DEMYELINATIVE DISEASES

Demyelinative diseases of the central nervous system are

characterized by loss of myelin with relative sparing of axons. In
contrast, infarcts, contusions, encephalitis and other conditions
destroy myelin and axons equally. The main demyelinative disease of
the CNS is multiple sclerosis (MS) and its variants. Its counterpart
in the peripheral nervous system is inflammatory demyelinative
polyradiculoneuropathy (Guillain-Barre syndrome-GBS) and its
chronic variants. Both these are autoimmune inflammatory diseases.
There are also virus-induced demyelinative diseases. Demyelinative
diseases should be distinguished from leukodystrophies, which are
inherited metabolic disorders of myelin lipids.

MULTIPLE SCLEROSIS AND VARIANTS

MS affects one in every 500 persons. It is more frequent in young

adults and causes a variety of neurological deficits (visual loss,
paralysis, sensory loss, ataxia, nystagmus, psychiatric disorders,
dementia). Most cases have a long course (20-30 years), with
remissions and exacerbations. Some cases are progressive from the
start or go into a progressive phase later. The pathology of MS
develops around blood vessels. Acute lesions (MS plaques) show
perivascular mononuclear cells (Figure 6.1), stripping and
fragmentation of myelin, and variable loss of oligodendrocytes. In
most cases, the inflammatory reaction subsides only to appear at
another location or at another time. Some lesions expand at their
periphery while activity in their center subsides. The pathological
process may be arrested at any time, sometimes after partial
demyelination. Macrophages remove damaged myelin. A tangle of
astrocytic processes fills the gaps of lost tissue. Remaining
oligodendrocytes attempt to make new myelin, but this process is
ineffective because gliosis creates a barrier between the myelin
producing cells and their axonal targets. With time, plaques reach a
burned-out stage consisting of demyelinated axons traversing glial
scar tissue. Although myelin is preferentially affected, axon loss may
be significant and is an important cause of permanent disability in
MS. In H&E stains, plaques appear pale compared to normal white
matter. Active lesions are cellular because they contain inflammatory
cells, macrophages, and reactive astrocytes. Activity is often confined
to the borders of plaques. Myelin stains reveal the lesions
unequivocally. The"normal appearing white matter" around MS
plaques is not entirely normal but shows milder pathology (Figure
6.2).

Grossly, MS plaques appear as irregular, sharply demarcated, gray

areas in the white matter. They are usually multiple. Long-standing
plaques are firm (sclerosis) because of gliosis. Plaques are randomly
distributed. They have a predilection for the periventricular white
matter, (Figure 6.3) optic nerves, and spinal cord (Figure 6.4) but
spare no part of the CNS. They may involve gray matter such as
cerebral cortex, deep nuclei and brainstem. In these locations, they
involve selectively myelinated axons while sparing the neuronal
bodies.

The pathology of MS is highly variable and its clinical course

unpredictable. Some patients have a few lesions that do not progress.
In others, new crops of lesions or expansion of already existing ones
develop with each exacerbation. Some patients have a relentless
progression, leading to extensive confluent demyelination. This
variant of MS is called Schilder disease (Figure 6.5) and has been
confused in the past with X-linked adrenoleukodystrophy. Because
of the predilection of plaques for the optic nerves and the spinal cord,
some patients present with visual loss or transverse myelitis
(paralysis, sensory loss). Neuromyelitis optica (Devic disease) is a
form of MS that combines optic nerve and spinal cord lesions. Usually,
these patients have plaques elsewhere in the brain or develop them
later. These other plaques may be clinically silent, whereas the optic
and spinal lesions always cause symptoms. Perivascular inflammation,
in the acute phase, damages the blood-brain barrier. Fluid (and
contrast) leak into the lesions, accounting for their low density on T1
MRI images, bright signal on T2, and contrast enhancing quality.
Unlike brain tumors, acute MS lesions cause little or no mass effect.
However, a subacute onset of neurological symptoms with a single
contrast-enhancing lesion may mimic a neoplasm. Schilder disease, in
particular, tends to cause bilateral lesions that join across the corpus
callosum, which is also seen in some glioblastomas. Biopsy diagnosis
of acute MS, especially with stereotactic needle biopsies, may be
tricky because cellularity and reactive astrocytes in the lesions may
be misinterpreted as a neoplasm.

CSF FINDINGS. CSF protein is moderately elevated, and there is

mild mononuclear pleocytosis. The latter is a measure of the activity
of the disease. Total protein exceeding 110 mg/dl and cell counts
higher than 50/cubic mm make the diagnosis of MS unlikely. The IgG
fraction is elevated above 11 percent of total CSF protein, especially
in chronic MS. The IgG/albumin index in CSF is elevated in 90 percent
of MS patients, including some who have normal total protein.
Elevation of IgG/albumin index in CSF but not in serum means that
IgG is produced intrathecally. Oligoclonal IgG bands are detected on
agarose electrophoresis in 90 percent of patients. This pattern may be
present even when the total amount of IgG is normal. Oligoclonal
bands indicate that IgG represents antibodies to specific antigens.
About 70 percent of MS patients and only 5 percent of controls have
antibodies to measles. A smaller number have antibodies to rubella,
mumps, and herpes simplex. Similar CSF changes are seen in some
chronic CNS infections such as chronic measles encephalitis and
syphilis. Myelin proteins such as myelin basic protein leak from
plaques into the CSF and can be detected by radioimmunoassay.

