1. “Of MS and Men” Morbidity & Mortality Outcomes Mitchell T. Wallin, MD, MPH MS Clinic Director Department of Veterans Affairs Medical Center Washington, DC Assistant Professor of Neurology Georgetown University Medical School

2. “Of MS and Men” Morbidity & Mortality Outcomes I. Definitions II. Morbidity Data III. Mortality & Survival Data IV. Conclusions

3. Multiple Sclerosis Subtypes (Coyle P, 2002; adapted from Lublin F, et al Neurology 1996)

4. Secondary Progressive MS vs. Primary Progressive MS RR-SP MSPP MS Age at onset (mean) 30 yrs40 yrs Sex ratio (M:F) 2:11:1 Race  disability progression in AA Onset symptoms Sensory, visualParaparesis

5. “Of MS and Men” Morbidity & Mortality Outcomes I. Definitions II. Morbidity Data III. Mortality & Survival Data IV. Conclusions 2

6. Prevalence of Subtypes of MS (N = 3019) Relapsing-remitting (RR) 55% Secondary-progressive (SP) 30% Primary- progressive (PP) 10% Progressive- relapsing (PR) 5% Jacobs et al. Mult Scler. 1999;5:369-376.

7. Veteran Integrated Service Network (VISN)-5 MS Subtypes

8. Veteran Integrated Service Network (VISN)-5 MS Demographic Data

9. MS Morbidity in the US n Nationwide Prevalence u 58/100,000 population (Baum, 1981) u 102-139/100,000 population (Anderson, 1992) u 85/100,000 population (Noonan, 2002) n Olmsted County, MN (Mayr 2003) u Raw Incidence: 7.5/100,000 person-yrs u Raw Prevalence: 177/100,000 person-yrs

10. Estimated prevalence of MS per 100,000 by report in the US NHIS Survey, 1982-1996 (Noonan, 2002)

11. Estimated number of persons with MS in the US Noonan, 2002

12. Persons per 100,000 with MS Noonan, 2002

13. Vietnam and later military service MS cohort Study Population Flow Chart (Wallin, et al 2004) MS Cases Analyzed 4951 Controls Analyzed 9378 Eligible MS patients 55345 Eligible Controls 10683 3941305

14. Adjusted case-control ratios for MS by race and sex at EAD WWII-KC CohortVietnam and later Cohort Race-sex category # of MS cases Case-control ratio (95% CI) # of MS cases Case-control ratio (95% CI) White female1821.86 (1.44 – 2.38) 6042.85 (2.49-3.25) Black female41.33 (0.23 – 9.10) 1232.74 (2.00-3.52) Other race-female 2 ---- 163.37 (1.52-7.56) White male4,9231.04 (0.98 – 1.10) 3,7580.96 (0.90-1.00) Black male1770.45 (0.38 – 0.54) 4150.64 (0.57-0.43) Other race-male 170.23 (0.14 – 0.39) 350.29 (0.20-0.41) TOTAL5,3051.004,9511.00

15. Vietnam & Later Service 103 46 55 74 59 56 73 62 81 67 83 67 63 81 54 75 83 86 152 138 111 144 160 143 116 141 169 147 216 Case Control Ratios x 100 < 60 61 to 90 91 to 120 121 to 149 >150 81 116 141 113 230 126 115 101 80 79 108 110 180 92 107 WWII-KC 61 172 44 61 59 132 52 56 52 74 61 95 64 61 41 48 50 72 92 198 145 200 131 161 211 133 183 138 203 Case Control Ratios x 100 < 60 61 to 90 91 to 120 121 to 149 >150 66 131 117 118 105 101 116 86 109 118 121 127 67 78 129 167 85 94 64

16. Time from MS onset to EDSS 4.0 Confavreux, 2000

17. Risk of Bone Loss in Men Weinstock-Guttman, 2004 40 male MS patients, mean: EDSS 5.8; Age 51yrs n 32 (80%) with reduced bone loss of lumbar spine or femur u 17 (43%) had osteopenia u 15 (38%) had osteoporosis n 8/38 (21%) with fractures of ribs, vertebrae or extremities n Risk factors for low bone mineral density u Femoral neck: EDSS and BMI u Lumbar spine: EDSS

18. “Of MS and Men” Morbidity & Mortality Outcomes I. Definitions II. Morbidity Data III. Mortality & Survival Data IV. Conclusions 2

19. MS Survival n 10 years shorter than age-matched general population (Brønnum-Hansen, 2004) n US Veteran WWII Cohort (Wallin, 2000) u Men: median survival F Black males: 30 yrs F White males: 34 yrs u White women: median survival 43 yrs n Secular trend for improved survival over the past 50 years

20. Survival in VA MS Cases: Sex/Race

21. Survival in VA MS Cases: Age at Onset

22. Survival in VA MS Cases: SES

23. Risk Factors for MS Survival Study Year of Study RegionTotal cases Age at onset SexClin course Leibowitz1967Israel266+/-+ Visscher1980USA941+NS Phadke1980UK1055+NS+ Riise1986Norway598+NS+ Poser1981Germany224/1429++ Wynn1984USA206++ Brønnum-Hansen1986Denmark6727++ Midgard1991Norway251+NS+ Wallin1996USA2489++

24. MS Cause-specific mortality n MS as underlying or contributing cause of death in 47%-83% of cases (Sadovnick, 1991; Larsen, 1985) n Other causes (Brønnum-Hansen, 2004) u Cardiovascular disease: SMR 1.32 (1.22-1.43) u Cancer: SMR 0.85 (0.77-0.94) u Suicide/Accidents: 1.42 (1.22-1.64)

25. Conclusions  Despite a lower prevalence of MS, men are more likely to present with the PP subtype and generally have increased morbidity and mortality compared to women  Implications for clinical studies  Differential pathology by sex  Endocrine effects  More large longitudinal studies needed to evaluate sex differences in MS 9

26. National WWII Memorial