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New TRENDS IN Multiple Sclerosis Epidemiology Global Burden of Disease Brain Summit Auckland, New Zealand Mitchell Wallin, MD, MPH Director, VA MSCoE-East Associate Professor of Neurology Georgetown University & University of Maryland
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Disclosures No Conflicts of Interest to Declare
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Learning Objectives Assess the current diagnosis and classification of Multiple Sclerosis (MS) Summarize the prevalence, incidence and progression of MS Briefly characterize MS risk factors Recognize the utility of the Global Burden of Disease approach to understand disease morbidity and integrate findings across the world
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L. Kurland (Chairman) J. Kurtzke (Vice-Chairman) M. Alter (Secretary) Founding Officers AAN Section of Neuroepidemiology (1967-1971)
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New Trends in Multiple Sclerosis Epidemiology Diagnosis and Morbidity Updates NMSS MS Prevalence Project Global Burden of MS Risk Factors for MS & Prevention VA MSCoE
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Multiple Sclerosis Chronic, inflammatory-degenerative disease of CNS Precipitated by environmental factors (PMSA) in genetically susceptible individuals The hallmark of MS is inflammatory, demyelinating plaques and axonal loss in the CNS Characterized by relapses and remissions of neurological symptoms and progression of disability over time Most common progressive neurological disease of young adults
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Diagnostic Criteria for MS: 2017 Revisions to McDonald Criteria Central nervous system lesions separated in space & time The following changes were made for patients with typical clinically isolated syndromes: Positive CSF allows for MS dx where DIS criteria is met Cortical lesions can be used to demonstrate DIS Eliminate more likely diagnoses Solomon, Neurology 2016 Further refinement of criteria needed for: Optic nerve involvement Pediatric, Asian and Latin American populations Thompson, Lancet Neurol 2018 7
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MRI and MS FLAIR T2 T1 GD T2-weighted hyperintense T1-weighted hypointense T1-weighted+ GD
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EDSS = Expanded Disability Status Scale. Wolinsky/Kurtzke JF. Neurology. 1983;33:1444-1452. MS Disease Progression Disability Time SPMS RRMS Preclinical Measures of Brain Volume Relapses and Impairment MRI Burden of Disease MRI Activity 20% of RRMS convert to progressive form in 10yrs
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MS Phenotypes Lublin, Neurology 2014 Relapsing Disease Clinically Isolated Syndrome (CIS) Not active Active Relapsing-remitting disease (RRMS) Not active Active Progressive Disease Progressive Disease (PP and SP) Not active with or w/o progression Active with or w/o progression .
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Myelocortical MS Trapp, Lancet 2018 Possible new MS subtype 12/100 in Cleveland Clinic autopsy series Features demyelination of spinal cord and cerebral cortex but not cerebral white matter Cortical neuronal loss was greater in myelocortical MS vs. typical MS
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MS Mortality and Changing Age Distribution (Rotstein, Neurology 2018; Marrie, Neurology 2010) MS mortality in Ontario declined from 27.6 to 18.0 per 1000 person-yrs (1995-2013) The MS mortality sex rate ratio (women/men-Ontario) increased from 0.70 in 1996 to 0.86 in 2013 Manitoba 20yr MS cohorts: peak age-specific prevalence shifted to older age groups Increasing MS prevalence in large part due to declining mortality
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MS Prevalence in New Zealand 1968-2001 vs. 2006 Alla S, Neuroepidemiology 2014
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GW MS Cohort: Average Annual MS Incidence Rates Wallin, Brain 2012; Duessing, Mil Med 2012
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Incidence of MS in Kaiser Permanente Southern California Langer-Gould, Neurology 2013
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Primary: Obtain scientifically sound & economically feasible US national prevalence estimate Demographic and regional stratified prevalence estimates Secondary: Assess burden of disease Health care utilization and costs Tertiary: Develop a long-term strategy to assess MS prevalence at regular intervals US MS Prevalence Workgroup Mission (National MS Society):
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17 Options for case finding & data acquisition
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MS Prevalence Group Case Finding Algorithm Culpepper, Neurology in press We reviewed 8,041 medical records (VHA: 3,452, KPSC: 2,935, MB: 1,654) Sensitivity [86.6-93.2%], specificity [66.7-82.5%], positive predictive value [95.4-97.8%], and inter-rater reliability [Youden’s J=0.60-0.69]) were generally stable across datasets for 1 or 2 yrs We recommend that future MS studies using AHC datasets employ this algorithm.
