July 16, 2012 (Prague, Czech Republic) — Low vitamin D levels in patients with clinically isolated syndromes (CIS) predict a near-term conversion to clinically definite multiple sclerosis (CDMS), meaning a confirmed diagnosis of multiple sclerosis (MS).
Presenting trial results here at the 22nd Meeting of the European Neurological Society (ENS), Vittorio Martinelli, MD, from the Neurological Unit and the Multiple Sclerosis Centre at San Raffaele Scientific Institute in Milan, Italy, said that the presence of at least 3 negative prognostic factors confers a 5-fold higher risk for conversion among these patients. He also showed evidence that women with low levels of vitamin D are more at risk than are men.
The term CIS has been used to describe a first neurologic episode lasting at least 24 hours caused by inflammation/demyelination at 1 (monofocal) or more (multifocal) sites in the central nervous system (CNS).
Various studies have shown a geographical gradient of MS prevalence, with higher prevalence in regions farther from the equator, and the intensity of sun exposure is less in these regions. Sun exposure is a factor in the conversion of dietary vitamin D to its active form in the skin. Similarly, studies have shown an association of vitamin D supplement intake with a lower risk for MS, as well as lower risk with higher serum 25-hydroxyvitamin D [25(OH)D] levels. One putative mechanism for these findings is the immunomodulatory effects of vitamin D on macrophages and dendritic cells and their influence on the activity of effector and memory T cells and on B cells and antibody-secreting cells.
In their retrospective study, Dr. Martinelli and colleagues measured baseline levels of 25(OH)D levels in patients with CIS at the time of hospital admission and correlated them with the development of CDMS. The study included patients aged 18 to 60 years who were discharged from San Raffaele Hospital with a diagnosis of CIS between January 2000 and December 2008 and for whom a serum sample was available from the time of admission.
The 70 women and 37 men in the study had a mean age of 34.1 ± 8.0 years and a mean follow-up period of 7.0 years; 70% had monofocal clinical onset. Baseline brain magnetic resonance imaging (MRI) showed that 11% had fewer than 2 T2 lesions, 17% had 2 to 3 lesions, 42% had 4 to 9 lesions, and 30% had more than 9 lesions.
Dr. Martinelli showed evidence of seasonal variation in serum 25(OH)D levels, with a peak in these Italian patients in September and a nadir in March. Fifty-three percent of the patients had vitamin D deficiency (<20 ng/mL), 22% had vitamin D insufficiency (20 - 30 ng/mL), and 25% had normal values (>30 ng/mL), he reported.
At 12 months, 21.5% of the patients had converted from CIS to CDMS. At 24 months, 36.5% had converted, and at 60 months, 44.2% had converted. Low levels of 25(OH)D were associated with a high risk for CDMS (P = .038).
The patients in the lowest quartile of vitamin D levels experienced the highest rate of conversion to CDMS; the rate decreased through the third quartile, but for unexplained reasons, the rate of conversion among patients with the highest vitamin D levels was not much different from that of patients with the lowest level (see table below). The time to develop CDMS was longer in the upper 3 quartiles of vitamin D level compared with the lowest quartile (P = .01).
The patients who developed CDMS had lower serum vitamin D levels in the summer months than did the patients who did not convert (P = .019). "The patients with the multifocal symptoms had lower vitamin D levels than patients with monofocal symptoms, especially during summertime," Dr. Martinelli said.
Sex also appeared to play a role in the development of CDMS. "Considering the patients with vitamin D deficiency — that is, the patients with the lowest value of vitamin D, and more than half of our patients are in this group — 70% of females developed clinically definite multiple sclerosis vs only 42% of males,” Dr. Martinelli said. He suggested that a possible synergy between vitamin D and estrogens could account for the greater incidence of MS among women.
The number of MRI T2 lesions at baseline also appeared to be predictive of CDMS. For patients with fewer than 9 lesions, the conversion rate to CDMS was 50% vs 66% for the patients with 9 or more lesions. The level of 25(OH)D added a prognostic contribution to the MRI data. For patients with fewer than 9 lesions, 67% of those with the lowest levels of vitamin D developed CDMS vs 41% who had vitamin D levels in the combined top 3 quartiles. For patients with 9 or more T2 lesions, 70% in the bottom vitamin D quartile converted to CDMS vs 60% of those in the top 3 quartiles.
An approximately similar prognostic pattern emerged when vitamin D levels were combined with the presence or absence of oligoclonal bands in cerebrospinal fluid (CSF). Of 105 CIS patients, 26% lacked oligoclonal bands. For these patients with the highest vitamin D levels, only 7% developed CDMS vs 33% with the lowest levels. For the 67% of patients who tested positive for oligoclonal bands, 62% with higher vitamin D levels converted to CDMS vs 76% of patients in the lowest quartile of vitamin D levels.
In summary, Dr. Martinelli said several factors predicted the short-term risk of developing CDMS, including the presence of oligoclonal bands in CSF (P < .05) and multifocal vs monofocal clinical onset (P < .01). Lower vitamin D levels were associated with a shorter interval to a second clinical attack (P < .05). Other prognostic factors were multimodal evoked potential abnormalities (P < .05) and the presence of periventricular lesions on brain MRI at baseline (P < .01).
He concluded that 75% of Italian patients with CIS have low levels of vitamin D at clinical onset, and these patients are at increased risk of developing CDMS. In addition, women with low levels are at greater risk than are men. So vitamin D levels have prognostic value in CIS patients. He calculated that the presence of at least 3 negative prognostic values is highly predictive of conversion to CDMS in the near term (odds ratio, 5.39; P < .005).
Session moderator Xavier Montalban, MD, PhD, chairman of the Department of Neurology and director of the Multiple Sclerosis Center of Catalonia at Vall d'Hebron University Hospital and professor of neurology at the Autonomous University of Barcelona in Barcelona, Spain, who was not involved in the study, commented toMedscape Medical News that it is becoming increasingly clear that vitamin D plays a role in the genesis or evolution of MS.
"If this means that we have to make a global preventive plan giving vitamin D to the whole population at highest risk, we still don't know, or if we have to measure vitamin D levels in our patients with MS and treat those patients with low levels — that's a good question that is being now studied," he said. He speculated that vitamin D supplementation may be able to slow the progression of the disease or decrease the number of relapses.
Dr. Montalban said the prevalence of MS has doubled in the past 50 years, "so apart from vitamin D, which is important, there are other factors that escape our knowledge."
He noted that it was not clear from the presentation whether vitamin D levels were an independent predictor of conversions to CDMS. "So I didn't understand if they performed a logistic regression analysis that [showed vitamin D] was independent from the MRI status.... So some statistical analysis should be performed," he advised.
Table: Proportion of Patients Converting to CDMS
| Serum 25(OH)D Level (ng/mL) | Conversion to CDMS |
| <13.3 | 72% |
| 13.3 - 19.3 | 52% |
| 19.3 - 27.8 | 36% |
| >27.8 | 60% |
Dr. Martinelli and Dr. Montalban have disclosed no relevant financial relationships.
22nd Meeting of the European Neurological Society (ENS). Abstract O-291. Presented June 11, 2012.
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