Multiple sclerosis and newer concept in management till 2014 may


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Multiple sclerosis and newer concept in management till 2014 may

  3. 3. Multiple Sclerosis (MS) A chronic neurological disorder that affects the central nervous system, in which myelin is destroyed in the brain and spinal cord and causes scarring at multiple sites in the CNS.
  4. 4. • first described by French neurologist Jean- Martin Charcot in 1868. • Yet, after more than 140 years of research , much remains a mystery. • There is no known cause, and as yet, no cure.
  6. 6. • The exact cause remains unknown, but researchers believe that a combination of several factors may be involved-  Immunologic Reaction - MS is generally believed to be an autoimmune disease  Viral or other Infectious Agents - Some factor – probably infectious – must be encountered before the age of 15 in order for MS to develop later in life.
  7. 7.  Environmental Factors - MS occurs in geographic locations that are farther from the equator probably because of vitamin –D deficiency.  Genetic Factor - Family history is associated with risk of MS. It is strongly associated with MHC on ch 6, HLA DR B1-1501.
  9. 9. • When brain is inflammed –lymphocytes cross BBB. • If there is antigen cross reactivity –lymphocytes get activated and secrete cytokines- which cause inflammation and axon degeneration.
  10. 10. Extravasation astrocytes BRAIN TISSUE M Y E L I oligodendrocyte B cell Rolling Adhesion a4 Integrin VCAM B L O O D F L O W LUMEN OF VENULE B A S A L L A M I N A Circulation Activated T cell Proteases Antigen presenting cell (Astrocyte or Microglial cell) Activated microglia/macro phages T CELL REACTIVA TION Activated Macrophage Autoantibodies Complement IL-1, IL-12, chemokines Cytokines and chemokines Proteases TNF-a O2 •- NO• AXONAL DAMAGE MS DISEASE PATHOLOGY
  11. 11. Pathogenesis of Multiple Sclerosis Microscopic Pathology
  13. 13. > Predominant age: 20-40 MULTIPLE SCLEROSIS AFFECT: 0.1%Worldwide incidence PREVALENCE IS HIGH IN TEMPERATE ZONE(NORTH AMERICA AND EUROPE,AUST RALIA) The ratio is increasing now people in US have MS 400, 000 1–3% risk of MS among 1st-degree relatives worse prognosis
  15. 15. The most common initial symptoms •changes in sensation (33%) •Optic neuritis (20%) •Weakness(exercise induced) (13%) •double vision- internuclear opthalmoplegia (7%) •unsteadiness while walking (5%) •and balance problems (3%) Lhermitte's sign (25-40%) is an electrical sensation that runs down the back and into the limbs and is produced by bending the neck forwards. The sign suggests a lesion of the dorsal columns of the cervical cord or of the caudal medulla. Uhthoff's phenomenon is the worsening of neurologic symptoms in multiple sclerosis when the body gets overheated from hot weather, exercise, fever,
  16. 16.  Partially demyelinated axons have property to – 1. Discharge spontaneously, causes sensory symptoms like tingling, parasthesia. 2. Stimulated by mechanical stimulation like neck flexion causes electric shock like sensation (Lhermitte's symptom). 3. Stimulated by temp. change –visual blurring after hot shower or after exercise (Uhthoff's symptom). 4. Can stimulate adjacent normal neuron causes trigeminal neuralgia, hemifacial spasm.
  17. 17. HOW TO CLASSIFY ?
  18. 18. PRMS Progressive Relapsing MS SPMS Secondary Progressive MS PPMS Primary Progressive MS RRMS Relapsing/ Remitting MS CLASSIFICATION OF MULTIPLE SCLEROSIS Gradual progression of the disease from its onset with no relapses or remissions in 50% of the cases. More common in older patients above 40. Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission accounts for 85% of total cases. Initial RRMS that suddenly begins to decline without periods of remission and relapses. Steady decline since onset with super-imposed attacks.
  19. 19. HOW TO DIAGNOSE ?