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MS Prevalence in the United States Wallin, Neurology in press Validated MS algorithm applied to national administrative health claims datasets in the US: private insurance (Optum, Truven, Kaiser So.CA), government (Medicaid, Medicare, VA). Estimated 10-year period prevalence (2000-2010) for MS: Overall: 309.2 per 100,000 (95% CI: 308.1-310.1) Cases with MS: 727,344 Estimated “Life-time” prevalence for 2017 Overall: 362.6 per 100,000 Cases with MS: 914,651 10-year US Period Prevalence (2000-2010) for MS per 100,000 (2010 US Census)
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Time to EDSS 6 from first symptoms onset of MS *From MS onset by Kaplan-Meier estimates
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Clinical Progression of MS in the DMT-era Manouchehrinia, MS Journal 2017 Swedish MS Register Data (n=12,703) with at least 3 EDSS scores in 2015 Majority of patient exposed to DMTs (14% never exposed, 15% unknown) Median age to reach: EDSS 3.0: 55 yrs, EDSS 4.0: 61 yrs, EDSS 6.0: 64 yrs Median age to onset of SPMS was 57yrs and median time from disease onset to SPMS was 23 yrs Kaplan–Meier curves of time from birth (left) and multiple sclerosis onset (right) to EDSS score milestones 3.0, 4.0, 6.0 and SPMS
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Global Burden of Disease 2016 Approach to MS Morbidity and Mortality Unique source for integrated global estimates of prevalence, incidence, and deaths from MS Morbidity and mortality data stratified by country, region and development level GBD 2016 results are more accessible to researchers and clinicians with interest in MS Data helpful for clinical planning and health policy makers Models for estimating outcomes improve with more robust data
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Global Burden of Neurological Disorders 1990-2015 (GBD Neuro Disease Collaborators, Lancet Neurol 2017) Neurological disorders ranked as the leading cause group of DALYs in 2015 (10.2%) Neurological disorders were the second leading cause of mortality (16.8% global deaths) Most prevalent neurological conditions (millions): Tension type headache (1,506) Migraine (959) Medication overuse headache (59) Dementia (46) Multiple Sclerosis (2)
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Global Burden of Multiple Sclerosis (GBD 2016, Lancet Neurol in press) MS morbidity estimates derived with GBD methods using 123 unique sources on prevalence and 65 unique sources on incidence (prevalence, DALYs, YLL, mortality) 2,221,188 MS cases in 2016 worldwide (95% UI: 2,033,866- 2,436,858) & prevalence of 30.1 per 100,000 population. Geographic gradients diffusing but persist in 2016 MS ranked 14th among major neurological conditions as a cause of DALYs
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MS Morbidity & Mortality-GBD 2016 Global age-standardized MS death rates decreased -11.5% (-35.4 to -4.7) between 1990-2016 YLL of MS greatest in 6th decade of life YLD rises to peak to age 55 years then climbs in the 80-90s DALYs for MS in 2016 were 1,151,478 representing a non-significant drop of -4.2 (-16.4 to 0.8) from 1990 MS made up 0.42% (0.37 to 0.46) of the overall DALYs from all neurological disorders
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Risk Factors for MS Onset Genes (HLA DRB) Demographic Female sex Geography Infections Smoking Sunlight/Vitamin D Obesity
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Candidate Genes in MS (adapted from Baranzini SE, Oksenberg JR. Trends Genet 2017, Boullerne A, et al. ASN Neurol 2015)
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Genetic Susceptibility and MS Based on sibling studies, the 200+ identified MS genetic alleles explains only 27% of heritability with the majority (20%) from HLA DRB1*15:01(Lill C, 2014) HLA Complexity & Interactions (Hollenbach J, 2015) Complex allelic hierarchical lineages, cis/trans haplotypic effects Killer-cell immunoglobulin-like receptors (KIRs), Environmental and epigenetic modifications on genome require study (Baranzini, 2010) Susceptibility genes “prime the pump”
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Female Sex and Risk for MS Equivalent or higher male sex ratio in early 20th century (Brain W, 1930) Sex ratio (F:M) has trended towards an increase with time & incidence and decrease with latitude For repeated surveys over time, the F:M ratio has increased Potential explanations Epigenetic effects with environmental exposures (HLA) (Chao, 2011) Differential smoking (Hedstrom, 2009) Changing rates and timing of pregnancy (Magyari 2016) Oral contraceptives (Alonso 2009) Female:male sex ratio by latitude, time & incidence. Koch-Henriksen, Lancet Neurol 2010
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Migration and MS Morbidity in Australia Australian-born MS cases were reassessed in Hobart, Tasmania MS Incidence: 1.63 per 100K 1941-65 3.48 per 100K 1966-81 Most UKI immigrants migrated after 15 yrs with interval between immigration year & MS onset 6 yrs (vs. 22 yrs for migrants < 15 yrs) Support for transmissible environmental factor associated with high rates in Tasmania
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Viruses & Endogenous Retroviruses in MS (Mentis A, et al. Acta Neurol Scand 2017) Viral associations with MS: EBV VZV HHV-6 Measles & Morvilliviruses LCMV Corona virus Saffold virus Human Endogenous Retroviruses Integrated into human genome as a result of ancestral retroviral infection Transposable elements change position within genome & have repetitive sequences Association between environmental viruses & HERV through Encoding RNAs HERV protein expression on B cells HERV activation by viruses (HSV1, HHV-6, EBV) MSRV-Env protein stimulate immune response
