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An holistic approach to MS

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Talk to the Department of Neurology, Norwich 11 July 2012
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  • 1. An holistic approach to MSGavin GiovannoniBarts and The London School of Medicine and Dentistry
  • 2. CLINICAL SERVICEVACP TR L UL U REEEIC AS HN QC AEUIS HA A EC LI RRIAS NC TL YGH
  • 3. “All those who work on the frontline should be thinking carefully,and imaginatively, about how we can do things differently. TheQIPP process is a home for this in the NHS and the way that wecan implement the best and brightest ideas across the service.As the Prime Minister said: ‘Don’t hold back – be innovative, beradical, challenge the way things are done.”Andrew Lansley, Secretary of State for Health – 2 July 2010.
  • 4. “We need to fashion a vibrant, creative NHS that really fizzeswith ideas of how to improve quality and how to reducecosts........ So, instead of relying on ever more funds flowingfrom the Treasury, we must look to ourselves to make savings.This practical imperative is what QIPP is all about......... Wehave the resources, we have the knowledge and we have theability to give the people of this country a truly first class NHSand to deliver it within our means.”Earl Howe, Minister for QIPP - 2 July 2010
  • 5. Dr Janet WilliamsonNational Director, NHS Improvement
  • 6. A ‘holistic’ approach to MSRestless legsdisease-freeSexual dysfunction SwallowingmonitoringBalance problems Pressure soresadverse events risksSeizuresmaintenancePrevention escalation Bowel 2nd lineFallsinduction1st line Oscillopsia Pseudobulbar affectSexual dysfunction Tremor family DMTs counselling Palliative Care Gait Nurse DMTs RelapsesRehab Social specialistsSpasticity vDCounsellingLegal aidservicesBladder Occupational Clinical trials Tendonotomy Therapy Driving Assisted suicide Advanced directivePrimary Care ReferralDiagnosis MinimalModerate Severe End ofNeurophysiologyimpairmentimpairmentimpairmentlife care FertilityIntrathecal baclofernNeuroimmunologyColostomyRelationshipsPain Speech therapyTravel vaccinationFatigue NeuroradiologyPhysiotherapy Studying DepressionGastrostomy AnxietyFunctionalEmploymentneurosurgery Insomnia Cognition Suprapubiccatheter
  • 7. www.ms-res.org
  • 8. Who of you routinely measures bloodvitamin D levels in people with MS?
  • 9. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial Goodman et al. Lancet 2009; 373: 732–38.
  • 10. A ‘holistic’ approach to MSRestless legsdisease-freeSexual dysfunction SwallowingmonitoringBalance problems Pressure soresadverse events risksSeizuresmaintenancePrevention escalation Bowel 2nd lineFallsinduction1st line Oscillopsia Pseudobulbar affectSexual dysfunction Tremor family DMTs counselling Palliative Care Gait Nurse DMTs RelapsesRehab Social specialistsSpasticity vDCounsellingLegal aidservicesBladder Occupational Clinical trials Tendonotomy Therapy Driving Assisted suicide Advanced directivePrimary Care ReferralDiagnosis MinimalModerate Severe End ofNeurophysiologyimpairmentimpairmentimpairmentlife care FertilityIntrathecal baclofernNeuroimmunologyColostomyRelationshipsPain Speech therapyTravel vaccinationFatigue NeuroradiologyPhysiotherapy Studying DepressionGastrostomy AnxietyFunctionalEmploymentneurosurgery Insomnia Cognition Suprapubiccatheter
  • 11. Bone Health
  • 12. Fracture risk in multiple sclerosis Dobson et al. Submitted 2012.
  • 13. Risk of fractures in patients with MS: record-linkage studyRamagopalan et al. Unpublished data 2012
  • 14. Osteoporosis in multiple sclerosis Dobson et al. Submitted 2012.
  • 15. What is the prevalence of falls in MS?
  • 16. Sosnoff et al. PLoS One. 2011;6(11):e28021.
  • 17. Sosnoff et al. PLoS One. 2011;6(11):e28021.
