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Demyelinating Diseases

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Title: Demyelinating Diseases


1
Demyelinating Diseases Multiple sclerosis( MS )
Prof Mohammad Salah Abduljabbar
2
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.
3
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-  Follow
ing 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)
4
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.
5
Introduction to Multiple Sclerosis (MS)
  • 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

6
Multiple Sclerosis
  • Multiple Sclerosis (MS) is a chronic inflammatory
    demyelinating disease of the brain and spinal
    cord.

7
Epidemiology of MS
  • 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

8
Risk of Developing MS and Region of Origin
9
What Causes MS?
  • Despite extensive research, we still dont know
    what causes MS (O'Connor 8). However they have
    found associations and links between many factors
    including genetic and environmental.
  • Genetic
    Environmental
  • Sex
    Latitude
  • Racial Group
    SES
  • Family history
    Migration

  • Infections

10
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?)

11
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.

12
RECENT LESIONS
OLD LESION
LATER
  • Myelin destruction
  • Relative axon sparing
  • Perivenous infiltration with MNP
  • Breakdown of BBB
  • Relatively acellular
  • More clearly demarcated.
  • Bare axons are surrounded by astrocytes.

Astrocyte proliferation
13
Pathology
These lesions have a predilection for the
following sites within the brain SC.
  • Optic nerves
  • Periventricular region
  • Brainstem
  • Cervical SC. (CS. Tract PC.)

14
Pathogenesis
Genetic predisposition
Environmental Exposure (Virus)
Autoimmune attack by CD4 T-cell
Demyelination
Multiple Sclerosis
15
Role of Vitamin D in MSBackground 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 Nurses 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.

16
Symptoms of MS
  • Vision problems
  • Numbness
  • Difficulty walking
  • Fatigue
  • Depression
  • Emotional changes
  • Vertigo dizziness
  • Sexual dysfunction
  • Coordination problems
  • Balance problems
  • Pain
  • Changes in cognitive function
  • Bowel/bladder dysfunction
  • Spasticity

17
Initial Presentation of MS
Incidence ()
Optic nerve inflammation 1429
Poor balance (ataxia) 218
Dizziness (vertigo) 29
Weakness 1040
Double visions (diplopia) 818
Bladder, bowel dysfunction 014
Pain 2140
Sensory loss 1339
18
Clinical Features
  • Sensory Symptoms
  • Numbness Paraesthesia
  • Impaired vibration Joint position sensation
  • Lhermittes Sign ( Shock-like sensation in the
    limb)
  • Dysaesthesia Sensory loss to pain Temp.

19
Clinical Features
  • Motor Symptoms
  • Monoparesis
  • Paraparesis
  • Signs
  • Increased tone
  • Hyperactive tendon reflexes
  • Absent abdominal reflexes
  • Pyramidal distribution weakness

20
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
21
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

22
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

23
Clinical Course
1- Acute MS
  • Explosive onset
  • Death may occur in months
  • Dramatic recovery and prolonged remission may
    occur

24
2- Slowly Progressive MS
  • Common in older age group
  • No relapse/remission
  • Takes the form of a Progressive myelopathy

Disability
Time
25
3- Relapsing MS
  • Accumulating disability

Disability
Time
26
4- Benign form
  • Abrupt onset
  • Good remission
  • Long latent period

Disability
Time
27
Multiple Sclerosis Clinical Subtypes
Lublin FD et al. Neurology. 199646907-911.
28
Diseases to rule out
  • Viral infections
  • Lyme disease
  • CVA
  • Lupus
  • B12 deficiency
  • Rheumatoid arthritis
  • Other connective tissue disorders
  • Vasculitis
  • Syphilis
  • Tuberculosis
  • HIV
  • Sarcoidosis

29
MS Diagnosis
  • Neurological examination
  • Magnetic resonance imaging (MRI) Scan
  • Blood tests
  • Lumbar Puncture (spinal tap) occasionally
    performed
  • Other testing infrequently performed

30
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.

31
normal
CSF examination by lumbar puncture











  • Mild pleocytosis mainly lymphocytes.
  • Total protein maybe elevated
  • ?gammaglobuline in 50
  • Electrophoresis of CSF using agar shows discrete
    bands which are not present in serum.

Oligoclonal band
32
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
33
Demyelination in the Cervical Spinal Cord
MRI finding are not necessarily diagnostic
34
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35
Management Of MS
  • Drug therapy
  • 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

36
Treatment of New MS Exacerbations
  • Drug therapy
  • Corticosteroids
  • Intravenous immunoglobulin
  • Plasma exchange
  • Physical therapy

37
Prevention of Future Attacks and Disease
Progression
  • Immune modulating drugs
  • Beta-Interferon
  • Glatiramer acetate
  • Humanized monoclonal antibodies
  • Immunosuppressant drugs
  • Anti-cancer agents
  • Combination therapies

38
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
39
Existing Therapies and Emerging Therapies for MS
2005
2011
2006
2007
2010
2012
2013
Orals
Injectables
BG 12 Oral Fumarate
Oral Cladribine
Rebif
Teriflunomide
Betaseron
FTY 720
Laquinimod
Copaxone
SB683699
Fampridine ambulation indication?
Avonex
IV
Novantrone
IV
Campath
Tysabri
Rituximab II - RRMS III - PPMS
Generic Mitoxantrone (oncology)
(MS)
Daclizumab
MLN1202
MBP 8298
40
Agents Year of Approval
Interferon beta-1b, subcutaneous (Betaseron-Bayer Extavia-Novartis) 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
41
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.

42
Tysabri PML
  • Risk factors
  • JC antibody status
  • Length of treatment
  • Prior immunosuppressant use
  • Immuran (Azothrioprine)
  • Cytoxan
  • Novantrone
  • Methotrexate
  • Cellcept

43
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
44
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.

45
Side effects of MS medication
  • 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)

46
Bladder problems
  • Referral to urologist for further evaluation and
    treatment
  • Rule out UTI
  • Bladder training
  • Strengthen pelvic muscles
  • Medication
  • Anti-spasticity
  • Vesicare
  • Detrol
  • Ditropan

47
Depression
  • Selective Serotonin Reuptake Inhibitors
  • Paxil
  • Prozac
  • Zoloft
  • Lexapro
  • Celexa
  • Tricyclic Antidepressants
  • Elavil
  • Pamelor
  • Tofranil
  • Norpramin
  • Some other medications
  • Desyrel
  • Serzone
  • Welbutrin
  • Effexor
  • Referral for counseling
  • Psychologist
  • Encourage expression of feelings will entire team
    and caregivers
  • Work on solution together

48
Cognitive Changes
  • 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
  • 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

49
Fatigue
  • Medications
  • Amantadine
  • Ritalin drugs
  • Focalin
  • Adderall
  • Provigil/Nuvigil

50
Constipation
  • Increase oral intake
  • Increase fiber intake
  • Miralax
  • Metamucil
  • Citrucel
  • Colace

51
Sexual Dysfunction
  • Medications
  • Viagra
  • Cialis
  • Levitra

52
AUTOLOGOUS Stem Cell Treatment
  • 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

53
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

54
Key Decision Pointsin the Treatment of MS
Initiating therapy When to start Choice of
first-line therapy
Diseaseprogression
Escalating therapy Evaluating clinical response
Choice of second-line therapy
55
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.

56
ACUTE DISSEMINATED ENCEPHALOMYELITIS
57
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.

58
  • 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.

59
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.

60
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.

61
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.

62
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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