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Demyelinating disorders
in central nerve system
Myelin in CNS is formed by the
oligodendrocytes
Chemical composition:
proteolipid,
myelin basic protein,
2’-3’ cyclic nucleotide
phosphohydrolase,
myelin-associated
glyco-protein,
myelin-oligodendrocyte
glyco-protein.
Intact myelin is required for action potential
conduction
Myelined nerve fiber are rich in white
matter of cerebral 、cerebella、brain stem、
spinal cord，optic nerve
Demyelinating ——
myelin is broken,
axon remains intact
Demelinated
disorders in CNS
Congenital
leukodystrophy
obtained
inflammatory
primary
others
secondary
MS
NMO
ADEM
Balo’s
Inflammatory demyelinating
disorders in central nerve system
1
Multiple Sclerosis(MS)
2
Neuromyelitis optica (NMO)
3
Acute Disseminated Encephalomyelitis (ADEM)
4
Concentric sclerosis(Balo’s disease)
Inflammatory demyelinating disorders In CNS
Multiple Sclerosis (MS)
What is Multiple Sclerosis?
Multiple Sclerosis (MS)


“sclerosis” comes from
the Greek word
“skleros”, meaning hard.
In multiple sclerosis,
hard areas called
“plaques” .
“Multiple” refers to the
many different areas of
the nervous system that
may have damaged
myelin.
What is Multiple Sclerosis ?





chronic inflammatory disease of CNS
malfunction of the immune system which leads
to attacks against myelin sheath
insulating myelin is damaged.
The loss of myelin insulation degrades the
nerve transmission ability.
Thus a multitude of various neurological
disabilities can be observed in patients affected
by this disease depending on which nerves are
damaged.
Epidemiology




approximately 1.1 million
people are affected in US
in all parts of the world and
in all races, but whites of
northern European descent
have the highest incidence.
occur in any age. usually
diagnosed in aged 15-45 years;
average age at diagnosis is 29
years in women and 31 years
in men.
female to male ratio is 2:1.
symptoms
MS was first described by Cruveilhier
in 1835.
 A generally valid description of MS
symptoms was made by Charcot in the
year 1868.
 In 1904 the description was
supplemented by Müller.

Multifocal lesions
Multifocal lesions
symptoms
Common symptoms:
 Sensory disturbance
 Weakness
 Problems in
walking/balance/
coordination
 Visual problems：
optic nerve
Other possible symptoms:
 Bladder problem
 Spasticity
 Fatigue
 Facial weakness
 Trigeminal neuralgia
 slurred speech
 trouble swallowing
 Deafness
 temporary blindness
 Cognitive problems
 Epilepsy
 Depression
signs
Local weakness
 Local sensory disturbances
 poor coordination of upper and lower
extremity movements, wide-based gait with
inability to tandem walk.
 nystagmus, internuclear ophthalmoplegia,
 visual disturbances, pallor of the optic disc,
 Lhermitte sign, traverse spinal myelopathy
，Brown-sequard syndrome in different
levels of spinal cord

Courses (multiple phases)
Laboratory findings



Magnetic Resonance Imaging (MRI) will
show patches of tissue
CSF：WBC，protein，MBP，OB，
specific Abs
Evoked Potentials：
visual evoked potentials（VEP）
auditory evoked potentials（BAEP）
somatosensory evoked potentials （SEP）
How is multiple sclerosis
diagnosed?

