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Demyelinating Diseases
Definition
In both the central and the peripheral nervous systems, large-diameter axons
are myelinated. Myelin is formed and maintained by oligodendrocytes within the
central nervous system and by Schwann cells in the peripheral nervous system.
Myelin both insulates the invested axons and organizes surface membrane
constituents of the axon--functions that are critical for the rapid transfer of
signals necessary for coordinated motor activity, proper integration and
interpretation of sensory stimuli, and facile cognition. Diseases that affect
the integrity of the oligodendrocyte and its ability to produce and maintain
myelin or diseases that directly damage the myelin sheath disturb conduction in
myelinated white matter pathways and produce a broad array of motor, sensory,
and cognitive dysfunctions [see Figure 1].
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Figure 1. (click image to zoom) Figure 1. Structure of
Neuron and Mechanism of Demyelination. A single oligodendrocyte may support
myelin internodes for 60 or more neighboring axons. A major consequence of
myelination is organization of the microenvironment of the larger-diameter
axons. Sodium channels are clustered at segments of the axon between myelin
segments (the nodes of Ranvier), and potassium channels are diffusely
distributed under the myelin-invested segments of the axons. This arrangement
allows myelinated axons to rapidly propagate action potentials from the axonal
cell body distally to its synapse by saltatory con-duction.
Depolarization of the nodes of Ranvier in sequential fashion results in rapid
propagation of the neural impulses in the largest-diameter nerve fibers at rates
in excess of 100 m/sec.
The upper part of the figure depicts a neuron
with a myelinated axon. At the right corner, the neuron is magnified and cut in
cross section, demonstrating the concentric lamellar structure of myelin. The
middle of the figure shows a neuron with a myelinated axon forming a synapse
with another neuron. Two oligodendrocytes are shown; each cell myelinates
multiple segments of more than one axon. The bottom neuron has been partially
demyelinated, and it is surrounded by T cells, which secrete inflammatory
cytokines (interleukin-2 [IL-2], interferon gamma [IFN-and tumor necrosis
factor-
[TNF-]), and by macrophages, which are stripping myelin from the axon. The
macrophages contain myelin debris in phagocytic vacuoles. Conduction in the
demyelinated axon is blocked. A blood vessel in cross section shows T cells
adhering to the lumen and crossing from the vessel into the
brain.
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Demyelinating diseases disturb the integrity of myelin, but the axons are
relatively spared [see
Table 1]. These diseases primarily affect oligodendroglial survival (e.g.,
progressive multifocal leukoencephalopathy), oligodendroglial metabolism (e.g.,
vitamin B12 deficiency), and the myelin sheath, with secondary
effects on the oligodendrocytes (e.g., multiple sclerosis [MS]).
Immune-mediated demyelinating diseases include recurrent or chronically
progressive demyelinating diseases (MS and its variants) and monophasic
demyelinating diseases (optic neuritis, acute disseminated encephalomyelitis,
and transverse myelitis). Monophasic demyelination may be the first clinical
sign of MS.
Multiple Sclerosis
MS is characterized clinically by recurrent or chronically progressive
neurologic dysfunction caused by lesions in the CNS. Pathologically, the lesions
are multiple areas of demyelination that affect the brain, optic nerves, and
spinal cord. Full detail on MS can be found here http://www.medscape.com/viewarticle/453515_2
Optic Neuritis
Optic neuritis is an acute inflammatory optic neuropathy. The cardinal
symptoms are unilateral vision loss and retrobulbar pain with eye movement.
Differential diagnosis includes anterior ischemic optic neuropathy, which is
usually painless and found in patients older than 50 years; hereditary diseases,
such as Leber hereditary optic neuropathy; and toxic or nutritional optic
neuropathies. Treatment with intravenous methylprednisolone at a
dosage of 1 g/day for 3 days followed by oral prednisone for 11 days hastens
recovery of vision but has little residual benefit at 1 year. One study showed
that prednisone at 1 mg/kg/day for 14 days had no benefit and was associated
with an excess of recurrences. Even without treatment, almost all
patients begin to recover vision within 4 weeks.
The relation of optic neuritis to MS is controversial. Some regard optic
neuritis as a distinct entity, but others consider it part of the clinical
continuum of MS. More than half of all patients with MS have optic neuritis at
some time during the disease. Of patients who present with optic neuritis and
who have no other neurologic deficit, almost 40% have one or more ovoid or
periventricular lesions, as revealed on brain MRI; clinically definite MS
eventually develops in 60%. Patients with completely normal
results on MRI and comprehensive CSF evaluation seldom progress to
MS.
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is a monophasic syndrome that is
usually preceded by a viral exanthem, an upper respiratory infection, or
vaccination. The most commonly associated viruses are measles, paramyxovirus,
varicella, rubella, and Epstein-Barr virus. Onset is often rapid and is
characterized by meningeal signs, headache, seizures, and altered mental status.