ETIOLOGY-PATHOGENESIS OF MS. MS is probably an

autoimmune disorder. Genetic susceptibility and environmental
factors play important roles in its pathogenesis.

Genetic factors: The risk of MS in relatives of patients is 7 times

higher than in the general population. Monozygotic twins are 25.9
percent concordant for MS; dizygotic twins are only 2.3 percent
concordant. Genetic susceptibility is probably conferred by MHC
molecules that modulate the immune response (particularly
autoimmunity) and cell-cell interactions. MS patients express with
high frequency certain class I and II HLA antigens, particularly DW2
and DR2.

Environmental factors:The incidence of MS is higher in high

latitude zones. Prevalence in the northern US is 4-6 times higher than
in the South. Individuals who grow up in high prevalence areas retain
the high risk even if they subsequently migrate to low-risk regions.
These findings suggest that an unknown predisposing factor is
acquired by prolonged exposure to some environments. Viruses,
particularly measles and HTLV-1, have been suspected but there is no
proof that they are involved in the pathogenesis of MS.

There are several immunological abnormalities apparent in MS,

but how these damage myelin is unclear. The immune phenomena
include perivascular lymphocytes and monocytes, T-cell abnormalities
(alterations of T4 and T8 cells, activated T-cells), B-cell changes
(intrathecal plasma cells and intrathecal immunoglobulin production),
and the presence of cytokines in the plaques. Pregnancy, which causes
a diffuse immunosuppression, suppresses MS activity. The disease
flares up postpartum. Interferon (INF) gamma, which enhances the
immune response, provokes MS attacks. Infections such as URIs
stimulate secretion of INF gamma by immune cells and exacerbate
MS. On the other hand, INF beta, which suppresses the immune
response, decreases the frequency of attacks.
In order for MS to develop, there have to be antigens in the brain that
elicit a T-cell mediated reaction. These antigens are unknown. They
may be components of bacteria and viruses or myelin proteins.
Antigens are presented to T4 cells by MHC class II molecules on
macrophages and astrocytes. Interaction of the T-cell receptor with
the MHC-antigen complex stimulates T-cells which proliferate, release
cytokines and activate B-cells and macrophages. The perivascular
lymphocytes in acute MS plaques are T-cells. Cytokines damage the
blood-brain barrier causing efflux of fluid, humoral factors, and cells.
Oligodendrocytes are either directly attacked by cytotoxic T-cells or
damaged by cytokines, such as tumor necrosis factor, produced by
activated T-cells. Antibody-complement action can also cause
demyelination. Macrophages ingest myelin debris.

PATHOPHYSIOLOGY OF MS. Demyelination causes loss of

saltatory conduction. Linear conduction along demyelinated axons
is slow because the internodal axon membrane has few ion channels.
In addition, lack of insulation of axons allows impulses to disperse
laterally to adjacent demyelinated axons. The abnormal physiology of
demyelinated axons results in inefficient conduction or
conduction block. This is reflected by abnormal evoked response
potentials, an electrodiagnostic test that measures conduction
velocity in the CNS.

It is now clear that loss of axons is a prominent and early feature of

MS. Most of the axonal damage occurs during the active inflammatory
phase of the disease but continues to smolder for a long time after
that. Axonal damage is probably caused by glutamate, nitric oxide
(NO), and other toxic substances released by macrophages and
microglia at the sites of inflammation.

While loss of function is easy to explain, clinical recovery is not. As we

saw, remyelination is inefficient because it is blocked by glial scar.
Therefore, remyelination does not explain the remissions. The
neurological deficit from an acute MS plaque is caused not only by
myelin (and partial axon) loss, but also by inflammation, cytokines and
edema that involve a wide area around the lesion. Even without
remyelination, neurological function returns to some extent when the
inflammatory reaction subsides and homeostasis is restored. In tracts
that are partially involved by MS lesions, remaining axons may
partially carry out the function. New ion channels may develop on
axonal membrane, helping demyelinated axons conduct more
efficiently. Conductivity in demyelinated areas is also influenced by
electrolyte concentration and other changes in the extracellular fluid
and by physical factors such as body temperature. These factors
explain why the severity of neurologic deficits fluctuates. Recovery
probably depends on structural and functional reserves and on a
potential for regeneration that we do not fully understand. Anatomical
observations alone do not adequately explain the recovery seen in
some MS patients. The autopsy is like a snapshot and is not ideally
suited to follow the changes of an evolving disease. MRI imaging is
better for this purpose.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