  • 18. A ‘holistic’ approach to MSRestless legsdisease-freeSexual dysfunction SwallowingmonitoringBalance problems Pressure soresadverse events risksSeizuresmaintenancePrevention escalation Bowel 2nd lineFallsinduction1st line Oscillopsia Pseudobulbar affectSexual dysfunction Tremor family DMTs counselling Palliative Care Gait Nurse DMTs RelapsesRehab Social specialistsSpasticity vDCounsellingLegal aidservicesBladder Occupational Clinical trials Tendonotomy Therapy Driving Assisted suicide Advanced directivePrimary Care ReferralDiagnosis MinimalModerate Severe End ofNeurophysiologyimpairmentimpairmentimpairmentlife care FertilityIntrathecal baclofernNeuroimmunologyColostomyRelationshipsPain Speech therapyTravel vaccinationFatigue NeuroradiologyPhysiotherapy Studying DepressionGastrostomy AnxietyFunctionalEmploymentneurosurgery Insomnia Cognition Suprapubiccatheter
  • 19. Who delegates bladder dysfunction to the continence advisor?
  • 20. A ‘holistic’ approach to MSRestless legsdisease-freeSexual dysfunction SwallowingmonitoringBalance problems Pressure soresadverse events risksSeizuresmaintenance escalation BowelPrevention 2nd lineFallsinduction1st line Oscillopsia Pseudobulbar affectSexual dysfunction Tremor family DMTs counselling Palliative Care Gait Nurse DMTs RelapsesRehab Social specialistsSpasticity vDCounsellingLegal aidservicesBladder Occupational Clinical trials Tendonotomy Therapy Driving Assisted suicide Advanced directivePrimary Care ReferralDiagnosis MinimalModerate Severe End ofNeurophysiologyimpairmentimpairmentimpairmentlife care FertilityIntrathecal baclofernNeuroimmunologyColostomyRelationshipsPain Speech therapyTravel vaccinationFatigue NeuroradiologyPhysiotherapy Studying DepressionGastrostomy AnxietyFunctionalEmploymentneurosurgery Insomnia Cognition Suprapubiccatheter
  • 21. Preserving cognitive function for patients with overactivebladder: evidence for a differential effect with darifenacin Kay et al. Int J Clin Pract. 2008 Nov;62(11):1792-800.
  • 22. Systemic infections and inflammation affect chronic neurodegenerationPerry et al. Nat Rev Immunol. 2007 Feb;7(2):161-7.
  • 23. Who agrees that after making a diagnosis of MS the main role of the neurologist is to prescribe DMTs?
  • 24. A ‘holistic’ approach to MSRestless legsdisease-freeSexual dysfunction SwallowingmonitoringBalance problems Pressure soresadverse events risksSeizuresmaintenance escalation BowelPrevention 2nd lineFallsinduction1st line Oscillopsia Pseudobulbar affectSexual dysfunction Tremor family DMTs counselling Palliative Care Gait Nurse DMTs RelapsesRehab Social specialistsSpasticity vDCounsellingLegal aidservicesBladder Occupational Clinical trials Tendonotomy Therapy Driving Assisted suicide Advanced directivePrimary Care ReferralDiagnosis MinimalModerate Severe End ofNeurophysiologyimpairmentimpairmentimpairmentlife care FertilityIntrathecal baclofernNeuroimmunologyColostomyRelationshipsPain Speech therapyTravel vaccinationFatigue NeuroradiologyPhysiotherapy Studying DepressionGastrostomy AnxietyFunctionalEmploymentneurosurgery Insomnia Cognition Suprapubiccatheter
  • 25. Theoretical model: treat early and aggressivelyNatural courseof diseaseLater treatmentDisability Later intervention Treatmentat diagnosisInterventionat diagnosis TimeDisease Onset
  • 26. Who discusses mortality with their patients?
