Practical issues in MULTIPLE SCLEROSIS
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MULTIPLE SCLEROSIS PATHOGENESIS BIOMARKERS TREATMENT DIAGNOSIS PROGNOSIS TREATNMENT OPTIMIZATION
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Practical issues in MULTIPLE SCLEROSIS
- 1. Amr Hassan, M.D. Associate professor of Neurology - Cairo University 2016 Practical Issues in Multiple Sclerosis
- 2. AGENDA • Immunopathogenesis • Diagnosis • Biomarkers • Treatment options • Optimization of treatment 2
- 6. 6 Peripheral Immune System 1) Engagement of T cell receptor by crossreactive microbial antigen CD282) B7 3) IL-12 THP auto- reactiv e TH1 auto- reactive VLA-4 VCAM TH1 auto- reactive TH1 auto- reactive Inflammed Tissue Immunopathogenesis of M.S.
- 7. 7
- 8. Immunopathogenesis of M.S. 8 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 9. Immunopathogenesis of M.S. 9 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 10. 10 Tissue Damage IL-2 IFN- TNF- CD154 CD40 IL-12 tissue APC autoantigens CD28 B7 TH1 auto- reactive Peripheral Immune System 1) Engagement of T cell receptor by crossreactive microbial antigen CD282) B7 3) IL-12 TH P auto-reactive Immunopathogenesis of M.S.
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- 12. Immunopathogenesis of M.S. 12 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 13. Immunopathogenesis of M.S. 13 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 14. 14
- 17. 17 More Than a Demyelinating Disease
- 18. 18
- 19. Helper T-Cell Differentiation IL-12/STAT4 IFN- Pro-inflammatoryTH1 TH2 IL-4 IL-5 IL-10 IL-13 Anti-inflammatory/ Allergy IL-4/STAT6 IL-23 IL-17 Pro-inflammatoryTH17IL-6 + TGF-β TGF-β Regulatory Treg TGF-β Graphic courtesy of Dr. Scott Zamvil.
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- 21. Immunopathogenesis of M.S. 21 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 22. 22 More Than a Demyelinating Disease Time (Years) DiseaseParameter INFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY NEURODEGENERATIONNEURODEGENERATION PROGRESSIONPROGRESSION RelapsesRelapses cMRIcMRI WMLsWMLs FLAIRFLAIR T1 Gd+T1 Gd+ FLAIRFLAIR Rx effectRx effect Poor Rx effectPoor Rx effect No NewNo New WMLsWMLs
- 23. 23 Inflammation and Neurodegeneration in MS Diseas e Stage Dominant Component Main Clinical Outcome MRI Early INFLAMMATION Edema Demyelination (axonal loss, brain atrophy) Relapses Gd enhancement Late NEURODEGENERATION Severe axonal injury Permanent tissue loss Disability Black Holes Gd enhancement Brain Atrophy Filippi et al., EJN 2001, 8:291-297
- 24. 24
- 25. 25
- 27. 27 Mechanism of action of DMD (Fingolimod)
- 28. 28 Mechanism of action of DMD (Fingolimod)
- 29. 29 Diagnosis
- 30. Multiple Sclerosis Diagnosis 30 • Diagnosis relies on clinical judgment. • MS is extremely variable. • There is no specific test. • The diagnosis has dramatic implications.
- 31. Multiple Sclerosis Diagnosis 31 Diagnosis of MS includes To prove it is M.S To exclude other diagnoses
- 32. How to diagnose MS? 32 Clinical: • History and examination. • Evidence of CNS involvement. • Dissemination in space and time. Paraclinical: • Neuroimaging. • Evoked potentials. • CSF analysis.
