J Neurol (2013) 260:832–838 DOI 10.1007/s00415-012-6712-2
ORIGINAL COMMUNICATION
Decreased serum vitamin D in idiopathic benign paroxysmal positional vertigo Seong-Hae Jeong • Ji-Soo Kim • Jong Wook Shin • Sungbo Kim Hajeong Lee • Ae Young Lee • Jae-Moon Kim • Hyunjin Jo • Junghan Song • Yuna Ghim
•
Received: 9 August 2012 / Revised: 3 October 2012 / Accepted: 5 October 2012 / Published online: 25 October 2012 Ó Springer-Verlag Berlin Heidelberg 2012
Abstract Previous studies have demonstrated an association of osteopenia/osteoporosis with idiopathic benign paroxysmal positional vertigo (BPPV). Since vitamin D takes part in the regulation of calcium and phosphorus found in the body and plays an important role in maintaining proper bone structure, decreased bone mineral density in patients with BPPV may be related to decreased serum vitamin D. We measured the serum levels of 25-hydroxyvitamin D in 100 patients (63 women and 37 men, mean age ± SD = 61.8 ± 11.6) with idiopathic BPPV and compared the data with those of 192 controls (101 women and 91 men, mean age ± SD = 60.3 ± 11.3) who had lived in the same community without dizziness or
S.-H. Jeong J. W. Shin S. Kim A. Y. Lee J.-M. Kim H. Jo Department of Neurology, Chungnam National University College of Medicine, Chungnam National University Hospital, Daejeon, Korea J.-S. Kim (&) Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea e-mail:
[email protected] H. Lee Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea J. Song Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea Y. Ghim Division of Health and Nutrition Survey, Osong Health Technology Administration Complex, Chungbuk, Korea
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imbalance during the preceding year. The selection of the controls and acquisition of clinical information were done using the data from the Fourth Korean National Health and Nutrition Examination Survey, 2008. The serum level of 25-hydroxyvitamin D was lower in the patients with BPPV than in the controls (mean ± SD = 14.4 ± 8.4 versus 19.1 ± 6.8 ng/ml, p = 0.001). Furthermore, patients with BPPV showed a higher prevalence of decreased serum vitamin D (\20 ng/ml, 80.0 vs. 60.1 %, p \ 0.001) than the controls. Multiple logistic regression analyses adjusted for age, sex, body mass index, hypertension, diabetes, proteinuria, regular exercise and the existence of decreased bone mineral density demonstrated that vitamin D insufficiency (10–20 ng/ml) and deficiency (\10 ng/ml) were associated with BPPV with the odds ratios of 3.8 (95 % confidence interval = 1.51–9.38, p = 0.004) and 23.0 (95 % confidence interval = 6.88–77.05, p \ 0.001). Our study demonstrated an association between idiopathic BPPV and decreased serum vitamin D. Decreased serum vitamin D may be a risk factor of BPPV. Keywords Benign paroxysmal positional vertigo Vertigo Nystagmus Vitamin D
Introduction Benign paroxysmal positional vertigo (BPPV) is one of the most common vestibular disorders [1]. The mechanism of BPPV has well been established as free-floating otolith debris (canalolithiasis) [2] or debris attached to the cupula (cupulolithiasis) [3]. Until now, advanced age, head trauma, various disorders affecting the inner ear, and female sex are known predisposing factors of BPPV. However, there is a paucity of data on the underlying cause
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of otoconial degeneration and detachment from the otoconial beds. The otoconia are composed of calcium carbonate as calcite crystals and an organic core consisting predominantly of glycoproteins [4, 5]. Recently, we reported that the prevalence of osteopenia/osteoporosis was higher in both women and men with idiopathic BPPV than in controls [6]. These findings suggest a deranged calcium metabolism in idiopathic BPPV. In a number of epithelia, transmural absorption of Ca2? is modulated by a set of genes that encodes the epithelial Ca2? channel transport system. This system includes the apical entry channels (TRPV5 and TRPV6), the cytosolic Ca2? buffering proteins (calbindin-D9 K and calbindin-D28 K), and the basolateral Ca2?-extruding transporters (sodium–calcium exchangers and plasma membrane calcium ATPases) [7]. A recent experimental study demonstrated that all components of this epithelial Ca2? channel transport system are expressed as transcripts in the semicircular canal duct and cochlea. Even though lesser than the bone, the utricular otolith is also generated by dynamic Ca2? uptake, and this process is related to Ca2?-binding proteins that are up-regulated by vitamin D. In addition, while the wild type mice have robust vitamin D receptor expression in the vestibular organs, the mice without vestibular D receptor show vestibular dysfunction [8–10]. Based on these findings, we hypothesized that low serum vitamin D could be associated with development of BPPV.
