Multiple Sclerosis

Multiple Sclerosis PowerPoint PPT Presentation

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Learning Points . MS is a major disease affecting young womenIt is treatableMS is an immune- mediated disorder involving genes and environmental exposuresIt takes either a relapsing (disease attacks) or progressive (slow worsening) course. Case 1 . 18 year old freshman presents with one day of right eye pain and vision lossOn exam VA 20/100, 20/20; red color loss right eye with central scotoma; right afferent pupil defectBrain MRI.

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Multiple Sclerosis

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2. Learning Points MS is a major disease affecting young women It is treatable MS is an immune- mediated disorder involving genes and environmental exposures It takes either a relapsing (disease attacks) or progressive (slow worsening) course

3. Case 1 18 year old freshman presents with one day of right eye pain and vision loss On exam VA 20/100, 20/20; red color loss right eye with central scotoma; right afferent pupil defect Brain MRI

5. Optic Neuritis Clinically isolated syndrome (CIS) 70% have relapsing MS Mandatory evaluation May be offered MS therapy (first attack high risk MS)

6. Case 2 45 year old man with one year history of slowly worsening gait becomes much weaker in hot/ humid weather Exam shows mild paraparesis, bilateral extensor plantar responses, vibration felt to 5 seconds in toes

7. Primary Progressive MS Unusual clinical subtype (10-15%) Slow worsening from onset without relapses Male to female ratio 1:1 Older age at onset (late 30s, early 40s)

8. Case 3 54 year old woman with 18 year h/o MS Uses cane or walker to get around tends to trip over her toes frequent falls Appears apathetic and sad overwhelming fatigue in the afternoons

9. Case 3 Rarely leaves the house because of bladder accidents Complaining of painfully spasms at night with poor sleep; during the day her right leg will suddenly stiffen painfully for < 1 minute; this limits her mobility

10. Case 3 Moderate/ severe disability Multiple symptoms poorly managed if at all ambulation / foot drop depression fatigue neurogenic bladder spasticity pain

11. Case 3 Poor sleep hygiene, social isolation, fall risk, unsafe environment

12. MS Major acquired neurologic disease of young adults Confined to CNS Characterized by suggestive features

13. MS Female predominance (70-75%) Young age at onset (peak early 20s, average 28 to 30 yrs, 90% between ages 15 and 50) under age 10 < 1% pediatric MS (? 16 yrs 3-5%) over age 60 < 1%

14. MS Variable course and severity Caucasian predominance (but now increasing in other populations) Significant morbidity for untreated disease

15. MS Outcome Life span mildly shortened; mortality reflects 2º complications in severely disabled patients brainstem involvement suicide 90% to 95% of untreated patients become disabled ambulation vocational cognitive

16. MS Subtypes Asymptomatic Symptomatic relapsing benign progressive primary progressive progressive relapsing secondary progressive

17. Etiology Update Genetic factors increasing identification of susceptibility/risk, protection, disease- severity genes Environmental factors vitamin D deficiency EBV exposure tobacco use Host-derived damage factors

18. MS Epidemiology Low, medium, high risk zones Latitude: little MS at the equator, increases north and south Clusters and epidemic(s) Migration studies 400,000 affected in the United States; up to 2.5 million worldwide MS cases are increasing, as natural infections are decreasing

19. MS Genetics Only 20% of MS patients have + FH No single gene Risk of MS in Caucasian population 0.2% Risk with first degree relative 2-5% Risk with identical twin at least 25% (much higher for females then males)

20. MS in French West Indies* Study of MS in Martinique, Guadeloupe very low rate(14.8 per 100,000) vs. 57-180 per 100,000 in US Evaluated natives who emigrated to France in 1950s and 1960s, then returned *Brain 2005; 128: 2899

21. MS in French West Indies* MS prevalence 2 fold higher in those who returned from France vs. non migrants esp those in France before age 15 Conclusions: environmental factor plays a role in MS ? loss of protective effect of intestinal parasites (? from 70% to 8% in children aged 5-15) *Brain 2005; 128: 2899

22. MS And Infections MS associated with childhood infections at a later age Infections can trigger MS relapses Infection with Epstein Barr virus may be required to develop MS Is MS an infection? chlamydia pneumoniae human herpes virus type 6 Do infections trigger an immune attack against the CNS?

23. EBV and MS 100% of adult MS patients are EBV seropositive (80% of pediatric MS) EBV infectious mononucleosis in adolescents and young adults is risk factor for MS (13x)

24. EBV and MS In stored blood samples from military personal, IgG to EBNA or EBNA-1 was strongest predictor of MS after age 20 ? 2 to 3 fold in those destined to develop MS (up to 5 years before onset)

25. EBV and MS Potential mechanisms EBV activation of myelin cross-reactive T cells infection of autoreactive B cells superantigen activation ? ?? crystallin expression two EBV peptides (one from EBNA-1) identified as CSF immune response targets EBV related to autoimmune disease such as SLE