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Cortical Pathology and Leptomeningeal Inflammation in MS Longitudinal MRI, Postmortem 7-T MRI and immunohistochemistry Absinta, et al 2015 Neuroimaging advances have facilitated improved detection of cortical pathology (Zurawski J, JAMA Neurol 2017) Gray matter demyelination, cortical atrophy, and leptomeningeal inflammation may be important components of progressive MS pathology Leptomeningeal enhancement may prove a useful surrogate marker for such pathology Implications for EBV or another infection (Hassani A, et al. PLoS One 2018)
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Smoking and risk for MS onset (Handel, PLoS One, 2012) Search for studies between 1960-2010 (n=1490) Overall RR=1.48 (95% CI: 1.35-1.63) Effect sizes uniformly distributed around the meta-analysis effect size indicating no major publication bias Clear dose-response relationship between smoking and MS onset
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Obesity & MS Risk for Onset For women in the Nurses Health Study, obesity at age 18 years was associated with a 2.25 adjusted RR (95% CI: 1.50-3.37) for MS onset. (Munger, Neurology 2009) A Swedish population-based case-control study found a two-fold significant risk for MS in men and women with BMI > 27 kg/m2 at age 20 years (Hedstrom, Mult Scler 2012) In a pediatric MS cohort in Kaiser Southern California, obesity was associated with an increased odds of developing CIS/MS in girls (Langer-Gould A, Neurology 2013): Overweight vs. normal weight: OR: 1.58 (95% CI: 0.71-3.50) Moderately obese : OR 1.78 (95% CI: 0.70-4.49) Moderately obese vs. normal weight: OR 3.76 (95% CI: 1.54-9.16)
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Interaction among adolescent obesity, carriage of HLA-DRB1*15 (Hedstrom, Neurology 2014) In the EIMS incident cohort, obese subjects with the most susceptible genotype (DRB1*15 & absence of A*02) had an OR of 16.2 (95% CI 7.5–35.2) vs. nonobese subjects without the genetic risk factors. Corresponding OR in the KPNC prevalent study was 13.8 (95% CI 4.1–46.8). Significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status Prevention of adolescent obesity may lower the risk of developing MS
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Vitamin D & MS Risk Two to three sera samples from the DoDSR were seasonally adjusted and stratified by quintile of 25-OH vitamin D and the odds of developing MS was assessed Those in the highest quintile of 25-OH vitamin D among non-Hispanic whites had a significantly attenuated risk for MS (Odds ratio (OR) 0.38, 95% Confidence Interval (CI) 0.19-0.75). No significant risk for MS was shown for any quintile of 25-OH vitamin D for blacks or the other race group that included Hispanics and Asians. Munger K, JAMA 2006
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MS Sunshine Study-KP Southern California Langer-Gould , Nutrients 2018 Multi-race/ethnic case-control study in KP Southern California Higher lifetime UV exposure reduced risk for MS in blacks (OR 0.53, p=0.007), whites (OR 0.68, p=0.020) and Hispanics (OR 0.66, p=0.071) independent of serum 25-OH Vitamin D levels Lifetime sun exposure appears to reduce the risk of MS regardless of race/ethnicity Higher serum 25OHD levels were associated with a lower risk of MS only in whites These reports challenges the biological plausibility of vitamin D deficiency as causal for MS
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Vitamin D and MS Onset Optimal dose and normal range of Vitamin D not clear (IOM, 2011) Differences in polymorphisms in vitamin D-binding protein gene and bio-available Vitamin D between racial groups (Powe, 2013) Reverse causation between Vitamin D and MS not ruled out Goal of 40 nmol/L 25-OH for adults is reasonable
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New Trends in MS Epidemiology Conclusions MS prevalence is higher than previously reported in many world regions. Lower mortality is in part driving this trend. Geographic gradients for MS risk persist Use of algorithms with large population datasets will provide a basis for efficient morbidity and mortality surveillance in the future (US Neurological Disease Surveillance System, Public Law 114-255) Modifiable risk factor for MS onset should be targeted for MS prevention: smoking, obesity, sunlight exposure Use of large diverse cohorts of MS cases and controls with appropriate technology should be used to understand risk factors that trigger and perpetuate MS
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US Department of Veterans Affairs Multiple Sclerosis Centers of Excellence Mission: To support and maintain the health, independence, quality of life and productivity of Veterans with MS through clinical care, education, research and informatics. Purpose: Coordinate clinical, educational and research activity across VHA; providing consultative direction on care, promoting collaborative research and utilizing VHA big data to study the disease course. Multiple Sclerosis System of Care-VHA Directive 1011.06 (April 2017) 40
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Multiple Sclerosis Centers of Excellence Multiple Sclerosis CoE-East: (Baltimore, MD & Washington, DC) Special expertise in basic science research, imaging, epidemiology and telehealth. Multiple Sclerosis CoE-West: (Portland, OR & Seattle, WA) Special expertise in translational research, clinical research, rehabilitation, and integrative medicine.
