nFrancesca M. Snoeijen-Schouwenaars MDa,*,1, Kaily C. van Deursen d,1,In Y. Tan MDa, Pauline Verschuure PhD e, Marian H. Majoie PhDb,c

d Faculty ofe Laborator

lation, such as our residents, we advise monitoring 25-hydroxyvitamin D concentrations, adjusting supplemen-

: 160-164reserved.

g in a higher frac-uscle weakness,1,2

ith various chronicbetes mellitus, car-

with vitamin D deciency are pigmented skin, winter sea-son, inadequate exposure to sunshine, obesity, older age,and several chronic diseases inuencing vitamin D meta-bolism.1,2,5,6 In The Netherlands, the recommendations onvitamin D supplementation made by the Dutch HealthCouncil should be followed,7 although the exact denitionof what constitutes a sufcient vitamin D status is still amatter of discussion.8-12

Article History:Received June 11, 2014; Accepted in nal form October 1, 2014* Communications should be addressed to: Dr. Snoeijen-

Schouwenaars, Sterkselseweg 65; 5590 AB Heeze the Netherlands.E-mail address: schouwenaarsf@kempenhaege.nl

1 Both authors were equally responsible for the work described in this

Contents lists availab

Pediatric N

journal homepage: www.e

Pediatric Neurology 52 (2015) 160e164paper.population, can induce rickets, a lower peak bone mass, diometabolic diseases, and cancer.1-5 Factors associatedtation accordingly and following patients to ensure they reach sufciency.

Keywords: vitamin D, supplementation, children, epilepsy, intellectual disabilityPediatr Neurol 2015; 52

2015 Elsevier Inc. All rights

Introduction

Vitamin D has an important role in bone metabolism.Vitamin D deciency, which is common in the general

osteomalacia, and osteoporosis resultinture risk.1-5 Furthermore, it can cause mand a lack of vitamin D is associated wdiseases, such as multiple sclerosis, diaafter supplementation at least equal to the amount recommended by the Dutch guidelines. In a high-risk popu-0887-8994/$http://dx.do64% of the residents in the decient category and 30% of those with an insufcient level at baseline failed to attaina sufcient vitamin D status after 15 months. CONCLUSIONS: Not all residents reached a sufcient vitamin D statustions. The mean 25-hydroxyvitamin D concentration incto 89.47 26.77 nmol/L after 15 months (P < 0.001). In snt of Neurology, Maastricht University Medical CenterHealth, Medicine and Life Sciences, Maastricht Universityy for Clinical Chemistry & Pharmacology, Kempenhaeghe

abstract

BACKGROUND: Children with epilepsy and intellectual disability have an increased risk of vitamin D deciency. Inthis patient group, it is neither clear which factors are associated with the level of 25-hydroxyvitamin D nor whatthe therapeutic results are when Dutch guidelines are followed. METHODS: This retrospective study included 30patients who, in October 2012, were residents of the childrens wards of a tertiary epilepsy center in TheNetherlands (Kempenhaeghe). From November 2012 onward they received cholecalciferol supplementation indoses that met or exceeded Dutch guidelines. At baseline, after 6, and 15 months, serum 25-hydroxyvitamin Dconcentration was measured. RESULTS: At baseline, the vitamin D status in 11 (36.7%) residents was found to bedecient, in 10 (33.3%) to be insufcient and in 9 (30.0%) sufcient. Supplementation dose, diet, body mass index,intellectual disability, and mobility were signicantly associated with baseline 25-hydroxyvitamin D concentra-

reased signicantly from 57.40 22.00 nmol/L at baselinepite of supplementation ranging from 400 to 1200 IU/day,aDepartment of Residential Care, KempenhaeghebDepartment of Neurology, Academic Center for Epileptology KempenhaeghecDepartmeOriginal Article

Vitamin D Supplementation in ChildreIntellectual Disability- see front matter 2015 Elsevier Inc. All rights reserved.i.org/10.1016/j.pediatrneurol.2014.10.001With Epilepsy and

le at ScienceDirect

eurology

lsevier .com/locate/pnu

Results

Patient characteristics

We included 30 of the 36 residents of the childrenswards of the epilepsy center. Six were excluded becausefollow-up was incomplete (two died, four moved). Patientcharacteristics are listed in Table 1. All those included areaged between 5 and 22 years, are Caucasian, and haveunimpaired renal function.

