J Neuropathol Exp Neurol
Copyright Ó 2006 by the American Association of Neuropathologists, Inc.
Vol. 65, No. 4
April 2006
pp. 305Y318
REVIEW ARTICLE
The Pathogenesis of Multiple Sclerosis: Relating Human
Pathology to Experimental Studies
Samuel K. Ludwin, MB, BCh, FRCP(C)
Abstract
Multiple sclerosis (MS) is a complex disease of unknown
etiology. A careful study of the pathology of its component
elements in relation to relevant experimental models has helped
to understand some of the mechanisms that might be present in the
disease. However, the autoimmune nature of the disease has
recently come under question and there is a growing recognition
of the importance of axonal, cortical, and white matter changes in
the genesis and evolution of the lesions, their clinical diagnostic
characteristics, and their response to treatment. This review highlights the emerging issues in MS from experimental, imaging and
clinical perspectives.
Key Words: Autoimmunity, Demyelination, Multiple sclerosis,
Remyelination.
INTRODUCTION
Despite the explosion of knowledge in immunology,
molecular biology, genetics, and cell biology, the ultimate
etiology of multiple sclerosis (MS) remains uncertain.
Intensive study of the pathology of MS lesions and its
relationship to relevant experimental animal models has
helped show how the individual components of the disease
may develop, and has moved the pathological basis of MS
from the descriptive to the comparative and the interpretive.
The increasing sophistication of in vivo imaging has created
a whole field of dynamic imaging pathology, which has
begun to be correlated with classical pathological changes.
Over the last decade, treatment modalities have been
developed from experimental observations that have offered
MS patients relief from many of the debilitating relapses
characteristic of the disease: the disease may continue on an
inexorable course, however, prompting the search for new
treatments (1, 2). The prominent genetic overlay, identified
by meticulous population and family studies (3, 4), may interact
with environmental factors from viruses to vitamin D levels
From Department of Pathology, Queens University and Kingston General
Hospital, Kingston, Ontario, Canada.
Send correspondence and reprint requests to: Samuel K. Ludwin, Department of Pathology Queens University, Richardson Laboratories, Stuart
Street, Kingston, Ontario, K7L 4V1, Canada; E-mail: Ludwin@cliff.
path.queensu.ca
J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
and sun exposure (5, 6). This has led to genome screening with
some putative gene identification (7, 8).
Pathogenetic and therapeutic considerations have
framed new questions around the scientific investigation of
the MS lesion and its experimental substrates. The long-held
belief that MS is an inflammatory autoimmune demyelinating disease occurring in genetically susceptible individuals
and triggered by an unknown, possibly infectious process
has begun to be challenged. Many authors now talk about
MS as a biphasic disease, with an early inflammatory period
and a later degenerative process, characterized by a
progression to brain and spinal cord atrophy in the absence
of overt relapses and significant inflammation. Is this latter
phase a true degeneration or a very protracted inflammatory
process? Here, the etiology of axonal damage becomes
important given the emerging interest in axonal and neuronal
neuroprotection. It is increasingly being recognized that
cognitive decline related to cortical pathology and widespread damage in the white matter is an integral part of the
disease.
Is MS a homogeneous disease or one made up of
heterogeneous pathologies, etiologies, and pathogenetic
pathways leading to a single end-result? What is the
potential for significant remyelination in the nervous system
and the role of gliosis in facilitating or preventing brain
repair?
The individual components of the lesion include
inflammation and breakdown of the blood-brain barrier
(BBB), demyelination following destruction of myelin and/
or oligodendrocytes, axonal damage, cortical involvement,
remyelination, and gliosis. This review will focus on
components these in relation to their experimental, clinical,
and imaging counterparts.
Basic Pathology
The pathology of MS, known since the time of
Charcot, has been extensively reviewed in numerous
publications (9Y11) as well as in standard texts and will not
be repeated here in detail. The plaques, predominantly in the
white matter (Fig. 1) but extending also into the grey matter,
are seen in the cerebral hemispheres and are also common in
the brainstem, spinal cord, optic nerves and chiasm, and the
cerebellum. The lesions show demyelination and gliosis and,
often, a striking loss of oligodendrocytes in the center.
Scattered macrophages and lymphocytes are frequently
identified, especially with special stains. Axons are lost to
a variable degree, although the degree of myelin loss is often
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Ludwin
J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
active edge, or else one with a low level of inflammatory
activity. The active edge of plaque may represent continual
expansion of a lesion whose core has become inactive, or it
could represent new activity around the edge of a previous
plaque. The stage of myelin breakdown can also be more
accurately determined by assessing the contents of macrophages. Early activated macrophages may stain positively
for MRP14 and 27E10; these early lesions will also show
reactivity for myelin oligodendrocyte glycoprotein (MOG)
and myelin-associated glycoprotein (MAG), which disappears within a week or two, while myelin basic protein
(MBP) and proteolipid protein (PLP) are retained for up 3 to
4 weeks (17).
Inflammation: Is MS an Autoimmune Disease?
FIGURE 1. Chronic multiple sclerosis. A periventricular
plaque (short arrow) extends well into the corpus callosum
and has caused severe atrophy indicating myelin and axon
loss. In addition, throughout the white matter there are areas
of grayish discoloration indicating tissue damage away from
classical plaques (long arrows). Reprinted from Neuroimaging
Clinics of North America, Vol. 10, Ludwin SK, et al. Neuropathology of multiple sclerosis, pp. 625Y648, Ó 2000, with
permission from Elsevier (9).
more obvious than axonal loss. In the chronic lesion the
presence of thinly myelinated sheaths, together with areas of
shadow plaque, often suggest that remyelination has taken
place. New evidence is emerging that the extent of the
lesions is far greater than originally believed. Involvement of
the deep grey matter is quite common, and as will be
discussed below, there is often widespread involvement of
the white matter that had appeared normal on gross
examination, the so-called normal appearing white matter
(NAWM). In addition, evidence suggests that cortical
pathology and demyelination is widespread and very
common.