Experimental allergic encephalomyelitis (EAE) can be induced in

mice, rats and guinea pigs by intradermal injection of whole CNS
tissue or myelin basic protein (MBP) and complete Freunds adjuvant.
Two weeks after the injection, the experimental animals develop
ascending paralysis. The injection of MBP triggers a cell- mediated
immune reaction against the recipient's own myelin. MBP-specific T-
cells traverse brain capillaries. Interaction of these cells with MBP
activates them and results in secretion of cytokines, damage of the
blood-brain barrier, and recruitment of macrophages. Microscopical
examination shows perivenular lymphocytes, similar to acute MS, but
little or no demyelination. EAE can be induced by injection of MBP-
specific T-cells. Classic EAE is a monophasic reaction. A chronic
relapsing EAE can be produced in guinea pigs. EAE can also be
induced by other myelin proteins that are chemically different from
MBP and by nonmyelin proteins such as S100 protein. Injection of
MOG (myelin oligodendrocyte glycoprotein) along with transfer of
anti-MOG lymphocytes can cause demyelination. EAE has been used
for years as an experimental model of MS. While it proves that an
autoimmune reaction can cause inflammation in the white matter, the
analogy stops there. The immunology and pathology of MS are far
more complex than EAE.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Acute disseminated encephalomyelitis (ADE), also known as

postinfectious, postvaccinal, or allergic encephalomyelitis, is an acute
demyelinative disease that usually develops a few days to two weeks
following a respiratory illness due to Epstein-Barr virus,
cytomegalovirus, or mycoplasma pneumoniae. It may also follow a
variety of other viral and nonviral infections or vaccinations.
Sometimes it appears without a preceding infection. It is a
monophasic disease that usually runs a mild course with recovery but
sometimes may be severe or fatal. Clinically, it presents with
drowsiness, headache, stiff neck, focal deficits, paraplegia and
sensory loss. ADE following varicella often presents with ataxia.
Severe ADE with confluent lesions causes cerebral edema and
herniations. Pathologically, ADE is characterized by microscopic
perivenous demyelination and mononuclear cells in the brain and
spinal cord. ADE is not an infection. It is thought to be an immune
reaction triggered by the preceding viral infection or vaccination. Old
rabies vaccines were prepared from brains of inoculated rabbits. ADE
following such vaccination was due to sensitization against myelin
antigens that were present in the vaccines. Similarity between viral
and myelin proteins (molecular mimickry) probably causes ADE
following infections. The pathogenesis of ADE is not clear in all cases.
Acute hemorrhagic leukoencephalitis is a fulminant, frequently fatal
form of ADE with extensive, confluent white matter lesions
characterized by vascular necrosis, acute inflammation, hemorrhage,
and edema.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Progressive multifocal leukoencephalopathy (PML) is a selective

infection of oligodendroglia by an ubiquitous opportunistic
polyoma virus, JC virus (not to be confused with CJD). It occurs in a
setting of immunodeficiency and is common in AIDS. Clinically, PML
is characterized by a variety of neurologic deficits (visual loss,
paralysis, dementia) evolving rapidly and causing death in a few
months. Neuroimaging shows multiple hypodense white matter
lesions. The CSF is either normal or shows a few lymphocytes.

Pathologically, PML begins with small demyelinative foci at the cortex-

white matter junction (Figure 6.6). Confluence of these foci results in
large irregular white matter lesions that involve the cerebrum,
cerebellum, and brainstem (Figure 6.7). Myelin is destroyed; axons
are relatively spared. The nuclei of infected oligodendrocytes are
packed with viral particles (Figure 6.8) that cause them to enlarge
and develop a ground glass appearance (Figure 6.9). PML is a lytic
infection leading to oligodendrocyte destruction. Polyoma viruses can
also become incorporated into the host genome and cause neoplastic
transformation. In PML, astrocytes are also infected by JC virus in a
non-lytic manner and show pronounced atypia, suggesting neoplastic
change (Figure 6.10). Inflammation is usually minimal. There is no
peripheral nerve demyelination or disease in any other organ system.
In addition to its clinical significance, PML is interesting as a model of
demyelination due to a lytic infection of myelin-producing cells.
Neurotrophic mouse hepatitis virus and canine distemper virus are
animal models of virus-induced demyelination, similar to PML.

CENTRAL PONTINE MYELINOLYSIS (CPM)

CPM is a degeneration of a symmetrical midline patch of the basis

pontis (Figure 6.11). There is loss of myelin and less severe loss of
axons. Neurons of the nuclei pontis are relatively spared. No
inflammation is seen. There is no selective involvement of fiber
systems. In severe cases, the lesion becomes necrotic and extends to
the cerebral hemispheres (extrapontine myelinolysis). CPM is usually
an incidental autopsy finding. It may be suspected in life if spastic
bulbar paralysis and quadriplegia develop in the appropriate clinical
setting. Similar but rare lesions occur in the corpus callosum
(Marchiafava-Bignami Disease) and in the spinal cord. Initially, CPM
was thought to be a complication of alcoholism and malnutrition but
has now been proven to be caused by osmotic disturbances. In some
cases, it follows rapid correction of hyponatremia. It has been
reported in nonalcoholic patients with rapid shifts in osmolality, e.g. in
extensive burns. An experimental model has been produced in dogs.