26. Host-Derived Damage Factors Myelin reactive T cells do not explain MS Evidence for diverse damage mechanisms activated microglia, oligodendrocytes astrocytes, endothelia cells (B cells, CD8+ T cells, CD4+ T cells/Th17 cells/T Meg cells, NK cells, M?, dendritic cells) Nitric oxide, glutamate, cytokines/ chemokines

27. Host-Derived Damage Factors Myelin reactive T cells do not explain MS Evidence for diverse damage mechanisms activated microglia, oligodendrocytes astrocytes, endothelia Cells (B cells, CD8+ T cells, CD4+ T cells/ Th17 cells, Treg cells, NK cells, M?, dendritic cells) Nitric oxide, glutamate, cytokines/ chemokines

29. MS And The Immune System Unknown whether in situ CNS (oligo) process initiates inflammation The host immune system does attack the CNS; blood immune cells (inflammation) move into the CNS in increased numbers

30. MS And The Immune System Local immune reactions then damage tissue These damaged areas (plaques) disrupt nerve conduction Plaques occur all the time, in waves

31. MS Pathophysiology Ongoing macroscopic and microscopic damage Disruption of neuronal circuitry, nerve conduction Eloquent disruptions result in clinical attacks Pathologic changes

32. MS Pathology Both inflammatory and neurodegenerative components Macroscopic plaques inflammation demyelination axonal damage gliosis variable cell (oligodendrocyte, neuron) loss remyelination

33. MS Pathology Microscopic/ molecular changes normal appearing white matter, brain tissue abnormalities blood vessel injury ion channel changes receptor changes

34. Diagnosis Of MS Clinical criteria appropriate age CNS white matter disease lesions disseminated in space and time objective abnormalities relapsing or progressive course no better diagnosis

35. MS Clinical Syndromes Relapsing MS Unilateral optic neuritis (with pain) Incomplete transverse myelitis Brainstem syndrome internuclear ophthalmoplegia trigeminal neuralgia diplopia Cerebellar syndrome Multifocal white matter disease Paroxysmal attacks Progressive MS Myelopathy

36. Diagnosis Of MS Blood studies to rule out other diagnoses, co-diagnoses Cerebrospinal fluid studies document supportive immune disturbances (oligoclonal bands, intrathecal IgG production) document that there is no evidence for another diagnosis (WBCs > 50, ? protein > 100, + cytology) Magnetic resonance imaging (MRI)

37. MRI Most valuable diagnostic test Best laboratory marker of disease activity Prognostic value (particular at first attack, early years) Evaluates response to therapy therapeutic trials clinical practice

38. Images of an RRMS Patient

40. MRI in MS Brain MRI abnormal in 98% + limited value over age 50 Spinal cord MRI abnormal in 80% + asymptomatic lesions suggest MS minority of patients show only cord lesions (PP, milder RR) indicated for spinal cord presentation, nonsupportive brain MRI, age > 50 Minimal correlation between cervical cord and brain lesions

41. Brain MRI Features Suggestive of MS Multiple T2/ FLAIR, predominantly white matter lesions > 3mm diameter Ovoid shape Perpendicular to ventricles (Dawson’s finger)

42. Brain MRI Features Suggestive of MS Brainstem/ infratentorial lesions Juxtacortical lesions Corpus callosum lesions (sagittal T2, pointing away, moth eaten changes, atrophy) Enhancing lesions open ring enhancement

43. MRI: Novel Disease Insights MS is an active, ongoing disease process even when a patient appears clinically stable 80% to 90% of new brain MRI lesions are silent brain lesion burden ? by 5%-10% each year CNS atrophy ? each year at a rate 3 to 10x greater than controls

44. MRI: Novel Disease Insights MRI research techniques indicate normal appearing brain shows widespread abnormalities changes appear long before new lesion obvious MRI is suggesting importance of new targets axon blood vessel

45. Acute Relapse Treatments First line glucocorticoids Second line plasma exchange IVIG

46. Glucocorticoids Steroids are accepted treatment for acute relapse can speed up recovery ultimately believed not to affect degree of recovery considered symptomatic therapy (not DMT)

47. Glucocorticoids Most common regimen involves methylprednisolone one gram IV once daily for 3 to 5 days oral taper now uncommon probable that high dose oral steroids work just as well (1000-1250 mg prednisone; formulated capsules of methylprednisolone or dexamethasone)

48. Glucocorticoids Steroids have anti-inflammatory, immunosuppressive properties probably best used early Unclear if continued use ? response Unclear if pulse steroids do have DMT activity

49. MS DMT Immunomodulators Interferon (IFN?) IFN?1b 250 mcg (8MIU) SC QOD IFN?1a 30 mcg IM weekly 44 mcg SC 3x weekly Glatiramer acetate 20 mg SC QD

50. MS DMT Natalizumab 300 mg IV monthly Fingolimod 0.5 mg po daily

51. MS DMT Immunosuppressants Mitoxantrone 12 mg/m2 IV Q3mos (to lifetime maximum of 140 mg/m2)

52. MS DMT IFN? Anti-inflammatory, regulatory cytokine ? MMPs, adhesion molecule expression, cell trafficking ? Suppressor regulatory cells ? T cell activation Antiviral activity