Methods Study design and patients At the dizziness clinic of the Chungnam National University Hospital, 100 consecutive patients, 63 women (age range = 26–81 years, mean ± SD = 60.0 ± 12.2 years) and 37 men (age range = 42–83 years, mean ± SD = 64.8 ± 9.7 years), with a diagnosis of idiopathic BPPV had been recruited between September 2010 and May 2011, after excluding 26 patients with a history of inner ear diseases, four patients with a history of head trauma during the preceding month, and three patients who declined the study. Eighty-four patients who reported a typical history suggestive of BPPV but did not exhibit positional nystagmus during the positional maneuvers were also excluded. We compared the serum levels of 25-hydroxyvitamin D in the patients with those of 192 community-based controls without dizziness or imbalance within 1 year. The control data were obtained from the Fourth Korea National Health and Nutrition Examination Survey, 2008, which had been previously conducted by the Korea Centers for Disease Control and Prevention. Since immobilization due to
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dizziness itself may affect the serum vitamin D level, we also compared serum vitamin D levels among the controls and 397 persons who were excluded from the controls because of a history of vertigo/dizziness or imbalance during the preceding year. This comparison also allowed us to determine the effect of possible selection bias from excluding the controls with a history of dizziness and imbalance irrespective of underlying etiologies. This study received an approval from Institutional Review Board of Chungnam National University Hospital. Selection of the control group The controls were selected from the data base of the National Survey based on the following criteria: (1) no history of vertigo/dizziness or imbalance within one year, (2) measurement of bone mineral density and serum vitamin D, and (3) living in Daejeon city and Chungchung province. Of the 10,065 national survey responders (2008), 193 community-based controls met the above inclusion criteria. Neurotological evaluation All patients underwent detailed evaluation for spontaneous nystagmus, vibration-induced nystagmus, head-shaking nystagmus, hyperventilation-induced nystagmus, and positional nystagmus in addition to routine neurological examination. Examinations of the patients were conducted by a trained neurotologist (SHJ) and two residents (JWS and SBK) who had training for more than three years in the neurology department. Positional maneuvers included (1) bending the head toward the knees while sitting, (2) lying down from a sitting upright posture, (3) turning the head to either side while supine, (4) sitting up from supine, (5) straight head hanging, and (6) the Dix-Hallpike maneuver to either side. A diagnosis of BPPV was based on (1) a history of a brief episode of vertigo induced by head motion, (2) a typical positioning nystagmus characteristic of BPPV, and (3) no other identifiable disorders of the central nervous system. When the nystagmus suggested that two or more canals were involved (different patterns of nystagmus depending on the provoking positional maneuvers), the mixed type BPPV was diagnosed. When repeated canalith repositioning maneuvers did not result in resolution of the symptoms and positional nystagmus, brain imaging was performed to rule out central pathologies [6]. Recurrent BPPV was defined when the patients reported two or more previous episodes of positional vertigo similar to those experienced at the time of diagnosis, at least one month apart [6].