Baseline vitamin D

At baseline, the vitamin D status of 11 (36.7%) residentswas decient, of 10 (33.3%) was insufcient, and of 9(30.0%), sufcient. The residents received standard care atbaseline. This means that most residents (n 23, 76.7%)already received vitamin D supplementation, up to amaximum of 400 IU/day. Baseline 25-(OH)D concentrationsdiffered signicantly between subgroups of supplementa-tion dose, diet, BMI, severity of intellectual disability, andmobility (Table 2). Univariate analysis showed no signicantcorrelation of 25-(OH)D with age, duration of antiepileptic

TABLE 1.Patient Characteristics (n 30)

Gender (male/female) 17/13Age (year) 14.33 4*Skin type, n (%)Light 22 (73.3)Dark 8 (26.7)

Adequate sun exposure, n (%) 3 (10.0)BMI, n (%)Underweight 4 (13.3)Healthy weight 21 (70.0)Overweight 5 (16.7)

Diet, n (%)Oral intake 23 (76.7)

Pediatric Neurology 52 (2015) 160e164 161Children with epilepsy are at increased risk of poorbone health. They often have additional risk factors forvitamin D deciency.13-17 Enzyme-inducing antiepilepticdrugs cause an increased catabolism of vitamin D. Non-enzyme-inducing antiepileptic drugs, polytherapy, long-term use of antiepileptic drugs, intellectual disability,and impaired mobility are also associated with vitamin Ddeciency.13,14,17-24 The optimal strategy for preventingand treating a deciency in this high-risk population isnot clear.14,15,25 Only a few studies have investigatedthe effects of supplementation in children with epilepsy.It seems that the effect in these children differs from thatin healthy children.26-31 We investigated the factors thatare associated with serum 25-hydroxyvitamin D (25-(OH)D) concentrations in children with epilepsy and intellec-tual disability. We will also determine whether supple-mentation in doses which were at least equal to theamount recommended by the guidelines leads to a suf-cient vitamin D status in all these children after 6 and15 months.

Materials and Methods

Patient selection and intervention

We selected all residents of the childrens wards of a tertiary epilepsycenter in The Netherlands (Kempenhaeghe) in October 2012. They hadbeen diagnosed with epilepsy and intellectual disability. Those in whomfollow-up of vitamin D status was incomplete were excluded.

Up to November 2012, residents received standard care. FromNovember 2012 onward, they all received supplementary vitamin D atdoses that were at least equivalent to the dose recommended by theDutch Health Council. Doses were prescribed by either the physician forpeople with an intellectual disability or the pediatrician, depending onthe individual results of the 25-(OH)D serum concentration. All vitaminD preparations contained cholecalciferol.

Data collection

This study was a retrospective cohort study. We retrieved the foll-owing information from the electronic patient les: gender, age, bodymass index (BMI) using Dutch BMI-tables according to age for boys andgirls,32 mobility using Barthel index for walking, severity of intellectualdisability using intelligence quotient, creatinine, supplementation doseof vitamin D, antiepileptic drug use, and data about epilepsy. The care-givers completed a questionnaire about the amount of sun exposure,skin type, and diet. Sun exposure and skin type were analyzed using thesame denitions as the Dutch guidelines.7 Serum 25-(OH)D concentra-tion was measured by routine automated analysis. The samples werecollected for routine blood monitoring in the autumn of 2012 (baseline),spring of 2013 (6 months), and at the end of winter, 2014 (15 months).We dened a 25-(OH)D concentration of 75 nmol/L or more as suf-cient vitamin D status, of 50 to 75 nmol/L as insufcient, and of lessthan 50 nmol/L as decient.

