Early effective treatments

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Early effective treatments

  1. 1. Early and effective treatment Gavin Giovannoni Barts and The London
  2. 2. Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni. Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation. Professor Giovannoni’s trip to Australia is being sponsored by Novartis.
  3. 3. .
  4. 4. Thomas Blizard Curling 1811 – 1888 • Assistant-surgeon to The Royal London Hospital in 1883 and full surgeon in 1849 • President of the Royal College of Surgeons • Seminal work on tetanus, winning the Jacksonian prize for his work • Famous for his skill in treating diseases of the testes and rectum
  5. 5. Objectives 1. Early therapy 2. Highly-effective therapy 3. Induction therapy
  6. 6. Why early?
  7. 7. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial Goodin et al. Neurology 2012;78:1315-1322.
  8. 8. Natalizumab STRATA: stable EDSS scores for up to 5 years Cessation/ Treatment Gap* Original Placebo Original Natalizumab Mean EDSS Score Original Placebo – Now on Natalizumab n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 1 Year 2 Years 3 Years *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 14 194 427 4 Years 174 393 5 Years
  9. 9. TOP: earlier natalizumab treatment favors annualized relapse rate outcomes P<0.0001 P<0.0001 <3.0 ≥3.0 0 Baseline EDSS Score 1 ≥2 Prior DMTs Used P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor of interest. Error bars represent 95% CIs. DMT=disease-modifying therapy; CI=confidence interval. Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372. 15
  10. 10. Theoretical model: treat early and effectively Time is brain Natural course of disease Disability Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis Time Disease Onset
  11. 11. Does the biology of MS change with time?
  12. 12. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  13. 13. May be MS is not autoimmune? Can we learn anything from animal models?
  14. 14. Induction and assessment of chronic relapsing experimental allergic encephalomyelitis Day 0 Clinical Score Day 7 0 1 Spinal cord homogenate in Freund’s complete adjuvant in ABH Normal (1) Limp tail Remission 2 Impaired righting reflex 3 partial paralysis 4 hindlimb paralysis 5 Moribund Slide courtesy David Baker
  15. 15. Average disease course RELAPSE 3 ACUTE RELAPSE 1 CHRONIC RELAPSE 2 Slide courtesy Sam Jackson & Ian Duncan.
  16. 16. Prevention of relapsing CREAE after three paralytic episodes does not inhibit secondary progression and deterioration of mobility Pryce et al. J Neuroimmunol 2005.
  17. 17. The current dogma RIS RRMS CIS Disease Severity Inflammation Axonal loss Brain volume Time (Years) MRI Events Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17. SPMS
  18. 18. The current paradigm safe & slow
  19. 19. S&S treatment paradigm High Efficacy Intermediate Efficacy Moderate Efficacy E X M A D Y 3rd-line N 2nd-line B C 1st-line
  20. 20. 100 MSers Who are the responders?
  21. 21. ~20% responders ~40% sub-optimal responders ~40% non-responders
  22. 22. 1 Clinical vs. 2 MRI 3 NABs
  23. 23. S&S treatment paradigm High Efficacy Intermediate Efficacy Moderate Efficacy E X M A D Y 3rd-line N 2nd-line B C 1st-line
  24. 24. How bad is MS?
  25. 25. Untreated MS is a devastating disease Cognitive Dysfunction • Prevalence: 43% to 65%1,2 • Affects employment, activities of daily living, and social functioning2 Life Shortening • • • 5- to 11-year decrease in life expectancy3-7 2- to 7-fold increase in suicide risk5,8 50% MS patients die of disease-related causes5,6,8 QOL EDSS and utility* have shown a significant inverse relationship9 MS has a negative impact on… Mortality Mortality ratio of patients with MS exceeds CV disease,†,10 stroke,‡,11 and early breast cancer12 Employment 50% of patients with MS are unemployed as of EDSS 3.0 and/or after 10 years from diagnosis13 Healthcare costs Relationships Bulk of cost attributed to services (28.5%) and long-term sick leave and early retirement (30%)§,14 Compared with general population, patients with MS have a higher probability of separating/divorcing and doing so sooner13 *In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County, Minnesota; §MS patients with EDSS ≥6. EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular; EQ-5D=European Quality of Life-5 Dimensions. 1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994; 4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler. 2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196; 9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126; 14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.