A great deal of information about the acute lesion has
been obtained because of the increased number of biopsies
performed for evolving lesions seen on imaging studies. The
elements of the acute inflammatory response (Fig. 2A, B)
help to interpret the nature and etiology of the lesion.
Inflammatory neo-vascularization has recently been
described in MS (12) (Fig. 2C, D), which may extend
outside the lesion to the peri-plaque and even the NAWM,
and may have consequences both for diagnosis and for the
generation of future lesions. cDNA microarray studies to
detect gene regulation abnormalities (13, 14) have demonstrated only upregulation of inflammation-related molecules
and have failed to show any definitive etiological agents.
Staging of MS lesions is very important in defining the
lesion under discussion (15, 16). Most people use a variation
of active/acute, chronic-active and chronic-inactive or
classical to stage MS lesions. Active/acute lesions have
traditionally been defined as showing demyelination with
inflammatory infiltrates, whereas chronic lesions show
demyelination with little or no activity. The subacute or
acute and chronic lesion is one with a chronic core and
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The arguments for the immune basis of MS have been
well summarized (1,18). The hallmark of the acute lesion is
a robust inflammatory response, consisting of lymphocytes,
macrophages, occasional plasma cells or even eosinophils,
which may also be scattered in chronic lesions. They form
the active rim of expanding acute-on-chronic or subacute
lesions. The T-cells seen in MS consist of both CD4+
(Fig. 2B) and CD8+ types. CD4+ T-cells have two subtypes
based on the array of cytokines they produce; these are
commonly known as TH-1 and TH-2 responses, which
are, respectively, pro-inflammatory (i.e. interleukin 2,
+-interferon, and tumor necrosis factor) and anti-inflammatory. Activated T-cells gain access to the nervous system,
particularly after BBB disruption, although some can be seen
to cross the intact BBB. Cell adhesion molecules such as
ICAM-1, VCAM-1, and E-selectin facilitate the entry of Tcells into the brain, as does matrix- metalloproteinase 9
(MMP 9). Once inside the central nervous system, T-cells
are presented with specific antigenic peptides in the context
of the major histocompatibility complex (MHC) molecules.
CD8-positive cells recognize antigens through class I MHC
molecules, whereas CD4 cells recognize antigens using class
II MHC antigens. The final immune component consists of
co-stimulatory molecules. These components, including proinflammatory cytokines TNF!, + interferon, and IL2, can be
shown on cells within the lesion, either macrophages or
lymphocytes.
Much of the information regarding the immune basis
of MS has been gleaned from experiments using the animal
model of experimental allergic encephalomyelitis (EAE),
induced by the injection of myelin or myelin peptides into
genetically susceptible animals, with or without adjuvant.
This has produced many MS-like features. Classical EAE
resembles acute MS and also acute disseminated encephalomyelitis, but by manipulating strain and experimental
procedures, researchers have been able to convert this
uniphasic experimental disease into more typical progressive
and relapsing remitting forms that more closely resembles
MS. In spite of this resemblance and the indications that
EAE is a Th1-mediated disease, many authors have
questioned the relevance of EAE as a model for MS (see
below).
Recently, interest has shifted to CD8 cytotoxic cells
(19), which cells have been shown in vitro to have major
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J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
The Pathogenesis of Multiple Sclerosis
FIGURE 2. Acute multiple sclerosis. Prominent inflammatory infiltrate is seen around the vessels and in the parenchyma (A).
Perivascular lymphocytes stained for CD4 markers (B). A normal control case stained for CD34. Only small numbers of vessels are
present (C). Acute MS (D). Increased numbers of vessels are present. Panel (B) reprinted from Neuroimaging Clinics of North
America, Vol. 10, Ludwin SK, et al. Neuropathology of multiple sclerosis, pp. 625Y648, Ó 2000, with permission from Elsevier (9).
destructive effects on myelin and oligodendrocytes. In the
MS lesion, CD8 cells predominate and are clonally
expanded. They interact with MHC Class I present on
oligodendrocytes and neurons and axons, as well as other
tissue elements. In recent years the importance of B-cells in
the pathogenesis of MS has also achieved prominence.
Immunoglobulins and complement, especially the C9neo
component, are deposited on the myelin and on the axon
sheaths; in addition, antibodies against MOG and MBP have
been commonly demonstrated in CSF and sera of MS
patients (20). These may be related to the characteristic
oligoclonal bands.
Despite the features of immune activation in MS, some
have suggested that MS is a neurodegenerative disease
rather than an autoimmune disease (21, 22). These authors
have pointed out that inflammation can be seen in many
infectious and degenerative diseases and have suggested that
MS immune phenomena could also be secondary events.
The idea that it is caused by an infectious agent still remains;
however, after more than a century a search for an infectious
agent has proven elusive. Cells auto-reactive to myelin
proteins, as well as anti-myelin antibodies, may well be seen
in healthy controls and indeed may be part of the normal
repertoire of the immune system. Inflammatory cellular
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infiltrates may be seen in adrenoleukodystrophy, poliomyelitis, and ALS, and the complement deposition seen in
MS is also found in numerous other conditions including
ischemia. The specificity of oligoclonal banding has also
been called into question. In contrast to rheumatoid arthritis,
no association with disease-specific immune markers exists
in patients with multiple sclerosis. Finally, extrapolations
from the EAE model may be flawed. Besides the artificiality
of the situation, they have also pointed out that the treatment
of EAE has often yielded beneficial results not always seen
with the same treatment in MS. This remains the subject of
some intense debate in the literature. Some authors have also
suggested that in many cases the autoimmune response may
be secondary rather than primary and may follow a primary
CNS event (e.g. infection or ischemia), with the target
antigens subsequently presented to the lymph nodes (21).