  20. 20.  There is no definitive diagnostic test . We need certain investigation to support the clinical diagnosis – 1. MRI 2. CSF EXAMINATION 3. EVOKED POTENTIAL
  21. 21. • MRI has revolutionized the diagnosis and management of MS. • Lesion mainly involve ---- a) Periventricular b) ant. Portion of corpus callosum c) juxtra cortical d) infratentorial (brainstem ,cerebellum ,spinal cord) MRI
  22. 22. DAWSON'S FINGERS APPEARING ON AN MRI SCAN The condition is thought to be the result of inflammation around long axis of medular veins.
  23. 23. CSF EXAMINATION  Intrathecal synthesis of IgG detected as oligoclonal band.  95% accurate when combined with MRI.
  24. 24.  EP testing assesses function in afferent (visual, auditory, and somatosensory) or efferent (motor) CNS pathways.  These tests provide the most information when the pathways studied are clinically uninvolved.  Abnormalities occur in 80–90% of MS patients. EVOKED POTENTIALS
  25. 25. 1. If history of two clinical attacks are present. 2. If history of only one attack is present. 3. If disease is continously progressive. MCDONALD’S DIAGNOSTIC CRITERIA
  26. 26. Associated with one objective lesion, then you need positive CSF oligoclonal banding and MRI lesion to diagnose MS.  If CSF is negative for OCB then one gd –enhancing lesion and another gd-enhansing lesion after 3 month on different location is needed for the diagnosis. DIAGNOSTIC CRITERIA IF SINGLE ATTACK IS PRESENT
  27. 27.  Most difficult to suspect MS in this kind of patient because of no history of relapse and recur.  For diagnosis – a) 1 year progression with b) two of the following –  >9 T2 lesion or >4 T2 lesion with abnormal visual evoked potentials.  >2 spinal cord lesion.  Oligoclonal banding in CSF. DIAGNOSTIC CRITERIA FOR PRIMARY PROGRESSIVE MS
  28. 28.  The possibility of an alternative diagnosis should always be considered , particularly when – a) Symptoms are localized exclusively to the posterior fossa, or spinal cord. b) The patient is aged <15 or >60 years; c) The clinical course is progressive from onset; d) The patient has never experienced visual, sensory, or bladder symptoms ; e) Laboratory findings (e.g., MRI, CSF, or EPs) are atypical. DIFFERENTIAL DIAGNOSIS
  29. 29. 1) ADEM(acute disseminated encephalomyelitis) 2) APLAS , Behcet’s disease, Sjogren, SLE, Sarcoidosis 3) Syphilis 4) Vit. B 12 def. 5) Congenital leucodystrophies 6) HIV , neoplasms DISORDERS THAT CAN MIMIC MS (CAN INVOLVE MULTIPLE LOCATION IN BRAIN)
  30. 30. • Early age of onset. • Female sex. • Optic neuritis as presenting episode. • Sensory symptoms as presenting episode. • Acute onset. • Little residual disabilty. • Long inter exacerbation period. • Small lesion load. FAVORABLE INDICATORS:
  31. 31.  Patients with first attack with a normal brain MRI, the likelihood of developing MS is <20%.  With three or more typical T2-weighted lesions, the risk of developing MS after 20 years is 80%. PROGNOSIS
  32. 32.  Therapy for MS can be divided into several categories: 1) Treatment of acute attacks. 2) Treatment with disease-modifying agents that reduce the biological activity of MS. 3) Symptomatic therapy. TREATMENT
  33. 33.  I/V Methylprednisolone 1 gm/d for 3 to 5 days.  Fulminant attacks -- unresponsive to glucocorticoids.  Treatment is Plasma exchange. ACUTE ATTACKS
  34. 34. Treatment options for MS have changed dramatically since 1993, when the first disease-modifying drug, Betaseron®, became commercially available.  These drugs are not a cure .  However, they can alter the course by decreasing the number and severity of relapses by slowing the progression . TREATMENT WITH DISEASE- MODIFYING AGENTS
  35. 35. 10 such agents are approved by the US (FDA) till april 2014, 1) IFN--1a (Avonex) 2) IFN--1a (Rebif) 3) IFN--1b (Betaseron) 4) glatiramer acetate (Copaxone) 5) natalizumab (Tysabri) 6) fingolimod (Gilenya) 7) mitoxantrone (Novantrone) 8) dimethyl fumurate (Tecfidera ) 9) teriflunomide( Aubagio ) 10) interferon beta-1b kit(Lyophilized EXTAVIA) DISEASE-MODIFYING THERAPIES
  36. 36. • Avonex, • Betaseron • Extavia, • Copaxone • Rebif FIRST-LINE THERAPIES
  37. 37. Therapy with a disease-modifying drug should be initiated as early in the disease course as possible.  Treatment should be continued indefinitely except in the case of clear lack of benefit, intolerable side effects. TREATMENT GUIDELINES:
  38. 38.  Avonex, Betaseron, Extavia, and Rebif are all interferon beta products.  The interferon drugs seal off blood brain barrier and inhibit T cells from being activated.
