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Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments. Aaron Boster M.D. Assistant Professor of Neurology Division of Immunology The Ohio State University. Objectives. 1. Learn to diagnosis MS

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Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments


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    1. Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments Aaron Boster M.D. Assistant Professor of Neurology Division of Immunology The Ohio State University

    2. Objectives • 1. Learn to diagnosis MS • 2. Learn to assess the risk of developing MS after a Clinically Isolated Syndrome • 3. Become more familiar with MS therapeutics and treatment algorithms

    3. Questions: • 1. When faced with a clinically isolated syndrome, which tests can help delineate the risk to develop MS?  • 2. True or False: Starting MS therapies early improves long term outcome. • 3. True or False: MS patients have high risk pregnancies.

    4. What Is MS? Trapp, 1998 An chronic inflammatory demyelinating disorder of the CNS of uncertain etiology, likely autoimmune, associated with destruction of myelin sheaths and axons

    5. MS Signs and Symptoms • Fatigue • Heat intolerance • Visual symptoms • Numbness, tingling, loss of sensation • Weakness • Imbalance • Urinary and sexual dysfunction • Cognitive deficits

    6. Epidemiology Peak age 15 to 45 Women : Men 2.5 : 1 Geographic variation USA prevalence 0.1% Approx ½ million MS patients in USA Life expectancy essentially normal Total lifetime cost > $2,200,000

    7. Natural History of Multiple Sclerosis Relapses and impairment cMRI activity (T2, T1+Gd) Axonal loss Measures of brain volume Secondary progressive Preclinical Relapsing-remitting Adapted from Goodkin DE. UCSF MS Curriculum. January 1999.

    8. Natural History of RRMS and PPMS 22 years from onset 5years 50% need a cane 50% bed bound 15% PPMS 85% RRMS 26 years from onset 50% SPMS and 50% need a cane 90% SPMS 11-15 years 30 years from onset 83% need cane ~ 34% bed bound Weinshenker, 1989

    9. Pathologically Radiographically CLINICALLY Rx Response Clinically IsolatedSyndrome Relapsing- Remitting Pre-Clinical Secondary Progressive INFLAMMATORY ACTIVITY Relapses Atrophy Active WML Poor Rx effect Rx effect No New WMLs PROGRESSION NEURODEGENERATION Time (Years)

    10. CASE 1 30yo Science Teacher

    11. CASE 1 30yo WF science teacher 1year ago, 3 week history of urinary urgency & frequency, one episode of fecal incontinence and bilateral foot numbness with frequent tripping 6 months ago, 2 week history of clumsy gait and poor balance, tremors of the right hand 1 month history of blurry vision with right gaze only

    12. CASE 1 EXAM Left intranuclear ophthalmoplegia Hyper-reflexia of the bilateral legs Bilateral upgoing toes (+ babinski) Absent vibration, poor proprioception in feet Mildly dysmetric finger-nose-finger and ataxic fine finger movements R>L + Romberg Ataxic gait

    13. CASE 1 • Does she have MS? • How do we diagnose MS?

    14. MS Diagnosis“Dissemination in space and time”

    15. Diagnostic Criteria • Dawson criteria: 1916 • Schumacher criteria: 1965 • Poser criteria: 1983 • McDonald criteria: 2001 • Revised McDonald criteria: 2005 • All criteria require dissemination in time and space

    16. Summarized Diagnostic Criteria August November 1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS 2. Dissemination in Time: Onset of neurological deficits separated by at least one month 3. Rule out other explanations!

    17. New Diagnostic Criteria DIS August November DIT • Incorporate use of MRI • Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis

    18. MRI - Dissemination in Space 3 of the following: • 9 T2 or 1 Gd+ • 3 Periventricular • 1 Infratentorial • 1 Juxtacortical lesion

    19. MRI - Dissemination in Time Gd Gd > 3 months T2 T2 > 1 month > 1 month CIS Polman, 2005

    20. DIAGNOSTIC WORK UP • History & Physical Exam • Brain and Spinal Cord MRI • Labs: rule out mimics of MS • Connective tissue diseases, infections, metabolic disorders • Cerebrospinal Fluid (when clinical and MRI evidence inconclusive) • Evoked Potentials: • Identify damage to visual, auditory, & touch perception systems • Less sensitive than MRI or cerebrospinal fluid

    21. CSF Analysis • • Most helpful for suggesting an alternative Dx • -high protein, marked pleocytosis, PMNs • Elevated IgG Index >0.7 • Increased CNS IgG synthesis, with normal serum IgG consistent with MS • Oligoclonal Bands • Presence of 2 distinct bands in CSF is consistent with MS

    22. CSF OCB are not specific to MS! • Lupus 25% • Sarcoidosis 51% • Behcet’s dz 8% Syphillis CJD Whipple’s disease Lyme disease Vaculitidies Devic’s disease Healthy siblings of MS patients adapted from a lecture by Peter Riskind MD PhD 11/19/05