Activated lymphocytes then reenter the central nervous
system and cause damage (21).
A spirited defense of MS as an inflammatory, T-cell
mediated autoimmune disease has been made by other
authors (23). They have pointed out the similarities between
the pathology of MS and Th-1 type bias in EAE such as
activated T-cells in the blood and cerebrospinal fluid, T-cell
reactivity to myelin antigens, Th1-type inflammation in the
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Ludwin
brain, chemokine expression, and deposition of immune
globulins. The T-cells reactive against myelin antigens have,
of course, been found in normal patients. Until recently it
has not been proven that the myelin reactive T-cells
circulating in MS patients are capable of inducing tissue
damage. Recently, a model using transgenic mice humanized for the human T-cell receptor has shown that MS
patient T-cells, when passively transferred to these mice, are
capable of inducing inflammation, demyelination, and
axonal damage (24, 25) (Fig. 3). These experiments
demonstrate that MS T-cells at least have the potential to
cause damage. The response to therapy with interferons,
glatiramer acetate, natalizumab, and immunosuppression,
even though not conclusive, has been used to bolster this
argument, as have the relationships to other autoimmune
diseases in family members, and the reduction of disease
during pregnancy. However, it should be pointed out that
although the incidence of relapses and new gadolinium
enhancing lesions indicative of breakdown of the BBB are
reduced in patients on these disease-modifying therapies, the
long-term inexorable progression of the disease is not altered
by them. Hemmer et al suggest that there may be two
pathways to immunity, one originating with activated
immune cells in the periphery, and the other secondary to
tissue destruction and the development of subsequent autoimmunity (21); this will continue to be explored.
Demyelination and Its Causes: Is MS a
Homogeneous Process or the End Result of
Diverse Processes?
The plaque is a sharply defined area of demyelination,
sometimes extending out from the main lesion in a
perivascular sleeve called Dawson’s finger (Fig. 2A). The
amount of myelin preservation within a plaque may be
highly variable. Immunochemical stains for myelin proteins
(MBP, PLP, and MOG) have shown more subtle degrees of
myelin loss than classical staining. Demyelination is also
J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
seen early in the acute plaque (and this often distinguishes it
from acute disseminated encephalomyelitis) in which, as in
EAE, the demyelination is often less prominent than the
inflammation. Demyelination can occur in a variety of
different ways. Experimentally, this can occur either due to
oligodendrocyte loss, as in the cuprizone, ethidium bromide,
and antibody-mediated EAE models, or by direct attack on
the myelin sheath, as in lysolethicin- induced membrane
damage and at times in EAE. Observations in these models
have been applied to MS. In many acute cases of MS where
there is infiltration by T-cells and deposition of immunoglobulins, the breakdown of myelin can occur with a significant
degree of preservation of oligodendrocytes, suggesting a
direct attack on the myelin sheath. In other plaques there is a
significant decrease in the number of oligodendrocytes,
especially in the center, indicating direct damage to the
oligodendrocyte (26, 27). Oligodendrocytes and their precursors may be killed by necrosis, and a variety of in vitro
experiments have demonstrated their susceptibility to
numerous toxic inflammatory mediators (28). Such dying
oligodendrocytes may be also seen in MS lesions. Most
authors accept the fact that oligodendrocytes undergo
apoptosis in MS (29), although the extent varies (26, 30).
Another form of oligodendrocyte destruction is the so-called
dying-back gliopathy demonstrated experimentally in
chronic cuprizone poisoning (31). Here the inner cell tongue
of the oligodendrocyte is seen to degenerate before the
perikaryon of the oligodendrocyte (Fig. 5A). This has also
been shown in MS tissue by Rodriguez et al (32), as well as
more recently by Lucchinetti et al (33). All three mechanisms (necrosis, apoptosis, and dying-back) may cause
demyelination (Fig. 4A), as can direct damage to the myelin
sheath. The tempo and pace of demyelination varies
according to how myelin is primarily damaged. In early
EAE, macrophage stripping of myelin occurs in the first few
days. Traditionally, it has been held that in models where
oligodendrocytes are damaged, demyelination may be much
FIGURE 3. EAE in a transgenic mouse humanized for TCR receptor with activated T-cells from an MS patient. There is severe
inflammatory infiltrate in the parenchyma of the spinal cord (A) extending into the nerve root. Demyelination and inflammation
in the brainstem of a similar animal (B). Panel (A) reproduced from the Journal of Experimental Medicine 2004;200:223Y34 by
copyright permission of the Rockefeller University Press (25).
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J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
The Pathogenesis of Multiple Sclerosis
although they may be found anywhere in the nervous system
(Fig. 1). Experimental studies have shown that myelin in
different parts of the nervous system has differing susceptibilities to damage. In the cuprizone model the superior
cerebellar peduncle, the corpus callosum, and the centrum
semiovale are routinely affected, whereas the optic nerve
and spinal cord are unaffected. Interestingly, demyelination
and remyelination in a transgenic mouse model (34) in
which there is over-expression of DM-20 occur in an almost
identical distribution (Fig. 4B, C). It is interesting to consider why two conditions, both systemic in etiology, should
preferentially affect oligodendrocytes in certain areas.
Epigenetic modifying factors must be rendering certain
oligodendrocytes more susceptible to damage. This may be
operating in MS as well. To date, however, no obvious
developmental pathway or other cause for this location
difference can be detected.
Are There Different Pathways to Demyelination
and the Heterogeneity of MS?