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MSCoE Four Functional Cores support our national VA MS System of Care
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MSCoE-East Director Associate Director Clinical Care Associate Director Research Associate Director Education Administrative Officer Statistician Associated Staff -Nurse Case Manager -Social Worker Regional Programs Each VISN will have at least one MS Regional Program that will be a source of MS specialty consultation. Located at VA Medical Centers that are capable of providing the full spectrum of tertiary care, support for the use of all FDA-approved MS therapies and are capable of providing services. Support Programs MS Support Program will collaborate with local Regional Programs. Primary care for people with MS will occur at local VA Medical Centers. Veterans Health Administration Directive 1011.06: MS System of Care
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Clinical Care VHA Handbook 1011.06: MS System of Care Procedures 18,000-20,000 patients with MS annually (40,000 unique patients since 1998) National Consultations (e-consults) and telehealth MS Disease Management: safe access to all FDA approved Disease Modifying Therapies: Pharmacy Benefits Management Criteria for Use Monitoring guidelines Cost of Medications vs. Private Sector Coordinate Regional Programs and Support Program Network
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Telehealth Clinical Options
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MS Home Telerehabilitation Project VA Office of Rural Health funding 3 month trial with weekly PT CVT-home follow-ups Govshpere & Jintronix integrated home exercise system with adherence tracking
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Informatics & Epidemiology MS Surveillance Registry (https://vaww.mssr.registries.aac.va.gov) VA MS Care Network VA Office of IT programming & support Web-based MSAT integrated into EMR & secure website 1800 MS patients enrolled Dashboard & menu-driven reporting system for clinicians
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Research Studies: Bench and Clinical Neuroimmunology Health Services and Epidemiology Rehabilitation Clinical trials Grants and Publications: unique VA/DoD funding sources Mentoring Opportunities for collaboration Research & Development
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Education & Training Webinar Lectures & Discussions: Provider (physician & nursing), patients: partner with “Can Do MS” Video Library: www.va.gov/ms Newsletters: MS Veteran and provider e-letter National Conferences: International Gait and Balance Conference ACTRIMS (Americas Research Committee on MS) Annual Meeting Consortium of MS Centers (CMSC) Annual Meeting Paralyzed Veterans of America (PVA) Summit and Expo Advanced Fellowships in MS Collaborating Organizations Paralyzed Veterans of America (PVA) Multiple Sclerosis Association of America (MSAA) Consortium of Multiple Sclerosis Centers (CMSC) International Organization of Multiple Sclerosis Nurses (IOMSN)
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MS Prevalence Workgroup (NMSS) Nicholas LaRocca (NMSS Director) Ruth Ann Marrie (U Manitoba) Annette Langer-Gould (Kaiser Permanente-So CA) Lori Nelson (Stanford U) Helen Tremlett (U British Columbia) John Campbell (U Colorado) Steve Buka & Al Lo (Brown U) Joel Culpepper (U MD/MSCoE) Wendy Kaye (McKing Consulting) Mitch Wallin (Georgetown U/MSCoE-Chair)
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Neuroepidemiology Research Collaborators Global Burden of Disease Neurology Collaborators: Kate Muller, MPH Theo Vos, MD, MS, PhD Mari Smith VA MSCoE and University of Maryland, George Washington University, Johns Hopkins University and University of Washington School of Medicine Kate Fitzgerald, PhD Jodie Haselkorn, MD, MPH Heidi Maloni, PhD Shan Jin, PhD VA Office of Post Deployment Health-Washington, DC Joel Culpepper, PhD Aaron Schneiderman, PhD Funding: VA Merit Review, NMSS, VA MSCoE, Biogen-Idec, Bill & Melinda Gates