Sun Exposure, Vitamin D Intake and Progression to Disability among Veterans with Progressive Multiple Sclerosis

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1 Originl Pper Neuroepidemiology 2011;37:52 57 DOI: / Received: December 13, 2010 Accepted: My 11, 2011 Published online: August 5, 2011 Sun Exposure, Vitmin D Intke nd Progression to Disbility mong Veterns with Progressive Multiple Sclerosis Tzu-Yun McDowell, b Sni Amr b Willim J. Culpepper, d Ptrici Lngenberg b Wlter Royl, c Christopher Bever, c Dougls D. Brdhm, e MS Center of Excellence Est, Bltimore VAMC, Deprtments of b Epidemiology nd Public Helth nd c Neurology, University of Mrylnd, Bltimore School of Medicine, nd d Deprtment of Phrmceuticl Helth Services Reserch, University of Mrylnd, Bltimore School of Phrmcy, Bltimore, Md., nd e Deprtment of Preventive Medicine nd Public Helth, University of Knss, School of Medicine Wichit, Wichit, Kns., USA Key Words Multiple sclerosis Sun exposure Vitmin D Progression Disbility Abstrct Bckground: Erly life events hve been suggested to influence multiple sclerosis (MS) susceptibility, nd to potentilly modulte its clinicl course. We ssessed vitmin D-relted exposures from childhood to disese onset nd their ssocitions with MS progression. Methods: Among veterns in the Multiple Sclerosis Surveillnce Registry, 219 reported hving the progressive form nd met the inclusion criteri. Prticipnts reported their pst sun exposure, vitmin D-relted intke nd ge t disbility milestones using the Ptient-Determined Disese Steps (PDDS). The Cox proportionl hzrds model ws used to exmine the ssocition between vitmin D-relted exposures nd time (yers) to disbility. Results: Low verge sun exposure in the fll/winter before disese onset ws ssocited with n incresed risk of progressing to PDDS score of 8 (hzrd rtio, HR: 2.13, 95% confidence intervl, CI: ), wheres use of cod liver oil during childhood nd dolescence ws ssocited with reduced risk (HR: 0.44, 95% CI: ). Conclusions: These results suggest tht exposure to vitmin D before MS onset might slow disese-relted neurodegenertion nd thus dely progression to disbility mong ptients with the progressive subtype. Copyright 2011 S. Krger AG, Bsel Introduction Cumultive evidence supports vitmin D s strong immune modultor nd protective fctor ginst the development of multiple sclerosis (MS) [1, 2]. High sun exposure, cod liver oil intke nd fish consumption, especilly during childhood nd dolescence, were reported to reduce the risk of MS [3 5]. Little is known bout the role of vitmin D in modulting the clinicl course of MS. In experimentl llergic encephlomyelitis, n niml model of MS, dministrtion of n ctive form of vitmin D, fter immuniztion but before the ppernce of symptoms, ws found to prevent MS onset [6 9], nd lso to reduce disese severity nd prolong survivl [7, 8, 10]. In humns, few studies Fx E-Mil krger@krger.ch S. Krger AG, Bsel /11/ $38.00/0 Accessible online t: Tzu-Yun McDowell Tel E-Mil hotmil.com

2 hve shown tht very erly exposures, probbly relted to mternl vitmin D level, influence MS risk nd possibly its clinicl course [11 15]. Whether or not vitmin D levels before MS onset hve long-lsting effects on disese progression remins unknown. In this study we exmined the influence of sun exposure nd vitmin D intke (diet nd supplements) during childhood nd erly dolescence (6 15 yers), nd up to symptom onset, on long-term disese disbility mong veterns with progressive MS. M e t h o d s The University of Mrylnd Institutionl Review Bord nd the Veterns Helth Administrtion (VHA) Reserch nd Development Committee t Bltimore VA Medicl Center pproved this study. Study Popultion The study popultion ws recruited from the VHA Multiple Sclerosis Surveillnce Registry, popultion-bsed, self-reported registry of veterns with MS [16]. Questionnires were miled to rndomly selected MS vetern cohort to obtin informtion for both clinicl outcomes nd epidemiologicl reserch purposes s previously reported [15]. Among the 1,328 prticipnts who completed the questionnire, 245 (18.4%) reported hving progressive MS defined s progressively