  26. 26. Consequences of increasing EDSS scores: loss of employment1 Proportion of Patients ≤65 Years Old Working (%) Work Capacity by Disability Level Austria Belgium Germany Italy Netherlands Spain Sweden Switzerland United Kingdom 90 80 70 60 50 40 30 ~10 yrs2 20 10 0 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0 EDSS Score The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger. 1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926; 2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
  27. 27. The effect of MS on quality of life a EDSS and utility show a significant inverse relationship 1,b Utility • MS is one of the most common causes of neurological disability in young adults2 • Natural history studies indicate that it takes a median time of 8, 20, and 30 years to reach the irreversible disability levels of EDSS 4, 6, and 7, respectively3 EDSS Status aUtility measures are derived from EQ-5D using the EuroQoL instrument. bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5. bError 1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF. http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 34 &codcol=15&codcch=747. Accessed October 6, 2010. 3. Confavreaux, Compston. 2005. 4. Compston A, Coles A. Lancet 2008
  28. 28. What about benign MS?
  29. 29. What is benign MS? 163 patients with “benign” MS (disease duration >15 years and EDSS <3.5): 45% cognitive impairment 49% fatigue 54% depression
  30. 30. Impact of MS: cognitive functioning in the CIS stage 60% Patients failing ≥ 2 cognitive tests 40% 57% Deficits were found mainly in memory, speed of information processing, attention and executive functioning 20% 7% 0% p < 0.0001 -20% CIS Patients n = 40 Healthy Controls n = 30 Feuillet et al. MSJ 2007
  31. 31. Relapses don’t count!
  32. 32. Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.
  33. 33. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  34. 34. Predictors of long-term outcome in MSers treated with interferon beta-1a Treatment vs. Natural History Bermel et al. Ann Neuol 2012.
  35. 35. Relapse on IFNβ Therapy Increases Risk of Sustained Disability Progression HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment HR No relapses (reference=1) SE P Value 95% CI 1 One relapse 3.41 1.47 0.005 1.46–7.98 Two or more relapses 4.37 1.74 0.000 1.90–9.57 EDSS Progression Survival Probability 1.00 No Relapses One Relapse Two or More Relapses 0.75 0.50 0.25 HR=hazard ratio; SE=standard error 0 0 20 40 60 Analysis Time (Months) 80 Bosca et al. Mult Scler. 2008;14:636-639.
  36. 36. Relapses and residual deficits Lublin FD et al. Neurology. 2003;61:1528-1532.
  37. 37. MRI activity doesn’t count!
  38. 38. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  39. 39. MRI to monitor treatment response to IFNβ: a meta-analysis One New T2 Lesion Study or Subgroup Kinkel 2008 Pozzilli 2005 Prosperini 2009 Sormani 2011 Total (95% CI) 2.69 (0.72, 10.04) 0.01 Odds Ratio IV, Random, 95% CI 0.1 1 10 Disease Less Likely Disease More Likely 100 Two or More New T2 Lesions Study or Subgroup Kinkel 2008 Prosperini 2009 Total (95% CI) 9.86 (2.33, 41.70) Odds Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favors Experimental Favors Control Dobson et al. Neurology 2013.
  40. 40. MRI to monitor treatment response to IFNβ: a meta-analysis One New Gd+ Lesion Odds Ratio IV, Random, 95% CI Study or Subgroup Kinkel 2008 Pozzilli 2005 Tomassini 2006 Total (95% CI) 3.34 (1.36, 8.22) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Two or More New Gd+ Lesions Odds Ratio IV, Random, 95% CI Study or Subgroup Kinkel 2008 Rio 2008 Total (95% CI) 5.46 (2.48, 12.04) 0.01 0.1 Disease Less Likely 1 10 100 Disease More Likely Dobson et al. Neurology 2013.
  41. 41. Disease progression doesn’t count!
  42. 42. Strongest predictor of disability progression on IFNβ therapy is progression itself Disease activity during 2 years of treatment and prediction of disability progression* at 6 years Sensitivity (%) (CI) Specificity (%) (CI) A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97) B. Occurrence of any relapse 80 (58–92) 51 (41–61) C. Occurrence of two or more relapses 45 (26–66) 81 (72–82) D. A decrease in relapse rate less than 30% compared with 2 years before therapy 40 (22–61) 86 (77–91) E. A decrease in relapse rate less than 50% compared with 2 years before therapy 40 (–61) 81 (72–88) F. No decrease or identical relapse rate compared with 2 years before therapy 35 (18–57) 88 (79–93) G. Definition A or B 90 (70–97) 48 (38–58) H. Definition A or E 85 (64–95) 76 (66–83) I. Definition A and B 75 (53–89) 97 (91–99) J. Definition A and E 40 (22–61) 99 (94–99) Group *EDSS score ≥6.0 or increase in at least 3 EDSS steps. Río J et al. Ann Neurol. 2006;59:344-352.
