protein (Fig. 4A) extends further outwards
Fig. 1. Diagrammatic representation of the features of different lesions in multiple sclerosis. The top ro~ shows established plaques; the bottom row shows perivenous lymphocyte cuffs with and without demyelination. Glial cells and perivenous infiltration are indicated by black dots; lipid phagocytes are shown as grey circles ; demyelination is indicated by white circles.
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Fig. 2. Hyperactive plaque in cerebral white matter of Case 2 to show gila and lipid phagocytes throughout the lesion. Sudan black, x 64.
Fig. 3. A : perivenous infiltration at centre of hyperactive plaque in cortical white matter o f Case 2; B: note mixed lymphocyte-monocyte population. HE, x 236, × 960. (Reproduced by courtesy o f the editor of the Journal of Neurochemistry).
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Fig. 4. ,4 : loss of basic protein (arrow) outside zone of lipid loss at edge of hyperactive plaque in conicui white matter of Case 2. Trypan blue, × 64. B: corresponding acid proteinase activity. Clear areas digestion of gelatin film (blackened photograph plate). Gelatin-silver autogram, x 64. (Reproduced b} courtesy of the editor of the Journal qf Neurochemistrv).
than the loss of myelin lipid as shown by histochemical staining methods (Adams, Hallpike and Bayliss 1971 ). This suggests that it is a basic protein rather than lipid that is first degraded in the outward extension of the plaque. The differential staining for protein and lipid, as well as the only slightly increased water content at the edge of plaques compared with the adjacent white matter (11.2 o~ + 7.5, n = 6; J. Csejtey, personal communication), exclude local cerebral oedema as the cause of this outer rim of diminished staining for basic protein. The loss of basic protein is confined to the limits of the plaque in the less active and chronic established lesion (HaUpike and Adams 1969; Hallpike, Adams and Bayliss 1970a). Polyacrylamide gel electrophoresis also shows that myelin basic proteins are reduced at the edge of the active plaque and virtually disappear from the centre of all plaques (Einstein, Dalal and Csejtey 1970; Riekkinen, Palo, Arstila, Savolainen, Rinne, Kovalo and Frey 1971 ; Riekkinen, Rinne, Savolainen, Palo, Kovalo and Arstila 1971 ; Einstein, Csejtey, Dalai, Adams. Bayliss and Hallpike 1972). The activity of acid proteinase and certain peptidases is markedly increased at the edge of active plaques (Fig. 4B; Adams 1968; Hallpike and Adams 1969; Einstein et al. 1970, 1972; Hallpike, Adams and Bayliss 1970b; Riekkinen, Clausen, Frey, Fog and Rinne 1970; Riekkinen, Rinne, Arstila and Frey 1970; Arstila, Riekkinen, Rinne and Laitmen 1973 ; Bowen and Davison 1974a, b). Activity is also moderately increased around inactive lesions and in "normal" white matter in the MS brain, but
PROGRESSION OF THE MS LESION
169
is variable in the centre of the plaque. Acid proteinase has been thought to be derived from lysosomes and, in this connection, Bowen and Davison (1974a) suggest that increased catheptic activity around plaques in MS might at least be partly derived from lysosomes in macrophages or other phagocytes. Certainly, cells seem to be a source of some proteolytic activity around MS plaques (see Fig. 8 in Adams 1968), but it is doubtful whether any of these cells are metabolically typical monocytes, histiocytes or macrophages in that they do not stain intensely for catalase, which is a characteristic of typical reticulo-endothelial cells (Adams, Bayliss and Turner 1975}. Arstila et al. (1973) noted a marked increase of lysosomes in astrocytes--but little in oligodendroglia--in biopsies from MS brains; this source cannot be excluded as one possible origin for the proteolytic enzyme or enzymes in question. The relation between increased proteolytic activity and loss of basic protein around the plaque led us to consider that digestion of this supposedly vulnerable protein is a preliminary--but not necessarily exclusive-event in myelin breakdown in the