53. MS DMT GA ? Regulatory T cells TH1 ?TH2 cytokine profile ? Myelin reactive cells

54. MS DMT Natalizumab Blocks ?4 integrin adhesion molecule, ? cell trafficking Binds to fibronectin, osteopontin Mitoxantrone Anthracenedione Intercalates into DNA, blocks repair enzyme

55. MS DMT Fingolimod Sphingosine 1 phosphate (SIP)-1 receptor modulator Blocks lymphocyte egress from lymph nodes; also enters CNS directly

56. Future Directions Biomarkers for diagnosis, disease activity, response to therapy Novel Therapies oral agents monoclonals new approaches (vaccines, transplant, new agents) combination/ induction strategies CNS repair

57. CNS Repair Strategies Cell transplantation stem cells and others Neurotrophic factors Immune modulation - remyelinating autoantibodies

58. CNS Repair Strategies Nogo gene blockade (synthetic peptide) Removal of the glial scar Gene transfer Neuroprotective agents

59. Multiple Sclerosis Summary MS is the major acquired neurologic disorder of young adults Recent studies have provided new insights on disease pathogenesis, heterogeneity, targets, therapy

60. Multiple Sclerosis Summary The last decade has seen an untreatable and disabling disease become treatable and (hopefully) mild Future studies will lead to a better understanding of MS, improved therapy, and ultimately a cure

61. Other Disorders of Demyelination

62. Neuromyelitis Optica (NMO) – Devic Disease Necrotizing inflammatory demyelinating disorder that targets spinal cord and optic nerves Distinct from MS (pathology, MRI, CSF)

63. NMO – Devic Disease Humoral immune attack against blood–brain barrier antigen anti-aquaporin-4 IgG (47-91% sensitivity, 85-100% specificity) aquaporin-4 (composed of 4 subunits) is predominant water channel in astrocytic foot processes at BBB May have CNS involvement outside optic nerve and spinal cord

64. NMO – Devic Disease* Rarely a causal disease identified autoimmune collagen vascular disease (SLE, Sjogren, MCTD, p-ANCA, antiphospholipid syndrome) infection (TB, HIV, VZV, EBV) associated endocrinopathies/familial cases neurosarcoidosis MS (10%) idiopathic NMO Devic Disease

65. NMO – Devic Disease: Clinical Features* Relapsing attacks in 80% (4:1, F:M ratio) Monophasic in 20% (1:1, F:M ratio) Outcome often poor (can see respiratory failure, ventilator dependency) *Neurology 1999; 53:1107

66. NMO – Devic Disease: Clinical Features Onset over age 35 (61%) Racial predilection for non-Caucasians (38.5%) No phase 3 treatment trials response to glucocorticoids, azathioprine/mycophenolate, plasma exchange, IVIG, mitoxantrone, rituximab*, cyclophosphamide

67. NMO Diagnostic Criteria* Optic neuritis Acute myelitis At least two of three supportive criteria contiguous spinal cord MRI lesion ?3 vertebral segments brain MRI does not meet MS diagnostic criteria NMO IgG seropositivity *Neurology 2006; 66:1485

68. NMO – Devic Disease: Pathology Extensive demyelination (+cavitation, necrosis, axon spheroids in white and gray matter) marked loss of oligos; no apoptosis inflammation involved ?? M?, ? perivascular granulocytes/ eosinophils, rare CD3+/ CD8+ T cells

69. NMO – Devic Disease: Pathology Perivascular Ig deposition (IgM), complement (C9 neoantigen) in active lesions in perivascular rosette, rim pattern Prominent vascular fibrosis, hyalinizations in all lesions (but distinct from necrotizing vasculitis)

70. Postinfectious Encephalitis/ Encephalomyelitis (ADEM) CNS inflammatory and demyelinating pediatric disorder predominantly children, young adults rare in very young (ages 2–3 y) and in elderly no strong sex preference (? slight male predominance) Reflects indirect immune-mediated syndrome

71. ADEM Not a sequelae of direct organ infection May account for 20% of acute encephalitis cases onset over days (occasionally weeks) Prototypic syndrome: diffuse encephalopathy with superimposed multifocal involvement

72. ADEM Antecedent prodromal event in ?70% (occasionally follows or occurs during neurologic illness) infection occasionally immunization (<10%) rarely other events

73. ADEM Acute/ subacute onset Multifocal involvement One or more encephalopathy features behavioral changes (irritability, lethargy) altered consciousness (somnolence, coma) seizures Includes any new symptoms within 3 month period

74. ADEM Occasionally repeated (recurrent or multiphasic/new) attacks (10% to 20%): up to 4 relapses within 32 mos Excellent prognosis (except hemorrhagic variant) Brain MRI has multifocal or monofocal lesions gray as well as white matter, often one or more large lesions (?1-2 cm)

75. How to tell Multiphasic ADEM and MS apart? ADEM can recur several times, months/years later with same (recurrent) or new (multiphasic) symptoms particularly following steroid taper ADEM by definition is associated with a change in mental status; this is rare in MS Over time MRI lesions resolve in ADEM; in MS they increase in number gray matter involved in ADEM not MS Oligoclonal bands more commonly positive in MS vs. ADEM

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