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Measurement of serum vitamin D Fasting early morning venous blood was collected from patients and controls to measure serum 25-hydroxyvitamin D. In the patients, the serum level of 25-hydroxyvitamin D was measured using a chemiluminescence immunoassay (CLIA) on Liaison equipment (DiasorinÒ, USA). Since the serum concentration of 25-hydroxyvitamin D was measured with 125I-radioimmunoassay (RIA, DiasorinÒ, USA) in the controls, we standardized the values using the central laboratory data. For standardization, we got a regression equation between the CLIA and LC–MS/MS by measuring serum vitamin D in 40 samples using both methods and we also obtained another regression equation between the RIA and LC–MS/MS with the same procedures. Using both equations, we finally deducted the regression equation between CLIA and RIA methods, and converted the CLIA values to RIA values using this final regression equation; CLIA = 1.119 9 RIA - 1.887. These standardization procedures followed the CLSI EP-9 guidelines recommended by the Clinical and Laboratory Standards Institute Consensus Process [11]. The serum vitamin D level was classified as normal ([20 ng/ml), insufficient (10–20 ng/ml), or deficient (\10 ng/ml) [12–14]. Bone densitometry Bone densitometry (BMD) was performed using dual x-ray absorptiometry (HologicÒ, USA) in the lumbar spine and femur. Detailed methods have been described previously [6]. Osteoporosis was determined when the T score was -2.5 or less [15]. Statistical analyses Statistical analyses included v2 test for dichotomous variables and t test for continuous variables for comparison among the groups. Multiple logistic regression analyses were adjusted for the same relevant covariates. All tests were performed using SPSS (version 17.0, SPSS, Chicago, IL), and p \ 0.05 was considered significant.
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evaluation varied from 1 to 14 days (mean = 5.8, median = 1.0). Most (82 %) of the patients were evaluated within a week from the symptom onset. There was no difference either in the age and sex ratio between the patients and controls (Table 1). The BMI was rather higher in the patients (24.9 ± 3.4 vs. 23.3 ± 3.6, p = 0.001). Characteristics of BPPV BPPV most commonly involved the posterior canal (n = 51, 51 %), which was followed by the horizontal (n = 39, 39 %) and anterior canal (n = 8, 8 %). In two patients (2 %), both posterior and horizontal canals were affected. Isolated horizontal canal BPPV included 22 geotropic and 17 apogeotropic types. Recurrent attacks of BPPV were reported in 44 patients. 25-hydroxyvitamin D Serum level of 25-hydroxyvitamin D was lower in the patients with BPPV than in the controls (mean ± SD = 14.4 ± 8.4 vs. 19.0 ± 6.8 ng/ml, p = 0.001), both in men (16.2 ± 8.9 vs. 19.1 ± 6.8 ng/ml, p = 0.048) and women (13.4 ± 8.0 vs. 18.9 ± 6.7 ng/ml, p \ 0.001). Furthermore, the patients with BPPV showed a higher prevalence of decreased serum vitamin D (\20 ng/ml, 80.0 vs. 60.4 %, p \ 0.001, Fig. 1) than the controls. However, these features were not observed in the 397 community inhabitants who were excluded from the controls due to an experience of dizziness or imbalance during the preceding year (mean ± SD = 18.1 ± 6.8 vs. 19.0 ± 6.8 ng/ml, p [ 0.05). In the patients, the vitamin D level did not differ between the recurrent and de novo groups. Bone mineral densitometry The proportions of osteoporosis (T score B -2.5, 45.0 vs. 9.4 %, p \ 0.001) were higher in patients with BPPV than in controls. Multiple logistic regression analysis