Time——mutiple phases

Space—— mutifocal lesions

Exclude others
The Diagnostic Criteria of MS
（Poser, 1983 )
Number of
Attack
Evidence of More
Than One Lesion
Clinical
Lab.
CSF OCB or
IgG
A. Clinically Definite
A1
2
2
A2
B. Lab-Supported Definite
2
1
and
1
B1
2
1
or
1
B2
1
2
1
1
C1
2
1
C2
1
2
1
1
2
0
B3
C. Clinically Probable
C3
D. Lab-Supported Probable
D1
+
+
and
and
1
+
1
0
+
Diagnostic Criteria for Multiple Sclerosis
(McDonald Criteria，2001）（1）
Clinical Presentation
Additional Data Needed
2 or more attacks (relapses)
2 or more objective clinical lesions
None; clinical evidence will suffice
(additional evidence desirable but must be
consistent with MS)
2 or more attacks
1 objective clinical lesion
Dissemination in space, demonstrated by: MRI
or a positive CSF and 2 or more MRI lesions
consistent with MS
or further clinical attack involving different site
1 attack
2 or more objective clinical lesions
Dissemination in time, demonstrated by: MRI
or second clinical attack
1 attack
1 objective clinical lesion
(monosymptomatic presentation)
Dissemination in space by demonstrated by: MRI
or positive CSF and 2 or more MRI lesions
consistent with MS
and Dissemination in time demonstrated by: MRI
or second clinical attack
Diagnostic Criteria for Multiple Sclerosis
(McDonald Criteria，2001）(2)
Insidious neurological
progression
suggestive of MS
(primary progressive MS)
Positive CSF and
Dissemination in space demonstrated by:
MRI evidence of 9 or more T2 brain lesions
or 2 or more spinal cord lesions
or 4-8 brain and 1 spinal cord lesion
or positive VEP with 4-8 MRI lesions
or positive VEP with <4 brain lesions plus 1
spinal cord lesion and
Dissemination in time demonstrated by: MRI
or continued progression for 1 year
Differential diagnosis
First attack: single lesion or multiple
lesions:
infection, tumor, infarction,
 Relapse type:
infarction, embolism, vasculitis,
 Progressive:
inherited, degenerating,

Pathology of MS

Gross neuropathology
grey plaques (acute plaque may be pink)
may occur anywhere

Microscopic neuropathology
perivascular lymphocytes infiltrate;
loss of oligodendrocytes;
myelin stripping;
macrophage infiltrate;
astrogliosis;
relative sparing of axons
What Causes MS?
The exact cause of MS is not known
 Environmental Factors：
Geography is clearly an important factor
the rate is approximately twice as below
the 37th parallel.
 Genetic Factors：
MS is not strictly an inherited disorder.
Susceptibility to MS probably has a genetic
component.
Pathogenesis of MS: incompletely
understood.




Immune-mediated
disorder with an initial
trigger
Molecular mimicry
Oligodendrocyte
susceptible
CNS infections may
also lead to the
transmigration of
activated T
lymphocytes into the
CNS, which initiate
the process
How is MS Treated?
Immunotherapy
 Corticosteroids
corticosteroids can reduce the duration of
symptoms, they do not cure MS.
Used in Acute attacks
intravenous methylprednisolone 1000 mg daily for
three days.
Prednisone: Clinicians differ on whether to taper
off treatment with oral prednisone for two weeks,
but this probably does not improve results and
increases side effects.

Interferons
Beta interferon drugs have shown to be
effective in treating the relapsingremitting type of MS.
Immunosuppressants
methotrexate,
cyclophosphamide,
cyclosporine,
mitoxantrone.
 Others
IvIg
plasma exchange

Symptomatic management
 Bladder frequency and urgency will often respond to
oxybutynin.
 Pain and spasms from spastic limbs usually respond
to baclofen.
 Emotional lability with pathological laughing or
crying can be managed with a tricyclic
antidepressant.
 Amantadine reduces fatigue in half the patients.
 More difficult to manage are pain, sexual
dysfunction, weakness, dysesthesia and other
sensory symptoms, tremor, ataxia, and cognitive
change, but even these may respond to various
therapeutic approaches.
 It is important to recognise that half of patients with
multiple sclerosis will become depressed and that
therapy and counselling may be necessary.
Prognosis
Mortality/Morbidity:
Life expectancy is shortened
only slightly with MS, and
the survival rate is linked
to disability.
Usually, death is due to
secondary complications
(50-66%), such as
pulmonary or renal causes,
suicide, primary
complications, and causes
other than MS seen in the
general population.

Inflammatory demyelinating disorders in CNS
Neuromyelitis optica (NMO)
Similarities with MS
mutifocal lesions
 mutiple phases
 immuno-mediated inflammatory
demyelination in CNS

Differences with MS
----mutifocal lesions
Myelitis：long lesion ≧ 3 vertebral
segments.
 Optis neuritis：
 Brain lesions： atypical for MS.
 Multiple phases： more frequently a
relapsing-remitting course.

