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MULTIPLE SCLEROSIS (MS)

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Title: MULTIPLE SCLEROSIS (MS)


1
MULTIPLE SCLEROSIS (MS)
2
CASE STUDY
  • 30 year old white female presents to family
    physician with acute loss of vision in left eye
  • Referred to neurologist
  • Diagnosis of optic neuritis
  • Treated with IV corticosteroids for 5 days
  • Normal vision over next 3 weeks
  • Family history (mother)
  • Magnetic resonance imaging (MRI)
  • Multiple lesions in white matter of brain under
    cortex and around ventricles

3
CASE STUDY
  • 3 years later
  • Muscle weakness on left side of face and fatigue
  • Radiology (MRI with gadolinium)
  • New lesions in left middle cerebellar peduncle
    and pons
  • Laboratory (CSF from lumbar puncture)
  • 12 lymphocytes/uL
  • IgG index of 1.2
  • Oligoclonal bands (high resolution protein
    electrophoresis)
  • 2 bands in gamma region of CSF and no bands in
    gamma region of serum
  • Diagnosis of MS
  • Treatment with 5 day course of IV
    methylprednisolone and weekly IM interferon-beta
    (Avonex)

4
CASE STUDY
  • 3 years later
  • Clinical symptoms
  • Weakness in left hand and left leg
  • Slurred speech, nystagmus, ataxia and fatigue
  • Laboratory
  • Myelin basic protein (CSF)
  • 3.4 ng/mL lt 1.5 ng/mL
  • Treatment
  • 5 day course of IV methylprednisolone
  • Weekly IM interferon-beta (Avonex) continued

5
CASE STUDY
  • Eight months later
  • Clinical symptoms recurred
  • Laboratory
  • Myelin basic protein (CSF)
  • 4.1 ng/mL lt 1.5 ng/mL
  • Treatment
  • IFN-beta (Avonex) stopped
  • High dose IV methylprednisolone and
    cyclophosphamide (Cytoxan) monthly for 3 months
    then quarterly
  • Following 9 months therapy
  • Asymptomatic
  • No new lesions on gadolinium MRI

6
MULTIPLE SCLEROSIS (MS)
  • Chronic unpredictable disease of CNS
  • Tends to follow certain patterns (clinical
    courses)
  • Initial symptoms 20 to 40 years
  • Not contagious
  • Rarely fatal
  • Autoimmune disease
  • Characterized by patches (plaques) of
    demyelination and inflammation of myelin sheath
    of axons and degeneration of axons in white
    matter of CNS

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ETIOLOGY OF MULTIPLE SCLEROSIS (MS)
  • Complex with multiple causal factors
  • Environmental agents
  • Chemicals (organic solvents)
  • UV light
  • Infectious agents
  • Viruses
  • EBV, HHV-6, measles virus, CDV, HERV
  • Bacteria
  • Chlamydophila pneumoniae
  • Genetic predisposition
  • HLA-DR2
  • IL-2R and IL-7 receptor mutations

9
EPIDEMIOLOGY OF MULTIPLE SCLEROSIS
  • Female to male ratio of 21
  • Prevalence of 1 case per 750/1000 population
  • Northern Europe
  • Continental North America
  • 350,000 to 400,000 in US
  • Australia (SE) and New Zealand
  • Incidence in US of 200 to 300 cases/week
  • Disease prevalence
  • Caucasians gt African Americans gt Asians

10
EPIDEMIOLOGY OF MULTIPLE SCLEROSIS (MS)
  • Hemisphere gradients for prevalence
  • North to south in northern hemisphere
  • South to north in southern hemisphere
  • Prevalence gradients in Northern Hemisphere
  • North of 37th parallel (125 cases/100,000
    population)
  • South of 37th parallel (70 cases/100,000
    population)
  • Migration risk
  • Geographic move and risk for developing disease
  • Disease rare or not seen in
  • Inuit, Lapps, American Indians, Aborigines, Maoris

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RISK OF MULTIPLE SCLEROSIS (MS)
  • A 12 year old female
  • Moves from Rochester, Minnesota to
  • Miami, Florida
  • Risk for MS is Increased Decreased
    Same
  • An 18 year old female
  • Moves from Rochester, Minnesota to
  • Miami, Florida
  • Risk for MS is Increased Decreased
    Same

13
PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS
  • Destruction of
  • Myelin, oligodendrocytes, nerve axons
  • Hypothesis of molecular mimicry
  • Antigens
  • Myelin basic protein (MBP)
  • Myelin oligodendrocyte glycoprotein (MOG)
  • Proteolipid protein (PLP)
  • Myelin associated glycoprotein (MAG)

14
PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS
  • Cells
  • CD4 TH1, CD4 TH2 and CD8 T cells
  • Macrophages and microglial cells
  • Mast cells
  • B cells
  • Cytokines, chemokines and adhesion molecules
  • IL-12
  • IFN-gamma
  • ALCAM (Activated leukocyte cell adhesion
    molecule)

15
DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)
  • McDonald Criteria (2005 Revision)
  • History and clinical symptoms
  • Radiology
  • Magnetic resonance imaging (MRI) with and without
    gadolinium enhancement
  • Head and spinal column
  • Laboratory
  • MS panel