FIGURE 4. Demyelination following oligodendrocyte degeneration in cuprizone toxicity (A). Demyelination in the
superior cerebellar peduncle of a transgenic mice overexpressing DM-20 (B). Spinal cord from the same animal showing no
myelin degeneration or demyelination (C).
slower (2 to 3 weeks in the cuprizone model), however,
recent observations in MS (30), as well as in ischemic
damage, have suggested that this may occur much more
rapidly. Dying-back gliopathies are thought to be the slowest
forms of demyelination, as seen in chronic disease.
The individual mediators of oligodendrocyte and
myelin damage are very similar to those that have been
invoked as causing axon damage. They include direct and
indirect attack by CD8 T-cells with the discharge of
cytotoxic granules and FAS ligation, excitotoxicity through
glutamate, antibody and terminal complement component
attack on the membranes, and pro-inflammatory molecules
(TNF!, +-interferon, IL12, lymphotoxin, etc.). Nitrous oxide
and other reactive oxygen species are also important
mediators of damage. Finally, the release of components of
tissue damage such as the matrix metalloproteinases,
perforin, granzyme, caspases, and calpain have all been
implicated (18).
Is All Myelin Equally Susceptible to Demyelination?
The location of plaques around the ventricles in the
optic nerves and spinal cord has always aroused interest,
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Over the course of several years, Luchinetti and
colleagues have described a large, unique, international
series of acute MS cases (33, 35). They relied mainly on
biopsies but also used autopsy material and suggested new
ways interpretations of the pathology and pathogenesis of
plaques. Morphologically, they described 4 lesion patterns
and although the patterns varied from patient to patient, all
the lesions in any one patient were of the same type.
Furthermore, in those patients with more than one biopsy,
separated by time, the pattern type held up. Pattern 1 (15%)
showed inflammatory demyelination marked by macrophage
infiltration. Pattern 2, the most common pattern (58%),
presented with well-demarcated zones of demyelination and
striking T cell inflammation. When lesions were studied with
antibodies against myelin proteins, all of these were lost
simultaneously (Fig. 6). This pattern was marked by the
striking deposition of complement, especially the C9neo
component, around blood vessels and on the myelin. The
edges of these lesions also showed gadolinium enhancement
on MRI, indicative of BBB breakdown. Oligodendrocytes
FIGURE 5. Oligodendrocyte inner tongue degeneration (A),
suggesting a dying-back gliopathy in the DM-20 mouse.
Oligodendrocyte apoptosis (B) with nuclear condensation in
the DM-20 mouse.
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Ludwin
FIGURE 6. Differential myelin protein loss in acute MS
lesions. In pattern 2 (upper panels), loss of MBP (left) and
MAG (right) are equivalent. In pattern 3 (lower panels), the
loss of MAG (right) is far more extensive than that of MBP
(left). Image reprinted from Lucchinetti C, Bruck W, Parisi J,
et al. Heterogeneity of multiple sclerosis lesions: Implications
for the pathogenesis of demyelination. Annals of Neurology
2000;47:707Y17 with permission from John Wiley & Sons,
Inc. (33).
were relatively well preserved, and remyelination, often in
the form of shadow plaques, was frequently found. In all, the
morphological features resembled those seen in T cell
antibody-mediated, MOG-induced EAE. In Pattern 3, the
next most common type at 26%, demyelination and
inflammation occur. However, the plaque is less sharply
delineated and there is a great loss of oligodendrocytes, with
reduced subsequent remyelination. The finding that the loss
of MAG is greater than that of MBP or PLP (Fig. 6)
suggested pathology in the inner cell tongue of the
oligodendrocyte and recalled the dying-back gliopathy seen
in cuprizone demyelination (31) and in MS lesions. This has
been called a distal oligodendrogliopathy. In these cases,
Balo-like rings were often found (Fig. 7). These cases tended
to have little gadolinium-enhancement on MRI. Significantly, the changes also resembled the damage seen with
anoxic and toxic damage to the oligodendrocyte (36). Pattern
4, a very rare form, shows oligodendrocyte degeneration in
the peri-plaque white matter. The demographic and clinical
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J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
features of these patients have been found to be comparable
to a cohort of typical MS patients (37).
These authors have now studied a total of 286 acute
cases, and in their hands the distinction between the patterns
holds up. Differences in the chemokine receptor expression
between Patterns 2 and 3 suggest differing inflammatory
microenvironments. In addition, patients with Pattern 2
lesions show a greater response to plasmapheresis than
those with Pattern 3 disease, confirming the antibody/
complement-mediated nature of the former (38).
These various patterns have suggested varying etiologies and pathogenesis between patients and pointed to the
possibility of MS as a heterogeneous disease. The studies
have provoked much discussion as to the etiology of MS and
represent a real opportunity to analyze MRI and clinical
outcomes, and the possibility of defining a group of
surrogate markers. However, these findings have been
difficult to confirm because few other groups have access
to a similar population of acute cases. It is also possible that
the variability in the pathology represents not differences in
etiology, but a difference in severity from one case to
another. In addition, others have found an overlap of features
from one type to another (Fig. 7). Finally, clinical segregation between patterns has not been shown to be exclusive.
Another approach to etiopathogenesis has been postulated in a recent study by Barnett and Prineas (30). In a
young girl who died 17 hours after the onset of symptoms, in
addition to more typical MS lesions, they demonstrated an
unusual brainstem lesion represented by areas with apoptotic
oligodendrocytes and macrophage activity with a paucity of
inflammatory cells. The authors called this the early
apoptotic oligodendrocyte lesion, and on the basis of a
further 12 cases with similar lesions, postulated that this was
indeed the way that all MS lesions started. Again, they
postulated an ischemic or metabolic insult to the oligodendrocyte. They rejected the notion of MS as a primary
autoimmune disease and postulated that the immune reactions were secondary to this change. They also suggested
that the experimental models at the basis of the autoimmune
theory of MS were baseless, a point of view shared by
Chadhouri and Behan (22). These provocative findings need
to be confirmed, as this theory does not explain why people
with strokes and other CNS damage do not regularly develop
immune autoreactions. In addition, these findings, and
indeed their explanations, are not that different from those
found in Pattern 3 of Luchinetti et al., where a similar
anoxic/toxic insult was suggested. It remains to be confirmed
that these lesions are in fact MS lesions and not some other
process such as ischemic necrosis.