Statistical analysis

To describe continuous variables we used mean (standard devia-tion) for normally distributed variables and median (minimum-maximum) for not normally distributed variables. We used numbers(percentages) to describe categorical variables. Paired t test, unpaired ttest, analysis of variance, correlation, and linear and multiple regression,or nonparametric equivalents (Wilcoxon singed rank test, Mann-Whitney test, Kruskal-Wallis test) were applied to the data using SPSS,

F.M. Snoeijen-Schouwenaars et al. /version 21 (IBM Corp, Armonk, NY). The level of signicance was a Pvalue of

IU/day. The mean 25-(OH)D concentration increasedsignicantly from 57.40 22.00 nmol/L at baseline to82.40 32.80 nmol/L after 6 months (P < 0.001) and89.47 26.77 nmol/L after 15 months (P < 0.001). Thedifference change in 25-(OH)D between 6 and 15 monthswas not statistically signicant (P 0.021). Figure sum-marizes the levels of 25-(OH)D for subgroups with a de-cient or insufcient vitamin D status at baseline.

After 15 months, 64% of the residents with a decientvitamin D status at baseline had not reached a sufcientvitamin D status. In fact, one (9%) still had a decientvitamin D status, in spite of supplementation with 1200 IU/day. Comparable results were found in 30% of the residentswith an insufcient vitamin D status. The effects of sup-plementation on the vitamin D status are listed in Table 3.

Factors associated with vitamin D at 15 months

After 15 months, the 25-(OH)D concentration wassignicantly higher in the group with tube feedingcompared with oral feeding (P 0.032). The 25-(OH)Dconcentration at 15 months was signicantly associatedwith baseline 25-(OH)D (r 0.722, P < 0.001) and inverselycorrelated with BMI (r 0.452, P 0.012). The signicantassociation with diet and BMI disappeared when correctedfor baseline 25-(OH)D concentration in multivariate

25-(OH)D concentration in residents with epilepsy and in-

TABLE 2.Factors Associated With Baseline 25-(OH)D

Factors 25-(OH)D [nmol/L] P Value

Supplementation dose 0.004*

0 IU/day (n 7) 51.86 13.38y200 IU/day (n 15) 49.00 22.22400 IU/day (n 8) 78.00 14.07

Diet

mo

Pediassociated with lower 25-(OH)D concentrations both atbaseline and at 15 months. Obesity has already been iden-tied as a risk factor for vitamin D deciency in healthychildren and also in patients with epilepsy.6,21,30 This can beexplained by the storage of the fat-soluble vitamin D inadipose tissue.2,5,6

Tube feeding resulted in higher baseline 25-(OH)Dconcentrations in comparison with oral diet, because theproduct administered contains more vitamin D (28-80 IU/100 mL).33

Residents with a profound intellectual disability orimpairedmobility had the highest 25-(OH)D concentrationsat baseline. This is in contrast to other studies in whichintellectual disability and impaired mobility are seen as riskfactors for deciency.19-22 A possible explanation for ournding is that standard care for our residents with profoundintellectual disability or impairedmobility involves a higherlevel of vitamin D as they receive larger supplementationdoses and are more likely to have tube feeding.

Previous studies established an inuence of anticon-vulsive treatment on vitamin D status.13,17-20 The presentstudy, however, found no difference in vitamin D statusrelated to duration of antiepileptic drug use, number ofantiepileptic drugs, or use of enzyme-inducing antiepi-leptic drugs. A possible explanation may be the smallstudy population and the many different antiepilepticdrugs.

