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Demyelinating Diseases
Multiple sclerosis( MS )
Prof Mohammad Salah Abduljabbar
Introduction
-Demyelinating disorders of the CNS affect myelin and/or oligodendroglia
with relative sparing of axons.
-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.
-Oligodendrocyte are present in gray matter near neural cell bodies and in white matter near
axons.
-Myelin is composed of protein 20% & lipids.
Classification of the Demyelinating diseases:
- Multiple sclerosis:
A- Chronic relapsing encephalomyelopathic form.
B- Acute multiple sclerosis.
C- Neuromyelitis optica.
- Diffuse cerebral sclerosis (encephalitis periaxalis diffuse) or Schilder and concentric sclerosis
of Balo.
Acute disseminated encephalomyelitis.
A- Following measles, rubella & influenza.
B- Following rabies or smallpox vaccination.
Acute and subacute necrotizing hemorrhagic encephalitis.
A- Acute encephalopathic form (hemorrhagic leukoencephalitis of Hurst)
B- Subacute necrotic myelopathy
C- Acute brain purpura(acute pericapillary encephalorrhagia)
Multiple Sclerosis (MS)
-MS referred by the British as disseminated sclerosis & by French as Sclerose en plaques.
-MS is a common demyelinating disease, characterized by focal disturbance of function and a
relapsing and remitting course.
-Higher incidence of the disease found in the northern most latitude of the northern & southern
hemispheres compared to southernmost latitudes.
-MS usually occur in young adults with a peak age incidence of 20-40 years.
-more female than males are affected.
-The risk of MS in relative patients increases 20 folds.
Introduction to
Multiple Sclerosis (MS)
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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
Multiple Sclerosis
Multiple Sclerosis (MS) is a chronic
inflammatory demyelinating disease of the
brain and spinal cord.
Epidemiology of MS
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Age onset 20 – 50 years old
Women are 2 times more likely to develop MS
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
Risk of Developing MS and Region
of Origin
What Causes MS?
“Despite extensive research, we still don’t
know what causes MS” (O'Connor 8).
However they have found associations
and links between many factors including
genetic and environmental.
Genetic
Environmental
Latitude
Racial Group
Family history
Sex
SES
Migration
Infections
Not Everyone with a Genetic Risk
Will Develop MS – Why?
• Risk is modified by Environmental
factors
– Sunlight
– Diet (e.g., vitamin D)
– Other lifetime experiences (infections?)
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 & SC.:
•Optic nerves
• Periventricular region
• Brainstem
• Cervical SC. (CS. Tract & PC.)
Pathogenesis
Genetic predisposition
Environmental Exposure (Virus)
Autoimmune attack by CD4 T-cell
Demyelination
Multiple Sclerosis
Role of Vitamin D in MS
Background Information
1.
US cohort study found that 3.5 times more women residing in northern states were
diagnosed with MS than southern states
2.
Incidence of MS highest in North Temporal Climate
3.
MS more prominent in areas reporting less than 2000 hours of sunshine annually
4.
MS displays seasonable variability with increased activity in the Spring and lowest in
the Fall.
5.
A Finnish study found in MS patients lower serum vitamin D levels in the Spring.
6.
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.
7.
Levels of 11 25 hyroxy D3 and 1
8.
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.
Symptoms of MS
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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
Initial Presentation of MS
Optic nerve inflammation
Poor balance (ataxia)
Dizziness (vertigo)
Weakness
Double visions (diplopia)
Bladder, bowel dysfunction
Pain
Sensory loss
Incidence (%)
14–29
2–18
2–9
10–40
8–18
0–14
21–40
13–39
Clinical Features
Sensory Symptoms
• Numbness & Paraesthesia
• Impaired vibration & Joint position sensation
• Lhermitte’s Sign ( Shock-like sensation in
the limb)
•Dysaesthesia + Sensory loss to pain & Temp.
