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Demyelinating Disease
Multiple Sclerosis (MS)
Prof Mohammad Salah Abduljabbar
-Demyelinating disorders of the CNS affect myelin and/or oligodendroglia
with relative sparing of axons.
Introduction
 Oligodendrocytes, like Schwann cells in the peripheral nervous system, are responsible
for the formation of myelin around CNS axons.
 One Schwann cell myelinates one axons but one oligodendrocyte may myelinate several
contiguous axons, and the close proximity of cell to axon may not be obvious by light
microscopy.
 Myelin is composed of protein 20% & lipids.
 Oligodendrocyte are present in gray matter near neural cell bodies and in white matter
near axons.
Chronic, progressive, degenerative
disorder of the CNS characterized by
disseminated demyelination of nerve
fibers of the brain and spinal cord
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Chronic autoimmune disease
Progressive disease
Involves Immune System & Neurological
System
Multifocal areas of demyelination
Disrupts ability of the nerve to conduct
electrical impulses
Leads to symptoms
-MS referred by the British as disseminated sclerosis & by French as Sclerose en plaques.
Multiple Sclerosis (MS)
MS is a common demyelinating disease, characterized by
relapsing and remitting course.
More female than males are affected.
MS usually occur in young adults (20-40 years)
The risk of MS in relative patients increases 20 folds
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Age onset 20–50 years old
Women are 2 times more likely to be
affected
500,000 cases in US
Over 2.5 million people around the world
More prevalent whites of northern European
ancestry
Vitamin D3 deficiency
Genetic Influences
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Unknown cause
Related to infectious, genetic and
immunological factors
Possible precipitating factors
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Infection
Physical injury
Emotional stress
Excessive fatigue
Pregnancy
Poor state of health
Myelin sheath
 Segmented lamination that wraps axons of
many nerve cells.
 Increases velocity of nerve impulse
conduction in the axons.
 Composed of myelin, a substance with high
lipid content.
- Characterized by chronic inflammation,
demyelination, and gliosis (scarring) in the
C
 Initially triggered by a virus in genetically
susceptible individuals.
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Subsequent antigen-antibody reaction
leads to demyelination of axons
Fig. 57-1
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Disease process consists of loss of myelin,
disappearance of oligodendrocytes, and
proliferation of astrocytes
Changes result in plaque formation with
plaques scattered throughout the CNS
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Initially the myelin sheaths of the neurons in
the brain and spinal cord are attacked, but
the nerve fiber is not affected
Patient may complain of noticeable
impairment of function
Myelin can regenerate, and symptoms
disappear, resulting in a remission
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Myelin can be replaced by glial scar tissue
Without myelin, nerve impulses slow down
With destruction of axons, impulses are
totally blocked
Results in permanent loss of nerve
function
Pathology
•Scattered lesions with a greyish color.
• 1mm to several cm in size.
• Are present in the white matter of the brain and spinal cord and are
referred to as plaques.
Perivenous distribution.
RECENT LESIONS
•Myelin destruction
•Relative axon sparing
•Perivenous infiltration with
MNP
•Breakdown of BBB
LATER
Astrocyte
proliferation
OLD LESION
•Relatively acellular
•More clearly demarcated.
•Bare axons are
surrounded by astrocytes.
Pathology
These lesions have a predilection for the
following sites within the brain & spinal cord
 Optic nerves
 Periventricular region
 Brainstem
 Cervical spinal cord.
Pathogenesis
Genetic predisposition
Environmental Exposure (Virus)
Autoimmune attack by CD4 T-cell
Demyelination
Multiple Sclerosis
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US cohort study found that 3.5 times more women residing in northern states
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Incidence of MS highest in North Temporal Climate
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MS more prominent in areas reporting less than 2000 hours of sunshine
annually
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MS displays seasonable variability with increased activity in the Spring and
lowest in the Fall.
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A Finnish study found in MS patients lower serum vitamin D levels in the
Spring.
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were diagnosed with MS than southern states
A line between dietary intake of vitamin D and the incidence of MS has been
suggested in Norway along the coastal areas where fatty fish, dairy products,
and cereals are all fish in vitamin D consumed in higher amounts. The
incidence is lower then the rest of Norway.
Dietary information from the Nurse’s Health Study of 187,000 women
showed those with a history of vitamin D supplementation as low as 400 units
daily had a 40% less chance of developing MS.
