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MULTIPLE SCLEROSIS (MS)
CASE STUDY  <ul><li>30 year old white female presents to family physician with acute loss of vision in left eye </li></ul>...
CASE STUDY  <ul><li>3 years later </li></ul><ul><ul><li>Muscle weakness on left side of face and fatigue </li></ul></ul><u...
CASE STUDY  <ul><li>3 years later </li></ul><ul><ul><li>Clinical symptoms </li></ul></ul><ul><ul><ul><li>Weakness in left ...
CASE STUDY  <ul><li>Eight months later </li></ul><ul><ul><li>Clinical symptoms recurred </li></ul></ul><ul><ul><li>Laborat...
MULTIPLE SCLEROSIS (MS) <ul><li>Chronic unpredictable disease of CNS </li></ul><ul><ul><li>Tends to follow certain pattern...
 
ETIOLOGY OF MULTIPLE SCLEROSIS (MS) <ul><li>Complex with multiple causal factors </li></ul><ul><ul><li>Environmental agent...
EPIDEMIOLOGY OF MULTIPLE SCLEROSIS <ul><li>Female to male ratio of 2:1 </li></ul><ul><li>Prevalence of 1 case per 750/1000...
EPIDEMIOLOGY OF MULTIPLE SCLEROSIS (MS) <ul><li>Hemisphere gradients for prevalence </li></ul><ul><ul><li>North to south i...
 
RISK OF MULTIPLE SCLEROSIS (MS ) <ul><li>A 12 year old female </li></ul><ul><ul><li>Moves from Rochester, Minnesota to  </...
PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS <ul><li>Destruction of  </li></ul><ul><ul><li>Myelin, oligodendrocytes, nerve axons ...
PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS <ul><li>Cells </li></ul><ul><ul><li>CD4 TH1, CD4 TH2 and CD8 T cells </li></ul></ul>...
DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) <ul><li>McDonald Criteria (2005 Revision) </li></ul><ul><ul><li>History and clinical ...
CLINICAL SYMPTOMS OF MULTIPLE SCLEROSIS (MS) <ul><li>Fatigue </li></ul><ul><li>Visual disturbances </li></ul><ul><ul><li>B...
CLINICAL CONDITIONS ASSOCIATED WITH MS <ul><li>Optic neuritis </li></ul><ul><ul><li>Inflammation of optic nerve </li></ul>...
 
PATTERNS (CLINICAL COURSES) OF MULTIPLE SCLEROSIS <ul><li>Relapsing-Remitting (85%) </li></ul><ul><ul><li>Relaspes (attack...
 
 
RADIOLOGY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) <ul><li>McDonald Criteria </li></ul><ul><ul><li>3 of 4 criteria for “positi...
 
 
LABORATORY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) <ul><li>Oligoclonal bands </li></ul><ul><li>CSF IgG Index </li></ul><ul><l...
LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS) <ul><li>Marker for intrathecal antibody synthesis </li></ul><ul><li>Associa...
LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS) <ul><li>Specimens </li></ul><ul><ul><li>CSF and serum </li></ul></ul><ul><l...
 
 
 
LABORATORY DIAGNOSIS OF MS (CSF IgG INDEX)   <ul><li>CSF IgG to CSF albumin ratio compared to serum IgG to serum albumin r...
TREATMENT OF MULTIPLE SCLEROSIS <ul><li>Two categories </li></ul><ul><ul><li>Symptom management agents </li></ul></ul><ul>...
TREATMENT OF MULTIPLE SCLEROSIS <ul><li>Disease modifying agents </li></ul><ul><ul><li>Immunomodulating </li></ul></ul><ul...
NATALIZUMAB (TYSABRI) <ul><li>Chimeric IgG4 monoclonal antibody </li></ul><ul><li>Indicated for relapsing forms of MS </li...
 
NATALIZUMAB (TYSABRI) <ul><li>FDA approval in November, 2004 </li></ul><ul><li>Manufacturer withdrawal in February, 2005 <...
INTERFERON BETA-1b (BETASERON) <ul><li>Protein from human interferon beta-1b gene on plasmid in Escherichia coli </li></ul...
INTERFERON BETA – 1a (AVONEX) <ul><li>Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary Cells </li>...
INTERFERON BETA – 1a (REBIF) <ul><li>Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary Cells </li><...
DIFFERENCE BETWEEN AVONEX AND REBIF <ul><li>% Patients </li></ul><ul><li>  Avonex  Rebif </li></ul><ul><li>Relapse free (2...
 