Axonal Damage: Is This the Cause of Continuing
Widespread Symptomatology, Progression
and Atrophy, and Is It the Result of Inflammation
or a "Degenerative"" Process?
In the recent past, theories of immunity against myelin
have been dominant, and only passing reference was made
to the loss of axons. The major destruction of axons in acute
MS lesions (Fig. 8B) was highlighted by Trapp et al (39),
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The Pathogenesis of Multiple Sclerosis
FIGURE 7. Multiple lesion patterns in a case of chronic MS. A classical well-demarcated chronic white matter plaque (p) is seen
extending into the cortex of the cingulate gyrus. There is an adjacent shadow plaque (s) indicating remyelination. On the other
side there is a plaque with fuzzy borders, showing the tigroid alternating patterns seen in Balo’s concentric sclerosis (B). Reprinted
from Neuroimaging Clinics of North America, Vol. 10, Ludwin SK, et al. Neuropathology of multiple sclerosis, pp. 625Y648,
Ó 2000, with permission from Elsevier (9).
Axonal degeneration is correlated with increasing disability
and with transition to progressive forms from relapsingremitting disease. It is one of the striking features of primary
progressive MS. It correlates with brain (Fig. 8A) and
especially spinal cord atrophy and with extensive areas of
rarefaction and necrosis (40). Axonal loss is also one of the
substrates for the presence of the black holes seen on MRI
(41, 42), for the reduction in the neuronal marker N-acetyl
aspartic acid found on MR-spectroscopy, and for the reduced
magnetization transfer ratio.
The extent of axonal loss varies from 20% to 90%, and
can be found within plaques, in the peri-plaque zone, and
in the normal white matter away from the lesion. Axonal
degeneration and loss is also found as part of the Wallerian
degeneration in tracts distal to lesions. It can be demonstrated by conventional silver stains as well as by antibodies
to neurofilaments. Early damage to axons can be demonstrated by an accumulation of !-amyloid precursor protein,
non-phosphorylated neurofilaments proteins, and the demonstration of axonal swellings or spheroids. Using these
methods, Peterson and Trapp have shown that while normal
white matter contains less than one transected axon per cubic
millimeter, active lesions contained more than 11,000
terminal ovoids and core of chronic active lesions contained
about 900 (43). Bruck and colleagues (40, 44) have
confirmed this finding, showing that even in chronic
(inactive) lesions, a slow but perceptible damage and loss
occurs over the years.
Neuroprotection is increasingly important (45) and
requires an understanding of the etiology of axon degeneration. It seems certain that in the first instance axons are
damaged by inflammatory (46) and immune factors, either as
a direct auto-target of the immune attack or as a bystander
reaction secondary to an attack primarily directed at myelin.
Although anti-neurofilament antibodies can be demonstrated
in MS patients, anti-myelin antibodies are far more
FIGURE 8. Axonal loss in multiple sclerosis. Severe white matter atrophy with ventricular dilatation and diffuse plaques are seen
in a longstanding chronic case with severe axonal loss (A). Axonal damage in acute MS (B) is denoted by a decrease in number
of axons, axonal swelling, (arrows) and edema as shown with antibodies against neurofilament proteins. Panel (B) reprinted from
Neuroimaging Clinics of North America, Vol. 10, Ludwin SK, et al. Neuropathology of multiple sclerosis, pp. 625Y648, Ó 2000,
with permission from Elsevier (9).
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Ludwin
FIGURE 9. Remyelination. Panel (A) shows a remyelinated
mouse superior cerebellar peduncle following cuprizone
demyelination. Panel (B) shows thinly remyelinated fibers
(short arrows) concurrently with myelin breakdown products
in a macrophage (large arrow) in a case of MS.
prevalent. It is also important to note that axons can be
damaged by the same agents that have been implicated in
oligodendroglial damage, including cytotoxic T cells, complement, pro-inflammatory molecules, free-radicals including
nitric oxide, cytokines, granzyme, matrix metalloproteases,
and glutamate. Voltage-gated Ca channels also accumulate at
sites of axonal damage and allow for calcium influx leading to
damage. However, it is far less clear what causes the ongoing
axonal degeneration in chronic progressive cases. It is
possible that a slow subclinical inflammatory process (47) is
continuing throughout the disease course, not manifest
through the usual indicators of acute inflammation such as
clinical relapses or gadolinium enhancement. In most
plaques, even chronic ones, occasional inflammatory cells
can be found, and in culture it has been found that a single
cell releasing proteolytic enzymes can destroy an axon.
However, the paucity of these cells, the lack of gadolinium
enhancement even during clinical progression, and the
progression of the disease even when anti-inflammatory
therapies control the relapse rate have suggested that other
factors are operating in this situation. Axonal loss occurs in
animal models of chronic demyelination following mutations of MAG and PLP; either the loss of trophic factors
from oligodendrocytes and myelin (48), or the loss of a
physical barrier protecting the axon from exposure to
destructive factors could be the cause. Remyelination may
be the best neuroprotective strategy possible (49). In
addition, the rearrangement of Na and K channels on
demyelinated axons may place an undue metabolic stress
on the axons by increasing the need for ATP. There is,
therefore, an opportunity for therapeutic intervention.