The associated neurologic deficits are variable and may include hemiplegia,
paraplegia, sensory loss, vision loss, and transverse myelitis. ADEM can be
fatal, but most patients begin to recover within 2 to 4 weeks. Acute hemorrhagic
encephalomyelitis is probably a fulminant variant of ADEM. The main pathologic
features of ADEM are multiple areas of perivascular inflammation and
demyelination, without evidence of active viral infection. ADEM may be caused by
an autoimmune response against myelin antigens elicited by cross-reactive viral
proteins. Usually, multiple white matter lesions are present on MRI, and the
majority of the lesions can be enhanced with contrast.
Corticosteroid treatment is often used, although the efficacy of this approach
has not been proved in clinical trials. Plasmapheresis may also be
useful.[66] Prognosis varies with the inciting virus, but mortality
may be as high as 30%, and survivors may be left with residual
symptoms.
Transverse Myelitis
Acute transverse myelitis is a syndrome of spinal cord dysfunction; it has a
rapid onset. Like ADEM, it may occur after infection or vaccination or it may
occur with no discernible precipitant. It may also be the initial presentation
of MS. Symptoms include paraparesis, which is initially flaccid and then
spastic; loss of sensation with a sensory level on the trunk; and bowel and
bladder dysfunction. Back pain precedes the neurologic symptoms, and the sensory
symptoms may begin distally and ascend. The thoracic cord is most often
affected. The differential diagnosis includes other causes of acute myelopathy,
such as compression of the cord by an extradural structural lesion, spinal cord
neoplasms, ischemia, and systemic lupus erythematosus. MRI is extremely useful
for excluding structural lesions and for confirming the presence of an
intramedullary lesion at the level in the spinal cord commensurate with the
symptoms. The lesions of acute transverse myelitis are typically hyperintense on
T2-weighted imaging; they involve the majority of the cross-sectional
area of the cord over several segments and may be enhanced with contrast. The
lesions may cause swelling of the spinal cord. No treatment
has proved beneficial, but corticosteroids are often used. Prognosis is
variable: one third of patients have a good outcome, one third have a fair
outcome, and one third do not recover. Spinal shock, back pain,
and catastrophic onset are associated with poor outcome.
Inherited Demyelinating Diseases
Adrenoleukodystrophy is an inherited disorder that is associated with
progressive demyelination and dysfunction of the adrenal cortex.
The inheritance pattern may be either autosomal recessive or X-linked recessive.
The X-linked form is caused by the mutation of a gene encoding an integral
membrane protein found in the peroxisome. Defects in this gene lead to
accumulation of very long chain fatty acids (VLCFAs). The phenotypes may vary
considerably, even within the same family. In the childhood form, the patient
presents with cognitive deficits; rapid neurologic deterioration then occurs,
with death occurring in 2 to 5 years. The adult form, called
adrenomyeloneuropathy, presents at a mean age of 28 years as progressive spinal
cord dysfunction with spastic paraparesis, sensory loss, and bowel and bladder
symptoms. Cerebral involvement may be minimal. Only half of patients with
adult-onset disease have brain abnormalities on MRI; these are most often found
in the corticospinal tracts. Most patients have diffuse atrophy
of the spinal cord. Diagnosis is made on the basis of the combination of
neurologic and adrenal involvement, family history, and elevated levels of serum
VLCFAs. Dietary treatment with unsaturated fatty acids lowers the level of
VLCFAs but does not significantly affect the progression of
symptoms. Bone marrow transplantation may be effective if
performed before severe symptoms develop. Prognosis is poor for patients with
the childhood form of disease. Patients with adult-onset disease usually require
assistance with ambulation within 10 to 15 years, and rapidly progressive
cerebral lesions develop in a large percentage of patients 5 to 10 years after
the onset of spinal cord symptoms.
Metachromatic leukodystrophy is an autosomal recessive disorder that results
in demyelination of axons in the central and peripheral nervous systems. It is
caused by mutations in the gene for arylsulfatase A that lead to accumulation of
metachromatically staining sulfatides. Onset usually occurs in
infancy or childhood; adult onset is rare. The symptoms of adult-onset disease
are progressive behavioral abnormalities, dementia, ataxia, and
neuropathy. MRI or CT of the brain demonstrates atrophy and
diffuse white matter abnormalities, particularly in the frontal lobes. Diagnosis
is confirmed by measurement of arylsulfatase A activity in peripheral blood
leukocytes, urine, or skin fibroblasts. True arylsulfatase deficiency must be
distinguished from a common pseudodeficiency state that is caused by an allele
with low enzymatic activity. The symptoms of metachromatic
leukodystrophy are relentlessly progressive, and earlier onset is associated
with more rapid progression. The mean survival for adult-onset disease is about
12 years. No effective treatment is available, but allogeneic bone marrow
transplantation and gene therapy are under investigation.