- 33. Diagnostic Criteria • Dawson criteria: 1916 • Schumacher criteria: 1965 • Poser criteria: 1983 • McDonald criteria: 2001 • McDonald criteria: 2005 • McDonald criteria: 2010 All criteria require dissemination in time and space
- 34. Summarized Diagnostic Criteria 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! 2010 2014
- 35. Diagnostic Criteria 2005 • Incorporate use of MRI • Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis August DIS DIT November
- 36. New Diagnostic Criteria 2010 • Incorporate use of MRI • Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis August DIS DIT August
- 38. Magnetic resonance imaging T1 weighted Pre & Post Contrast 38
- 39. 39
- 40. 40
- 41. Magnetic resonance imaging T2 weighted images showing plaques 41
- 42. 42
- 44. 44
- 45. INVESTIGATIONS
- 46. CSF examination 46 IgG index: • [IgGCSF/albuminCSF]/[IgGserum/albuminserum] MS patients elevated IgG index (>1.7). (normal is <0.77)
- 47. 47 Oligoclonal Bands in CSF
- 48. Mental map for diagnosis of MS 48 Clinical/Paraclinical/Imaging Typical for MS Fulfills Criteria Atypical for MS Red Flags Present Work Up for Alternative Diagnoses Clinical/Imaging Follow Up Alternative Diagnosis Established Further clinical/imaging typical for MS MS Diagnosis Typical for MS not Fulfilling Criteria Clinical/Imaging Follow Up
- 49. PRESENTING SYMPTOMS IN MS Total % SENSORY LOSS IN LIMBS 30.7 VISUAL LOSS 15.9 MOTOR WEAKNESS 14.2 DIPLOPIA 6.8 GAIT DISTURBANCE 4.8 INCOORDINATION 2.9 SENSORY LOSS-FACE 2.8 LHERMITTE’S 1.8 VERTIGO 1.7 BLADDER SYMPTOMS 1 AUTE TRANSVERSE MYELOPATHY 0.7 PAIN 0.5 OTHERS 2.5 POLYSYMPTOMATIC 13.7
- 50. The Red Flags 50
- 51. Red flags 51 • Major red flags point fairly definitively to a non-MS diagnosis • Intermediate red flags point to poor agreement and uncertainty among raters about the weighting of the flag for differential diagnosis in MS • Minor red flags suggest that a disease other than MS should be considered and fully explored, but an MS diagnosis is not excluded.
- 52. Outline The Red Flags 52 • Clinical • Lab • Imaging
- 53. Outline The Red Flags 53 • Clinical • Lab • Imaging
- 55. Clinical Red Flags (Major) 55 Bone lesions Lung involvement Multiple cranial neuropathies or polyradiculopathy Peripheral neuropathy Tendon xanthomas Cardiac disease Myopathy Renal involvement Extrapyramidal features Livedo reticularis Retinopathy Diabetes insipidus Increase serum lactate level Hematological manifestations Mucosal ulcers Myorhythmia Hypothalamic disturbance Recurrent spontaneous abortion or thrombotic events Rash Arthritis, polyarthalgias, myalgias Amyotrophy Headache or meningismus Persistently monofocal manifestations
- 56. Clinical Red Flags (Intermediate) 56 Sicca syndrome Gastrointestinal symptoms Loss of hearing Fulminant course Increase serum ACE level Prominent family history Constitutional symptoms Progressive ataxia alone Neuropsychiatric syndrome Seizure Uveitis Pyramidal motor involvement alone Gradually progressive course from onset
- 57. Clinical Red Flags (Minor) 57 Brainstem syndrome Myelopathy alone Onset before age 20 Abrupt onset Onset after age 50
- 58. 58 Clinical Red Flags • Optic neuritis: Absence of pain, retinal exudates or hemorrhages, severe disc swelling, bilateral involvement, no visual recovery after 1 month, uveitis. • Brainstem syndrome: Hyperacute onset, vascular territory distribution (e.g. lateral medullary syndrome), age >50 years, isolated trigeminal neuralgia, fluctuating ocular/bulbar weakness, non-remitting symptoms, fever, meningismus, complete external ophthalmoplegia, third nerve palsy, focal dystonia or torticollis. • Marked LMN signs: Areflexia, proximal weakness, bilateral LMN facial palsy, cauda equina lesion. • Spinal cord syndrome: Hyperacute onset or insidiously progressive, complete transverse myelitis, sharp sensory level, Radicular pain, failure to remit, anterior spinal artery distribution (sparing posterior columns only), complete Brown-Sequard syndrome. • Cerebral hemisphere: obtundation, confusion, cortical blindness, dementia, aphasia, Clinical Red Flags