Clinical Features
Motor Symptoms
• Monoparesis
• Paraparesis
Signs
• Increased tone
•Hyperactive tendon reflexes
•Absent abdominal reflexes
•Pyramidal distribution
weakness
Clinical Features
Optic Neuritis
•Inflammatory demyelination of one or both optic nerves
• Pain around one eye
• Blurred vision
• Loss of color vision
• Swollen optic disc( Papillitis)
• Visual field defect
• Diplopia & Vertigo
Uhthoff phenomenon
Types of MS
• Relapsing-remitting MS (RRMS)
– Affects 85% of newly diagnosed
– Attacks followed by partial or complete recovery
– Symptoms may be inactive for months or years
• Secondary-progressive MS (SPMS)
– Occasional relapses but symptoms remain constant,
no remission
– Progressive disability late in disease course
Types of MS
• Primary-progressive MS (PPMS)
– Affects approximately 10% of MS
population
– Slow onset but continuous worsening
condition
• Progressive-relapsing MS (PRMS)
– Rarest form Affects approx. 5%
– Steady worsening of condition
at onset
Clinical Course
1- Acute MS:
•Explosive onset
•Death may occur in months
•Dramatic recovery and prolonged remission may occur
2- Slowly Progressive MS:
•Common in older age group
•No relapse/remission
•Takes the form of a Progressive myelopathy
Disability
Time
3- Relapsing MS:
•Accumulating disability
Disability
Time
4- Benign form
•Abrupt onset
•Good remission
•Long latent period
Disability
Time
Multiple Sclerosis Clinical Subtypes
Relapsing-remitting
Secondary-progressive
Time
Time
Progressive-relapsing
Disability
Disability
Primary-progressive
Time
Time
Lublin FD et al. Neurology. 1996;46:907-911.
Diseases to rule out
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Viral infections
Lyme disease
CVA
Lupus
B12 deficiency
Rheumatoid arthritis
Other connective
tissue disorders
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Vasculitis
Syphilis
Tuberculosis
HIV
Sarcoidosis
MS Diagnosis
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Neurological examination
Magnetic resonance imaging (MRI) Scan
Blood tests
Lumbar Puncture (spinal tap): occasionally
performed
• Other testing: infrequently performed
Investigation
No diagnostic test. Only support the clinical suspicion.
Neuropsychological measurement of conduction within the CNS to detect second a
symptomatic lesion.:
•Visual evoked potential(VEP): in optic nerve the latency of the large positive wave is delayed . the
amplitude may also be reduced.
•Somatosensory evoked response (SSEP) may detect central sensory pathway lesion.
•Brain stem auditory evoked potential (BAEP) may detect brain stem lesion.
CSF examination by lumbar puncture
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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.
normal
Oligoclonal
band
MRI
MRI is more sensitive showing white matter disease.
On T-2 weighted images, patchy area of abnormal white matter are found most
commonly in cerebral hemisphere in paraventicular areas; often lesions can be
present in the cerebellum , brain stem, cervical and or thoracic spinal cord
Area of demyelination in cerebral hemisphere
Demyelination in the Cervical Spinal Cord
MRI finding are not necessarily
diagnostic
Magnetic Resonance Imaging in MS
Optic nerve
Spinal cord
Brain
Management Of MS
• Drug therapy
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Treat new attacks (exacerbations)
Prevent the occurrence of future attacks
Slow or prevent disease progression
Treat the chronic symptoms of the disease
• Physical therapy
• Psychosocial support
Treatment of New MS
Exacerbations
• Drug therapy
– Corticosteroids
– Intravenous immunoglobulin
– Plasma exchange
• Physical therapy
Prevention of Future Attacks and
Disease Progression
• Immune modulating drugs
– Beta-Interferon
– Glatiramer acetate
– Humanized monoclonal antibodies
• Immunosuppressant drugs
– Anti-cancer agents
• Combination therapies
Medications and MS
Therapies
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
Existing Therapies and
Emerging Therapies for MS
2005
2006
2007
2010
2011
2012
2013
Orals
Injectables
Oral
Cladribine
Rebif
BG 12 Oral
Fumarate
Teriflunomide
Betaseron
FTY 720
Copaxone
Laquinimod
Fampridine
SB683699
ambulation indication?