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Multiple Sclerosis

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Transcript of "Multiple Sclerosis"

  1. 1. MULTIPLE SCLEROSIS (MS)
  2. 2. CASE STUDY <ul><li>30 year old white female presents to family physician with acute loss of vision in left eye </li></ul><ul><li>Referred to neurologist </li></ul><ul><ul><li>Diagnosis of optic neuritis </li></ul></ul><ul><ul><li>Treated with IV corticosteroids for 5 days </li></ul></ul><ul><ul><ul><li>Normal vision over next 3 weeks </li></ul></ul></ul><ul><ul><li>Family history (mother) </li></ul></ul><ul><ul><li>Magnetic resonance imaging (MRI) </li></ul></ul><ul><ul><ul><li>Multiple lesions in white matter of brain under cortex and around ventricles </li></ul></ul></ul>
  3. 3. CASE STUDY <ul><li>3 years later </li></ul><ul><ul><li>Muscle weakness on left side of face and fatigue </li></ul></ul><ul><ul><li>Radiology (MRI with gadolinium) </li></ul></ul><ul><ul><ul><li>New lesions in left middle cerebellar peduncle and pons </li></ul></ul></ul><ul><ul><li>Laboratory (CSF from lumbar puncture) </li></ul></ul><ul><ul><ul><li>12 lymphocytes/uL </li></ul></ul></ul><ul><ul><ul><li>IgG index of 1.2 </li></ul></ul></ul><ul><ul><ul><li>Oligoclonal bands (high resolution protein electrophoresis) </li></ul></ul></ul><ul><ul><ul><ul><li>2 bands in gamma region of CSF and no bands in gamma region of serum </li></ul></ul></ul></ul><ul><ul><li>Diagnosis of MS </li></ul></ul><ul><ul><li>Treatment with 5 day course of IV methylprednisolone and weekly IM interferon-beta (Avonex) </li></ul></ul>
  4. 4. CASE STUDY <ul><li>3 years later </li></ul><ul><ul><li>Clinical symptoms </li></ul></ul><ul><ul><ul><li>Weakness in left hand and left leg </li></ul></ul></ul><ul><ul><ul><li>Slurred speech, nystagmus, ataxia and fatigue </li></ul></ul></ul><ul><ul><li>Laboratory </li></ul></ul><ul><ul><ul><li>Myelin basic protein (serum) </li></ul></ul></ul><ul><ul><ul><ul><li>3.4 ng/mL [< 1.5 ng/mL] </li></ul></ul></ul></ul><ul><ul><li>Treatment </li></ul></ul><ul><ul><ul><li>5 day course of IV methylprednisolone </li></ul></ul></ul><ul><ul><ul><li>Weekly IM interferon-beta (Avonex) continued </li></ul></ul></ul>
  5. 5. CASE STUDY <ul><li>Eight months later </li></ul><ul><ul><li>Clinical symptoms recurred </li></ul></ul><ul><ul><li>Laboratory </li></ul></ul><ul><ul><ul><li>Myelin basic protein (serum) </li></ul></ul></ul><ul><ul><ul><ul><li>4.1 ng/mL [< 1.5 ng/mL] </li></ul></ul></ul></ul><ul><ul><li>Treatment </li></ul></ul><ul><ul><ul><li>IFN-beta (Avonex) stopped </li></ul></ul></ul><ul><ul><ul><li>High dose IV methylprednisolone and cyclophosphamide (Cytoxan) monthly for 3 months then quarterly </li></ul></ul></ul><ul><ul><li>Following 9 months therapy </li></ul></ul><ul><ul><ul><li>Asymptomatic </li></ul></ul></ul><ul><ul><ul><li>No new lesions on gadolinium MRI </li></ul></ul></ul>
  6. 6. MULTIPLE SCLEROSIS (MS) <ul><li>Chronic unpredictable disease of CNS </li></ul><ul><ul><li>Tends to follow certain patterns (clinical courses) </li></ul></ul><ul><ul><li>Initial symptoms 20 to 40 years </li></ul></ul><ul><ul><li>Not contagious </li></ul></ul><ul><ul><li>Rarely fatal </li></ul></ul><ul><li>Autoimmune disease </li></ul><ul><li>Characterized by patches (plaques) of demyelination and inflammation of myelin sheath of axons and degeneration of axons in white matter of CNS </li></ul>