16
CLINICAL SYMPTOMS OF MULTIPLE SCLEROSIS (MS)
  • Fatigue
  • Visual disturbances
  • Blurred vision, diplopia, nystagmus, red-green
    color desaturation
  • Motor
  • Spasticity, paresis, dysarthria, spasms, ataxia,
    muscle weakness
  • Sensory changes
  • Paraesthesia, neuralgia
  • Cognitive deficits
  • Memory loss
  • Bladder / bowel urgency and incontinence

17
CLINICAL CONDITIONS ASSOCIATED WITH MS
  • Optic neuritis
  • Inflammation of optic nerve
  • Internuclear ophthalmoplegia
  • Paraylsis of ocular muscles
  • Transverse myelitis
  • Inflammation of spinal cord

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PATTERNS (CLINICAL COURSES) OF MULTIPLE SCLEROSIS
  • Relapsing-Remitting (85)
  • Relaspes (attacks, exacerbations) followed by
    remission (rest periods)
  • Attack symptoms (old may flare, new may appear)
  • Secondary Progressive (50)
  • Primary Progressive (10)
  • Progressive-Relapsing (5)

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22
RADIOLOGY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)
  • McDonald Criteria
  • 3 of 4 criteria for positive MRI
  • 1 gadolinium (Gd) enhancing lesion or 9 T2
    hyperintense non-Gd enhancing lesions
  • 1 or more infratentorial lesions
  • 1 or more juxtacortical lesions
  • 3 or more periventricular lesions
  • 1 brain lesion 1 spinal cord lesion

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LABORATORY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)
  • Oligoclonal bands
  • High resolution protein electrophoresis
  • Isoelectric focusing (IEF)
  • CSF IgG Index
  • Myelin basic protein (MBP)
  • Primary protein component (30) of myelin
  • Elevated level indicates active demyelination
  • CSF reference range of lt 1.5 ng/mL

26
LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS)
  • Marker for intrathecal antibody synthesis
  • Associated with
  • MS, Sjogrens syndrome, SLE
  • AIDS, Creutzfeldt-Jakob disease (CJD),
    Lyme disease, Syphilis
  • Subacute sclerosing panencephalitis (SSPE)
  • Guillain-Barre syndrome (GBS)
  • Neoplasms

27
LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS)
  • Specimens
  • CSF and serum
  • Method
  • High resolution protein electrophoresis
  • Concentration of CSF (80-100 X)
  • Agarose gel
  • 250 V for 20 minutes
  • Coomassie brilliant blue stain
  • Interpretation
  • 2 or more bands in gamma region of CSF and no
    bands in gamma region of serum

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31
LABORATORY DIAGNOSIS OF MS (CSF IgG INDEX)
  • CSF IgG to CSF albumin ratio compared to serum
    IgG to serum albumin ratio
  • CSF IgG / CSF albumin
  • serum IgG / serum albumin
  • Reference value
  • lt 0.85

32
TREATMENT OF MULTIPLE SCLEROSIS
  • Two categories
  • Symptom management agents
  • Disease modifying agents
  • Symptom management agents
  • Corticosteroids
  • Prednisone, methylprednisolone, dexamethasone
  • Indicated for acute exacerbations

33
TREATMENT OF MULTIPLE SCLEROSIS
  • Disease modifying agents
  • Immunomodulating
  • Interferon beta-1b (Betaseron)
  • Interferon beta-1a (Avonex)
  • Interferon beta-1a (Rebif)
  • Glatiramer acetate (Copaxone)
  • Natalizumab (Tysabri)
  • Immunosuppressant
  • Mitoxantrone (Novantrone)

34
NATALIZUMAB (TYSABRI)
  • Chimeric IgG4 monoclonal antibody
  • Indicated for relapsing forms of MS
  • Monotherapy
  • MOA
  • Binds to alpha4 family of integrins on leukocytes
    (except neutrophils)
  • Prevents leukocytes from leaving blood
  • Receptors for alpha 4 family
  • VCAM-1
  • MadCAM-1

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NATALIZUMAB (TYSABRI)
  • FDA approval in November, 2004
  • Manufacturer withdrawal in February, 2005
  • Adverse event (Boxed Warning)
  • Increased risk of
  • Progressive multifocal leukoencephalopathy (PML)
  • PML
  • Viral encephalitis caused by JC virus
  • FDA reapproval in March, 2006

37
INTERFERON BETA-1b (BETASERON)
  • Protein from human interferon beta-1b gene on
    plasmid in Escherichia coli
  • Serine for cysteine at 17
  • Indications
  • Relapsing forms
  • Initial clinical episode with MRI
  • Mechanism of action is unknown
  • Administration
  • Subcutaneous injection every other day

38
INTERFERON BETA 1a (AVONEX)
  • Glycoprotein from human interferon beta-1a gene
    in Chinese Hamster Ovary Cells
  • Indications
  • Relapsing forms
  • Mechanism of action is unknown
  • Beta 2 microglobulin
  • Neopterin
  • Dose and administration
  • 30 mcg IM / week

39
INTERFERON BETA 1a (REBIF)
  • Glycoprotein from human interferon beta-1a gene
    in Chinese Hamster Ovary Cells
  • Indications
  • Relapsing forms
  • Mechanism of action is unknown
  • Beta 2 microglobulin
  • Neopterin
  • Dose and administration
  • 22 mcg or 44 mcg SC 3x /week

40
DIFFERENCE BETWEEN AVONEX AND REBIF

  • Patients
  • Avonex
    Rebif
  • Relapse free (24 w) 63
    75
  • Relapse free (48 w) 52
    62
  • Injection site reactions 33
    85

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