  • 27. Survival in MSers is shortened by 8 to 12 yearsSurvival Probability of Norwegian Patients with RRMS(Hordaland County, Western Norway, 1953–2003) 100General Population90RRMS95% CI8070Survival (%)605040302010 0 05 10 152025 303540 4550Years After Onset 30 354045505560 65 70 75 80RRMS=relapsing-remitting MS. Approximate Patient AgeAdapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.
  • 28. The survival disadvantage in MS is greater than in other chronic diseases Standardized Mortality Ratios in Chronic Diseases DiseaseSMR (range) Cardiovascular disease1*1.34 (1.23–1.44) Ischemic stroke2† 1.75(1.38–2.19) Early breast cancer32.0 (1.6–2.7) Crohn’s disease42.8 MS5 2.8 (2.6–3.1) MS (2–9.9 years after diagnosis)5 2.4 (1.9–2.9) MS (≥10 years after diagnosis)5 3.1 (2.8–3.4) Parkinson’s disease63.66 (3.37–3.95) Type 2 diabetes14.47 (3.91–5.10)*In patients with type 2 diabetes; †in patients with valvular heart disease in Olmsted County, Minnesota.1. De Marco R et al. Diabetes Care. 1999;22:756-761; 2. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008; 3. Hooning MJ et al. Int J Radiat OncolBiol Phys. 2006;64:1081-1091; 4. South East England Public Health Observatory, Mortality trends. 2006; 5. Sumelahti ML et al. Mult Scler.2010;16:1437-1442; 6. Hristova DR. Folia Medica. 2009;51:40-45.
  • 29. Population-based MS mortality studiesPopulation Size First Author and Time Period of Cohort SMR Additional Survival Measures GryttenTorkildsenWestern Norway 8782.66 • Median survival time from onset: 41 years Mult Scler 20081953–2003(95% CI: 2.31–3.06) MS vs 49 years general population– 8 years of life lost in MS SmestadOslo 3682.47 • Reduction of median life expectancy Mult Scler 2009 1940–1980 (95% CI: 2.09–2.90) vs general population – Female: 11.2 years – Male: 7.4 years Bronnum-HansenDanish MS9881 2.89• Median survival time (from disease onset) Brain 2004 Registry(95% CI: 2.81 2.98)vs general population: 1949–1996 – ≈10 years of life lost in MS HirstSouth Wales3732.79 • Median age of death: 63.1 years MS JNNP 2008 1985–2006 (95% CI: 2.44–3.18) vs 70.6 years general population – 7.5 years of life lost in MS SumelahtiFinland 15952.8• Survival decreases with disease progression Mult Scler 2010 1964–1993(95% CI: 2.6–3.1) – SMR, 2–9.9 years after diagnosis: 2.4– SMR, ≥10 years after diagnosis: 3.1 Wallin USA 24892.18 • Healthy soldier effect speculated to have a Brain 20001956–1996 (not specified) favorable effect on survival LerayWest France 18791.3• Mean follow-up duration = 12.7 years from Mult Scler 20071976–2004(95% CI: 1.01–1.7)clinical onset; may be basing estimate on relatively immature datasetMS=multiple sclerosis; SMR=standardized mortality ratio; CI=confidence interval.
  • 30. 21-year long-term follow-up of IFNb-1b studytime from study randomization to deathEarly treatment (3 years) with IFNb-1b was associated with a 47% reduction in therisk of dying over 21 years compared with initial placebo treatment100% Proportion of patients who are still alive 95% IFNB-1b 250 µg 90% Placebo 85% 80% 75%HR=0.532 (95% CI: 0.314–0.902) 70%46.8% reduction in hazard ratioLog rank, P=0.0173 65%02 4 6 8 10 12 14 16 18 20 22 At risk:Time (Years) IFNB-1b 250 µg124124121118 104 Placebo 12312011710988Goodin et al. Neurology. 2012 Apr 24;78(17):1315-22..
  • 31. Relapsing MS Placebo 1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS ActiveDisability 6 months12 months6 months 24 monthsTime
  • 32. Long-term follow-up 16 years % Risk Relative to Low Exposure IFN-beta exposure 80% vs. 20% Any Negative EDSS=6 SPMS WheelchairGoodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.
