MULTIPLE SCLEROSIS (MS)

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MULTIPLE SCLEROSIS (MS)
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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

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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)

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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

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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

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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

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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

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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

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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)

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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)

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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

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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

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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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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

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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

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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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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

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TREATMENT OF MULTIPLE SCLEROSIS

• Two categories
• Symptom management agents
• Disease modifying agents
• Symptom management agents
• Corticosteroids
• Prednisone, methylprednisolone, dexamethasone
• Indicated for acute exacerbations

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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)

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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

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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

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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

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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

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DIFFERENCE BETWEEN AVONEX AND REBIF

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

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