Cortical Pathology in MS: Is This the Cause of
Cognitive Decline, and Does It Have the Same Basis
as the Axonal Degeneration?
Involvement of the gray matter in MS is not a new
concept, having been reported in up to 93% of cases. Interest
in cortical lesions has been stimulated by an increasing
awareness of cognitive changes in patients. A recent paper
has described fully the spectrum of pathology in the cortex
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of 50 MS patients using antibodies to myelin proteins (a
more sensitive modality than Luxol fast blue), and described
three different types of cortical lesions (50). Type1 lesions
occurred at the cortico-medullary junction, often in continuity with a lesion in the white matter, whereas Type2 lesions
were found completely within the cortex. A form of lesion
found in the cortex, but abutting on the pia adjacent to the
CSF most commonly in the depths of the sulci, has been
called Type3. Type 3 lesions may have a different pathogenesis altogether, and may depend on the access of
oligodendrocytic or other demyelinative factors from the
CSF to the cortex. Demyelination, macrophage activation
and axonal and neuritic changes, including transaction,
spheroids, apoptosis, and neuronal dropout are seen; but,
significantly, in all types the amount of inflammation was
much less than that seen in white matter lesions, even when
the two are adjacent (51). This may be explained by the
differences in the expression of cell-adhesion molecules in
the cortex and the white matter. However, this cortical
feature, together with a similar inflammatory lack in chronic
MS with axonal disease, is thought by some to comprise a
degenerative phase that follows the classical demyelination
phase and is responsible for progression. Significantly, MTR
imaging studies in primary progressive cases show significant changes in the normal appearing gray matter (52).
Pathology of the Normal Appearing White
Matter: Is This the Substrate for the Subsequent
Development of New Lesions, and the Cause
of Widespread Symptomatology?
The term normal appearing white matter or NAWM is a
misnomer, because most contemporary studies have consistently demonstrated that it is anything but normal. Early
studies showed loss of myelin and axons in the NAWM and,
indeed, a variety of biochemical and histological changes
have suggested that this structure was the site of active
pathology. These include the presence of hydrolases, proteases, and cathepsins, as well as a decrease in the amount of
myelin proteins. Of interest is the suggestion that the myelin
in MS patients is abnormal, rendering it more susceptible to
damage. Changes in the charge isomers of MBP in the
NAWM have prompted the idea that the myelin is in a more
immature form than normal (53). Two factors have drawn
attention to the NAWM. The first is the realization that in
many patients, the volume and location of plaques does not
seem to be sufficient to explain the severity or the nature of
many of the clinical signs and symptoms. Progressive brain
atrophy (Fig. 8A), even in patients with a relatively
moderate plaque load, suggests that more widespread loss
in the NAWM is present. Secondly, sophisticated forms of
MR examination have highlighted white matter changes,
which previously were not examined pathologically as the
white matter appeared grossly normal (54). These modalities
include reduced magnetization transfer ratios, changes in
diffusion coefficient, and decreases in N-acetyl aspartic acid
(NAA), a neuronal marker, on MR spectroscopy. Pathological examination of these image-guided areas has shown
active demyelination, with macrophages filled with myelin
components in varying stages of degradation, scattered
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J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
inflammatory cells, axonal spheroids, and even some
remyelination. The finding of reactive astrocytes is always
a reasonable indicator of ongoing or recent activity.
These changes raise some interesting questions. It is not
clear whether they represent primary damage or secondary
Wallerian degeneration, as has been elegantly shown in a
study of the corpus callosum in areas emanating from deep
white matter plaques (55). A more intriguing suggestion is
that they represent the first stages of lesions. Serial imaging
studies have shown that there are changes seen in the white
matter, which subsequently show typical plaque formation in
the same areas. Again, it is not clear whether these areas
have previously been sites of prior plaque formation. It is
known that lesion formation is accompanied by vascular
changes, also seen in the NAWM, which alter the background vascular architecture, potentially rendering the tissue
more susceptible to subsequent attack (12).
The Pathogenesis of Multiple Sclerosis
Remyelination and Shadow Plaques: What Are
the Factors Contributing to the Success or Absence
of Remyelination?
The central nervous system is capable of remyelination
and this occurs with surprising regularity in MS (9, 10, 56,
57). The mechanism and enabling factors allowing for
remyelination have been best identified in a number of
animal models such as cuprizone (Fig. 9A) and ethidium
bromide toxicity affecting oligodendrocytes, and in models
of autoimmune inflammatory disease such as EAE and
Theiler virus demyelination. Most of the observations have
been shown to be true for MS as well (Fig. 10B).
Experimental remyelination, either because of age or species
adaptability, is generally more robust and complete than is
usually seen in the human. Remyelination is the best and
most physiological way of protecting the axon from
FIGURE 10. Balo’s concentric sclerosis. Typical layers of alternating demyelination and preserved myelin in a circular lesion are
seen in the white matter. Both axon loss (A) (Bielschowsky stain) and myelin loss (B) (Luxol fast blue) are present. In addition,
small chronic plaques are also seen in the white matter. Panel (C) shows alternating bands of demyelination, cellular reactivity,
and preserved myelination stained for different factors. (c:a) Immune staining for iNOS shows staining in the active and the
demyelinating areas. There is little staining in the myelinated and periplaque white matter layers. The small inset (c:b) shows
staining in the glial cells under high power. The converse pattern is seen with staining for hypoxia-inducing factor (c:c), HSP-70
(c:e), and D-110 (c:f), all hypoxia-activated proteins, where the major staining is seen in the bands of preserved myelin and the
periplaque white matter. (c:d) Staining of the cells at higher power. Panel (C) reprinted from Brain, Vol. 128, pp. 979Y87,
Ó2005, Stadelmann C, Ludwin SK, Tabira T, et al. Tissue conditioning may explain concentric lesions in Balo’s type of multiple
sclerosis, with permission from the Oxford University Press (67).