outward extension at the edge of the established plaque. Myelin basic protein in the brain is sensitive to cerebral acid proteinase (Einstein, Csejtey and Marks 1968), while proteolytic digestion of the proteins in myelin leads to loss of the attached lipids and in vitro myelin breakdown (Adams and Tuqan 1961 ; Tuqan and Adams 1961; Adams, Ibrahim and Leibowitz 1965; Hallpike, Adams and Bayliss 1970c). Thus, catheptic activity at the edge of the plaque could account for the breakdown of myelin in the expanding edge of the established lesion. However, it does not account for axonal preservation, nor is it clear what cells are involved in the formation and release of the relevant proteinase or proteinases (Adams 1972). Moreover, other proteins than the basic sorts may be digested by proteolysis during myelin breakdown (see Bignami and Eng 1973). THE EARLY LESION
Previous observations
It is widely recognized that demyelinating lesions in MS that are apparently early may show a zone of lymphocytic infiltration--including monocytes (macrophages) --around the central vein from which the lesions expand (Figs. 1 and 3 ; Greenfield and King 1936; Adams and Kubik 1952; Adams and Richardson 1961; Lumsden 1970, 1972; see Fog 1964). These lesions bear some histological resemblance to those seen in rabies post-vaccinial encephalomyelitis (Uchimura and Shiraki 1957). Dawson (1916a, b) considered that lymphocyte cuffs in MS are only found in older lesions, and concluded that they were a response rather than an early event in the pathological chain of events. Dawson evidently considered that lymphocytes were associated more with chronic plaques. What seems to have largely escaped comment or attention for the last 50 years is that perivenous infiltration of lymphocytes may occur in MS without any obvious surrounding demyelination, that is a morphological appearance with some--but not complete--similarity to the perivenous infiltration in experimental allergic encephalomyelitis in smaller animals, where demyelination is trivial or absent. Attention has previously been called to such perivenous infiltrations without demyelination in
170
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multiple sclerosis by Siemerling and Raecke (1914), Birley and Dudgeon (19211 and by Symonds (1924). Roizin and Kolb (1957) illustrated such a lesion, but withoul comment on its nature or significance. Possibly these early reports have been discounted or ignored because of the statement by Dawson (1916a, b) in his well-known authoritative review, that such infiltration is a late or unimportant feature.
Analysis of present material Among 44 cases of multiple sclerosis that we have studied since 1962, 5 died suddenly from apparently acute involvement of mid-brain centres. All 5 of these acute cases showed various degrees of perivenous lymphocytic infiltration in and around areas of demyelination. In all but the second case, the pons and medulla were principally involved in the acute episode. Clinical abstracts Case 1. a woman o f 47 yr with a 24-yr history of multiple sclerosis : 1 week before her death she developed an acute episode which evolved into pseudobulbar palsy. Case 2.* a woman of 18 yr with an indefinite 2-yr history of depressive disease; she had recently complained of giddy attacks and 2 days later was found dead in her bath. Case 3. a man of 54 yr with a 6-yr history of multiple sclerosis; he became unconscious while driving an invalid car and subsequently developed partial respiratory paralysis; he died 6 weeks later. Case 4.* a woman of 57 yr with a long history ( ~ 20 yr) of multiple sclerosis ; she died suddenly while watching television. Case 5. a woman o f 31 yr with a 1-month history of multiple sclerosis; 5 days before her death she developed intractable vomiting and then lapsed into coma.
Fig. 5. Meningeal vein adjacent to hyperactive plaque in pons of Case 3. Note mixed lymphocyte-monocyte population. HE, x 940. * Professor Keith Mant (Dept. of Forensic Medicine, Guy's Hospital) kindly provided the material for Cases 2 and 4.