  43. 43. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon-beta-1b trial Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  44. 44. Why highly-effective treatments?
  45. 45. Can we prevent end-organ damage? Control Multiple sclerosis
  46. 46. Brain atrophy occurs across all stages of the disease n= 963 MSers De Stefano, et al. Neurology 2010
  47. 47. Treatment-effect on atrophy correlates with treatment-effect on disability Sormani et al. Ann Neurol 2013, In Press.
  48. 48. Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75:43-49.
  49. 49. AFFIRM Study: natalizumab and brain atrophy Mean (SE) percentage change in BPF 0.0% Years 0-2 Year 0-1* -0.2% -0.24% -0.4% -0.40% -0.6% -0.43% P=0.004† -0.56% P=0.002† -0.8% -0.80% -0.82% -1.0% P=0.822† Placebo (N=315) †Difference Year 1-2 Natalizumab (N=627) between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
  50. 50. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM TRANSFORMS, 1 year FREEDOMS, 2 years Time (months) -0.2 -0.4 12 *** −40% vs IFNb-1a IM p<0.001 -0.6 -0.8 -1.0 Change in mean BV from baseline (%) Change in mean BV from baseline (%) 0 0.0 Time (months) 0 6 12 0 24 ** -0.4 -0.8 -1.2 * *** −38% vs placebo p<0.001 -1.6 -2.0 Fingolimod 0.5 mg (n = 368) IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 356) Placebo (n = 329) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
  51. 51. Laquinimod: Percent of brain volume change from baseline to month 24 Placebo (n = 1006) Laquinimod 0.6 mg (n = 984) POOLED % Change From Baseline 0 -0.4 -0.8 -0.834 -1.188 -1.2 30% P<0.0001 -1.6 Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007
  52. 52. BRAVO: reduced rate of brain volume loss PLACEBO LAQUINIMOD 0.6mg AVONEX® 30mcg 27.5% Reduction P<0.0001 Percent Brain Volume Change* (Months 0-24) -1.14% -0.83% -1.25% -27.4% Improvement P<0.0001 +9% Deterioration P=0.14 *Adjusted for baseline characteristics. Reference: 1. Vollmer T et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in 62 Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507.
  53. 53. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 Lower limit of normal Average Upper limit of normal 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  54. 54. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -30% MS lower limit MS Average MS Upper limit 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  55. 55. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -30% MS Average 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  56. 56. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -20% late treatment 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  57. 57. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -18% early treatment late treatment 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  58. 58. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% early very highlyeffective treatment 30 35 late very highlyeffective treatment 40 45 50 55 Age (years) 60 65 70 75 80 -11% -15%
  59. 59. What is your treatment philosophy?
