Neurol Sci DOI 10.1007/s10072-015-2229-7

LETTER TO THE EDITOR

Reduced serum vitamin D levels in neuromyelitis optica ¨ zlem Ku¨c¸u¨khu¨seyin2 • Murat Ku¨rtu¨ncu¨3 • Recai Tu¨rkog˘lu4 Erdem Tu¨zu¨n1 • O I˙lhan Yaylım2



Received: 8 October 2014 / Accepted: 20 April 2015 Ó Springer-Verlag Italia 2015

Dear Sir, Vitamin D deficiency has been associated with several autoimmune disorders and increased autoimmune responses in healthy individuals. One of many potential factors underlying this association is the well-established anti-inflammatory action of vitamin D administration resulting in reduced proinflammatory cytokine production and enhanced regulatory T cell activity [1]. Although vitamin D deficiency is well known in multiple sclerosis (MS) [2], its significance in neuromyelitis optica (NMO), another autoimmune disease of the central nervous system (CNS), is less well understood. NMO, NMO spectrum disorder and recurrent transverse myelitis patients have been recently shown to display reduced vitamin D levels [3, 4]. Although, these studies have shed some light on the impact of vitamin D on NMO pathogenesis, associations between vitamin D levels and clinical–demographic features of NMO patients are yet to be characterized. In this study, 25-hydroxy vitamin D (25OH-VitD) levels were measured in sera of 24 NMO patients (20 women, 4 men; mean age ± standard deviation, 41.3 ± 11.6 years) & Erdem Tu¨zu¨n [email protected] 1

Department of Neuroscience, Institute for Experimental Medical Research (DETAE), Istanbul University, Vakif Gureba Street, Capa, 34390 Istanbul, Turkey

2

Department of Molecular Medicine, Institute for Experimental Medical Research (DETAE), Istanbul University, Istanbul, Turkey

3

Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

4

Department of Neurology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey

satisfying NMO diagnostic criteria [5] and age–gender matched controls (19 relapsing remitting MS patients and 22 healthy individuals) by an ELISA kit (DLD Diagnostika, Hamburg, Germany), as per manufacturer’s instructions. Measurements were made in the archived sera obtained during relapses prior to steroid treatment. Patients and controls who had received vitamin D supplementation at any time were not included. None of the NMO patients had a monophasic disease course or a concomitant autoimmune disease. All NMO patients had received pulse methylprednisolone treatment during attacks and azathioprine to prevent relapses. Serum aquaporin-4 antibody (Aqp-4 Ab) was investigated by a cell-based assay (Euroimmun, Luebeck, Germany). 25OH-VitD level differences were adjusted for age, gender, season during blood sampling (winter, spring, summer or fall) and EDSS scores by linear regression analysis. Since all patients belonged to the same ethnicity and were living in cities located on the same latitude, no statistical adjustment was done for these parameters. Both NMO and MS patients had significantly lower serum 25OH-VitD levels than healthy controls (p = 0.025 by ANOVA) (Fig. 1a). After adjusting for age, gender, season and EDSS, 25OH-VitD levels were still significantly lower in patients (p = 0.032, 95 % confidence interval 5.7–13.8). While gender and Aqp-4 Ab status did not affect 25OH-VitD levels, NMO patients with shorter disease duration (\10 years) and with cerebrospinal fluid oligoclonal bands (OCB) showed significantly lower 25OH-VitD levels (p = 0.017 and p = 0.046 by Student’s t test, respectively) (Table 1). Pearson’s test revealed a modest correlation between serum 25OH-VitD levels and disease duration in NMO (Fig. 1b). No significant correlation could be found between 25OH-VitD levels and age (p = 0.162, R = 0.211), number of relapses (p = 0.071, R = 0.309) and EDSS values (p = 0.262, R = 0.137) of NMO patients.

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Neurol Sci

Fig. 1 Neuromyelitis optica (NMO) and multiple sclerosis (MS) patients display significantly lower serum levels of 25-hydroxy vitamin D (ng/ml) as compared to healthy controls (a), horizontal

lines indicate mean values and asterisk denotes p \ 0.05 by Tukey’s post hoc test. Serum 25-hydroxy vitamin D (ng/ml) levels of NMO patients show a modest correlation with disease duration (years) (b)

Table 1 Comparison of serum 25OH-VitD levels (ng/ml) among different subgroups of neuromyelitis optica (NMO) patients Subgroup A (25OH-VitD level ± SE)

Subgroup B (25OH-VitD level ± SE)

p value for subgroup A vs. B by Student’s t test

Female (n = 20) (21.5 ± 2.3)

Male (n = 4) (14.8 ± 2.9)

0.117

Aqp-4 Ab? (n = 12) (19.2 ± 2.9)

Aqp-4 Ab? (n = 12) (21.5 ± 2.9)

0.310

Disease duration \10 years (n = 13) (16.6 ± 1.6)

Disease duration C10 years (n = 11) (25.6 ± 3.4)

0.017

OCB? (n = 6) (13.3 ± 3.8)

OCB- (n = 18) (21.6 ± 2.2)

0.046

Bold numbers indicate statistically significant p values SE standard error, Aqp-4 Ab aquaporin-4 antibody, OCB oligoclonal bands

Our results support previous studies that have shown vitamin D deficiency in autoimmune disorders and further identify disease duration and OCB positivity as potential determinants of vitamin D levels. Direct correlation between disease duration and 25OH-VitD levels might be explained with the fact that longer exposure to immunosuppressants is presumably reverting vitamin D-related pathway alterations induced by chronic autoimmunity. Vitamin D deficiency is known to promote anti-myelin autoimmunity [6]. Whether this might lead to autoreactive B cell increase in the intrathecal compartment and OCB positivity in 25OH-VitD-deficient NMO patients requires to be investigated. In contrast with our findings recent studies have found no significant correlation with disease duration and vitamin D levels [3]. Potential reasons for this discrepancy are different patient inclusion criteria (e.g., recurrent transverse myelitis vs. NMO patients) and ethnic–geographical differences. In all likelihood, the demonstration of an association between vitamin D and NMO does not necessarily imply a cause–effect relationship and 25OH-VitD deficiency might simply be a marker of chronic disease rather than a causative factor. Future studies focused on vitamin D supplementation of NMO patients might unravel the exact mechanisms by which vitamin D impacts the immune system functions.

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Conflict of interest

The authors report no conflict of interest.

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Reduced serum vitamin D levels in neuromyelitis optica.

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