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/71
The lesions identified were:
(1) Monocyte-lymphocyte infiltrations. These perivenous cuffs contain varying proportions of monocytes (macrophages), lymphocytes and occasional plasma cells (Fig. 3B). These are usually within or contiguous to plaques (Fig. 3A). may involve meningeal veins (Fig. 5), and, thus, seem merely to represent an escape of inflammatory cells from the lesion along the course of veins or venules. In addition they may in part reflect perivenous extensions of the plaque--particularly when the infiltrate is largely lymphocytic--ultimately to form what is known as a Dawson's finger (Figs. 6 and 7; Lumsden 1970). (2) Lymphocyte infiltrations. These perivenous cuffs contain a predominance of lymphocytes with some plasma cells and only a few--if any--monocytes. They are found in areas of apparently normal myelin in the neighbourhood of a plaque or in areas of myelin pallor (see 6 below). The number of cells in these cuffs varies from distinctly scanty (Figs. 1 and 8) to moderate (Figs. 9 and 10), is less than in the mixed infiltrate described above under (1) and is never comparable to that seen, for example, around small arterioles in "collagen" diseases or in gliomas (Ridley and Cavanagh 1971 ). These cuffs may be relatively close to or up to 3 cm from the nearest plaque. They are not found in areas where a lesion is not present in the vicinity, nor are these cuffs found in 10 cases of recent or old cerebral infarction (including 2 of recurrent infarction). However, 1 case of acute medullary infarction shows several mixed monocyte-lymphocyte cuffs of type 1. Serial section of tissue around four such predominantly lymphocytic infiltrates in Cases 2 and 3 shows that they do not merge with perivenous lymphocyte-monocyte
Fig. 6. Diagram to show relation of lymphocyte infiltrations to veins and plaques. Note extension o f plaque as a Dawson's finger, and isolated perivenous lymphocytic infiltrates.
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(,. l&,. M. ADAMS
Fig. 7. Perivenous lymphocyte cuff in pons of Case 3. This vein extends out of an active plaque, and !he lymphocyte infiltration represents the onset of a Dawson's finger, c,l Fig. 6 (bottom left). [ u x o l fast blue. × 600.
Fig. 8. Slight perivenous infiltration of lymphocyte> in medulla of Case 4. No continuity with plaque about 3 cm away. Note normal myelin, but some acute swelling of oligodendroglia. HE, x 600
PROGRESSION OF THE MS LESION
173
Fig. 9. Modest perivenous infiltration oflymphocytes in pons of Case 3. Otherwise as for Fig. 8. HE. x 600.
Fig. 10. Modest perivenous infiltration of lymphocytes in upper medulla of Case 5. Note apparently normal myelin. HE, × 600.
174
165
~=i,Elsevier ScientificPublishing Company, Amsterdam- Printed in The Netherlands
The Onset and Progression of the Lesion in Multiple Sclerosis* C. W. M. ADAMS
Department qf Pathology, Guy's Hospital Medical School. London. SEI 9RT (Great Britah~)
(Received 9 November, 1974)
INTRODUCTION The main theme of this paper is to consider the histopathological processes involved in the onset and enlargement of the plaque in multiple sclerosis (MS). It is proposed first to discuss the established plaque before considering what may be earlier lesions. ESTABLISHEDLESIONS Established lesions are often gross and destructive- such as those encountered around the ventricles and sometimes in the mid-brain and cord. The inert burnt-out plaque is repaired by dense isomorphic astrogliosis and shows neither hypercellularity at its edge nor lipid phagocytosis by gitter cells. Whether or not the inert lesion can be reactivated is not known, and the extent of remyelination remains problematical (P6rier and Gregoire 1965 ; Suzuki, Andrews, Waltz and Terry 1969). Active established lesions in MS can reasonably be characterized by hypercellularity, increased histochemical enzyme activity and prominent lipid-laden gitter cells near or at their edges (Fig. 1 ; see Friede 1961 ; Ibrahim and Adams 1963; Friede and Knoller 1964; Adams, Ibrahim and Leibowitz 1965). It is uncertain whether the lipid phagocytes in multiple sclerosis directly attack myelin (see Suzuki et al. 1969), in the same way as they do in experimental allergic encephalomyelitis (Lampert 1967a and b). The role of these phagocytes certainly includes that of resorbing the tissue debris and esterifying the free cholesterol of myelin to the ester form (Petrescu 1966, 1969; also see Day 1964). The hypercellularity at the rim of the active established plaque seems to be responsible for the increased enzyme activity here. Nevertheless, it is still uncertain in what proportion oligodendrocytes, astrocytes and microglia are present in this active rim: the nature of the reactive cells at this site remains unclear. Oligodendrocytes are, however, absent (Lumsden 1951) or substantially reduced in
* This paper was read at the Symposiumon MultipleSclerosis,organizedby the MedicalResearchCouncil and the MultipleSclerosis Society,held in London on 17-18 October, 1974.