Results Demographic characteristics The patients comprised of 63 women and 37 men (femaleto-male ratio = 1.7:1). The patient age ranged from 26 to 83 years (mean age ± SD = 61.8 ± 11.6 years). The BPPV most commonly occurred in the sixth decade of life in both women and men, but the mean age was slightly higher in men than in women (64.8 ± 9.7 vs. 60.0 ± 12.2, p = 0.044). The duration of symptoms until the initial
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Multiple logistic regression analyses adjusted for age, sex, BMI, the existence of decreased bone mineral density, vitamin supplements, diabetes, hypertension, proteinuria and regular exercise demonstrated that vitamin D insufficiency and deficiency were associated with BPPV with the odds ratios of 3.8 (95 % confidence interval = 1.51–9.38, p = 0.004) and 23.0 (95 % confidence interval = 6.88–77.05, p \ 0.001). Osteoporosis and increased BMI were also risk factors for BPPV (Table 2, Model 2). Even after excluding the decreased BMD from the variables, the association between BPPV and vitamin D
J Neurol (2013) 260:832–838 Table 1 Clinical characteristics of patients and controls
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Characteristics
BPPV (n = 100)
Controls (n = 192)
p value
Age, mean ± SD (years)
61.8 ± 11.6
60.3 ± 11.3
[0.05
Male sex (%)
37 (37.0)
92 (47.4)
[0.05
BMI (kg/m2)
24.9 ± 3.4
23.3 ± 3.6
0.001
25-hydroxyvitamin D (ng/ml)
14.4 ± 8.4
19.1 ± 6.8
0.001
Bone mineral density
<0.001
Normal
24 (24.0)
91 (47.4)
Osteopenia
31 (31.0)
83 (43.2)
Osteoporosis (%)
45 (45.0)
18 (9.4)
Yes (%)
22/100 (22.0)
33/173 (19.1)
Missing
0
19
10/100 (10.0)
21/192 (10.9)
[0.05
36 (36.0)
51/192 (26.6)
[0.05 [0.05
Vitamin supplements
BPPV benign paroxysmal positional vertigo, BMI body mass index, the body mass index is the weight in kgs divided by the square of the height in meters. SD standard deviation p values were calculated using independent t test or Chi-square test Bold values indicate statistical significance (p \ 0.05)
[0.05
Diabetes Yes (%) Hypertension Yes (%) Proteinuria Mild (trace to 1?)
10 (10)
15/183 (8.2)
Heavy (2? to 4?)
0 (0)
6/183 (3.3)
Missing
0
9
28 (28.0)
43/192 (22.4)
Regular exercise Yes
[0.05
Discussion Even though the impact of vitamin D deficiency on musculoskeletal health, and association of hypovitaminosis D with cancer, cardiovascular disease, diabetes and autoimmune disorders have been well established, the role of vitamin D in the generation of BPPV has not been considered [16, 17]. In this study, we found that the serum level of vitamin D is decreased in patients with idiopathic BPPV with an average difference of 4.5 ng/ml. This finding was independent of age, gender, BMI, and decreased BMD, which suggests that decreased serum vitamin D could be a risk factor for BPPV. Even though the clinical significance of the average difference at 4.5 ng/ml is unknown, a larger proportion of the patients had vitamin D insufficiency than the normal controls (80.0 vs. 60.4 %, p \ 0.001) with this average difference. Indeed, according to a recent study, the vitamin D insufficiency is associated with a 24 % increase in the risk for myocardial infarction, cancer, hip fracture, or death [18]. Fig. 1 Proportion of vitamin D deficiency and insufficiency in the patient and control groups. The proportions of vitamin D insufficiency (10–20 ng/ml) and deficiency (\10 ng/ml) were higher in patients with benign paroxysmal positional vertigo (BPPV) than in controls (p \ 0.001)
insufficiency/deficiency remained significant. The C-statistic was measured at 0.852 for the multiple logistic regression analysis model adopted in this study, which also indicated the validity of our model.