worsening from symptom onset with or without ny recovery from symptoms (remissions) lter in the course, including both primry progressive nd progressive relpsing MS. We excluded those born nd rised outside the USA (n = 12) nd those who were younger thn 18 yers or older thn 65 yers t symptom onset (n = 13) to limit heterogeneity due to differences in childhood onset, nd very lte ge of MS onset. Outcome: Time from MS Symptom Onset to Defined Stges of Disbility Prticipnts reported retrospectively their ge when they reched disbility milestones using the Ptient Determined Disbility Scle (PDDS), simple nd reproducible ssessment of functionl disbility in MS [17] tht correltes well with the Expnded Disbility Sttus Scle [18]. The PDDS primrily evlutes mbultion of MS ptients on scle of 1 9. Only disbility stges tht ech prticipnt hs experienced nd mintined for t lest 6 months were recorded. We selected ge t PDDS 8, stge when wheelchir or scooter is the min form of mobility, nd clculted the time from ge of MS symptom onset to disbility s our min study outcome. Ultrviolet Rdition Exposure/Vitmin D Intke We used prticipnts self-reported sun exposure to estimte the cumultive childhood nd erly dolescence sun exposure s previously reported [15]. The verge sun exposure before symptom onset (weeks per yer) ws clculted by summing up the totl hours of sun exposure from the ge of 6 yers to the ge t MS symptom onset nd then divided by number of yers in tht sme period. Seprte vribles of these sun exposure estimtes were clculted for fll/winter nd spring/summer. Bsed on the prticipnts self-reported dietry nd supplement intke, we derived vribles indicting frequency of ech food (fish, milk nd egg/cheese) nd supplement (cod liver oil, vitmin D/clcium nd multivitmins) between the ges of 6 nd 15 yers nd up to the ge t MS symptom onset. Other Covrites Ech prticipnt reported ge t MS symptom onset, MS subtype, nd type of onset symptoms (motor/coordintion, sensory, vision, systemtic, nd bowel nd bldder problems) in ddition to bsic demogrphics. Dignosis of mononucleosis before symptom onset (yes/no), smoking sttus before disese onset nd type of skin (using the Fitzptrick clssifiction [19] ) were lso documented. Sttisticl Anlyses Outcome mesure ws time from symptom onset to PDDS 8. When the end point ws not reported to hve been reched by the prticipnts, the time dt were right-censored t the dte of the survey. Kpln-Meier nlysis ws used to exmine the distribution nd medin of ech outcome vrible. Log rnk tests were used to exmine undjusted ssocitions between time to disbility (outcome) nd: (1) vitmin D-relted exposures before MS onset nd (2) set of potentil covrites tht could ffect outcome or confound the ssocition (i.e. other MS risk fctors like gender). Vribles hving undjusted ssocitions with time to disbility t the less thn 0.20 significnce level were considered for inclusion in the Cox proportionl hzrds models. Potentil effect modifiction nd colinerity were ssessed mong vribles in these models. Proportionl hzrd model ssumptions were tested for ech model. All nlyses were performed using SAS version 9.1. R e s u l t s The study smple consisted of 219 veterns with progressive MS. Tble 1 shows the demogrphic nd clinicl chrcteristics of study prticipnts, the mjority of whom were Cucsins (81%) nd mles (77%). The men ge t symptom onset ws 36.1 yers (SD = 10.9). The medin time from symptom onset to PDDS 8 ws 27 yers (95% confidence intervl, CI: 24 33). All sun exposure vribles were first grouped into qurtiles, which were exmined for their ssocitions with the outcome. Bsed on the observed trend, these vribles were subsequently dichotomized into low versus high sun exposure; for exmple, verge fll/winter sun exposure ws compred between ^1.6 weeks/yer (lowest qurtile) nd weeks/yer (top 3 qurtiles). The log rnk test indictes tht prticipnts with low verge fll/winter sun exposure before MS onset progressed to PDDS 8 fster thn those with higher verge Sun Exposure, Vitmin D Intke nd Progression of MS Neuroepidemiology 2011;37:

3 Tble 1. Sociodemogrphic nd clinicl chrcteristics of veterns with progressive MS (n = 219) Personl chrcteristics Men ge 8 SD, yers Rce, n White 178 (81.3) Blck 34 (15.5) Sex, n Femle 50 (22.8) Mle 169 (77.2) Men eduction 8 SD, yers Clinicl chrcteristics Men ge t onset 8 SD, yers Men disese durtion 8 SD, yers Current PDDS stge 8 SD Time from onset to PDDS 8 27 [24 33] DX of mononucleosis, n Yes 33 (15.4) No 166 (77.6) Unknown 15 (7.0) F igures in prentheses indicte percentges. The PDDS scle vries from 1 (norml) to 9 (bedbound). DX = Dignosis before onset of MS. Kpln-Meier estimtes of time to PDDS 8 (medin time nd 95% CI in brckets indicted in yers). Tble 2. Adjusted proportionl hzrd rtios of different fctors ssocited with time from disese symptom onset to PDDS 8 mong veterns with progressive MS (n = 151) Vribles Hzrd rtio p vlue Age t symptom onset 1.03 ( ) 0.02 Gender Mle vs. femle (reference) 1.19 ( ) 0.60 Averge fll/winter sun exposure before MS onset Low vs. high (reference) 2.13 ( ) 0.01 DX of mononucleosis before MS onset Yes vs. no (reference) 2.65 ( ) Cod liver oil intke t ges 6 15 yers Ever vs. never (reference) 0.44 ( ) 0.04 Fish consumption t ges 6 15 yers Sometimes vs. rrely (reference) 0.79 ( ) 0.43 Often/very often vs. rrely (reference) 0.58 ( ) 0.09 Sensory symptom t onset Present vs. bsent (reference) 0.56 ( ) 0.02 Only 1 51 out of 219 veterns with progressive MS were included in the model due to missing vlues. Figures in prentheses indicte 95% CI. DX = Dignosis before onset of MS. 14 veterns reported unknown for this vrible. sun exposure (p = 0.01; fig. 1 ). The medin time from disese onset to PDDS 8 ws 20 yers (95% CI: 16 29) for the former group, compred to 29 yers (95% CI: 14 42) for the ltter. Neither verge spring/summer sun exposure before MS onset nor cumultive exposure between the ges of 6 nd 15 were significntly ssocited with time to PDDS 8. Cod liver oil intke nd fish consumption between the ges of 6 nd 15 yers were ssocited with time to PDDS 8. Among prticipnts who ever took cod liver oil before MS onset (n = 26), 1 90% (n = 24) took it between the ges of 6 nd 15; thus, we used the ltter s the exposure period. Figure 1 b shows tht those who ever took cod liver oil reched PDDS 8 lter thn those who never took it (p = 0.01). Subjects, who rrely (less thn once week) te fish t the ge of 6 15, seemed to progress to PDDS 8 fster, lthough it ws not sttisticlly significnt (p = 0.08). Averge fish consumption, vitmin D- relted supplements nd other dietry intke before MS symptom onset, s well s skin type (known to interfere with sun exposure nd vitmin D synthesis), were not ssocited with time to disbility (p ). Covrites, including sensory symptom t onset nd dignosis of mononucleosis, were significntly ssocited with time to disbility (p! 0.05) nd thus considered for the finl model. We used the Cox proportionl hzrd model to exmine sun exposure nd vitmin D intke vribles simultneously, while djusting for selected covrites ( tble 2 ). We included in the model only prticipnts who hd completed dt for both exposure nd outcome vribles (151 out of 219). Subjects with low sun exposure before symptom onset hd bout 2.1 times (hzrd rtio, HR: 2.13, 95% CI: ) the risk of reching PDDS 8 compred to those with higher sun exposure during fll/winter. Conversely, prticipnts who reported tking cod liver oil between the ges of 6 nd 15 yers hd lower risk of reching PDDS 8 (HR: 0.44, 95% CI: ) thn those who never took it. High frequency of fish consumption between the ges of 6 nd 15 hd mrginl protective effect (p = 0.09). In ddition, dignosis of mononucleosis before onset ws ssocited with n incresed risk of progressing to PDDS 8 (HR: 2.65, 95% CI: ), while sensory symptom t onset ws ssocited with decresed risk (HR: 0.56, 95% CI: ). We conducted severl sensitivity nlyses. We compred time to disbility from ge t dignosis, insted of from ge t symptom onset, nd found similr results. Becuse 14 prticipnts replied unknown to the digno- 54 Neuroepidemiology 2011;37:52 57 McDowell /Amr /Culpepper /Lngenberg / Royl /Bever /Brdhm