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c.w.M.
ADAMS
number (Ibrahim and Adams 1963 : Lumsden 1970) in the central area of established mature lesions. It is of great interest that Simpson, Tourtellotte, Kokmen, Parker and Itabashi (1969) found a rim of IgG immunofluorescence around active cellular lesions. This prompted us to examine the edge of 6 active plaques in MS: a small proportion ( ~ 2 °/o)of cells had the light-microscopic appearance of small lymphocytes, but none were recognizable as plasma cells. The occurrence of lipid phagocytosis in the plaque is not necessarily evidence of very recent onset, for myelin in the central nervous system is -at least in Wallerian degeneration--only slowly broken down over the course of a year (chemistry see McCaman and Robins 1959; ultrastructure--see Lampert and Cressman 1966; Bignami and Rolston 1969). Plaques that are apparently newly-formed show great activity, as revealed by marked cellularity and numerous lipid-laden gitter-cells throughout the lesion (Figs. 1 and 2; Ibrahim and Adams 1965). Such plaques often show an infiltration of lymphocytes and macrophages around the vein running through the centre of the lesion (Fig. 3; see THE EARLY1.ESION).
Enlargement of the establishedplaque The cellularity and myelin breakdown at the edge of active plaques indicate that they expand outwards at their circumference. In hyperactive plaques, a rim of diminished histochemical staining for basic protein (Fig. 4A) extends further outwards
Fig. 1. Diagrammatic representation of the features of different lesions in multiple sclerosis. The top ro~ shows established plaques; the bottom row shows perivenous lymphocyte cuffs with and without demyelination. Glial cells and perivenous infiltration are indicated by black dots; lipid phagocytes are shown as grey circles ; demyelination is indicated by white circles.
PROGRESSION OF THE MS LESION
167
Fig. 2. Hyperactive plaque in cerebral white matter of Case 2 to show gila and lipid phagocytes throughout the lesion. Sudan black, x 64.
Fig. 3. A : perivenous infiltration at centre of hyperactive plaque in cortical white matter o f Case 2; B: note mixed lymphocyte-monocyte population. HE, x 236, × 960. (Reproduced by courtesy o f the editor of the Journal of Neurochemistry).
168
¢ w . M. ADAMS
Fig. 4. ,4 : loss of basic protein (arrow) outside zone of lipid loss at edge of hyperactive plaque in conicui white matter of Case 2. Trypan blue, × 64. B: corresponding acid proteinase activity. Clear areas digestion of gelatin film (blackened photograph plate). Gelatin-silver autogram, x 64. (Reproduced b} courtesy of the editor of the Journal qf Neurochemistrv).