Correlation between BPPV and Vitamin D BPPV is explained by otolithic debris dislodged from the otoconial bed [19, 20]. Since otoconia is composed of calcium carbonate, normal otoconial formation requires locally increased concentration of Ca2? and carbonate (CO3-) to initiate crystal formation on the proteinaceous core [21]. On the contrary, it is also important to maintain the
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Table 2 Independent predictors of BPPV using multiple logistic regression analyses Model/variables
Odds ratio
p value
95 % CI
Model 1 Age (continuous)
1.0
[0.05
0.97–1.03
Female BMI (continuous)
1.7 1.2
[0.05 0.002
0.91–3.35 1.06–1.28
2.4
0.025
1.12–5.06
14.1
<0.001
5.17–38.33
1.0
[0.05
0.95–1.02
Female
1.2
[0.05
0.58–2.54
BMI (continuous)
1.19
Serum vitamin D Insufficiency (10–19 ng/dl) Deficiency (\10 ng/dl) Model 2 Age (continuous)
0.002
1.07–1.33
3.8
0.004
1.51–9.38
23.0
<0.001
6.88–77.05
[0.05
0.61–3.31
<0.001
5.19–42.70
Serum vitamin D Insufficiency (10–19 ng/dl) Deficiency (\10 ng/dl) Bone mineral density Osteopenia (-2.5 \ T-score \ -1.0) Osteoporosis (T score B -2.5)
1.4 14.9
BPPV benign paroxysmal positional vertigo, BMI body mass index, the body mass index is the weight in kilograms divided by the square of the height in meters Model 1 age, sex, BMI, the existence of decreased bone mineral density, vitamin supplements, diabetes, hypertension, proteinuria and regular exercise Model 2 included bone mineral density as a variable in addition to those adopted in model 1 Bold values indicate statistical significance (p \ 0.05)
Ca2? concentration low in the vestibular endolymph to prohibit unnecessary mineralization of the rest of the endolymph [10]. Our previous study indicated an association between idiopathic BPPV and osteopenia/osteoporosis [6]. Also, it was suggested that increased calcium resorption reduces the capacity to dissolve the dislodged otoconia owing to increased concentration of free calcium in the endolymph [22]. Other experimental studies demonstrated an important role of epithelial calcium channels (calbindins), Na?/Ca2? exchangers, and plasma membrane Ca2? pumps in transepithelial absorption of Ca2? from the endolymph of the inner ear [10]. These structures mainly contribute to temporal and spatial modulation of Ca2? concentration in the endolymph to maintain the environment adequate for calcium homeostasis. Furthermore, the expression of some Ca2? binding proteins (epithelial Ca2? channels such as calbindin-D9 k and calbindin-D28 k) is up regulated by 1, 25-dihydroxyvitamin D3 in the epithelial cells of rat semicircular canal ducts [10]. Therefore, we may assume that vitamin D deficiency contributes to generation of BPPV via deranged calcium metabolism in the vestibular organs [22, 23]. However,
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establishment of the causal link between BPPV and decreased vitamin D would require animal experiments and eventually a clinical trial that looks for preventive effects of vitamin D supplementation on recurrence of BPPV in patients with BPPV and low serum vitamin D. Vitamin D receptor in the vestibular organs Vitamin D is best known for its role in homeostasis of calcium and phosphorus. However, the vitamin D receptor (VDR) is present in the cells throughout the body, and is involved in cell proliferation and differentiation as well as immunomodulation [24]. The functions of vitamin D are mediated through the nuclear VDR. A previous study detected the VDRs in the nuclei of the epithelium lining the crista ampullaris, membranous semicircular canal, and the surrounding osteocytes in mice [25]. Furthermore, VDR mutant mice showed decreased performance during evaluation of the balance function using the accelerating rotarod, tilting platform, rotating tube, and the swim test, which also suggests that decreased vitamin D could cause vestibular dysfunction, likewise in BPPV [25]. Low vitamin D in BPPV; cause versus just bystander? The serum level of vitamin D is influenced by various factors including nutritional status and exposure to sun. Accordingly, the nausea and vomiting frequently associated with vertigo attacks may have affected serum vitamin D level in patients with BPPV. To assess possible effects of malnutrition, we measured BMI in each group. However, BMI was rather increased in