  60. 60. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hard and early ”
  61. 61. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment
  62. 62. No evidence of disease activity: NEDA Treat-2-target No evidence of disease activity defined as: 1,2 × No relapses × No sustained disability progression × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Should brain volume loss and CSF neurofilament levels be included in our definition for ‘no evidence of disease activity’? Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
  63. 63. Treatment objectives in relapsing MS Treat Early Freedom from disease activity Reduced ongoing damage 73 T2T - NEDA Zero Tolerance
  64. 64. Treatment objectives in relapsing MS Treat Early Freedom from disease activity Reduced ongoing damage 74 Functional T2T - NEDA Improvement Maintain reserve Zero Tolerance capacity
  65. 65. Treatment objectives in relapsing MS Treat Early Freedom from disease activity CNS Repair Reduced ongoing damage 75 Functional T2T - NEDA Improvement Maintain reserve Zero Tolerance capacity Healthy ageing
  66. 66. Treatment objectives in relapsing MS Improved Quality of Life Treat Early Freedom from disease activity CNS Repair Reduced ongoing damage 76 Functional T2T - NEDA Improvement Maintain reserve Zero Tolerance capacity Healthy ageing
  67. 67. Pros and cons of maintenance vs. induction therapies Maintenance therapies • • • • • Continuous treatment Low to very high efficacy Reversible Perceived to be lower risk Examples • • • • • • • Rebound SPMS & progressive brain atrophy Less likely Unlikely to be life-threatening Pregnancy • • Marker for retreatment NEDA unreliable to assess efficacy Rebound activity • • • Mitoxantrone, cladribine, alemtuzumab, antiCD20 (?), BMT Breakthrough disease • • Contra-indicated No potential for a cure • • • Highly likely Can be life threatening Pregnancy Short-courses or pulsed therapy Very high efficacy Irreversible Perceived to be higher risk Examples • Suboptimal or failure to respond NEDA reliable metric for efficacy Rebound activity • • • • • • • Laquinimod, GA, IFN-beta, teriflunomide, BG12, fingolimod, natalizumab, daclizumab Breakthrough disease • • Induction therapies Strategy of choice Potentially curative • • 15-20 year experiment BMT, alemtuzumab, cladribine
  68. 68. Conclusions • MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc. • Early highly-effective induction therapy is the only realistic option of offering a cure (autoimmune paradigm) • Now an established treatment option • NEDA (DAF) and T2T are entering the neurology lexicon • Zero tolerance or ZeTo • We need an acceptable working definition of an MS cure • NEDA x 15 years? • Induction therapies (alemtuzumab, cladribine) • Improved risk mitigation tools • JCV testing • Autoimmune prediction for alemtuzumab • Is it fair to make people with MS wait 20 years for the outcome of an ongoing experiment? • Alemtuzumab, BMT, natalizumab, cladribine extension studies early + highly effective + induction
  69. 69. Cladribine an example of treat early and effectively
  70. 70. Questions?
  71. 71. Emerging concepts in MS NEDD – no evidence of detectable disease (oncology) NEDA - no evidence of disease activity (msologoy) DAF – disease activity free Biochemical relapse-free survival 1.0 Adjuvant (n = 50) Survival 0.8 0.6 0.4 Salvage (n = 118) p = 0.002 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 Time since radiotherapy (years) T2T; treat-2-target (rheumatology) Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340. ZeTo; zero tolerance
  72. 72. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate Early or late? natalizumab Monitoring ? fingolimod 82 JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord JCV high positive Annual MRI monitoring 3-monthly MRI monitoring
  73. 73. clinical Occup. & social What does the future hold? Splits from her partner Final year of school 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis 2000 Full time employment Graduate trainee marketing University depression , anxiety and fatigue clumsy left hand pins & needles in legs R optic neuritis 2001 2001 Off work ~3 months of the year Bladder dysfunction 2003 2004 Brainstem syndrome; diplopia and ataxia Dec 2007 Pregnancy New partner New job junior management position Occupational health assessment Reduced mobility Cervical cord relapse weak L arm with pain Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Jan 2008 treatment IFN-beta ? glatiramer acetate natalizumab monitoring ? fingolimod JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy 83 Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive 3-monthly MRI monitoring Old Age
  74. 74. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate Early or late? natalizumab Monitoring ? fingolimod JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 Dec 2007 High lesion load with brain atrophy Jul 2010 Gd-enhancing lesion of upper cervical cord JCV high positive Annual MRI monitoring 3-monthly MRI monitoring Jul 2013
  75. 75. Case studies
  76. 76. Ian Rogers. ACNR 2007: 7(3);14.
  77. 77. Baseline number of brain lesions predicts progression to EDSS Score ≥3.0 Queen Square Study The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study. The exact relationship between MRI findings and the clinical status of the patient is unknown. Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503; Brex PA et al. N Engl J Med. 2002;346:158-164.
  78. 78. The 2-stage model of disability progression 7 6 DSS Score 5 Phase 2 4 3 2 Phase 1 1 0 0 5 10 15 20 25 Years from Clinical Onset of Multiple Sclerosis PHASE 1 30 PHASE 2 • From MS clinical onset to Disability Status Scale 3 • From Disability Status Scale 3 to 6 • Multiple factors may influence disability progression (including gender, age, deficit after first relapse, number of relapses in first 2 years of disease) • Factors shown to be predictive of disability progression in phase 1 have no influence at this stage • Likely influenced by focal inflammation • Likely independent of focal inflammation Leray E et al. Brain 2010;133:1900-13.
  79. 79. Including brain atrophy!

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