than the loss of myelin lipid as shown by histochemical staining methods (Adams, Hallpike and Bayliss 1971 ). This suggests that it is a basic protein rather than lipid that is first degraded in the outward extension of the plaque. The differential staining for protein and lipid, as well as the only slightly increased water content at the edge of plaques compared with the adjacent white matter (11.2 o~ + 7.5, n = 6; J. Csejtey, personal communication), exclude local cerebral oedema as the cause of this outer rim of diminished staining for basic protein. The loss of basic protein is confined to the limits of the plaque in the less active and chronic established lesion (HaUpike and Adams 1969; Hallpike, Adams and Bayliss 1970a). Polyacrylamide gel electrophoresis also shows that myelin basic proteins are reduced at the edge of the active plaque and virtually disappear from the centre of all plaques (Einstein, Dalal and Csejtey 1970; Riekkinen, Palo, Arstila, Savolainen, Rinne, Kovalo and Frey 1971 ; Riekkinen, Rinne, Savolainen, Palo, Kovalo and Arstila 1971 ; Einstein, Csejtey, Dalai, Adams. Bayliss and Hallpike 1972). The activity of acid proteinase and certain peptidases is markedly increased at the edge of active plaques (Fig. 4B; Adams 1968; Hallpike and Adams 1969; Einstein et al. 1970, 1972; Hallpike, Adams and Bayliss 1970b; Riekkinen, Clausen, Frey, Fog and Rinne 1970; Riekkinen, Rinne, Arstila and Frey 1970; Arstila, Riekkinen, Rinne and Laitmen 1973 ; Bowen and Davison 1974a, b). Activity is also moderately increased around inactive lesions and in "normal" white matter in the MS brain, but
PROGRESSION OF THE MS LESION
169
is variable in the centre of the plaque. Acid proteinase has been thought to be derived from lysosomes and, in this connection, Bowen and Davison (1974a) suggest that increased catheptic activity around plaques in MS might at least be partly derived from lysosomes in macrophages or other phagocytes. Certainly, cells seem to be a source of some proteolytic activity around MS plaques (see Fig. 8 in Adams 1968), but it is doubtful whether any of these cells are metabolically typical monocytes, histiocytes or macrophages in that they do not stain intensely for catalase, which is a characteristic of typical reticulo-endothelial cells (Adams, Bayliss and Turner 1975}. Arstila et al. (1973) noted a marked increase of lysosomes in astrocytes--but little in oligodendroglia--in biopsies from MS brains; this source cannot be excluded as one possible origin for the proteolytic enzyme or enzymes in question. The relation between increased proteolytic activity and loss of basic protein around the plaque led us to consider that digestion of this supposedly vulnerable protein is a preliminary--but not necessarily exclusive-event in myelin breakdown in the outward extension at the edge of the established plaque. Myelin basic protein in the brain is sensitive to cerebral acid proteinase (Einstein, Csejtey and Marks 1968), while proteolytic digestion of the proteins in myelin leads to loss of the attached lipids and in vitro myelin breakdown (Adams and Tuqan 1961 ; Tuqan and Adams 1961; Adams, Ibrahim and Leibowitz 1965; Hallpike, Adams and Bayliss 1970c). Thus, catheptic activity at the edge of the plaque could account for the breakdown of myelin in the expanding edge of the established lesion. However, it does not account for axonal preservation, nor is it clear what cells are involved in the formation and release of the relevant proteinase or proteinases (Adams 1972). Moreover, other proteins than the basic sorts may be digested by proteolysis during myelin breakdown (see Bignami and Eng 1973). THE EARLY LESION
Previous observations
It is widely recognized that demyelinating lesions in MS that are apparently early may show a zone of lymphocytic infiltration--including monocytes (macrophages) --around the central vein from which the lesions expand (Figs. 1 and 3 ; Greenfield and King 1936; Adams and Kubik 1952; Adams and Richardson 1961; Lumsden 1970, 1972; see Fog 1964). These lesions bear some histological resemblance to those seen in rabies post-vaccinial encephalomyelitis (Uchimura and Shiraki 1957). Dawson (1916a, b) considered that lymphocyte cuffs in MS are only found in older lesions, and concluded that they were a response rather than an early event in the pathological chain of events. Dawson evidently considered that lymphocytes were associated more with chronic plaques. What seems to have largely escaped comment or attention for the last 50 years is that perivenous infiltration of lymphocytes may occur in MS without any obvious surrounding demyelination, that is a morphological appearance with some--but not complete--similarity to the perivenous infiltration in experimental allergic encephalomyelitis in smaller animals, where demyelination is trivial or absent. Attention has previously been called to such perivenous infiltrations without demyelination in
170
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multiple sclerosis by Siemerling and Raecke (1914), Birley and Dudgeon (19211 and by Symonds (1924). Roizin and Kolb (1957) illustrated such a lesion, but withoul comment on its nature or significance. Possibly these early reports have been discounted or ignored because of the statement by Dawson (1916a, b) in his well-known authoritative review, that such infiltration is a late or unimportant feature.
