Neurology -- Correspondence for Munger et al., 62 (1) 60-65

Correspondence published:

Vitamin D intake and incidence of multiple sclerosis: George C. Ebers, A. D. Sadovnick and Reinhold Veith (19 February 2004)

Reply to Ebers et al: Kassandra L Munger, Eilis O'Reilly, Alberto Ascherio (19 February 2004)

Vitamin D intake and incidence of multiple sclerosis 19 February 2004

George C. Ebers,
University of Oxford
Radcliffe Infirmary Woodstock Rd, Oxford UK OX2 6HE,
A. D. Sadovnick and Reinhold Veith
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Re: Vitamin D intake and incidence of multiple sclerosis

george.ebers{at}clneuro.ox.ac.uk George C. Ebers, et al.

We read with interest the article by Munger et al. A protective effect of sunlight on MS risk was first suggested by Acheson. [1] Vitamin D is a potential mediator of this relationship. We are sympathetic to the hypothesis being tested [2] by Munger et al. but have the following concerns:
1) NHS studied women age >30, but more than half of females with MS have onset below this age. Of those accrued, some 50,000 were excluded from analysis. [3] Was this done before testing the vitamin D hypothesis? What were the characteristics, when known, of exclusions for calculated vitamin D estimates compared to those retained? Perhaps MS risk can be altered after age 30, but earlier ages are implicated from migration studies.
2) 61 and then 130 questions were asked in the NHS and NHS II questionnaires. Was correction made for multiple analyses? Could the authors explain the assumptions and approach used to calculate the "p trend" statistic that forms the basis of this report?
3) The apparent association of low MS risk with intake of <400 units of vitamin D from supplements per day seems at odds with the recent report that those intakes of supplements have minimal effects on 25(OH)D levels. Furthermore, young women who took multivitamins were more likely to exercise outdoors. Multivitamin use correlated better with summer 25(OH)D levels than winter 4. Vitamin D production in the skin requires UVB that is not intense enough at latitudes >30 for at least one month each winter.
4) The association of MS with latitude seems unambiguous from Kurtzke�s US veteran�s studies and from Australia.[5] The lack of interaction with latitude in this study [3] is surprising if vitamin D intake in adulthood is causally related to MS risk, since D levels and putative functional effects are dependent on latitude related UVB.
5) We note that the NHSII cohort had more MS �cases /person �y� (97/7.5x10 5) compared to the NHS cohort (76/1.5x106). These data are difficult to compare. As age specific incidences seem less in NHSII3, is there evidence for a decreasing incidence or prevalence in the areas surveyed?
6) How does the nurses� D intake relate to that in the general population? Vitamin intake could vary by ethnicity. Did the definition of �white� include ethnic groups known to be resistant to MS? Recall bias has been reported within weeks of illness associated events. Has the accuracy of four yearly reports been validated for the measures in this paper?
References
1. Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation and other variables. Acta Psychiat (Scand.) 1960; 35 Suppl 147: 132.
2. Steckley J, Dyment D, Sadovnick D, Risch N, Hayes C, Ebers GC and the Canadian Collaborative Study Group. Genetic analysis of vitamin D related genes in multiple sclerosis patients. Neurology 2000; 54:729-732.
3. Hernan MA, Olek MJ, Ascherio A. Geographic variation of MS incidence in two prospective studies of US women. Neurology 1999; 53:1711 -1718.
4. Vieth R, Cole DE, Hawker GA, Trang HM, Rubin LA. Wintertime vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it. Eur J Clin Nutr 2001; 55:1901-1097.
5. Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000; 123:968-974.

Reply to Ebers et al 19 February 2004

Kassandra L Munger,
Department of Nutrition, Harvard School of Public Health
665 Huntington Ave, Boston MA 02115,
Eilis O'Reilly, Alberto Ascherio
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Re: Reply to Ebers et al

kgorham{at}hsph.harvard.edu Kassandra L Munger, et al.

We thank Ebers et al for their interest in our study. We excluded women with an incomplete baseline food frequency questionnaire. This exclusion was made a priori following the same rules used in all previous dietary analyses in these cohorts. Adjustment for multiple analyses in our study was not necessary as only two measures of vitamin D intake were considered: the combined amount of vitamin D intake from food and from supplements. The P for trend was calculated using a proportional hazards regression model using the median intake values for each category of vitamin D from food or supplements as a continuous variable. This method tests the overall null hypothesis that vitamin D intake is unrelated to risk of MS without any specific assumptions.
In contrast with the results of Vieth et al [4] quoted by Ebers et al, in a sub-study among 323 healthy women from the NHS cohort, we found that vitamin D intake at levels below 400 IU does increase 25(OH)D levels. Average winter plasma levels of 25(OH)D were positively correlated with levels of vitamin D intake: 40 nmol/L in the lowest quintile of intake (median=108 IU), 55 nmol/L in the third quintile (median=301 IU), and 70 nmol/L in the highest quintile (median=703 IU). Further, in our cohorts, the association between vitamin D intake from supplements and risk of MS was not materially altered by adjustment for physical activity (unpublished data).
The women in the NHS cohort are older than those in the NHSII cohort and because of modest overlap between the two cohorts, age-specific incidence rates are difficult to compare. Further, the increasing use of MRI may reduce the time between onset of MS and diagnosis, possibly causing spurious changes in incidence rates.
The nurses� intake of vitamin D is similar to that of women in other US cohort studies. [6] Race was self-reported and �White� did not include ethnic groups with low risk of MS.
The lack of significant interaction between latitude and vitamin D in our study may be explained by the insufficient power to detect such an interaction.
As this was a prospective study, recall bias was not of concern as none of the women had MS or MS symptoms when completing the food frequency questionnaires.
References
6. Merlino LA, Curtis J, Mikuls TR, et al. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women�s Health Study. Arthritis and Rheumatism 2004; 50:72-77.