  7. 8. ETIOLOGY OF MULTIPLE SCLEROSIS (MS) <ul><li>Complex with multiple causal factors </li></ul><ul><ul><li>Environmental agents </li></ul></ul><ul><ul><ul><li>Chemicals (organic solvents) </li></ul></ul></ul><ul><ul><ul><li>UV light </li></ul></ul></ul><ul><ul><li>Infectious agents </li></ul></ul><ul><ul><ul><li>Viruses </li></ul></ul></ul><ul><ul><ul><ul><li>EBV, HH-6, measles virus, CDV, HERV </li></ul></ul></ul></ul><ul><ul><ul><li>Bacteria </li></ul></ul></ul><ul><ul><ul><ul><li>Chlamydophila pneumoniae </li></ul></ul></ul></ul><ul><ul><li>Genetic predisposition </li></ul></ul><ul><ul><ul><li>HLA-DR2 </li></ul></ul></ul><ul><ul><ul><li>IL-2R and IL-7 receptor mutations </li></ul></ul></ul>
  8. 9. EPIDEMIOLOGY OF MULTIPLE SCLEROSIS <ul><li>Female to male ratio of 2:1 </li></ul><ul><li>Prevalence of 1 case per 750/1000 population </li></ul><ul><ul><li>Northern Europe </li></ul></ul><ul><ul><li>Continental North America </li></ul></ul><ul><ul><ul><li>350,000 to 400,000 in US </li></ul></ul></ul><ul><ul><li>Australia (SE) and New Zealand </li></ul></ul><ul><li>Incidence in US of 200 to 300 cases/week </li></ul><ul><li>Disease prevalence </li></ul><ul><ul><li>Caucasians > African Americans > Asians </li></ul></ul>
  9. 10. EPIDEMIOLOGY OF MULTIPLE SCLEROSIS (MS) <ul><li>Hemisphere gradients for prevalence </li></ul><ul><ul><li>North to south in northern hemisphere </li></ul></ul><ul><ul><li>South to north in southern hemisphere </li></ul></ul><ul><li>Prevalence gradients in Northern Hemisphere </li></ul><ul><ul><li>North of 37 th parallel (125 cases/100,000 population) </li></ul></ul><ul><ul><li>South of 37 th parallel (70 cases/100,000 population) </li></ul></ul><ul><li>Migration risk </li></ul><ul><ul><li>Geographic move and risk for developing disease </li></ul></ul><ul><li>Disease rare or not seen in </li></ul><ul><ul><li>Inuit, Lapps, American Indians, Aborigines, Maoris </li></ul></ul>
  10. 12. RISK OF MULTIPLE SCLEROSIS (MS ) <ul><li>A 12 year old female </li></ul><ul><ul><li>Moves from Rochester, Minnesota to </li></ul></ul><ul><ul><li>Miami, Florida </li></ul></ul><ul><li>Risk for MS is: Increased Decreased Same </li></ul><ul><li>An 18 year old female </li></ul><ul><ul><li>Moves from Rochester, Minnesota to </li></ul></ul><ul><ul><li>Miami, Florida </li></ul></ul><ul><li>Risk for MS is: Increased Decreased Same </li></ul>
  11. 13. PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS <ul><li>Destruction of </li></ul><ul><ul><li>Myelin, oligodendrocytes, nerve axons </li></ul></ul><ul><li>Hypothesis of molecular mimicry </li></ul><ul><li>Antigens </li></ul><ul><ul><li>Myelin basic protein (MBP) </li></ul></ul><ul><ul><li>Myelin oligodendrocyte glycoprotein (MOG) </li></ul></ul><ul><ul><li>Proteolipid protein (PLP) </li></ul></ul><ul><ul><li>Myelin associated glycoprotein (MAG) </li></ul></ul>
  12. 14. PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS <ul><li>Cells </li></ul><ul><ul><li>CD4 TH1, CD4 TH2 and CD8 T cells </li></ul></ul><ul><ul><li>Macrophages and microglial cells </li></ul></ul><ul><ul><li>Mast cells </li></ul></ul><ul><ul><li>B cells </li></ul></ul><ul><li>Cytokines, chemokines and adhesion molecules </li></ul><ul><ul><ul><li>IL-12 </li></ul></ul></ul><ul><ul><ul><li>IFN-gamma </li></ul></ul></ul><ul><ul><ul><li>ALCAM (Activated leukocyte cell adhesion molecule) </li></ul></ul></ul>
  13. 15. DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) <ul><li>McDonald Criteria (2005 Revision) </li></ul><ul><ul><li>History and clinical symptoms </li></ul></ul><ul><ul><li>Radiology </li></ul></ul><ul><ul><ul><li>Magnetic resonance imaging (MRI) with and without gadolinium enhancement </li></ul></ul></ul><ul><ul><ul><ul><li>Head and spinal column </li></ul></ul></ul></ul><ul><ul><li>Laboratory </li></ul></ul><ul><ul><ul><li>MS panel </li></ul></ul></ul>