- 59. Outline The Red Flags 59 • Clinical • Lab • Imaging
- 60. Outline The Red Flags 60 • Clinical • Lab • Imaging
- 62. Laboratory Red Flags 62 • CBC: Marked cell count abnormality • High ESR • +ve ANA • Elevated lactate
- 63. Laboratory Red Flags CSF 63 • Cell count: >50 White blood cells • Cell differential: Neutrophilic predominance • Protein: Significant elevation(>100 mg/dl) • Glucose: Low glucose(<2/3 serum glucose)
- 64. Outline The Red Flags 64 • Clinical • Lab • Imaging
- 65. Outline The Red Flags 65 • Clinical • Lab • Imaging
- 67. 67 “The most common reason for falsely attributing a patient’s symptoms to multiple sclerosis is faulty interpretation of the magnetic resonance imaging.” Famous Dictum Loren A. Rolak 2007
- 68. 68
- 69. 69
- 71. D.D. OF M.S. IN MRI 71 1. Age-related changes 2. Acute disseminated encephalomyelitis 3. CNS vasculitis 4. Behçet disease 5. Sjögren syndrome 6. Sarcoidosis 7. Metastatic neoplasm 8. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) 9. Binswanger disease 10. Migrainous ischemia
- 72. D.D. OF M.S. IN MRI 72 11. Cerebrovascular disease 12. Progressive multifocal leukoencephalopathy 13. Inherited white matter diseases 14. Effects of radiation therapy or drugs 15. CNS lymphoma 16. Lyme disease 17. HTLV-1 infection 18. CNS lupus 19. Mitochondrial encephalopathies 20. Antiphospholipid antibody syndrome
- 73. MRI Red Flags (Major) 73 Cerebral venous sinus thrombosis Cortical infarcts Hemorrhages/microhe morrhages Meningeal enhancement Calcifications on CT scans Selective involvement of the anterior temporal and inferior frontal lobe Lacunar infarcts Persistent Gd- enhancement and continued enlargement of lesions Simultaneous enhancement of all lesions T2-hyperintensity in the dentate nuclei T1-hyperintensity of the pulvinar Large and infiltrating brainstem lesions Predominance of lesions at the cortical/subcortical junction
- 74. MRI Red Flags (Intermediate) 74 Hydrocephalus Punctiform parenchymal enhancement T2-hyperintensities of U-fibers at the vertex, external capsule and insular regions Regional atrophy of the brainstem Diffuse lactate increase on brain MRS Marked hippocampal and amygdala atrophy Symmetrically distributed lesions T2-hyperintensities of the basal ganglia, thalamus and hypothalamus Predominant brainstem and cerebellar lesions Lesions in the center of CC, sparing the periphery Diffuse abnormalities in the posterior columns of the cord
- 75. MRI Red Flags (Intermediate) 75 Lesions across GM/WM boundaries T2-hyperintensities of the temporal pole Complete ring enhancement Central brainstem lesions Dilation of the Virchow-Robin spaces Cortical/subcortical lesions crossing vascular territories Large lesions with absent or rare mass effect and enhancement No “occult” changes in the NAWM No enhancement No optic nerve lesions No spinal cord lesions Large lesions No T1 hypointense lesions (black holes) Marked asymmetry of WM lesions
- 76. Mental map for diagnosis of MS 76 Clinical/Paraclinical/Imaging Typical for MS Fulfills Criteria Atypical for MS Red Flags Present Work Up for Alternative Diagnoses Clinical/Imaging Follow Up Alternative Diagnosis Established Further clinical/imaging typical for MS MS Diagnosis Typical for MS not Fulfilling Criteria Clinical/Imaging Follow Up
- 78. HETEROGENEITY Pathological subtypes Clinical presentation Rates of progression Resonse to DMT 78
- 79. Timing of the therapy key to preventing disability Time (Years) Relapsing Remitting Multiple sclerosis Transitional Secondary Progressive MSCISPre- Clinical Demyelination Remission State of no disease activity, the period during which diminution of symptoms occurs due to the cessation of inflammatory processes and some degree of reparative remyelination of affected axons Relapses Acute Inflammation Demyelination First Clinical Attack Axonal loss Inflammation Brain Volume MRI Activity Disability progression Reflects reactive astrogliosis, Axonal Loss and Brain volume loss. Starts Reversible (remyelination) and ends in permanent disability Time window for early treatment Mark S. Freedman: Induction vs. escalation of therapy for relapsing Multiple Sclerosis: the evidence, Neurol Sci (2008) 29:S250–S252