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313
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Ludwin
exposure to damaging molecules. Morphologically, remyelination recapitulates the process seen in developmental
myelination, but the thickness of the myelin sheath never
achieves the same degree as seen in the normal; the usual
ratio of thickness to the axon diameter, once destroyed, does
not seem to return. Traditionally, remyelinated fibers are
identified by thin sheaths and short internodes (Fig. 9B).
Remyelination is carried out by the oligodendrocyte,
except under unusual chronic situations, where aberrant
Schwann cells in the central nervous system have been shown
to do this (58). Remyelinating cells are usually oligodendrocyte precursors that proliferate and mature, displaying the
markers of differentiation described below. Similar oligodendrocyte precursors have been demonstrated in the adult
human brain, and the finding of myelination markers in MS
plaques suggests that they play a similar role here. The role
of mature surviving oligodendrocytes in helping remyelination is unclear at present, although experimentally these cells
may be capable of cell division (59).
The actual extent of remyelination in MS varies, but is
more widespread than traditionally accepted. Up to 28% of
plaques are remyelinated, and nearly half of the lesional area
can be remyelinated. This raises the obvious question as to
why there is so much disability in the face of such extensive
remyelination. One should bear in mind that these figures
represent single snapshots of a 3-dimensional lesion seen in
a single plane, and it obvious that an axon that is myelinated
in one plane may very well be demyelinated at another level.
Efficient remyelination requires the presence of
undamaged axons and a sufficient number of residual
oligodendrocytes or oligodendrocyte precursors. The latter
can be recognized by typical precursor markers (e.g. O4
sulphatide, NG2, and PDGF receptors), and when remyelinating, by differential expression of certain exons of
myelination molecules such as the MBP-Golli complex
(34). A number of myelination-associated inhibitory molecules are found in MS lesions, whose presence correlates
with the presence of remyelination or its absence. Olig-1
and-2 are basic helix-loop-helix transcription factors found
on oligodendrocytes and differentially expressed either in
repair and MS (olig-1) (60) or in normal development
(olig2). The Jagged/Notch/Hes5 pathway, which in normal
development leads to the inhibition of oligodendrocyte
maturation, is expressed in non-remyelinated lesions but
absent in remyelinated lesions (61). Netrin, a migration
guidance molecule, may be absent in non-remyelinating
lesions, and NoGoA, a myelin-associated neurite outgrowth
inhibitor found on oligodendrocytes, is seen both during
myelination and during remyelination in MS (62). Neurotrophins, ILGF, BDNF, and PDGF (63) may all lead to
increased myelin repair through the promotion of proliferation, differentiation, survival, and regeneration of oligodendrocytes and their precursors.
Finally, it should be pointed out that whereas many
inflammatory molecules such as TNF and NO damage
oligodendrocytes and their precursors (28), under certain
circumstances, T cells (64) and macrophages and their
products may also be required for remyelination. The
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J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
importance of these soluble factors in remyelination has
been well established (28). Current research has shown that
transplantation of oligodendrocyte, neural, or stem cell
precursors can be a major source of remyelination, and the
possibility of extending that to therapeutic utility remains
exciting.
Balo’s Concentric Sclerosis: What Does
the Distinctive Alternating Pattern Tell Us About
Pathogenesis of This Variant and the Relevance
for Other Types of MS?
This uncommon condition has proven to be very useful in
trying to unravel the etiopathogenesis of MS. Originally
described as a distinct entity it presents clinically as an acute
condition similar to Marburg disease (65) and is more common
in Chinese. It consists of ring-shaped lesions composed of
alternating bands of demyelination and normally preserved
myelin (Fig. 10). The presence of similar tigroid lesions
associated with more typical MS lesions (Fig. 7) suggests that
it belongs within the spectrum of MS. The demyelinating
bands show inflammation, axonal loss, and astrocytic hyperplasia. The age of the demyelination bands varies, as judged
by the state of myelin degradation in the macrophages and the
tissue reaction, and the acuity usually increases at the
periphery of the lesions. Although earlier ultrastructural
studies (66) suggested that these were bands of remyelination,
many authors have subsequently shown that these probably
represent preserved zones of myelin. A recent study of 14
cases (67) has cast light on the pathogenesis of this condition.
The demyelinated bands contain high levels of iNOS (Fig.
10c:a, c:b), a typical mediator of inflammatory damage,
whereas the preserved myelin contains high levels of
hypoxia-inducing factor (HIF) (Fig. 10c:c, 10c:d), HSP-70
(Fig. 10c:e) and D-110 (Fig. 10c:f), epitopes associated with
hypoxic stress. These findings suggest that the inflammatory
process induces a pre-conditioning hypoxic response in the
periphery of the lesion, the preserved band, which renders this
area more resistant to subsequent ischemic assaults. These
observations are in keeping with the demonstration of Balolike changes in the pattern 3 cases described by Luchinetti et al
in which a possible hypoxic etiology has been postulated (36).
Neuromyelitis Optica (Devic Disease):
What Does This Disease Teach Us About Immune
Mechanisms of Demyelination and Pheno-/
Genotype Correlation?