  14. 16. CLINICAL SYMPTOMS OF MULTIPLE SCLEROSIS (MS) <ul><li>Fatigue </li></ul><ul><li>Visual disturbances </li></ul><ul><ul><li>Blurred vision, diplopia, nystagmus, red-green color dissociation </li></ul></ul><ul><li>Motor </li></ul><ul><ul><li>Spasticity, paresis, dysarthria, spasms, ataxia, muscle weakness </li></ul></ul><ul><li>Sensory changes </li></ul><ul><ul><li>Paraesthesia, neuralgia </li></ul></ul><ul><li>Cognitive deficits </li></ul><ul><ul><li>Memory loss </li></ul></ul><ul><li>Bladder / bowel urgency and incontinence </li></ul>
  15. 17. CLINICAL CONDITIONS ASSOCIATED WITH MS <ul><li>Optic neuritis </li></ul><ul><ul><li>Inflammation of optic nerve </li></ul></ul><ul><li>Internuclear ophthalmoplegia </li></ul><ul><ul><li>Paraylsis of ocular muscles </li></ul></ul><ul><li>Transverse myelitis </li></ul><ul><ul><li>Inflammation of spinal cord </li></ul></ul>
  16. 19. PATTERNS (CLINICAL COURSES) OF MULTIPLE SCLEROSIS <ul><li>Relapsing-Remitting (85%) </li></ul><ul><ul><li>Relaspes (attacks, exacerbations) followed by remission (rest periods) </li></ul></ul><ul><ul><li>Attack symptoms (old may flare, new may appear) </li></ul></ul><ul><li>Secondary Progressive (50%) </li></ul><ul><li>Primary Progressive (10%) </li></ul><ul><li>Progressive-Relapsing (5%) </li></ul>
  17. 22. RADIOLOGY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) <ul><li>McDonald Criteria </li></ul><ul><ul><li>3 of 4 criteria for “positive MRI” </li></ul></ul><ul><ul><ul><li>1 gadolinium (Gd) enhancing lesion or 9 T2 hyperintense non-Gd enhancing lesions </li></ul></ul></ul><ul><ul><ul><li>1 or more infratentorial lesions </li></ul></ul></ul><ul><ul><ul><li>1 or more juxtacortical lesions </li></ul></ul></ul><ul><ul><ul><li>3 or more periventricular lesions </li></ul></ul></ul><ul><ul><ul><ul><li>1 brain lesion = 1 spinal cord lesion </li></ul></ul></ul></ul>
  18. 25. LABORATORY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) <ul><li>Oligoclonal bands </li></ul><ul><li>CSF IgG Index </li></ul><ul><li>Myelin basic protein (MBP) </li></ul><ul><ul><li>Serum reference range of < 1.5 ng/mL </li></ul></ul><ul><li>Anti-myelin associated glycoprotein (Anti-MAG) </li></ul><ul><ul><li>IgM by IFA of < 1:10 </li></ul></ul>
  19. 26. LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS) <ul><li>Marker for intrathecal antibody synthesis </li></ul><ul><li>Associated with </li></ul><ul><ul><li>MS, Sjogrens syndrome, SLE </li></ul></ul><ul><ul><li>AIDS, Creutzfeldt-Jakob disease (CJD), Lyme disease, Syphilis </li></ul></ul><ul><ul><li>Subacute sclerosing panencephalitis (SSPE) </li></ul></ul><ul><ul><li>Guillain-Barre syndrome (GBS) </li></ul></ul><ul><ul><li>Neoplasms </li></ul></ul>
  20. 27. LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS) <ul><li>Specimens </li></ul><ul><ul><li>CSF and serum </li></ul></ul><ul><li>Method </li></ul><ul><ul><li>High resolution protein electrophoresis </li></ul></ul><ul><ul><ul><li>Concentration of CSF (80-100 X) </li></ul></ul></ul><ul><ul><ul><li>Agarose gel </li></ul></ul></ul><ul><ul><ul><li>250 V for 20 minutes </li></ul></ul></ul><ul><ul><ul><li>Coomassie brilliant blue stain </li></ul></ul></ul><ul><li>Interpretation </li></ul><ul><ul><li>2 or more bands in gamma region of CSF and no bands in gamma region of serum </li></ul></ul>
  21. 31. LABORATORY DIAGNOSIS OF MS (CSF IgG INDEX) <ul><li>CSF IgG to CSF albumin ratio compared to serum IgG to serum albumin ratio </li></ul><ul><li>CSF IgG / CSF albumin </li></ul><ul><li>serum IgG / serum albumin </li></ul><ul><li>Reference value </li></ul><ul><ul><li>< 0.85 </li></ul></ul>