patients BPPV. The recruitment of controls from the local community may have minimized the weather effects, if any. To avoid a bias from diurnal fluctuation of serum vitamin D level, we obtained the fast blood sample of the patients in the morning after complete resolution of BPPV. Also, the possible immobilization due to vertigo may have affected serum vitamin D level in patients with BPPV. To assess this effect, we also compared serum vitamin D among the controls and 397 community residents who were excluded from the controls due to a history of vertigo/dizziness or imbalance during the preceding year. However, the serum vitamin D level did not differ between the groups. This indicates that the presence of dizziness/vertigo itself may have not caused low serum vitamin D in our patients with BPPV. This study also confirms our previous observation that osteoporosis were associated with BPPV, which was the result of a study conducted in another area of Korea [6, 22, 26]. In that study, even though we did exclude the possible confounding effects of known predisposing factors for osteoporosis such as smoking, alcohol consumption, and
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glucocorticoid medication, chronic renal failure, serum levels of the calcium, phosphate, and uric acid, and decreased BMI, we did not measure the serum level of the vitamin D. The results of the current study suggest a relationship between decreased serum vitamin D and an association of osteoporosis with BPPV. Of interest, patients with BPPV showed increased BMI in this study. The association between BPPV and increased BMI has been debated in the previous studies [6, 27]. However, serum vitamin D decreases in obesity, and the lower vitamin D would induce a compensatory increase in serum parathyroid hormone. This in turn may promote weight gain by increased calcium influx into adipocytes and lipogenesis [28–30]. Furthermore, obesity itself is also considered to be a risk factor for hypovitaminosis D. One of the most plausible explanations is enhanced uptake of 25-hydroxyvitamin D by the adipose tissue [31]. Our study showed that the prevalence of vitamin D deficiency/insufficiency is around 60 % even in a ‘‘normal population’’. Since the optimal concentration of serum vitamin D is defined by the 25-hydroxyvitamin D level that maximally suppresses secretion of the parathyroid hormone, a large proportion of a normal population may have serum vitamin D below the optimal level [32, 33]. Indeed, the proportion of vitamin D deficiency/insufficiency varied from 8 to 90 % depending on the age, sex, and ethnicity. A previous study also measured serum vitamin D less than 20 ng/ml in 47.3 % of Korean men and 64.5 % of Korean woman, thus demonstrating that vitamin D insufficiency/ deficiency is also common in Koreans [34]. Acknowledgments Dr. J.S. Kim was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A080750). Dr. S-H. Jeong conducted the statistical analyses with the help of the Chungnam National University Hospital Research Institute of Clinical Medicine (Prof. Suk-Hoon Lee and Jieun Shin). Conflicts of interest
All authors have no conflicts of interest.
Ethical standard All human study must state that have been approved by the appropriate ethics committee and have, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
References 1. Hotson JR, Baloh RW (1998) Acute vestibular syndrome. N Engl J Med 339(10):680–685 2. Hall SF, Ruby RR, McClure JA (1979) The mechanics of benign paroxysmal vertigo. J Otolaryngol 8(2):151–158 3. Schuknecht HF (1969) Cupulolithiasis. Arch Otolaryngol 90(6):765–778 4. Ross MD, Pote KG, Rarey KE, Verma LM (1981) Microdisc gel electrophoresis in sodium dodecyl sulfate of organic material from rat otoconial complexes. Ann N Y Acad Sci 374:808–819