The place of neuromyelitis optica (NMO) within the
spectrum of MS has long been debated. It is a very severe
form of inflammatory demyelination located in the optic
chiasm and nerves and the spinal cord (65). It is particularly
common in Japanese patients and is found more frequently
in females. It can be either monophasic or relapsing. The
spinal cord lesions are characterized by extensive necrosis,
demyelination, and axonal damage, as well as inflammation
and the deposition of complement, especially C9neo, mainly
around vessels. B cells are prominent and T cells are less
common. Neutrophils and eosinophils are more common
than in typical cases of MS. Interestingly, Japanese patients
with established MS also have a high incidence of optic
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J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
nerve and spinal cord involvement. The genetic background
of these patients differs from Western patients, leading to the
suggestion that genetic makeup may be responsible for
phenotypic variability in MS. Recent observations by
Lucchinetti and colleagues have demonstrated that patients
with NMO have a very high incidence of a specific IgG
marker, related to aquaporin-4, which binds to laminin and
other elements of the BBB (10). So far, this marker reliably
distinguishes NMO patients from those with MS, and again
suggests that these may be different diseases.
Gliosis: Does This Facilitate or Inhibit Reparative
Responses?
Astrocyte reactivity is one of the most sensitive markers
of damage in MS plaques and in the NAWM where it draws
attention to subtle myelin and axonal damage. In the cortex,
reactive astrocytesYalthough presentYare less obvious. Gliosis
in MS has for a long time been defined by the dense astrocytic
scarring of the chronic plaque, with an excess of glial
filaments. Indeed, the astrocytic-filament protein GFAP was
first isolated from MS plaques. This astrocytic scar has long
The Pathogenesis of Multiple Sclerosis
been thought to be a barrier to successful remyelination and
axonal degeneration. The acute lesion, however, shows a
completely different picture. Reactive swollen gemistocytes
(Fig. 11A), often showing a proliferative response with
mitoses, and the so-called Creutzfeldt cells, characterize the
inflammatory lesion. Indeed, in contrast to inactive chronic
plaques where the astrocytes show diminished mRNA for
GFAP (Fig. 11F), the acute gemistocytes have a major
upregulation of this gene (Fig. 11D) as well as greatly
increased production of protein (Fig. 11B). They also show a
marked production of trophic factors such as BDNF and TrK
receptors (68), as well as VEGF (Fig. 11C); this indicates a
probable role in regeneration and protection. In the cuprizone model, once remyelination occurs the astrocytic
processes retract and show plasticity. Astrocytes also play
a role in antigen presentation in the immune reaction (69).
This suggests that gliosis is a complex bi-phasic reaction,
with the cells in the acute phase providing both structural
and neurotrophic support. As the lesion advances, the gliosis
becomes chronic, rigid and non-plastic, inhibiting regeneration. Indeed, experimental studies on chronic optic nerve
FIGURE 11. Gliosis in MS. Gemistocytic astrocytes (arrows) in acute inflammatory MS (A) stain heavily for GFAP (B), and also
show large quantities of VEGF (C). In situ hybridization for mRNA GFAP (D) shows extensive upregulation of this gene. (E)
Extensive glial scarring is seen in the optic nerve in a mouse undergoing Wallerian degeneration at 9 months. An autoradiograph
of in situ hybridization for mRNA for GFAP (F) in the white matter of a case of chronic multiple sclerosis. The plaque (arrow) is
inactive, and there is marked down regulation of message for RNA production. Panels (B) and (D) are reprinted from
Neuroimaging Clinics of North America, Vol. 10, Ludwin SK, et al. Neuropathology of multiple sclerosis, pp. 625Y648, Ó 2000,
with permission from Elsevier (9).
Ó 2006 American Association of Neuropathologists, Inc.
315
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Ludwin
J Neuropathol Exp Neurol Volume 65, Number 4, April 2006
FIGURE 12. Schematic diagram of astrocytic reactions in MS and other injuries to the nervous system.
Wallerian degeneration (Figs. 11E, 12) have shown that the
scar is impervious to axonal ingrowth (70), confirmed in
clinical studies on spinal cord trauma. Future therapies will
involve maximizing the period of facilitation while minimizing the development of inhibition.
Pathology Imaging Correlation
The increasing sophistication in imaging techniques
has allowed clinicians greater opportunities for the successful diagnosis, management, and monitoring of patients and
requires an accurate understanding of what the images
actually represent pathologically. It is widely accepted that
gadolinium enhancement represents BBB breakdown and, in
turn, inflammation. Indeed, lack of enhancement is generally
accepted as indicative of a non-acute or lesion. It should,
however, be remembered that lesions with low levels of
activity may not enhance, even if they are still active.
Experimentally, it has been shown that considerable traffic
of cells across the blood vessels can occur in the absence of
opening the BBB to marker molecules (71). The pathological basis of T2 lesions, the common marker of the
established acute or chronic lesion, is heterogeneous, and
includes inflammation, edema, demyelination, gliosis, and
axonal loss. The T2 lesion load is a marker of severity of
involvement, as is brain volume, which can be a marker for
atrophy (72). Loss of axons can be reflected in the development of non-resolving black holes. MR spectroscopy may
show a reduction in NAA, indicating a loss of axons (4) both
in the early and the late phases, and changes in the choline
peaks can also indicate myelin damage. Imaging studies
related to histopathology show differences between MS
subtypes with the progressive forms showing greater cord
316
atrophy (73). Reduction in the magnetization transfer ratio
and the diffusion coefficient also herald early white matter
changes that can precede plaque development and which can
be confirmed on pathological examination. Similarly, the
imaging of cortex (74) and spinal cord (75) is improving
steadily. Finally, attempts are underway to develop myelin
mapping as a tool to specifically show demyelination and
remyelination. The evolution of these lesions toward
normality often signals reparative processes, including
abatement of edema, remyelination (76), or diminution of
gliosis, with restoration of normal architecture.
Conclusion
The study of the components of experimental models
in the context of clinical presentation and progression yields
many insights into the possible pathogenesis of the MS
lesion. Imaging techniques will one day be able to accurately
reflect the pathology, which will aid in understanding the
progression and therapy of the disease. However, the MS
community awaits an etiological breakthrough that will tie
together the unknowns and provide an understanding of this
fascinating and complex disease.
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