  • 33. Treat early (and aggressively) Natural course of diseaseLatertreatment Laterintervention Treatment at diagnosisIntervention at diagnosisDisabilityTime Disease Onset
  • 34. Who likes doughnuts?
  • 35. The relapsing MS doughnutNatalizumab NatalizumabHighly active RRMSFingolimodSuboptimal responders ?ActiveIFNb / GA RRMS IFNb Inactive RRMSCISRIS
  • 36. Who discusses employment with their patients?
  • 37. UnemploymentProbability of Remaining in Active Employment After Onset of MS Control Persons1.0MS Patients0.8Probability0.60.40.2 0 05 10 152025Time (years)Pfleger CC et al. Mult Scler. 2010;16:121-126.
  • 38. Who discusses relationships with their patients?
  • 39. Divorce and separationCrude probability of remaining in a relationship after onset of MS*1.0Population ControlsMSers0.80.6Probability0.40.2 00 51015 20 25Time to Event or End of Observation (years)*Life table method.Pfleger CC et al. Mult Scler. 2010; 16:121-126.
  • 40. Who discusses QoL with their patients?
  • 41. The effect of MS on Quality of Life1† EDSS and Utility* Show a Significant Inverse Relationship• MS is one of the most common 0.9 0.8causes of neurological disability 0.7in young adults2 0.6 0.5• Natural history studies indicate 0.4Utilitythat it takes a median time ofUtility 0.3 0.28, 20, and 0.1 030 years to reach the irreversible–0.1disability levels of EDSS scores–0.2–0.34.0, 6.0, and 7.0, respectively3–0.4 0.0 1.0 2.0 3.0 4.0 5.0 6.06.5 7.08.09.0 EDSS Status *Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CIs. Half points on EDSS are not shown on graph axis, except at EDSS score 6.5. EDSS=Expanded Disability Status Scale; EQ-5D=European Quality of Life-5 Dimensions; QoL=quality of life. 1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MS International Foundation (MSIF). http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed March 6, 2012; 3. Confavreaux C et al. Brain 2003; 176:770-782. 4. Compston A, Coles A. Lancet. 2008;372:1502-1517.
  • 42. Who monitors prognostic factors of treatment response to DMTs?
  • 43. Breakthrough disease after treatment initiationPatients with breakthrough disease can be identified with• Clinical measures– Relapses– EDSS progression• MRI measures– T2 and Gd+ lesions• Biological markers– IFNβ NAbs/lack of MxA gene induction– Natalizumab antibodiesGd+=gadolinium-enhancing; IFNβ=interferon beta; NAbs=neutralizing antibodies; Abs=antibodies; MxA= myxovirus protein A.
  • 44. Relapse on IFNβ therapy increases risk of sustained disability progression • Risk is not much greater for 2 relapses or more • Sensitivity is only 50% 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 SEP Value 95% CI No relapses (reference=1) 1 One relapse3.411.470.0051.46–7.98 Two or more relapses 4.371.740.0001.90–9.57 1.00 No RelapsesOne RelapseSurvival ProbabilityTwo or More Relapses EDSS Progression 0.75 0.50 0.25HR=hazard ratio; SE=standard error. 0Bosca et al. Mult Scler. 2008;14:636-639. 0204060 80Analysis Time (Months)
  • 45. MRI to monitor treatment response toIFNβ: a systematic reviewOne New T2 Lesion Odds Ratio Study or SubgroupIV, Random, 95% CI Kinkel 2008Pozzilli 2005 Prosperini 2009 Sormani 2011Total (95% CI) 2.69 (0.72, 10.04) 0.010.11 10 100 Disease Less Likely Disease More LikelyTwo or More New T2 Lesions Odds RatioStudy or Subgroup IV, Random, 95% CI Kinkel 2008 Prosperini 2009Total (95% CI) 9.86 (2.33, 41.70) 0.01 0.11 10 100Favors Experimental Favors ControlDobson et al. Submitted 2012.
