In patients with multiple sclerosis (MS), low vitamin D levels and smoking are associated with worse long-term cognitive function and neuronal integrity, according to study results published in Neurology.

Previous studies reported that low vitamin D, cigarette smoking, and elevated antibodies against Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA-1) are risk factors for MS. However, it is not clear whether these factors can predict long-term cognitive status. The researchers previously reported on an association between higher vitamin D levels and fewer active lesions and less brain atrophy during 5 years of follow-up.  In the current study, they extended the follow-up to 11 years and assessed the importance of vitamin D, smoking, and anti-EBNA-1 antibodies as predictors of long-term cognitive function and neuroaxonal integrity.

BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment; Identifier: NCT00185211) was a multicenter, double-blind, phase 3 clinical trial of early vs delayed treatment with interferon beta-1b in patients with clinically isolated syndrome (CIS).

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The current study included 278 patients who completed the 11-year examination (BENEFIT-11; Identifier: NCT01795872). Serum biomarkers of vitamin D (25-hydroxyvitamin-D [25(OH)D]), smoking (cotinine), and EBV infection (EBNA-1 IgG) were measured at baseline and at 6, 12, and 24 months, and vitamin D was also assessed at 54 and 60 months. Cognitive function was assessed during neurologic examinations at baseline and repeatedly throughout the follow-up via the Paced Auditory Serial Addition Test (PASAT)-3 and neurofilament light chain (NfL) concentrations at 11 years.

Individuals with higher 25(OH)D during the first years following a CIS were less likely to score below the median in the PASAT performed at year 11. A 50-nmol/L higher mean level within the first 24 months after CIS was associated with 65% lower odds of obtaining a below median PASAT score at year 11 (adjusted odds ratio, 0.35; 95% CI, 0.14-0.89; P =.027).

Overall, smoking tended to predict worse long-term cognitive function, although the associations did not reach statistical significance in all analyses. Smokers tended to have worse long-term cognitive performance corresponding to clinically meaningful 5.4 points on the PASAT, most pronounced among patients considered heavy smokers (cotinine consistently >193 ng/mL).

There was no association between baseline anti-EBNA-1 IgG antibodies and PASAT scores.

The associations with long-term neuronal integrity corroborated the main findings regarding long-term cognitive performance: higher vitamin D levels were protective against neuroaxonal loss, as a 50 nmol/L higher mean 25(OH)D level in the first 2 to5 years was associated with a 20% lower serum NfL. Smoking within the first 24 months from onset was associated with a 20% higher NfL at year 11. Once more, there was no association between quartiles of anti-EBNA-1 IgG indices and 11-year NfL concentrations.

The researchers acknowledged several study limitations, including the population being limited to White patients, inability to assess the effects of even higher vitamin D levels (~100 nmol/L), and the limitations of the PASAT. In addition, the researchers noted the potential underestimation of the effect of smoking as ever-smokers were misclassified as nonsmokers if the patients quit smoking at or before CIS.

“These results suggest that correcting vitamin D insufficiency and abstaining from cigarette smoking after clinical MS onset might protect long-term cognitive function and CNS integrity,” concluded the researchers.

Disclosure: This clinical trial was supported by Bayer. Please see the original reference for a full list of authors’ disclosures.


Cortese M, Munger KL, Martínez-Lapiscina EH, et al; on behalf of the BENEFIT Study Group. Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT. Neurology. 2020;94(18):e1950‐e1960. doi:10.1212/WNL.0000000000009371