Avonex
IV
IV Novantrone
Tysabri
Campath
Rituximab
II - RRMS; III - PPMS
Generic Mitoxantrone
(oncology)
Daclizumab
(MS)
MBP 8298
approved
In phase III
In phase II
MLN1202
Agents
Interferon beta-1b, subcutaneous (BetaseronBayer; Extavia-Novartis)
Year of
Approval
1993, 2009
Interferon beta-1a, intramuscular (Avonex-Biogen)
1996
Glatiramer (Copaxone-Teva)
1997
Interferon beta-1a, subcutaneous (Rebif-EMD
Serono)
2002
Natalizumab (Tysabri-Biogen, Elan)
2006
Mitoxantrone (various generics)
2000
Fingolimod (Gilenya-Novartis)
2010
Disease-Modifying Drugs
Interferon Beta 1a •
(Avonex and Rebif):
is a protein that is a replica of
human interferon. It suppress
the immune system and helps to
maintain the blood-brain
barrier. You inject Avonex into
the muscle once a week and
Rebif is injected under the skin
three times a week. This drug
is useful to people who have
definite progressive MS. One
side effect of the drug is a flu
like symptom.
Interferon Beta 1b •
(Betaseron): is slightly
different from our own
interferon. This medication
does the same thing as beta 1a,
but is injected just under the
skin every two days. Side
effects include irritation,
bruising, and redness at the site
of injection and the flu like
symptoms. This is also given to
people who have definite
progressive MS.
Tysabri & PML
• Risk factors
– JC antibody status
– Length of treatment
– Prior immunosuppressant use
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Immuran (Azothrioprine)
Cytoxan
Novantrone
Methotrexate
Cellcept
Gilenya “Fingolimide”
Blocks S1 Phosphate receptor keeping T & B cells in lymphoid tissue
First oral pill released by FDA three years ago 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
Teriflunomide
• 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.
Side effects of MS medication
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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)
Bladder problems
• Rule out UTI
• Bladder training
– Strengthen pelvic
muscles
• Medication
• Anti-spasticity
– Vesicare
– Detrol
– Ditropan
• Referral to urologist
for further
evaluation and
treatment
Depression
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Selective Serotonin Reuptake
Inhibitors
– Paxil
– Prozac
– Zoloft
– Lexapro
– Celexa
Tricyclic Antidepressants
– Elavil
– Pamelor
– Tofranil
– Norpramin
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Some other medications
– Desyrel
– Serzone
– Welbutrin
– Effexor
Referral for counseling
Psychologist
Encourage expression of
feelings will entire team and
caregivers
Work on solution together
Cognitive Changes
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Use calendar for appointment
& special dates
Use tape recorder to help
remember information
Start a diary or memory
notebook
Organize environment
Teach to make lists
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Limit noise during
conversations
• Have patient repeat
information and write
down important points
• Encourage use of
crossword puzzles and
cognitive function tests
• Medications
– Aricept
– Namenda
– Exelon patch
Fatigue
• Medications
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Amantadine
Ritalin drugs
Focalin
Adderall
Provigil/Nuvigil
Constipation
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Increase oral intake
Increase fiber intake
Miralax
Metamucil
Citrucel
Colace
Sexual Dysfunction
• Medications
– Viagra
– Cialis
– Levitra
AUTOLOGOUS Stem Cell
Treatment
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10 SPMS patients
CDMS patient with HX of ON, abn VEPS, or clinical O. A. or HX of Uhthoffs
phenomenon
MRI of ON had a T2 lesion followed for 20 mo before IV of stem cells for 10 mo
afterwards
• 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 ration
• Reduction in general disability with improved in EDSS
• No change in MSFC, depression , cognition
• Dec. in T1 hypointense volume
• S.E.
• Infections
• Rash
• Pruritus
RIS (Radiological Isolated
Syndrome)
• 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
Key Decision Points
in the Treatment of MS
Initiating therapy
When to start
Choice of
first-line therapy
Disease
progression
Escalating therapy
Evaluating clinical response
Choice of second-line therapy
Summary
• MS is a common inflammatory disease of the CNS
that affects females more frequently than males.
• The cause of MS appears to be a combination of
genetic and environmental factors.
• The symptoms of MS can be quite variable.
• MRI is a sensitive test for making the diagnosis of
MS.
• Treatments are available for reducing the number
of MS attacks and for slowing MS disease
progression.
ACUTE DISSEMINATED
ENCEPHALOMYELITIS
ADEM
• 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.
• 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.
APPROPRIATE
INVESTIGATIONS
• 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.
TREATMENT
• Empirically treated as a meningitis with
cefotaxime +/- acyclovir.
• Once diagnosis is made then steroids
become the mainstay of management.
• Physiotherapy can also be helpful.
DIFFERENTIAL DIAGNOSIS
• 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 - 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.
PROGNOSIS OF ADEM
• 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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