  • 46. MRI to monitor treatment response toIFNβ: a systematic reviewOne New Gd+ LesionOdds RatioStudy or SubgroupIV, Random, 95% CI Kinkel 2008Pozzilli 2005 Tomassini 2006 Total (95% CI) 3.34 (1.36, 8.22)0.010.11 10100Disease Less Likely Disease More LikelyTwo or More New Gd+ Lesions Odds Ratio Study or SubgroupIV, Random, 95% CIKinkel 2008 Rio 2008Total (95% CI) 5.46 (2.48, 12.04)0.01 0.1 1 10 100Dobson et al. Submitted 2012.Disease Less Likely Disease More Likely
  • 47. Strongest predictor of disability progression onIFNβ therapy is progression itself Disease Activity During 2 Years of Treatment and Prediction of Disability Progression* at 6 Years Sensitivity (%) Specificity (%) Group(CI)(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 relapses45 (26–66)81 (72–82) D. A decrease in relapse rate less than 30% compared with 2 years40 (22–61)86 (77–91)before therapy E. A decrease in relapse rate less than 50% compared with 2 years40 (–61)81 (72–88)before therapy F. No decrease or identical relapse rate compared with 2 years35 (18–57)88 (79–93)before therapy 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 B75 (53–89)97 (91–99) J. Definition A and E40 (22–61)99 (94–99)*EDSS score ≥6.0 or increase in at least 3 EDSS steps.Río J et al. Ann Neurol. 2006;59:344-352.
  • 48. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis Sorensen et al. Lancet 2003; 362: 1184–91.
  • 49. Mean change in EDSSMalluci et al. Neurology 2004.
  • 50. Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosisTomassini et al. J Neurol (2006) 253 : 287–293.
  • 51. The incidence and significance of anti-natalizumab antibodiesResults from AFFIRM and SENTINEL Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.
  • 52. The incidence and significance of anti-natalizumab antibodiesResults from AFFIRM and SENTINEL Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.
  • 53. Metrics for DMTs• What proportion of your patients are on aDMT?– 1st line vs. escalation?– What proportion of your patient have NABs?• What proportion of your patients have failed afirst line DMT?• What proportion of your patients are in aclinical trial?• Etc.
  • 54. Treatment Strategy
  • 55. Theoretical model: treat early and aggressivelyNatural courseof diseaseLater treatmentDisability Later intervention Treatmentat diagnosisInterventionat diagnosis TimeDisease Onset
  • 56. Impact of MS: cognitive functioning in the CIS stageCognitive Test Performance in an Exploratory Study 60 Patients Failing ≥2 Cognitive TestsDeficits were found mainly in memory,speed of information processing, attention and executive functioning 40 57% 20P<0.0001 7%0CIS Patients(n=40)Healthy Controls(n=30)CIS=clinically isolated syndrome.Feuillet L et al. Mult Scler. 2007;13:124-127.
  • 57. What is benign MS?• 163 patients with “benign” MS(disease duration >15 yearsand EDSS score <3.5) – 45% cognitive impairment – 49% fatigue – 54% depressionAmato MP et al. J Neurol. 2006;253:1054-1059.
  • 58. Healthcare costs are linked to disabilityInformal CareInpatient Care(Disposable Income) (10.2%)(9.2%) Ambulatory Care (5.6%)Disease-Modifying Drugs (10.6%)Services(28.5%) Other RX & OTC Drugs (1.6%) Tests (0.4%) Investments (2.0%)Short-Term Absence (2.0%)Long-Term Sick Leave and Early Retirement (30.0%) Total mean annual cost per patient €53,601Rx=prescription drugs; OTC=over-the-counter.Berg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.
  • 59. Conclusion• Equity and excellence: Liberating the NHS– patients will be at the heart of everything we do • choice and control • easy access to the information they need about the best GPs and hospitals • patients will be in charge of making decisions about their care– a relentless focus on clinical outcomes • Success will be measured, not through bureaucratic process targets, but against results that really matter to patients – such as improving …… survival rates– we will empower health professionals
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