4 Low 1.6 weeks/yer High >1.6 weeks/yer Never Ever Ptients (%) 50 Ptients (%) Time to disbility (yers) b Time to disbility (yers) Fig. 1. Kpln-Meier estimte of medin time from MS symptom onset to PDDS 8 ccording to studied vribles: verge fll/winter sun exposure before MS symptom onset ( ) nd cod liver oil intke between the ges of 6 nd 15 yers ( b ). sis of mononucleosis, we lterntively ssigned yes or no to the unknowns nd refit the model: no significnt chnge in the results for ny of the vribles in the model. Furthermore, we exmined demogrphic nd clinicl chrcteristics of those who hd completed exposure nd outcome vribles (n = 151) nd compred them to those with missing dt (n = 68); we found no significnt differences. Discussion We investigted the dul influence of sun exposure nd vitmin D-relted intkes before MS onset on disese progression. We found tht mong veterns with progressive MS, low verge fll/winter sun exposure before disese onset ws ssocited with n incresed risk of disbility, wheres cod liver oil intke nd fish consumption during childhood nd dolescence were ssocited with lower risk. Exposures erly in life, probbly relted to mternl levels of vitmin D, were found to hve long-lsting effects on the clinicl course of MS [11 15]. These findings led investigtors to postulte tht ultrviolet rdition nd vitmin D exert their beneficil effects by modulting the development of the nervous system nd/or immune system in the fetus. Our dt extend the previous findings nd suggest tht vitmin D-relted exposures from childhood to the ge t MS onset might lso ffect long-term disese outcomes mong ptients with progressive MS. One previous study investigted the ssocition between disbility in MS nd ultrviolet rdition exposures during childhood (0 16 yers) nd dult life (17 40 yers) mong 448 Cucsin ptients nd did not find ny significnt effects [20]. The discrepncy in the results between tht study nd ours my be due to methodologicl differences including choice of the outcomes (Expnded Disbility Sttus Scle vs. PDDS), exposure mesurements (cumultive sun exposure in specified ge periods vs. verge sun exposure up to the ge t symptom onset) nd sttisticl pproches (logistic regression vs. survivl nlysis). Moreover, the previous study did not control for MS subtype, nd it is likely tht the mjority of the subjects in tht study hd relpsing MS. In our originl study s cohort, the mjority of ptients with relpsing MS hve not reched the disbility level to the studied end points, nd we did not find significnt ssocitions between sun exposure nd disbility (dt not shown). Becuse ptients with relpsing MS represent highly heterogeneous group with respect to clinicl course nd prognosis, it is possible tht the protective effect of sun exposure nd vitmin D intke is diluted nd difficult to detect mong these ptients. The effects re lso potentilly subject to other confounding fctors such s use of disese-modifying therpy. Sun Exposure, Vitmin D Intke nd Progression of MS Neuroepidemiology 2011;37:

5 There is evidence indicting tht vitmin D hs strong neuroprotective effects, nd thus could potentilly be used in the tretment of some neurodegenertive diseses [21]. In MS, neurodegenertive chnges re thought to be the mjor cuses of its progression nd disbility ccumultion [22], lthough utoimmunity nd inflmmtion drive the development of the disese nd its erly ctivities. Therefore, in conjunction with our present finding mong subjects with progressive MS, it is plusible tht the neuroprotective effect of vitmin D could dely disese-relted degenertion in the nervous system nd thus influence long-term disbility in MS. We found tht ptients with history of mononucleosis before their disese onset hd higher risk of progressing to disbility, compred to those with negtive history. Epstein-Brr virus hs been identified s risk fctor for MS [23]. Infectious mononucleosis, n indictor of lte-ge Epstein-Brr virus infection, ws lso ssocited with n incresed risk of MS [24]. However, the role of this infectious gent in disese progression is lrgely unknown, lthough few studies hve suggested tht virl or bcteril infections might trigger excerbtions mong ptients with relpsing-remitting