This retrospective cohort study demonstrated that sup-plementation in doses which were at least equivalent to thedose recommended by the guideline did not lead to a suf-cient vitamin D status in all residents with epilepsy andintellectual disability after 6 and 15 months. Residents witha sufcient vitamin D status at baseline (30%) remainedsufcient after 15 months. However, 64% of the residentswith a decient vitamin D status at baseline did not reach asufcient status after 15 months. Comparable results werefound in 30% of the residents with an insufcient vitamin Dstatus at baseline. Not reaching a sufcient vitamin D statusmight be because of the fact that our target concentrationwas higher than the guideline (75 vs 30 nmol/L). There isno consensus about the optimal 25-(OH)D concentration.

TABLE 3.Vitamin D Status

Vitamin D status at baseline Vitamin D Status at 6

Decient Insufcient

Decient (n 11) 4 4Insufcient (n 10) 0 7Sufcient (n 9) 0 1Total (N 30), n (%) 4 (13) 12 (40)

F.M. Snoeijen-Schouwenaars et al. /Most literature reports use a cutoff level of 75 nmol/L for asufcient vitamin D status.2,8-12 The Dutch guideline is, infact, aimed at prevention rather than treatment, so thus thechosen doses might not be appropriate for achieving amoreambitious goal. Furthermore, the guideline recommenda-tions are intended for the normal population and may nottake sufcient account of the cumulative risks in childrenwith epilepsy and intellectual disability. This is also the casein the UK guidance from the Department of Health.34 Incontrast, the guidelines from the Endocrine Society in theUnited States and Victorian Paediatric Clinical Network inAustralia do recommend screening for vitamin D deciencyin high-risk populations.35,36

Our results are in accordance with those of a randomizedcontrolled trial, in ambulatory children without intellectualdisability,27 using long-term antiepileptic drugs in doses of400 or 2000 IU/day. That study also showed that not allchildren reached 25-(OH)D concentrations of more than50 nmol/L (41% at baseline and 50% at 1 year). According toseveral other randomized controlled trials, performed inchildren who started with lower 25-(OH)D concentrationsthan our patients, even supplementation doses up to 2000IU/day did not lead to a sufcient vitamin D status in allhealthy children. They found many factors to be associatedwith reaching the desired level, such as baseline 25-(OH)Dconcentration, supplementation dose, and factors inu-encing vitamin D metabolism.30,31

According to the Dutch guidelines, supplementation isrecommended without measuring the vitamin D level.7,25

Based on multivariate analysis in our study, the onlyfactor signicantly associated with 25(OH)D concentra-tion at 15 months was baseline 25-(OH)D concentration.Therefore this nding favors the measurement of 25-(OH)D concentrations before starting supplementation inthis high-risk population. It would be advisable to mea-sure 25-(OH)D concentrations during the same periodeach year to limit seasonal inuences. But, because 90% ofthe residents unfortunately did not go out enough toreceive sufcient sun exposure, the seasonal inuenceson the 25-(OH)D concentration in our population werelimited.

We conclude that not all of our residents with epilepsyand intellectual disability reached a sufciently high25-(OH)D concentration after supplementation in doseswhich were at least equal to the amount recommended bythe Dutch guidelines. If our ndings are reproduced byother studies, this may lead to a critical reappraisal of thecurrent guidelines. We advise monitoring 25-(OH)D con-centrations in a high-risk population like our residents andadjusting supplementation dose accordingly. Finally,follow-up is necessary until the patient has reached asufcient vitamin D status.Vitamin D Status at 15 mo

Sufcient Decient Insufcient Sufcient

3 1 6 43 0 3 78 0 0 914 (47) 1 (3) 9 (30) 20 (67)

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Vitamin D Supplementation in Children With Epilepsy and Intellectual DisabilityIntroductionMaterials and MethodsPatient selection and interventionData collectionStatistical analysis

ResultsPatient characteristicsBaseline vitamin DEffect of supplementation on vitamin DFactors associated with vitamin D at 15 months

DiscussionReferences