Analysis of present material Among 44 cases of multiple sclerosis that we have studied since 1962, 5 died suddenly from apparently acute involvement of mid-brain centres. All 5 of these acute cases showed various degrees of perivenous lymphocytic infiltration in and around areas of demyelination. In all but the second case, the pons and medulla were principally involved in the acute episode. Clinical abstracts Case 1. a woman o f 47 yr with a 24-yr history of multiple sclerosis : 1 week before her death she developed an acute episode which evolved into pseudobulbar palsy. Case 2.* a woman of 18 yr with an indefinite 2-yr history of depressive disease; she had recently complained of giddy attacks and 2 days later was found dead in her bath. Case 3. a man of 54 yr with a 6-yr history of multiple sclerosis; he became unconscious while driving an invalid car and subsequently developed partial respiratory paralysis; he died 6 weeks later. Case 4.* a woman of 57 yr with a long history ( ~ 20 yr) of multiple sclerosis ; she died suddenly while watching television. Case 5. a woman o f 31 yr with a 1-month history of multiple sclerosis; 5 days before her death she developed intractable vomiting and then lapsed into coma.
Fig. 5. Meningeal vein adjacent to hyperactive plaque in pons of Case 3. Note mixed lymphocyte-monocyte population. HE, x 940. * Professor Keith Mant (Dept. of Forensic Medicine, Guy's Hospital) kindly provided the material for Cases 2 and 4.
PROGRESSION OF THE MS LESION
/71
The lesions identified were:
(1) Monocyte-lymphocyte infiltrations. These perivenous cuffs contain varying proportions of monocytes (macrophages), lymphocytes and occasional plasma cells (Fig. 3B). These are usually within or contiguous to plaques (Fig. 3A). may involve meningeal veins (Fig. 5), and, thus, seem merely to represent an escape of inflammatory cells from the lesion along the course of veins or venules. In addition they may in part reflect perivenous extensions of the plaque--particularly when the infiltrate is largely lymphocytic--ultimately to form what is known as a Dawson's finger (Figs. 6 and 7; Lumsden 1970). (2) Lymphocyte infiltrations. These perivenous cuffs contain a predominance of lymphocytes with some plasma cells and only a few--if any--monocytes. They are found in areas of apparently normal myelin in the neighbourhood of a plaque or in areas of myelin pallor (see 6 below). The number of cells in these cuffs varies from distinctly scanty (Figs. 1 and 8) to moderate (Figs. 9 and 10), is less than in the mixed infiltrate described above under (1) and is never comparable to that seen, for example, around small arterioles in "collagen" diseases or in gliomas (Ridley and Cavanagh 1971 ). These cuffs may be relatively close to or up to 3 cm from the nearest plaque. They are not found in areas where a lesion is not present in the vicinity, nor are these cuffs found in 10 cases of recent or old cerebral infarction (including 2 of recurrent infarction). However, 1 case of acute medullary infarction shows several mixed monocyte-lymphocyte cuffs of type 1. Serial section of tissue around four such predominantly lymphocytic infiltrates in Cases 2 and 3 shows that they do not merge with perivenous lymphocyte-monocyte
Fig. 6. Diagram to show relation of lymphocyte infiltrations to veins and plaques. Note extension o f plaque as a Dawson's finger, and isolated perivenous lymphocytic infiltrates.
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Fig. 7. Perivenous lymphocyte cuff in pons of Case 3. This vein extends out of an active plaque, and !he lymphocyte infiltration represents the onset of a Dawson's finger, c,l Fig. 6 (bottom left). [ u x o l fast blue. × 600.
Fig. 8. Slight perivenous infiltration of lymphocyte> in medulla of Case 4. No continuity with plaque about 3 cm away. Note normal myelin, but some acute swelling of oligodendroglia. HE, x 600
PROGRESSION OF THE MS LESION
173
Fig. 9. Modest perivenous infiltration oflymphocytes in pons of Case 3. Otherwise as for Fig. 8. HE. x 600.
Fig. 10. Modest perivenous infiltration of lymphocytes in upper medulla of Case 5. Note apparently normal myelin. HE, × 600.
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