  22. 32. TREATMENT OF MULTIPLE SCLEROSIS <ul><li>Two categories </li></ul><ul><ul><li>Symptom management agents </li></ul></ul><ul><ul><li>Disease modifying agents </li></ul></ul><ul><li>Symptom management agents </li></ul><ul><ul><li>Corticosteroids </li></ul></ul><ul><ul><ul><li>Prednisone, methylprednisolone, dexamethasone </li></ul></ul></ul><ul><ul><ul><li>Indicated for acute exacerbations </li></ul></ul></ul>
  23. 33. TREATMENT OF MULTIPLE SCLEROSIS <ul><li>Disease modifying agents </li></ul><ul><ul><li>Immunomodulating </li></ul></ul><ul><ul><ul><li>Interferon beta-1b (Betaseron) </li></ul></ul></ul><ul><ul><ul><li>Interferon beta-1a (Avonex) </li></ul></ul></ul><ul><ul><ul><li>Interferon beta-1a (Rebif) </li></ul></ul></ul><ul><ul><ul><li>Glatiramer acetate (Copaxone) </li></ul></ul></ul><ul><ul><ul><li>Natalizumab (Tysabri) </li></ul></ul></ul><ul><ul><li>Immunosuppressant </li></ul></ul><ul><ul><ul><li>Mitoxantrone (Novantrone) </li></ul></ul></ul>
  24. 34. NATALIZUMAB (TYSABRI) <ul><li>Chimeric IgG4 monoclonal antibody </li></ul><ul><li>Indicated for relapsing forms of MS </li></ul><ul><ul><li>Monotherapy </li></ul></ul><ul><li>MOA </li></ul><ul><ul><li>Binds to alpha4 family of integrins on leukocytes (except neutrophils) </li></ul></ul><ul><ul><li>Prevents leukocytes from leaving blood </li></ul></ul><ul><ul><li>Receptors for alpha 4 family </li></ul></ul><ul><ul><ul><li>VCAM-1 </li></ul></ul></ul><ul><ul><ul><li>MadCAM-1 </li></ul></ul></ul>
  25. 36. NATALIZUMAB (TYSABRI) <ul><li>FDA approval in November, 2004 </li></ul><ul><li>Manufacturer withdrawal in February, 2005 </li></ul><ul><li>Adverse event (Boxed Warning) </li></ul><ul><ul><li>Increased risk of </li></ul></ul><ul><ul><ul><li>Progressive multifocal leukoencephalopathy (PML) </li></ul></ul></ul><ul><li>PML </li></ul><ul><ul><li>Viral encephalitis caused by JC virus </li></ul></ul><ul><li>FDA reapproval in March, 2006 </li></ul>
  26. 37. INTERFERON BETA-1b (BETASERON) <ul><li>Protein from human interferon beta-1b gene on plasmid in Escherichia coli </li></ul><ul><ul><li>Serine for cysteine at 17 </li></ul></ul><ul><li>Indications </li></ul><ul><ul><li>Relapsing forms </li></ul></ul><ul><ul><li>Initial clinical episode with MRI </li></ul></ul><ul><li>Mechanism of action is unknown </li></ul><ul><li>Administration </li></ul><ul><ul><li>Subcutaneous injection every other day </li></ul></ul>
  27. 38. INTERFERON BETA – 1a (AVONEX) <ul><li>Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary Cells </li></ul><ul><li>Indications </li></ul><ul><ul><li>Relapsing forms </li></ul></ul><ul><li>Mechanism of action is unknown </li></ul><ul><ul><li>Beta 2 microglobulin </li></ul></ul><ul><ul><li>Neopterin </li></ul></ul><ul><li>Dose and administration </li></ul><ul><ul><li>30 mcg IM / week </li></ul></ul>
  28. 39. INTERFERON BETA – 1a (REBIF) <ul><li>Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary Cells </li></ul><ul><li>Indications </li></ul><ul><ul><li>Relapsing forms </li></ul></ul><ul><li>Mechanism of action is unknown </li></ul><ul><ul><li>Beta 2 microglobulin </li></ul></ul><ul><ul><li>Neopterin </li></ul></ul><ul><li>Dose and administration </li></ul><ul><ul><li>22 mcg or 44 mcg SC 3x /week </li></ul></ul>
  29. 40. DIFFERENCE BETWEEN AVONEX AND REBIF <ul><li>% Patients </li></ul><ul><li> Avonex Rebif </li></ul><ul><li>Relapse free (24 w) 63 75 </li></ul><ul><li>Relapse free (48 w) 52 62 </li></ul><ul><li>Injection site reactions 33 85 </li></ul>
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