- 80. 80 A Biomarkers for Multiple Sclerosis:WHY ? BIOMARKERS
- 81. 81 Biomarkers
- 82. 82 GENETIC/IMMUNOGENETIC: • Biomarkers specified via genomics and immunogenetic techniques. LABORATORY: • All other biomarkers that can be measured in body fluids. IMAGING: • Biomarkers provided by imaging techniques. BIOMARKERS
- 83. 83 A. GENETIC AND IMMUNOGENETIC BIOMARKERS BIOMARKERS HLA TOB-1 Apo lipoprotein-E
- 85. 85 I. Biomarkers of Immunological Activation II. Biomarkers of Neuroprotection III. Biomarkers of BBB disruption IV. Biomarkers of demyelination V. Biomarkers of Oxidative Stress VI. Biomarkers of Axonal Damage VII. Biomarkers of Glial Activation Dysfunction VIII. Biomarkers of Remyelination Repair IX. Biomarkers of Therapeutic Response X. Prognostic Biomarkers XI. Emering biomarkers B. Laboratory Biomarkers
- 89. Prediction of prognosis 89 GOOD EPIDEIOLOGICAL FACTORS BAD Female Sex Male < 40 y Age > 40 y
- 90. 90 GOOD RELAPSES BAD Mild, monofocal 1st relapse Severe , multifocal Sensory, ON Clinical presentation Motor, cerebellar Full recovery Response to ttt Residual Long Time to 2nd relapse Short Low Relapse rate High Prediction of prognosis
- 91. 91 GOOD DISABILITY BAD Long Time to EDSS 4-5 Short GOOD MRI BAD Low Lesion load High Absent CEL Present Prediction of prognosis
- 92. 92
- 93. 93
- 94. MRI brain and cervical cord (1) with Gd Abnormal [conversion rate 80%] (2) Wait till CDMS DMT Normal [conversion rate 20%] (2) Follow up 94 Conversion of CIS to CDMS
- 96. Relapsing remitting multiple sclerosis (R.R.M.S.) 96 • Treatment of a relapse • Disease modifying therapy (DMT) • Symptomatic ttt • Non pharmacological
- 97. 97 • Worsening of present symptoms or appearance of new symptoms • At least 24 h Relapse • 1 month from last attack. • Not during steroid withdrawal or infection. • ↑ EDSS ≥ 0.5 Definition of a relapse
- 98. Symptomatic ttt
- 99. DMT 99
- 100. Existing & Emerging MS therapies Modified from P. Vermersch Phase I Phase II Phase III Marketed Interferons Antiproliferative agents Cytolytic mAbs Symptomatic TxVaccine, tolerization Lymphocyte trafficking Immune regulation Other Idebenone BIIB033 Fingolimod Firategrast Siponimod ONO-4641 CS-0777 ELND-002 Tysabri Daclizumab Laquinimod BG12 NI-0801 AZD5904 GRC4039 CCX-140 AIN457 Cladribine NerispirdineOfatumumab Belimumab Ampyra Ocrelizumab Sativex Alemtuzumab Copaxone IPX-056 RPI-78M LY-2127399 Novantrone Rebif Betaferon Pixantrone Peg IFNb (BIIB017) ATX-MS-1467 PI2301 RTL1000 Copaxone generics x2 Azathioprine Teriflunomide LV Copaxone Avonex = Oral administration = Injectable Extavia Ponesimod
- 102. 10 2
- 103. BMT Cyclophosphamide Mycophenolate mofieil Mitoxantrone - Fingolimod – Natalizumab Mitoxantrone Β Interferons – Glatirmar Acetate Teriflunomide – Dimethyl fumarate - Leflunomide – Azathioprine – Methotrexate – Fingolimod*
- 104. Treatment failure
- 105. 10 5
- 107. DMDs Strategy • Rio score is adopted to determine failure of ttt or non responding patient in order to escalate. Escalation options include: – Up shifting (e.g. shifting from 1st line agent to 2nd line agent) – Lateral Shifting (shifting to another therapeutic agent classified within same line) – Combination with monthly methyl prednisolone.
- 109. Induction therapy: • Patients with poor prognostic factors (next slide) may be optioned to start on a second line agent or a more potent agent within the same line and then either to • Continue on such agent or • Shift to a first line option according to patient’s response. DMDs Strategy
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- 111. THANK YOU