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Vague symptoms occur intermittently
over months and years
MS may not be diagnosed until long
after the onset of the first symptom
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Vision problems
Numbness
Difficulty walking
Fatigue
Depression
Emotional changes
Vertigo & dizziness
Sexual dysfunction
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Coordination
problems
Balance problems
Pain
Changes in
cognitive function
Bowel/bladder
dysfunction
Spasticity
Clinical Features
Optic Neuritis
Clinical Features
Optic Neuritis
Inflammatory demyelination of one or both optic nerves
- Pain around one eye
- Diplopia & Vertigo
- Blurred vision
- Visual field defect
- Loss of color vision
- Swollen optic disc
Uhthoff phenomenon
Motor manifestations
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Weakness or paralysis of limbs
Diplopia (double vision)
Scanning speech
Spasticity of muscles
Clinical Features
Symptoms
Signs
 Monoparesis
 Increased tone
 Paraparesis
 Hyperactive tendon
reflexes
 Absent abdominal reflexes
 Pyramidal distribution
weakness
Clinical Features
Sensory Symptoms
 Numbness & Paresthesia
 Impaired vibration & Joint position
sensation
 Lhermitte’s sign ( Shock-like sensation in
the limb)
 Dysesthesia + Sensory loss to pain &
Temp.
(3) Cerebellar manifestations
 Nystagmus
 Ataxia
 Dysarthria
 Dysphagia
Bowel and bladder functions
 Constipation
 Spastic bladder: small capacity for
urine results in incontinence
 Flaccid bladder: large capacity for
urine and no sensation to urinate
Sexual dysfunction
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Erectile dysfunction
Decreased libido
Difficulty with orgasmic response
Painful intercourse
Decreased lubrication
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Relapsing-remitting MS (RRMS)
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Secondary-progressive MS (SPMS)
◦ Affects 85% of newly diagnosed
◦ Attacks followed by partial or complete
recovery
◦ Symptoms may be inactive for months or
years
◦ Occasional relapses but symptoms remain
constant, no remission
◦ Progressive disability late in disease course
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Primary-progressive MS (PPMS)
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Progressive-relapsing MS (PRMS)
◦ Affects approximately 10% of MS
population
◦ Slow onset but continuous worsening
condition
◦ Rarest form Affects approx. 5%
◦ Steady worsening of condition
at onset
Clinical Course
Acute MS
•Explosive onset
•Death may occur in months
•Dramatic recovery and prolonged remission may occur
Slowly Progressive MS
•Common in older age group
•No relapse/remission
•Takes the form of a Progressive myelopathy
Disability
Time
Relapsing MS
Accumulating disability
Disability
Time
Benign form
•Abrupt onset
•Good remission
•Long latent period
Disability
Time
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Viral infections
Lyme disease
CVA
Lupus
Vitamin B12
deficiency
Rheumatoid
arthritis
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Vasculitis
Syphilis
Tuberculosis
HIV
Sarcoidosis
Other connective
tissue disorders
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History and clinical manifestations
Ruling out other causes of symptoms
No definitive diagnostic test
MRI demonstrates presence of
plaques
Investigation
No diagnostic test. Only support the clinical suspicion.
Neuropsychological measurement of conduction within the CNS to detect second
asymptomatic lesion.
 Visual evoked potential(VEP)
 Somatosensory evoked response
 Brain stem auditory evoked potential
CSF examination
normal
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Mild pleocytosis mainly lymphocytes.
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Total protein maybe elevated
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gammaglobuline in 50%
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Electrophoresis of CSF using agar
shows discrete bands which are not
present in serum.
Oligoclonal
band
Magnetic Resonance Imaging
(MRI)
1- MRI is more sensitive showing white
matter disease.
2- On T-2 weighted images, patchy area of abnormal white matter found
most commonly in cerebral hemisphere in
periventricular areas. Lesions can be present in the
cerebellum , brain stem, cervical and or thoracic spinal cord .