MS [25, 26]. Additionl studies re required to investigte the potentil role of infections, either chronic or recurrent, in long-term MS disbility. Identifying relible MS prognostic fctors hs been chllenging, nd very few hve been consistently reported cross studies. We found tht younger ge t onset, previously considered s good prognostic fctor for MS [27], ws ssocited with longer time to disbility. However, severl studies hve found tht despite longer time to disbility stges, individuls with younger ge t onset reched disbility t younger ge [28, 29], results tht re supported by our finding when we used ge t disbility stge s the study outcome (dt not shown). Our finding tht presence of sensory symptoms t MS onset ws ssocited with better prognosis is consistent with recent study showing the existence of sensory symptoms t onset s min fctor for fvorble prognosis mong ptients with primry progressive MS [28]. Even though we hve identified some vitmin D-relted exposures ssocited with disese progression mong ptients with progressive MS, these results re preliminry nd should be interpreted with cution, considering the reltively smll number of ptients in the finl nlysis nd limittions ssocited with the nture of the study design. Repliction by future studies is required to confirm these findings. Limittions in the present study re potentil recll bis nd mesurement errors relted to self-reported dt. Although we used modified version of questionnire tht ws previously shown to be firly relible mens to record pst sun exposure mong MS nd other disese popultions [3, 30], possible misclssifiction of the sun exposure nd other vribles cnnot be excluded. A cross-sectionl study design is subject to potentil birth cohort effect. Prticipnts who belong to n older birth cohort might hve different exposure ptterns regrding vitmin D intke nd sun exposure compred to those in younger cohorts. In our regression model, we djusted for ge t MS onset nd thus indirectly controlled for potentil birth cohort effect. To ddress the ltter more directly, seprte regression model ws fitted controlling for the prticipnt s current ge (insted of ge t onset). The results showed tht current ge ws not significntly ssocited with time to disbility (p = 0.11) nd the effects of ll exposures remined the sme. Furthermore, despite the fct tht PDDS is useful tool for the ssessment of long-term disbility, it is highly weighted by mbultion functions nd does not consider other signs nd symptoms resulting from disese progression, such s cognitive dysfunction. In summry, the current study suggests protective effects of vitmin D-relted exposures before MS onset on disbility mong veterns with progressive MS. It is possible tht, through its immunomodultory nd/or neuroprotective functions, vitmin D slows disese-relted neurodegenertion, which my hve implictions for disese prevention mong popultions t high risk for MS. These findings, if proven, would hve clinicl implictions in terms of MS prevention mong popultions t risk s well s disese intervention. Only rndomized tril would provide more definitive nswers bout the effects of vitmin D on the progression of MS. Acknowledgement This study ws supported by Merit grnt (Exmining Helth Cre Ptterns nd MS Outcomes with VHA nd Medicre Dt- IIR ) funded by the Deprtment of Vetern Affirs, VHA, Office of Reserch nd Development, HSR & D Service nd the VHA MS Center of Excellence Est. 56 Neuroepidemiology 2011;37:52 57 McDowell /Amr /Culpepper /Lngenberg / Royl /Bever /Brdhm