Optic nerve atrophy
Differences with MS
----Pathological features of NMO



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
demyelination and necrosis
prominent vascular fibrosis and hyalinization
within the lesions
perivascular deposition of IgG and complement
perivascular infiltrates of polymorphonuclear cells,
leucocytes , plasma cells, eosinophils
glial scars are less frequent and usually only partial
in contrast to typical MS lesions
Differences with MS
----pathogenesis of NMO



humoral immunity
target antigen is
aquaporin-4, the
dominant water channel
in (CNS)
IgG-antibody to
aquaporin-4, named
NMO-IgG
Diagnositic criteria for NMO
Differential diagnosis



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Ischemia of optic nerve
Acute myelitis
Vascular disease of the spinal cord
Vasculitis
Connective tissue disease
Differences with MS
----Treatment
acute phase：intravenous steroids and
plasma exchange therapy.
 To prevent relapse：oral steroid
medication and immunosuppressive
drugs.

Inflammatory demyelinating disorders in CNS
Acute Disseminated Encephalomyelitis
(ADEM)
Acute Disseminated Encephalomyelitis







Quite rapid in onset, often getting sick over a
period of a few days
Multifocal neurological dysfunction, involving
brain、spinal cord、 meninges
MRI： multifocal lesions in CNS
CSF：WBC count normal or mild elevated ,
immune proteins level elevated
Good response to therapy ：corticosteroid
treatments
Precipitating Events ：recent infections and certain
recent vaccinations，certain medications, trauma,
idiopathic
Most ADEM are monophasic ， some are MDEM（
multiphasic Disseminated Encephalomyelitis), or
develop to MS
Inflammatory demyelinating disorders in CNS
Concentric sclerosis
(Balo’s disease)
Concentric sclerosis(Balo’s )



Balo disease
(concentric sclerosis) is
a rare variant of
inflammatory
demyelinating disease
Diagnosis is made
upon biopsy which
shows alternating
bands of myelinating
and demyelinating
fibers in white matter.
Monophasic, nonremitting
Other demyelinating disorders

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Progressive mutifocal
leukoencephalopathy
Central pontine myelinolysis
Marchiafava-Bignami disease
Toxic demyelination: chemical agents, CO
Irradiation encephalopathy
Cerebral vascular disease
Other demyelinating disorders
Central pontine
myelinolysis，CPM
Central pontine myelinolysis，CPM



Central pontine myelinolysis (CPM) is an
uncommon consequence of certain metabolic
derangements.
These include rapid correction of hyponatremia, as
well as hyperosmolar conditions, such as
hyperglycemia.
The microscopic appearance of CPM is loss of
myelin with sparing of axons, without evidence of
inflammation .
Other demyelinating disorders
Progressive multifocal leukoencephalopathy
(PML)





It is a demyelinating disease causes by a polyoma
virus (the JC virus).
The JC virus preferentially infects
oligodendrocytes, thus demyelination in CNS.
immunosuppressed patients and AIDS patients, are
at risk.
Neurologic symptoms depend on the location of the
lesions
relentlessly progressive.
Other demyelinating disorders
Delayed Encephalopathy of Acute Carbon
Monoxide Intoxication
Other demyelinating disorders
Marchiafava-Bignami disease
leukodystrophy
inherited dysmyelinating disease
 adrenoleukodystrophy
 metachromatic leukodystrophy
 spongy degeneration (Canavan disease)
 globoid cell (Krabbe) leukodystrophy
 Alexander disease
 Pelizaeus-Merzbacher disease
 Cockayne syndrome
adrenoleukodystrophy




X-linked recessive
demyelination of
cerebral white matter
adrenal insufficiency
(unresponsive to
ACTH)
CT: white-matter dz:
occipital regions -->
frontal


progression -->
generalized atrophy
MRI: hypointense
T1/hyperintense T2,
atrophic splenium of
corpus callosum
metachromatic leukodystrophy






dymyelinating disease
autosomal recessive
aryl sulfatase A -- absent from urine and
serum
most present by 2 yrs, die at 3-4 yrs
may arise at any age
MR: hypointense T1 / hyperintense T2, of
white matter, primarily in centrum
semiovale
metachromatic leukodystrophy
metachromatic leukodystrophy