    23. Metabolic: SCD (B12 def), Adrenomyeloneuropathy Connective Tissue Diseases: Sjogren’s, SLE Infectious: HIV, HTLV1, Lyme disease, Syphillis Structural: Chiari malformation, spinal cord compression Genetic: ataxias, paraplegias, mitochondrial Neoplastic: CNS lyphoma, paraneoplastic “MS variants”: ON, TM, ADEM, NMO Other: Neurosarcoidosis, CNS vasculitis Psychiatric Differential Diagnosis

    24. CASE 1 NEWLY DIAGNOSED RRMS • > 2 historical events with objective findings on examination • MRI consistent with MS • Normal “rule out labs” • CXR normal

    25. Disease Modifying Therapies: 1993-2002 Glatiramer Acetate (Copaxone®) 1997 IFN -1b (Betaseron®) 1993 IFN -1a (Rebif®) 2002 IFN -1a (Avonex®) 1996 Type PolypeptideRecombinant RecombinantRecombinant mixtureprotein proteinprotein Indication Reduce freq. Reduce freq. Reduce freq. Slow prog. of relapses of relapses of relapses in relapsing in RRMS Slow Delay forms disability in disability in Prevent 2nd relapsing forms relapsing forms attack in CIS Injection SC SCSC IM Administration Daily Every other day 3x/week Weekly Dosage 20 mg 250 g (8 MIU) 44 g 30 g

    26. Reduction in Relapse Rate: 2 year data from Phase III Studies 70 60 50 40 32 % Reduction vs Placebo 29 28 30 18 20 10 0 Copxone Avonex Betaseron Rebif

    27. Glatiramer Acetate Injection Site Reactions Idiopathic Injection Reactions Interferons Flu-like symptoms Liver dysfunction Bone marrow Endocrine abnormalities Other: Depression Spasticity Headaches DMT Side Effects

    28. Natalizumab • Humanized monoclonal Antibody against 41integrin • Selective adhesion-molecule inhibitor (SAM) • Prevents transendothelial migration of activated leukocytes from small venules into CNS

    29. “68% relative reduction in the annualized rate of relapse produced by natalizumab was maintained at two years (P<0.001)”

    30. Kleinschmidt-DeMasters, 2005

    31. Second Line Agents • When a patient has failed or is otherwise unable to tolerate IFN and GA • Tysabri • IVIG

    32. CASE 2 High School Football Star

    33. CASE 2 - 16yo AAM, High school Football star • History: Woke blind in left eye, complains of pain with extra occular movements • Exam: Va OD 20/20, OS 20/200. • Left disk pallor, Left Afferent pupillary defect. Optic Neuritis, a Clinical Isolated Syndrome

    34. CASE 2 • “Can I still play football?” “What is my son’s risk of developing Multiple Sclerosis?” “Yes” “We need an MRI and LP”

    35. CASE 2

    36. 415 CIS pts with MRI & CSF and 50 month follow-up +OBC doubled conversion risk to CDMS, independent of MRI findings

    37. Optic Neuritis, CIS • MRI Brain & C spine • CSF: IgGI, OCB, W,R,G,P • IVMP 1gm daily x 5 days WHAT ABOUT EARLY DMT?

    38. CHAMPS, ETOMS, BENEFIT, PRECISE STUDIES First ever attack Second attack placebo Avonex, Rebif, Betaseron, or Copaxone Time to Second Attack Delayed with Treatment

    39. CASE 3 26yo IRS agent

    40. CASE 3 • 26yo LH WF with RRMS diagnosed 2yrs ago • 3 day history of difficulty writing, clumsy and numb left hand • No signs/symptoms of infection • No prior history of similar symptoms

    41. CASE 3 ACUTE MS RELAPSE • IO & FE 4/5 on left hand • Hyper reflexia of left arm • Ataxic FFM & dysmetric FNF on left • Decreased LT on left face, arm, leg

    42. CASE 3 Expanded Disability Status Scale EDSS=0 last 3 visits

    43. CASE 3 Acute MS Relapse Expanded Disability Status Scale Current EDSS=3

    44. HOW TO IDENTIFY A RELAPSE? • CRITICAL,compare with previous examinations (history and examination), when ever possible • Relapses can be precipitated by infections and fever • Check U/A for occult UTI

    45. TREATMENT OF RELAPSE • INPATIENT • Severe deficits • Risk of fall or other injury • Poor social support • OUTPATIENT • All other relapses

    46. TREATMENT OF RELAPSE: • IV Solumedrol one gram daily for 5 days • Severe cases: up to 2 grams qd x 7d • Oral Prednisone for special circumstances • poor veins, insurance issues, travel, etc…

    47. TREATMENT OF RELAPSE: PLASMAPHERESIS • Severe relapses not responding to steroids • 5 to 7 courses done on alternate days for 2 weeks • One course takes place over 3 to 4 hours