Metabolic Demyelinating Diseases
Central pontine myelinolysis (CPM) is a syndrome in which neurologic deficits
occur after rapid correction of hyponatremia. CPM usually occurs
in young to middle-aged adults and is often associated with alcohol abuse or
malnutrition. Signs and symptoms usually begin 3 days after the start of sodium
replacement and consist of changes in mental status, dysarthria and other signs
of corticobulbar dysfunction, and spastic quadriplegia. Improvement usually
begins about 2 weeks after the onset of symptoms, but the degree of recovery is
variable. The most striking finding on pathologic examination is the presence of
symmetrical demyelinated lesions in the central pons. Demyelinated lesions may
also occur in a relatively symmetrical pattern in the basal ganglia, thalamus,
internal capsule, subcortical white matter, and cerebellum.
T2-weighted MRI usually demonstrates the presence of hyperintense
lesions. These lesions usually cannot be enhanced with contrast. CPM may also
occur after liver transplantation. There is no specific treatment once symptoms
have developed. Long duration and rapid correction of hyponatremia increase the
risk of CPM; the recommended rate for correction of hyponatremia is no faster
than 10 to 12 mEq in 24 hours.
Vitamin B12 deficiency results in demyelination of axons in the
central and peripheral nervous systems. The dorsal and lateral white matter
tracts of the spinal cord are most affected--a characteristic that has given
rise to the name subacute combined degeneration of the spinal cord. The most
common presenting symptoms are paresthesias, sensory loss that begins in the
feet and progresses proximally, and sensory ataxia. Weakness
almost always begins after sensory loss. Memory difficulties, irritability, and
confusion occur in a minority of patients. On examination, patients usually have
decreased vibration and position sense, which is worse in the feet than in the
hands, and may have spastic paraparesis. Pathologic examination reveals
symmetrical loss of myelin in the posterior and lateral columns of the spinal
cord and sometimes patchy demyelination in the cerebral white matter. MRI of the
spinal cord often demonstrates white matter lesions, which resolve with
treatment. Diagnosis is made on the basis of the clinical findings and a low
serum cobalamin level. Macrocytosis or anemia is present in most patients but
cannot be used in place of the cobalamin level as a diagnostic
measure. For patients who have symptoms and a low-normal
cobalamin level, demonstration of elevated levels of serum methylmalonic acid
and total homocysteine can confirm the presence of a functionally significant
cobalamin deficiency. If cobalamin deficiency is present, the underlying
etiology should be investigated. About 80% of patients with cobalamin deficiency
have pernicious anemia. Administration of cobalamin prevents progression of
symptoms and produces clinical improvement in most patients.
Nitrous oxide prevents the metabolism of cobalamin and can cause similar
symptoms after prolonged exposure; after a single exposure, it can unmask a
subclinical cobalamin deficiency.
Virus-Induced Demyelination
Progressive multifocal encephalopathy is a lethal demyelinating disease
caused by an opportunistic viral infection of oligodendrocytes in
immunocompromised patients. The causative agent is JC virus, a ubiquitous
papovavirus that infects the majority of the population before adulthood and
establishes a latent infection in the kidney. In immunocompromised hosts, the
virus can reactivate and productively infect oligodendrocytes. This previously
rare condition is now more common because it occurs in 4% of patients with AIDS.
Patients usually present with relentlessly progressive focal neurologic
deficits, such as hemiparesis or visual field deficits, or with alterations in
mental status. On brain MRI, one or more white matter lesions are present; they
are hyperintense on T2-weighted images and hypointense on
T1-weighted images. There is no mass effect, and contrast enhancement
is rare. Diagnosis can be confirmed by brain biopsy, with demonstration of virus
by in situ hybridization or immunocytochemistry. Polymerase chain reaction
amplification of JC virus sequences from the CSF can confirm diagnosis without
the need for biopsy.[80] Currently, there is no effective therapy.
Survival after diagnosis is about 3 to 5 months in AIDS patients.
Subacute sclerosing panencephalitis (SSPE) is a rare late complication of
measles virus infection. It occurs most often in patients who had the initial
infection with measles virus before 2 years of age; the mean lag between initial
infection and SSPE is 7 years. The use of measles vaccine has greatly reduced
the incidence of this complication in developed countries. The earliest symptom
is usually progressive cognitive deterioration, which is followed by motor
dysfunction and myoclonus associated with distinctive electroencephalographic
abnormalities. Pathologic examination reveals active viral infection in the
brain, with measles virus protein and RNA detectable in both oligodendrocytes
and neurons, and a vigorous inflammatory response. The course is progressive,
with occasional temporary remissions. There is no satisfactory treatment.
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