  39. 39. Beta Interferon  Avonex – 30 ug, I/M weekly  Rebif –44 ug S/C three times per week  Betaseron – 250 ug S/C every other day
  40. 40. Common Side Effects…  Typical Flu-like symptoms  headache, nausea, and fever  muscle aches Chills Irritation at the injection site Alcohol and exposure to sunlight may irritate side effects
  41. 41.  The glatiramer molecule resembles myelin basic protein.  T cells produced in response to glatiramer can suppress the immune attack on myelin.  S/E - • lipoatrophy at injection site • dilation of blood vessels, chest pain,  Previously it was given 20 mg daily S/C. But in 2014 FDA approve 3 times /week of 40mg/ml dose. GLATIRAMER ACETATE(COPAXONE)
  42. 42. Natalizumab (Tysabri) is a monoclonal antibody directed against the integrin, a cellular adhesion molecule expressed on the surface of lymphocytes. It is most effective. Only problem with it is its fatal side effect – progressive multifocal leucoencephalopathy(PML) Because of PML, natalizumab is currently recommended only for patients who have failed other therapies or who have particularly aggressive disease presentations. Natalizumab (300ug) is administered by IV infusion each month. NATALIZUMAB (TYSABRI)
  43. 43.  2010 - The first oral drug Fingolimod.  2012 – Teriflonamide  2013 - Dimethyl fumerate FDA APPROVED ORAL DRUG
  44. 44. Fingolimod is a sphingosine1-phosphate receptor modulator that sequesters lymphocytes  orally 0.5 mg od  The first dose of Fingolimod is given in a monitored setting, because of first-dose side effects- bradycardia and heart block. GILENYA (FINGOLIMOD)
  45. 45. Teriflunomide is a pyrimidine synthesis inhibitor that inhibits the function of specific immune cells. Teriflunomide (7 mg or 14 mg) OD AUBAGIO (TERIFLUNOMIDE)
  46. 46.  Dimethyl fumurate, an immunosuppressant, is thought to have anti-inflammatory and cytoprotective properties.  The starting dose of Tecfidera is 120 mg twice daily for seven days, then 240 mg twice daily thereafter.  Dimethyl fumerate, is expected by many investors to become the top-selling product for the treatment of multiple sclerosis. TECFIDERA (DIMETHYL FUMURATE),
  47. 47.  12mg/m2 of Novantrone by short IV infusion once every three months for 24 months.  Approval by the U.S. (FDA) for Patients with a) Secondary progressive MS b) Progressive-relapsing MS c) Worsening relapsing-remitting MS  mitoxantrone should not be used as a first-line agent.  Use mitoxantrone when other approved therapies have failed because it is responsible for heart faliure and low EF, acute leukemia. MITOXANTRONE
  48. 48.  2011 — The US (FDA) says it won't approve oral cladribine for multiple sclerosis (MS) without more safety information.  Cladribine was recently approved in Russia and Australia but received a negative opinion from European regulators. CLADRIBINE
  49. 49.  Monoclonal cd 52 antibody  Company could not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects. FDA DECLINES APPROVAL FOR ALEMTUZUMAB (LEMTRADA)
  51. 51.  Jan 2014-  Some preliminary data has indicted that Vitamin A may help alleviate symptoms of multiple sclerosis, and more research is on the way.  Antioxidant Shows Promise in Fight Against MS.  A vaccine used to prevent tuberculosis in other parts of the world may help prevent multiple sclerosis.  Vitamin D appears to block damage-causing immune cells from migrating to the central nervous system. Study Suggests Obesity Increases Risk of MS in Girls. FDA Approves Unique Stem Cell Therapy Trial in MS Patients in 2013
  52. 52. THANK YOU