6 References 1 Vn Amerongen BM, Dijkstr CD, Lips P, Polmn CH: Multiple sclerosis nd vitmin D: n updte. Eur J Clin Nutr 2004; 58: Munger KL, Levin LI, Hollis BW, Howrd NS, Ascherio A: Serum 25-hydroxyvitmin D levels nd risk of multiple sclerosis. JAMA 2006; 296: Vn der Mei IA, Ponsonby AL, Dwyer T, et l: Pst exposure to sun, skin phenotype, nd risk of multiple sclerosis: cse-control study. BMJ 2003; 327: Kmpmn MT, Wilsgrd T, Mellgren SI: Outdoor ctivities nd diet in childhood nd dolescence relte to MS risk bove the Arctic Circle. J Neurol 2007; 254: Islm T, Gudermn WJ, Cozen W, Hmilton AS, Burnett ME, Mck TM: Differentil twin concordnce for multiple sclerosis by ltitude of birthplce. Ann Neurol 2006; 60: Cntorn MT, Hyes CE, De Luc HF: 1,25-Dihydroxyvitmin D 3 reversibly blocks the progression of relpsing encephlomyelitis, model of multiple sclerosis. Proc Ntl Acd Sci USA 1996; 93: Lemire JM, Archer DC: 1,25-dihydroxyvitmin D 3 prevents the in vivo induction of murine experimentl utoimmune encephlomyelitis. J Clin Invest 1991; 87: Muthin G, Rikwr HP, Rjsingh J, Bright JJ: 1,25 Dihydroxyvitmin-D 3 modultes JAK-STAT pthwy in IL-12/IFNgmm xis leding to Th1 response in experimentl llergic encephlomyelitis. J Neurosci Res 2006; 83: Vn Etten E, Brnistenu DD, Overbergh L, Bouillon R, Verstuyf A, Mthieu C: Combintion of 1,25-dihydroxyvitmin D 3 nlog nd bisphosphonte prevents experimentl utoimmune encephlomyelitis nd preserves bone. Bone 2003; 32: Nshold FE, Hog KA, Govermn J, Hyes CE: Rg-1-dependent cells re necessry for 1,25-dihydroxyvitmin D 3 prevention of experimentl utoimmune encephlomyelitis. J Neuroimmunol 2001; 119: Willer CJ, Dyment DA, Sdovnick AD, Rothwell PM, Murry TJ, Ebers GC: Timing of birth nd risk of multiple sclerosis: popultion bsed study. BMJ 2005; 330: Sdovnick AD, Duquette P, Herrer B, Yee IM, Ebers GC: A timing-of-birth effect on multiple sclerosis clinicl phenotype. Neurology 2007; 69: Tremlett HL, Devonshire VA: Does the seson or month of birth influence disese progression in multiple sclerosis? Neuroepidemiology 2006; 26: McDowell TY, Amr S, Lngenberg P, Royl W, Bever C, Culpepper WJ, Brdhm DD: Time of birth, residentil solr rdition nd ge t onset of multiple sclerosis. Neuroepidemiology 2010; 34: McDowell TY, Amr S, Culpepper WJ, et l: Sun exposure, vitmin D nd ge t disese onset in relpsing multiple sclerosis. Neuroepidemiology 2010; 36: Culpepper WJ II, Ehrmntrut M, Wllin MT, Flnnery K, Brdhm DD: Veterns Helth Administrtion multiple sclerosis surveillnce registry: the problem of csefinding from dministrtive dtbses. J Rehbil Res Dev 2006; 43: Hohol MJ, Orv EJ, Weiner HL: Disese steps in multiple sclerosis: simple pproch to evlute disese progression. Neurology 1995; 45: Schwrtz CE, Vollmer T, Lee H: Relibility nd vlidity of two self-report mesures of impirment nd disbility for MS. North Americn Reserch Consortium on Multiple Sclerosis Outcomes Study Group. Neurology 1999; 52: Fitzptrick TB: The vlidity nd prcticlity of sun-rective skin types I through VI. Arch Dermtol 1988; 124: Woolmore JA, Stone M, Pye EM, et l: Studies of ssocitions between disbility in multiple sclerosis, skin type, gender nd ultrviolet rdition. Mult Scler 2007; 13: Grcion E, Wion-Brbot N, Montero-Menei CN, Berger F, Wion D: New clues bout vitmin D functions in the nervous system. Trends Endocrinol Metb 2002; 13: Huser SL, Oksenberg JR: The neurobiology of multiple sclerosis: genes, inflmmtion, nd neurodegenertion. Neuron 2006; 52: Ascherio A, Munger KL: Environmentl risk fctors for multiple sclerosis. I. The role of infection. Ann Neurol 2007; 61: Thcker EL, Mirzei F, Ascherio A: Infectious mononucleosis nd risk for multiple sclerosis: met-nlysis. Ann Neurol 2006; 59: Edwrds S, Zvrtu M, Clrke H, Irving W, Blumhrdt LD: Clinicl relpses nd disese ctivity on mgnetic resonnce imging ssocited with virl upper respirtory trct infections in multiple sclerosis. J Neurol Neurosurg Psychitry 1998; 64: Csett I, Grnieri E: Clinicl infections nd multiple sclerosis: contribution from nlyticl epidemiology. J Neurovirol 2000; 6(suppl 2):S147 S Lublin FD: Clinicl fetures nd dignosis of multiple sclerosis. Neurol Clin 2005; 23: Koch M, Kingwell E, Rieckmnn P, Tremlett H: The nturl history of primry progressive multiple sclerosis. Neurology 2009; 73: Vukusic S, Confvreux C: Nturl history of multiple sclerosis: risk fctors nd prognostic indictors. Curr Opin Neurol 2007; 20: Krgs MR, Zens MS, Nelson HH, et l: Mesures of cumultive exposure from stndrdized sun exposure history questionnire: comprison with histologic ssessment of solr skin dmge. Am J Epidemiol 2007; 165: Sun Exposure, Vitmin D Intke nd Progression of MS Neuroepidemiology 2011;37: