Demyelinating Diseases

Demyelinating Diseases
Are acquired conditions characterized by
preferential damage to myelin, with relative
preservation of axons.
Clinical deficits are due to the effect of
myelin loss on the transmission of electrical
impulses along axons.

 The natural history of demyelinating diseases

is determined, in part, by the limited capacity
of the CNS to regenerate normal myelin and
by the degree of secondary damage to axons
that occurs as the disease runs its course.
Other disease processes can involve myelin.
In Progressive Multifocal Leukoencephalopathy,
the JC virus infection of oligodendrocytes
results in loss of myelin.

 In addition, there are inherited disorders that

affect myelin synthesis and turnover.
These disorders are termed leukodystrophies.

Multiple Sclerosis
MS is an autoimmune demyelinating disorder
characterized by distinct episodes of neurologic
deficits, separated in time, attributable to white
matter lesions that are separated in space.
It is the most common of the demyelinating
diseases, with a prevalence of 1 per 1000 persons
in most of the USA and Europe.

 The disease becomes clinically apparent at

any age, although onset in childhood or after
50 years is relatively rare. Women are affected
twice as often as are men.
In most patients with MS, the clinical course
of the illness evolves as relapsing and remitting
episodes of neurologic deficit during variable
intervals of time (weeks to months to years),
followed by gradual, partial recovery of
neurologic function.

 The frequency of relapses tends to decrease

during the course of time, but there is a steady
neurologic deterioration in most patients.

Multiple Sclerosis
Pathogenesis:
The lesions of MS are caused by a cellular
immune response that is inappropriately directed
against the components of the myelin sheath.
The likelihood of developing this autoimmune
process is influenced by genetic and
environmental factors.

 The risk of developing MS is 15-fold higher when

the disease is present in a first-degree relative
and even an order of magnitude greater for
monozygotic twins.
Genetic linkage of MS susceptibility to the
DR2 extended haplotype of the major
histocompatibility complex is also well
established.
** The molecular basis for the influence of this
particular haplotype on the risk of developing MS
is unknown; other genetic loci are involved as well.

 Given the prominence of chronic inflammatory

cells within and around MS plaques, immune
mechanisms that underlie the destruction of
myelin have been the focus of much investigation.
The available evidence indicates that the disease
is initiated by CD4+ TH1 T cells that react against
self myelin antigens and secrete cytokines,
such as IFN-, that activate macrophages.

 The demyelination is caused by these

activated macrophages and their
injurious products.
The infiltrate in plaques and surrounding
regions of the brain consists of T cells
(mainly CD4+, some CD8+) and macrophages.

 Antibodies are also frequently present;

their role in demyelination is less clear.
How the autoimmune reaction is initiated is
also not understood; as in other autoimmune
disorders, microbial triggers and a number
of susceptibility genes are thought to play a role.

Clinical Features:
Although MS lesions can occur anywhere in the
CNS and, as a consequence, may induce a wide
range of clinical manifestations, certain patterns
of neurologic symptoms and signs are commonly
observed.
Unilateral visual impairment during the course
of a few days, due to optic nerve involvement,
is a frequent initial manifestation of MS. However,
only some patients with optic neuritis go on to
develop MS.

 Involvement of the brainstem produces

cranial nerve signs, ataxia, nystagmus, and
internuclear ophthalmoplegia from interruption
of the fibers of the medial longitudinal fasciculus.
Spinal cord lesions give rise to motor and
sensory impairment of trunk and limbs, spasticity,
and difficulties with the voluntary control of
bladder function.

 CSF examination in MS patients shows a

mildly elevated protein level, and in of cases,
there is moderate pleocytosis.
The proportion of gamma globulin is increased,
and most MS patients show oligoclonal (few)
bands. This increase in CSF immunoglobulin
is the result of proliferation of B-cells within the
nervous system; the target epitopes (simplest form
of an antigenic determinant) of these antibodies
are widely variable.

Multiple Sclerosis Variants

Some individuals, especially Asians, develop
a demyelinating disease similar to MS with
presenting symptoms of bilateral optic neuritis
and prominent spinal cord involvement. This is
neuromyelitis optica or Devic disease.
Lesions in Devic disease are considerably more
destructive, and gray matter involvement of the
spinal cord can be striking.

 Another variant, acute MS (Marburg form),

tends to occur in young individuals and is
characterized clinically by a fulminant course
during a period of several months.
On pathologic examination, the plaques are
large and numerous, and there is widespread
destruction of myelin with some axonal loss.

ADEM
Acute Disseminated Encephalomyelitis, ADEM,
or perivenous encephalomyelitis is a
monophasic demyelinating disease that
follows either a viral infection or, rarely a
viral immunization.
Symptoms typically develop a week or two after
the antecedent infection and include evidence
of diffuse brain involvement with headache,
lethargy, and coma rather than focal findings,
as seen in MS.

 Symptoms progress rapidly, with a fatal outcome in

as many as 20% of cases; in the remaining
patients, there is complete recovery.

ANHE
Acute Necrotizing Hemorrhagic Encephalomyelitis,
ANHE, or acute hemorrhagic leukoencephalitis
of Weston Hurst is a fulminant syndrome of
CNS demyelination, typically affecting young
adults and children.
The illness is almost invariably preceded by a
recent episode of URTI; sometimes, it is due to
Mycoplasma pneumoniae, but often it is of
indeterminate cause.
The disease is fatal in many patients, but some
have survived with minimal residual symptoms.

Other Diseases With Demyelination

Central pontine myelinolysis is characterized
by loss of myelin (with relative preservation of
axons and neuronal cell bodies) in a roughly
symmetric pattern involving the basis pontis and
portions of the pontine tegmentum.
Extra pontine lesions occur in the supratentorial
compartment, with similar appearance and
apparent etiology.

 The condition is believed to be caused by rapid

correction of hyponatremia; however, alternative
pathogenetic hypotheses attribute the disorder
to extreme serum hyperosmolarity or other
metabolic imbalance.
The clinical presentation of central pontine
myelinolysis is that of a rapidly evolving
quadriplegia; radiologic imaging studies
localize the lesion to the basis pontis.

 It occurs in a variety of clinical settings,

including alcoholism, severe electrolyte or
osmolar imbalance, and normal liver
transplantation.

 Marchiafava-Bignami disease is a rare disorder

of myelin characterized by relatively symmetric
damage to the myelin of central fibers of the
corpus callosum and anterior commissure.

Thank you!