Demyelination in the Cervical Spinal Cord
Corticosteroids
 Treat acute exacerbations by reducing
edema and inflammation at the site of
demyelination
 Do not affect the ultimate outcome or
degree of residual neurologic impairment
from exacerbation
Immunosuppressive Therapy
 Because MS is considered an
autoimmune disease
 Potential benefits counterbalanced
against potentially serious side
effects
Drugs
Administration
CLASS
Avonex
IM 1x a week
Interferon beta-1a
Betaseron
SC, every other day
Interferon beta-1b
Copaxone
SC 1x a day
Glatiramer acetate
Rebif
SC 3x a week
Interferon beta-1a
Gilenya
Oral capsule 1x day
Fingolimod
Tysabri
IV Monthly at Center
Natalizumab
Risk factors
◦ JC antibody status
◦ Length of treatment
◦ Prior immunosuppressant use
 Blocks S1 Phosphate receptor keeping T & B cells in
lymphoid tissue
 First oral pill released by FDA 2011 for treatment of MS
 Reduces relapse rate by 55-58%
 Shows benefit on MRI endpoints as T2 lesion load and Gad
enhancing lesions
 Side effects:
- Macular Edema
- Heart Block
- Liver Function Abnormalities
- Sudden Death
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Inhibits pyridine synthesis with mild lymphopenia
TEMSO Trial (Phase III) 1088 patients
◦ Follow for 2 years
◦ Randomized to 7 or 14mg tablets or placebo
◦ Results
 31% reduction ARR
 Decreased EDSS worsening by 30% (14mg)
 Decreased new lesion by 39% in 7mg & 67% in 14mg
◦ Safety: good
 Mainly diarrhea and LFT abnormal.
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Local injection site irritation/reactions
Flu like symptoms
Rise in liver enzymes
Decreased white cell count and platelets
Opportunistic infections
Depression
Progressive multifocal leukoencephalopathy
(PML)
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Rule out UTI
Bladder training
Medication
Anti-spasticity
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Referral to
urologist for
further
evaluation and
treatment
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Selective Serotonin
Reuptake Inhibitors
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Tricyclic
Antidepressant
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Psychologists
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Referral for
counseling
Encourage
expression of
feelings will entire
team and
caregivers
Work on solution
together
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Medications
◦ Amantadine
◦ Ritalin drugs
◦ Focalin
◦ Adderall
◦ Provigil/Nuvigil
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Increase oral intake
Increase fiber intake
Miralax
Metamucil
Citrucel
Colace
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Medications
◦ Viagra
◦ Cialis
◦ Levitra
10 SPMS patients
• Results
• Improved V.A. and low contrast V.A.
• But not in color vision or visual fields
• Reduction in V.E. latency & improved amplitudes
but no change OCT
• Increased ON area
• No change in macular volume, RFL, or MT ratio
• Reduction in general disability with improved in
EDSS
• No change in depression and cognition
• Decrease in T1 hypointense volume
• Side Effect:
• Infections
• Rash
• Pruritus
Physical therapy helps
 Relieve spasticity
 Increase coordination
 Train the patient to substitute
unaffected muscles for impaired ones
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White matter lesions suggestive of
demyelinating disease on MRI
Normal neurological exam
No medical history compatible with MS
Unclear whether RIS is subclinical MS or a
separated entity
About 33% of subjects with RIS develop a
CIS especially with spinal cord lesions
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This is an inflammatory demyelinating
disorder of the subcortical white matter.
Most frequently seen in children, often
evolving from antecedent infection or
immunization.
Typical presentation: encephalitic signs with
non specific CSF changes and minimal or no
changes on CT brain.
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Thought to be an autoimmune disease
via cross reactivity of the antiviral
antibodies with the myelin autoantigens.
Viruses associated include HSV,HIV,
HSV6, measles, hepatitis, influenza, EBV
etc.
There has also been an association post
immunization for MMR, Influenza, BCG.
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Lymphocytosis, raised CRP and ESR
CSF- can have a raised protein but can be
normal.
CT Brain - may be normal
MRI- gold standard for diagnosis
T2 weighted images show areas of
prolonged T2 in subcortical white
matter, usually asymmetrical.
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Empirically treated as a meningitis
with cefotaxime +/- acyclovir.
Once diagnosis is made then steroids
become the mainstay of management.
Physiotherapy can also be helpful.
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At first presentation, it is difficult to
differentiate between ADEM and MS.
New lesions and relapses, especially after
6/12 should alert to the possibility of
MS.
MS has no prodromal viral illness and no
fever or meninigism at presentation. It
presents as a monosymptomatic
syndrome like optic neuritis or
myelopathy and develops a relapsing
remitting course.
Most make excellent progress over the
following days, weeks and months
with no subsequent neurological
impairment.
 A minority have neurological
impairment such as motor disability,
visual/ cognitive or behavioral
impairment.
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