837 5. Johnsson LG, Rouse RC, Wright CG, Henry PJ, Hawkins JE Jr (1982) Pathology of neuroepithelial suprastructures of the human inner ear. Am J Otolaryngol 3(2):77–90 6. Jeong SH, Choi SH, Kim JY, Koo JW, Kim HJ, Kim JS (2009) Osteopenia and osteoporosis in idiopathic benign positional vertigo. Neurology 72(12):1069–1076 7. Hoenderop JG, Nilius B, Bindels RJ (2005) Calcium absorption across epithelia. Physiol Rev 85(1):373–422 8. Thalmann R, Ignatova E, Kachar B, Ornitz DM, Thalmann I (2001) Development and maintenance of otoconia: biochemical considerations. Ann N Y Acad Sci 942:162–178 9. Ross MD (1979) Calcium ion uptake and exchange in otoconia. Adv Otorhinolaryngol 25:26–33 10. Yamauchi D, Raveendran NN, Pondugula SR, Kampalli SB, Sanneman JD, Harbidge DG, Marcus DC (2005) Vitamin D upregulates expression of ECaC1 mRNA in semicircular canal. Biochem Biophys Res Commun 331(4):1353–1357 11. CLSI method comparison and bias estimation using patient samples; approved guideline, 2nd edn. (Interim Revision). CLSI document EP09-A2-IR, Wayne. PA: Clinical and Laboratory Standards Institute: 2010 12. Thacher TD, Clarke BL (2011) Vitamin D insufficiency. Mayo Clin Proc 86(1):50–60 13. Tangpricha V, Pearce EN, Chen TC, Holick MF (2002) Vitamin D insufficiency among free-living healthy young adults. Am J Med 112(8):659–662 14. Harris SS, Soteriades E, Coolidge JA, Mudgal S, Dawson-Hughes B (2000) Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population. J Clin Endocrinol Metab 85(11):4125–4130 15. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. (1994) World Health Organ Tech Rep Ser 843:1–129 16. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357(3): 266–281 17. Arabi A, El Rassi R, El-Hajj Fuleihan G (2010) Hypovitaminosis D in developing countries—prevalence, risk factors and outcomes. Nat Rev Endocrinol 6(10):550–561 18. de Boer IH, Levin G, Robinson-Cohen C, Biggs ML, Hoofnagle AN, Siscovick DS, Kestenbaum B (2012) Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. Ann Intern Med 156(9):627–634 19. Gardner GM, Shaari CM, Parnes SM (1992) Long-term morbidity and mortality in patients undergoing surgery for unilateral vocal cord paralysis. Laryngoscope 102(5):501–508 20. Parnes LS, McClure JA (1992) Free-floating endolymph particles: a new operative finding during posterior semicircular canal occlusion. Laryngoscope 102(9):988–992 21. Hughes I, Thalmann I, Thalmann R (1091) Ornitz DM (2006) Mixing model systems: using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development. Brain Res 1:58–74 22. Vibert D, Kompis M, Hausler R (2003) Benign paroxysmal positional vertigo in older women may be related to osteoporosis and osteopenia. Ann Otol Rhinol Laryngol 112(10):885–889 23. Zucca G, Valli S, Valli P, Perin P, Mira E (1998) Why do benign paroxysmal positional vertigo episodes recover spontaneously? J Vestib Res 8(4):325–329 24. Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26(5):662–687 25. Minasyan A, Keisala T, Zou J, Zhang Y, Toppila E, Syvala H, Lou YR, Kalueff AV, Pyykko I, Tuohimaa P (2009) Vestibular dysfunction in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 114(3–5):161–166
123
838 26. Jang YS, Kang MK (2009) Relationship between bone mineral density and clinical features in women with idiopathic benign paroxysmal positional vertigo. Otol Neurotol: Official Pub Am Otol Soc, Am Neurotol Soc Eur Academy Otol Neurotol 30(1):95–100 27. von Brevern M, Radtke A, Lezius F, Feldmann M, Ziese T, Lempert T, Neuhauser H (2007) Epidemiology of benign paroxysmal positional vertigo: a population based study. J Neurol Neurosurg Psychiatry 78(7):710–715 28. Snijder MB, van Dam RM, Visser M, Deeg DJ, Dekker JM, Bouter LM, Seidell JC, Lips P (2005) Adiposity in relation to vitamin D status and parathyroid hormone levels: a populationbased study in older men and women. J Clin Endocrinol Metab 90(7):4119–4123 29. DeLuca HF (2004) Overview of general physiologic features and functions of vitamin D. Am J Clin nutr 80(6 Suppl):1689S–1696S 30. Zemel MB (2002) Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications. J Am Coll Nutr 21(2):146S–151S
123
J Neurol (2013) 260:832–838 31. Cheng S, Massaro JM, Fox CS, Larson MG, Keyes MJ, McCabe EL, Robins SJ, O’Donnell CJ, Hoffmann U, Jacques PF, Booth SL, Vasan RS, Wolf M, Wang TJ (2010) Adiposity, cardiometabolic risk, and vitamin D status: the Framingham heart study. Diabetes 59(1):242–248 32. Vieth R (2006) What is the optimal vitamin D status for health? Prog Biophys Mol Biol 92(1):26–32 33. Lips P (2010) Worldwide status of vitamin D nutrition. J steroid biochem mol biol 121(1–2):297–300 34. Choi HS, Oh HJ, Choi H, Choi WH, Kim JG, Kim KM, Kim KJ, Rhee Y, Lim SK (2008) Vitamin D insufficiency in Korea—a greater threat to younger generation: the Korea national health and nutrition examination survey (KNHANES). J Clin Endocrinol Metab 96(3):643–651
