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MULTIPLE SCLEROSIS (MS)

MULTIPLE SCLEROSIS (MS). 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)

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MULTIPLE SCLEROSIS (MS)

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  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 [< 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 [< 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

  7. 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

  8. EPIDEMIOLOGY OF MULTIPLE SCLEROSIS • Female to male ratio of 2:1 • 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 > African Americans > Asians

  9. 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

  10. 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

  11. 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)

  12. 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)

  13. 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

  14. 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

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

  16. 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%)

  17. 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

  18. 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 < 1.5 ng/mL

  19. 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

  20. 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

  21. 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 • < 0.85

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

  23. 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)

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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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